Aryl Dithiocarbamate Thesis 25-10-22

ABSTRACT
Dithiocarbamates are significant from biological point of view as used for the treatment or
different infections like bacterial, viral and fungal. Dithiocarbamates also showed potent
biological activities such as anti-bacterial, anti-microbial, anti-cancer, anti-malarial, anti-
fungal, anti-viral, anti-inflammatory, anti-tumor and anti-T.B. Various methodologies have
been represented for the synthesis of substituted dithiocarbamate based derivatives. In the
present work various N-heterocyclic substituted aryl dithiocarbamates have been synthesized
under ultrasonic conditions. The prepared analogues will be characterized by FT- IR, NMR
(CNMR, HNMR) and Mass spectrometry. The synthesized compounds were evaluated for
biological potential and then subjected to antibacterial activities for calculating the potential
of these compounds against bacteria. Bacterial strains used for this study were Escherichia
coli (-) and Bacillis subtilis (+). Ampicillin and ibuprofen were used as standard drugs while
ciprofloxacin was used as positive control. The compound 115b exhibited best anti-bacteria
activity and showed MIC values 0.1mg/mL against Bacillis subtilis and Escherichia coli. A
compound 112c displayed least antibacterial potential and shown maximum zone of
inhibition by depicting ZI value 42 mm against Bacillis subtilis while 115a showed potency
against Escherichia coli having ZI value 44. The results depicted that ultrasonic techniques
best for the synthesis of aryl dithiocarbamate based derivatives with good yield.
i
CHAPTER 1
INTRODUCTION
Chemistry of Dithiocarbamates started from the early 20 th century (1930) (Zhou et al., 2021).
Dithiocarbamates are organo-sulfur ligand, which is also a functional group (Zhong, Chen, &
Xu, 2018). Dithiocarbamates have dithiocarbamate moiety as a functional group (Z. Wang et
al., 2020). The general formula of dithiocarbamates is N-CS 2. The International Union of Pure
and Applied Chemistry (IUPAC) named these dithiocarbamate derivatives as
carbamodithioates (Szolar, 2007). Structurally, dithiocarbamates (R2CNS2) comprise of a
wide class of 1, 1-dithioligand monoacids, an extensive variety of compounds have been
synthesized in this class (Shinde, Sakla, & Shankaraiah, 2020).
Figure 1.1: General structure of dithiocarbamate

1.1 Nature of dithiocarbamate
Dithiocarbamates have shown anomalous nature, because by self-condensation and under
mild conditions, compounds R2N-S-NR2 (thiourea crystals) may be formed (Runkle, Flocks,
Economos, & Dunlop, 2017). In thiourea crystals, the two S atoms minimize to one S atom
(Rogachev et al., 1998). It has a structural similarity with carbamate which have two oxygen
atoms while thiocarbamate has two sulfur atoms instead of oxygen (Raffa & Chiampo, 2021).
They have excellent capability to form complexes with metals, which are also stable in state
due to their incomparable coordination properties (Pastrana-Dávila et al., 2021). The anionic
CS2 group also participate in the formation of complexes with the transition metal atoms
(Nabipour, Ghammamy, Ashuri, & Aghbolaghc, 2010). Moreover, dithiocarbamates (N-CS2)
are consider as the versatile classes of ligands which have the ability to stabilize transition
metals with different range of oxidation states (Morita et al., 2020). Dithiocarbamates have
resonance structure which is in result of delocalization of the lone pairs of electron of N to the
S atom (Lu et al., 2022). The bonding arrangement is shown through a short C–N distance
and the co- planarity of the N-CS2 central also as the atoms attached to N- atom (Kaul, SŘss,
Zannettino, & Richter, 2021). The pi-donation of electrons from the Nitrogen makes the
dithiocarbamate more basic than other structurally related anions (dithiocarboxylates and
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xanthates). As a result, they tend to bind as bi-dentate ligands (Kaufman, 1967). Another
significance of the C–N multiple bonding is that rotation about that bond is subject to a high
barrier (Kane et al., 2016).
Figure 1.2: General reaction of dithiocarbamate

Dithiocarbamates commercially used 1st time as a fungicide in the field of agriculture during
World War II (Kanchi, Singh, & Bisetty, 2014). Dithiocarbamates are basically amides which
are formed from the dithiocarbamic acid (Hussain, Pu, Hu, & Sun, 2021). Dithiocarbamic
acids are known as chemical compounds which have been widely used in the manufacturing
of extensive variety of pharmacological drugs for the treatment of parasitic, fungal, viral and
bacterial infections (Hogarth, Ebony-Jewel, & Richards, 2009). Due to its strong binding
ability with metals, they also use for the inhibition of the activity of enzymes which have
considerable effect on the working of biological systems (Hogarth, Ebony-Jewel, Kabir, et
al., 2009). Dithiocarbamates are known for their potent biological activities, as a linkers in the
synthesis of organic compounds and vital role in the field of agriculture (He et al., 2018).
They are also used as vulcanization accelerators (in rubber industry) and in different
controlled techniques like radical polymerization (Hao et al., 2021). Many other applications
of dithiocarbamates also found in other departments like material science, biology, synthesis
of organic compounds, photo-stabilization of polymers and for the protection of radiators (Z.
Fu, Yuan, Chen, Yang, & Xu, 2018).
1.2 Types of dithiocarbamates
Dithiocarbamates could be generally classified in to various categories and this classification
is based on the number of attachment of -R group with the N-atom; which are as follow:
1.2.1 Mono-alkyl dithiocarbamates
Mono alkyls are those which have one R group attached with the N-atom of the compound, it
is known as a monomeric DTCs (W. Fu & Huang, 2018). Metam and PDTC (Pyrrolidine
dithiocarbamate) are example of mono-alkyl dithiocarbamate (Fanaru, Les, Creanga,
Dorohoi, & Sacarescu, 2022). PDTC is example of monomeric DTC which have ring of five
membered group which attach to the N-atom (Fan et al., 2019). It is a metabolic inhibitor that
used in the studies of physiology of cell (Eng et al., 2003).
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Figure 1.3: Examples of mono-alkyl dithiocarbamates
1.2.2 Di-alkyl dithiocarbamates
In di-alkyls dithiocarbamates, the two -R groups attached to the N-atom (Ejelonu, Olagboye,
Oyeneyin, Ebiesuwa, & Bada, 2018). The -R group may be of same or different kinds. If
different -R group attached it is called Asymmetric dithiocarbamate and if the attached
groups are same then it is called Symmetric dithiocarbamates (Timothy O Ajiboye, Oyewo,
& Onwudiwe, 2021c). Ziram, Thiram, Disulfiram, and Ferbam are examples of dialkyl
dithiocarbamates. These all have different -R group (Cvek & Dvorak, 2007). But Ziram and
Ferbam have different metal ions between their S atoms (N. Chen, Zhong, Li, & Xu, 2015).
Fi
gure 1.4: Examples of di-alkyl dithiocarbamates
1.2.3 Poly-alkyl dithiocarbamates
In poly alkyl DTCs, the metal ion binds to more than two molecules or –R groups and form
polymeric complex (Najmedin Azizi & Alipour, 2018). In EBDTC, the R groups of the two
dithiocarbamates molecules formed bridge between to ethylenes (Ayalew et al., 2020). For
example: Zineb, Maneb and Mancozab which are utilized in agricultural for the treatment of
different crop diseases (Timothy O Ajiboye, Oyewo, & Onwudiwe, 2021a).
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Figure 1.5: Examples of poly-alkyl dithiocarbamates
1.3 Applications of aryl dithiocarbamates

Organic dithiocarbamates have established extensive attention because of its numerous
biological activities in the field of medicines and its vital role in the field of agriculture. They
have also been used as the protection groups in peptide synthesis, as a linkers in the synthesis
of solid-phase organic compounds and apart from this also used during synthesis of ionic
liquids. Because of having a strong metal-binding capacity also use as enzyme inhibitor
(Timothy O Ajiboye, Oyewo, & Onwudiwe, 2021b). It has its applications in industrial field
as starting material (Timothy Oladiran Ajiboye, Oladoye, Olanrewaju, & Akinsola, 2022).
Figure 1.6: Applications of aryl dithiocarbamates

Additionally, dithiocarbamates (DTCs) have widely applications in pharmacology and used
in the treatment of cancer and for the treatment of many other diseases. Therefore, the
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synthesis of dithiocarbamates (DTCs) has been able to gain a lot of attention recently.
1.3.1 Applications of aryl dithiocarbamate in agriculture
Dithiocarbamates are very important organo-sulfur compounds. They are widely used in
agriculture as a fungicide for protecting different crops, fruits vegetables, ornamental plants
and seeds. Dithiocarbamates introduced about 40-70 years ago which is still represent an
important class which is used in agriculture. There are many dithiocarbamate compounds
such as Zineb, Maneb, Propioneb, Nabam, Metam sodium, Ziram, Metiram, Thiram,
Mancozeb and Ferbam which are known for their fungicidal, herbicidal and pesticide activity
in agriculture.
1.3.1.1 Aryl dithiocarbamates based pesticides
DTCs based pesticides are used for many different crops issues during different process like
growth, storage and shipment. Some pests release the larva, which kill by using aryl
dithiocarbamates based pesticides which may because plant’s and farm animal’s diseases. For
instance, tricylohexyltin and triphenyltin N-n-butyldithiocarbamate which is used as a
larvicide against Aedes aegpti and Anophelesstephesi mosquitoes, which found very effective
against these mosquito species (Aspatwar et al., 2020). The disease which is caused by
nematode is called Meloidogne incognite, was eradicted by using DTCs which deried from
the chitin oligisacchride (Cihlar & Fordyce, 2016). These derived DTCs based pesticides has
the high activity for eradicating the nematodes (Elahabaadi, Salarian, & Nassireslami, 2021).
1.3.1.2 Aryl dithiocarbamates based fungicide
Dithiocarbamates are very important organo-sulfur compounds (Timothy O Ajiboye,
Babalola, & Onwudiwe, 2021). They are widely used in agriculture as a fungicide for
protecting different crops, fruits vegetables, ornamental plants and seeds. Dithiocarbamates
introduced about 40-70 years ago which is still represent an important class which is used in
agriculture (Timothy O Ajiboye, Ajiboye, Marzouki, & Onwudiwe, 2022). DTFs
(Dithiocarbamate fungicides) are considered as a non-systemic pesticide. It has been implied
to control the various fungal diseases since 1940s. The most well-known and used fungicides
are propineb, zineb, manab, mancozeb and thiram (Timothy O Ajiboye et al., 2022). With the
advancement of the new and better fungicide molecules has continued. The most selling
fungicides are mancozeb, propineb and thiram (Adeyemi & Onwudiwe, 2020a).
On the basis of structures, DTFs are classified as follows:
● PBs-DTCs (Propylene-bis-DTCs, e.g.; propineb)
● EBs-DTCs (Ethylene-bis-DTCs, e.g.; mancozeb, menab and zineb)
● DDc-DTCs (Dimethyl-DTCs, e.g.; thiram, ziram and ferbam)
There are some TFs from different DTFs groups which shown different level of toxicity and
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cause damage to crop. Sometimes this damage become severe and affects the living
organisms as well. So, considering the toxicity, maximum residual limits (MRL) which is the
range of DTFs in ppm which imposed by various organizations throughout the world for
different food and agricultural products (Adeyemi & Onwudiwe, 2018).
Figure 1.7: Classes of DTFs and examples from each class

1.3.1.3 Aryl dithiocarbamates based herbicides
Propylene-bis-DTCs (PBs-DTCs), Ethylene-bis-DTCs (EBs-DTCs) and Dimethyl DTCs
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(DDs) are the dithiocarbamate based herbicide groups, e.g.; Metiram, Dazomet, Thiram,
Disulfiram, Propineb, Maneb, Ziram and Zineb, although there are few of them which are
also used as pesticides (Abulnaja & Harwood, 1991). These dithiocarbamate based herbicides
are used to stop and minimize the outgrowth of broad-leaf weeds along with the useful plants
like crabgrass, cheatgrass, foxtail and bromegrass (Abu-El-Halawa & Zabin, 2017). These
were also successfully used to eliminate oxidants generated by plant (active oxygen species).
Diallate [S-(2,3dichloroallyl-) diisopropylthiocarbamate], Sulfallate, Dazomet and Triallate
are the most commonly used dithiocarbamate based herbicides (Asadi et al., 2019).
Figure 1.8: Some common examples aryl dithiocarbamates based herbicides
1.3.2 Application of aryl dithiocarbamates as an enzyme inhibitor

Dithiocarbamates play very important role in the inhibition of the activity of the enzyme
during biological reactions, the hydroxyl (-OH) and carbonyls (-COO) group in
dithiocarbamate compounds efficiently bind to the active site of the enzyme, which lead to
enzyme inhibition (Gao et al., 2020). Enzymes inhibitors are actually used at the time when
the activity of the enzymes has to stop. Enzyme inhibitors work; in any reaction when have to
stop the activity of the enzyme any aryl-dithiocarbamate add. The added compound get attach
with the enzyme and stop enzyme activity. For example; for the inhibition of α-Glucosidase,
this is used for the conversion of carbohydrates and starch into glucose in diabetesmellitu
treatments (Ge et al., 2019). Coumarin dithiocarbamate and scaffold used as enzyme
inhibiting compounds which has been proved very effective and useful in the treatment of
diabetesmellitus (Mollazadeh et al., 2021). Pyrrolidine dithiocarbamate is also used as
enzyme inhibitor for the inhibition of nuclear factor which is kappa B (Raina-Fulton, 2014).
The derivatives of DTC-sulfonamide used for the inhibition of carbonic anhydrase (Rogachev
et al., 1998). Dithiocarbamate also used as a competitive inhibitor. For example: for the
inhibition of acetylcholine esterase and butyryl cholinesterase by coupling of DTC with
phthal imide in Alzheimer’s Disease treatment(Sağlık et al., 2020).
1.3.3 Pharmaceutical applications of aryl dithiocarbamates
Dithiocarbamate and its derivatives have attracted interest from the last few years because of
its wide use in pharmaceutical (Adokoh, 2020). They are also associated with a wide range of
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biological properties such as anti-cancer, anti-fungal, anti-bacterial, anti-Alzheimer, anti-
hyperglycemic, anti-cholinergic, anti-inflammatory, anti-influenza, Anti-tubercular, anti-
glaucoma (Bakthavatsalam, Wiangnak, George, Zhang, & Franz, 2020). Some other medical
applications of dithiocarbamates include medical imaging etc (Bhalla, Gupta, & Jaitak, 2013).
Figure 1.9: Biological active aryl dithiocarbamates based drugs

1.3.3.1 Anti-cancer activity of aryl dithiocarbamates
There are around about 9-10 million cancer cases are diagnoses every year all over the world.
This is the becoming the major cause of death in whole world (Hafeez, Zahoor, Rasul,
Ahmad, & Mansha, 2021). Hence, the finding of advance and new chemotherapeutical
mediators which would be capable of working as anticancer agent is always interested area
for the researchers (Hafeez et al., 2022). By keeping this point in mind, various derivatives of
dithiocarbamates have been explored for their proliferative activity since long (El-Aarag et
al., 2014). The typical approach behind explaining novel group of molecules is to combine
dithiocarbamates with the naturally occurring goods or the biologically active heterocyclic
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scaffold compounds to achieve more efficient activity (D.-J. Fu et al., 2019; J Berry, Torres
Martin de Rosales, Charoenphun, & J Blower, 2012). Moreover, derived dithiocarbamates
metal complexes have also shown quite attractive (Lawal et al., 2020).
Figure 1.10: strutures of anti-cancer aryl dithiocarbamate molecules obtained from natural
products
Phytoalexins have lower molecular weight, when plants exposed to various factors (chemical,
physical or biological stress) produced secondary metabolites (Milacic et al., 2008).
Brassinin, is one of the 1st dithiocarbamate having indole phytoalexin which was obtained
from Brassica campestris ssp a Chinese Cabbage and pekinensis (Morrison, Doudican, Patel,
& Orlow, 2010).
1-Methoxybrassinin showed the utmost compelling anti-cancer biological activity in Caco-2
cells (Omar, AboulWafa, El-Shoukrofy, & Amr, 2020). Additionally, the formation of 7, 12-
12 (DMBA)-induced precancerous lesions in mouse mammary gland were inhibited using
brassinin, spirobrassinin and cyclobrassinin (Reddy, Odhav, & Bhoola, 2003). Brassinin also
inhibit phosphatidylinositol 3-kinase by elevating the levels of p21 and p27 through the
signalling path which lead the cell cycle to arrest in G1 phase during the division of cell
(Syed Annuar, Kamaludin, Awang, & Chan, 2021; H. Wang et al., 2021).
1.3.3.2 Anti-bacterial activity of aryl dithiocarbamates
The dithiocarbamates have been using as an antibiotics since long due to its good
antibacterial activity. The interest has been increased when the requirement of antibacterial
substances increased for the treatment of anti-bacterial diseases. , β-lactamases and metallo β-
lactamases (MBL) are the antibiotics which have been using for the treatment of bacterial
infection from last many years (Adeyemi & Onwudiwe, 2020b). Ag (1) DTC
triphenylphosphine complex have better anti-bacterial properties than ciprofloxacin against
the bacteria Gram (+ve) and Gram (-ve). It has also been disclosed that dithiocarbamate
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complexes showed better results against Gram (+ve) bacteria than the Gram (-ve) bacteria.
The decrease in activity of the DTC complex would be due difference in their layers of cell
wall. The cell wall of Gram (+ve) bacteria made of single layer while the cell wall of Gram (-
ve) consist of many layers. So, the dithiocarbamate penetration is hindered by layers of cell
wall (Q. M. Chen, Li, Tian, Chen, & Wu, 2021). 1,2,3-triazole-DTC-naphthalimides also
showed impactful anti-bacterial activity against various bacteria like Bacillus subtilis,
Staphylococcus aureus, Candida albicans and Escherichia coli (Manoussakis, Bolos,
Ecateriniadou, & Sarris, 1987). Remarkably, 1,2,3-triazole-DTC-naphthalimides provide
antibacterial result than Cefuroxim against the B. subtilis. N-acyl-homoserine lactones DTC
derivative showed activity against Gram (+) bacteria and inhibited the Bacillus subtilis
(Mohammed & Leelon, 2021). The compounds with the side chain of N-Ph amide group are
more active than the hydrophobic -R chains. The substitution of EWD (-CF 3) and (–NO2) at
m-position considered more helpful for the activity as compared to EDG group (-CH 3).
Chalcone based DTCs derivatives used against the phosphoethanolamine to lessen bacterial
resistance. Is a tin dithiocarbamate derivatives also considered as an anti-bacterial agent
against the both types of bacterias. Gram (+ve) bacteria like Strep. Pneumonia and Staph.
Aureas Strep. Pneumonia. Gram (−ve) bacteria like Escherichia coli and Pseudaeruginosa
(Oladipo, Tolufashe, Mocktar, & Omondi, 2021). It also exhibited satisfactory anti-bacterial
activities as compared to some common drugs used against these bacteria.
Figure 1.11: Examples of some anti-bacterial aryl dithiocarbamate agents

1.3.3.3 Anti-fungal activity of aryl dithiocarbamates
The negative impact of fungal infections on the health of both plants and animals along with
the reduction in the yield of plants result in the synthesis of anti-fungal substances utmost
need. Dithiocarbamates considered one of various compounds that investigated for the
synthesis of anti-fungal drugs (Ferreira, De Lima, Paniago, Takahashi, & Pinheiro, 2014).
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Chiston was used for the treatment of fungal disease in plants but it showed better result when
chiston coupled with dithiocarbamate (Badawy & Rabea, 2016). Like this many other
dithiocarbamates complexes (Ni, Pt, Pd ) showed good result and found more effective
against many fungi (Aspergillus niger, Penicillium citrinum, Aspergillus parasiticus and
Aspergillus flavus). DTC complex of Ni showed antifungal activity against Aspergillus flavus
and DTC complex of Pd more effective anti-fungal agent against Aspergillus flavus (Menezes
et al., 2005). Complex of DTC containing benimidazole as ligand evaluated due to its anti-
fungal activity. The study of dithiocarbamate (DTCs) complexes exposed that substitution on
Sulfur of dithiocarbamate is responsible for the anti-fungal activity (Menezes et al., 2008).
Substitution of -allyl group at Sulfur exercised effective anti-fungal action as compared to –
ethyl (–Et), -propyl (-Pr) and –butyl (–Bu) substitutions (Qin et al., 2012).
F
igure 1.12: Some example of anti-fungal aryl dithiocarbamate agents
1.3.3.4 Anti-inflammatory activity of aryl dithiocarbamates
When immune system gives non-specific response is called inflammation. Inflammation
observed in many physiological conditions such as bodily injury which may result in
development of disease (Cuzzocrea et al., 2002). Many drugs like aspirin and non-steroidal
drugs have used as anti-inflammatory agent but these drugs have side effects (Dinarello,
2010). Consequently, to avoid or minimize the side effects, an alternative anti-inflammatory
substance has needed and which also show better efficiency (Ferraz et al., 2021).
Dithiocarbamate based anti-inflammatory substances have discovered which have anti-
inflammatory activity.
1,4-bis(diphenylphosphino)butane)palladium(II) chloridemonohydrate evaluated due to its
anti-pyretic, analgesics and anti-inflammatory properties in the models of albino mice
(Lamkanfi, 2011). All experimental models showed the inflammation signs like febrile action
and pain, 1,4-bis(diphenylphosphino)butane)palladium(II) chloridemonohydrate helped in the
inhibitions of all these inflammation signs (C.-W. Li et al., 2015). Moreover, this substance
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also not showed any side effects on vital organs. Indole based dithiocarbamate derivatives
also screened as anti-inflammatory substance (Song et al., 2019). These derivatives
expressively inhibited the release of tumor.3-Methyl-1H-indol-1-yl dimethyl
carbamodithioate also considerably improved pathological changes occurred in lung
tissue (Topping & Jones, 1988). It induced lipopoolysacchrides which help to reduce the
severe lung injury. Pyrrolidine has also been utilized as anti-inflammatory agent due to its
stability at physiological conditions, pH in solution; moreover it has ability to traverse the cell
membrane. Pyrrolidine dithiocarbamate found very effective against the chronic as well as in
acute inflammation (Vane & Botting, 2003).
Figure 1.13: Examples of anti-inflammatory aryl dithiocarbamate agents

1.4 Application of aryl dithiocarbamates in chromatography
The Dithiocarbamates has the strong chelating ability, due to which these compounds used as
a stationary phase component in ligand exchange chromatography (Bond & Wallace, 1984).
Yeh and coworkers used dithiocarbamates coated on silica as the stationary phase which used
to separate heavy metals (Chia-Fu, Sun-Dsong, Wei-Shi, Jia-Der, & Chuen-Ying, 1993). It
was also noticed that by using DTCs as the stationary phase up taken amount of mercury (Hg)
increased (Ali, Shen, & Yin, 1998). Diethyl dithiocarbamate and Pyrrolidine dithiocarbamate
were also deposited as a stationary phase in different heavy metals determination (Shepherd,
2003).
1.5 Application of aryl dithiocarbamates as a catalyst
Catalytic application of the DTCs is also aspect which attracted the researcher’s attention
toward. It not only used for catalyst synthesis during the organic synthesis but also in
polymerization (Aghbash, Alamgholiloo, Pesyan, Khaksar, & Rostamnia, 2021). The catalyst
showed good performance for the propargyl amines synthesis when morpholine,
phenylacetylene and benzaldehyde act as a starting material (Guan et al., 2021). The choice of
dithiocarbamate metal depends on its solubility in the organic solvents (good solubility means
better choice), chemical stability, and lastly that it can also use easily in the form of
anhydrous. The methods which used the Markovnik addition and the other is alkaline
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synthesis (Pitchaimani, Lo, & Elango, 2015). Guan et al. employed nickel DTCs compound
which is used as a catalyst for increasing the carbon fibres properties (surface energy,
chemical inertness and roughness) by using Markovnik addition as well as alkaline synthesis
(Vale, Faustino, Menezes, & de Sá, 2006).
Specific objectives and Scope of the aryl dithiocarbamates
Keeping in view these considerations, following aims have been set to perform.
● N-heterocycle based dithiocarbamate has been prepared under ultrasound conditions.
● Sonication technique will be employed for the synthesis of derivatives.
● Synthesized molecules will be characterized by NMR, FT-IR and Mass spectrometry.
● These molecules will be evaluated for biological potential.
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CHAPTER 2
REVIEW OF LITERATURE
Cancer is one of the utmost dangerous diseases. There are millions of cases reported every
year in the entire world and no particular drug available present time. Several drugs
synthesized and evaluated for the treatment of cancer but almost all have some side effects
like they effects the healthy cells along with the tumor cells during the course of treatment.
Researchers are looking for the drugs which show healthier therapeutic effects without any
considerable side effects. Ideal drugs are those which have less toxicity along with the high
activity but unfortunately fail to get the desire results. Researchers reported that artemisinin
and their derivatives have the ability to show better degree of the antitumor activity. World
Health Organization (WHO) suggested these compounds which are harmless for human. Yu
et al. reported the synthsis using one pot method for artemisinin piperazine based
dithiocarbamate derivatives. They synthesized about 12 derivatives and some compounds
exhibited cytotoxic activity in vitro such as activity against the SMMC-7721 cell-lines having
value of IC50 = 0.0025 ± 0.04 μM. Compound also has a better inhibitory-activity against the
colon, prostate cancer and breast cells (Yu, Li, & Wei, 2019).
Scheme 2.1: Synthesis of the derivatives of artemisinin piperazine dithiocarbamate

BTK is tyrosin kinase non-receptor which belongs to the Tec family and mostly stated in the
myeloid cell and β-cells. Its deficiency estimated the genetic disorder in Human as XLA and
14
revealed the symptoms of infection and immune deficiencies disorders which means have the
lack of antibiotics and blymphocytes in patient. BTK developed as attractive target against
Blymphocytes dysfunstions and the autoimmune disesease. Not till the determination of the
BTK functions ensured the researchers its significance until kinases and scaffold proteins
have achieved phosphorylation of the BTK-tyrosine residue. Due to its success in the clinical
trials has attracted the attention of many other researchers to its further modifications and
aimed in the improvement of the pharmaco-kinetic efficiency and property. Zhai et al.
reported the numbers of compounds with combination of the diphenylaminpyrimidine and
with the dithiocarbamates entities, which was the innovative approach for DTC-substituted
with the BTK inhibitors. He prepared the diphenylaminopyrimidine compound which had
amide substitution as a side chain. At preparing it, reacted with the carbon disulfide in the
presence of TEA/DMF at room temperature to 60 0C for 4 hours. The obtained product
displayed the effective inhibitory activity than the sperbrutinib with the value IC 50 = 2.12 ±
0.23 μM. The product also showed enhanced anti-proliferative activity against the
Blymphoma cell-lines, which is 10 times better than the sperbrutinib and ibrutinib. Moreover,
the derivative displayed the selectivity in the β-cell of lymphoma above the other cancer cell-
lines than the spebrutinib (Zhai et al., 2019).
Scheme 2.2: Synthesis of derivative of diphenylaminopyrimidine dithiocarbamate

From the past few years many therapeutic drugs have been synthesized and approved for the
treatment of cancer. These drugs have different mechanism of working, targeting the cancer
metabolism consider the one of the effective strategy in the establishment of the new and
latest tumor treatment. From the many evidences it have been proved that PKM2 (pyruvate-
kinases-M2) is regulated in the metabolism of cancer cells and is known because of its
effective therapeutic targeting in the oncology. Liu et al. proposed the synthesis of azaindole
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based dithiocarbamate derivatives by treating indole and 3-(aminomethyl)pyridine with CS 2
alongwith the TEA and DMF at room temperature with stirring for 6 hours. PKM2 exhibited
anti-cancer activity on the A375 cell-lines, shown substantial malignant cells suppression, not
causing any considerable toxicity. Furthermore the mechanistic studies showed that the
synthesized compound has the ability to effect the translocation of the PKM2 into the nucleus
and also the induction of the autophagy and apoptosis of the A375 cells. Collectively, the
compound has the ability to serve as the lead compound in the progress of effective PKM2
activators in the treatment of cancer (Liu et al., 2019).
Scheme 2.3: Synthesis of derivatives of indole dithiocarbamate

Chalcones derivatives exhibited the broad spectrum of many biological activities, especially
exhibited effective anti-cancer activity against the cancer cells and the anti-tumor activity.
The dithiocarbamates have also showed vital importance du to its significance as an active
agent which exhibited different biological activities. Due to these the chalcone based
derivatives of dithocarbamates were thought to synthesis and different researchers also
synthesized chalcones based dithiocarbamate. Fu et al. reported the synthesis of chalcones-
dithiocarbamate and evaluated the anti-cancer acitivity against the MCF7, PC3 and MGC803.
They treated the derivative of halo-acetamide with substituted piperazine using carbon
sulfide, acetone at room temperature. The synthesized compound exhibited the activity
against the PC3 cells having value of IC 50 = 1.05 μM , have the ability to inhibit the formation
of colony, which induce the damag DNA and arrest the cells cycle at G2/M phase (D.-J. Fu et
al., 2019).
16
Scheme 2.4: Synthesis of derivatives of chalcones dithiocarbamate
Derivatives of indole are one of the important agent because of its occurrence in the natural
and the biological active agents. It exhibited anti-inflammatory activities and widely utilized
in the synthesis of non-steroidal drugs as a basic of pharmacophore. Different drugs
containing indole derivatives employed in clinics for the treatment of inflammatory disease
like indomethacin (A), etodolac (B), tenidap (C) and acemetacin (D). Due to considerable
effectiveness of indole and dithiocarbamates researchers tried to design indole containing
dithiocarbamate derivatives.
Song et al. reported the synthesis of the indole-DTCs under the basic conditions by using tert-
BuOK as promoter at the room temperature and obtained moderate to the excellent yields.
The synthesized compounds have shown excellent activities with the IC 50 value in nano and
also inhibiting the release of TNF-α, IL-6. The derivatives of indole-dithioocarbamate also
employed for ALI treatment and further medicinal development (Song et al., 2019).
Scheme 2.5: Synthesis of indole dithiocarbamate derivative

Cancer is such kind of disease in the course of which tumors may happen and it threatens the
human health as well as life. Conferring to recent report, almost 60 million beings detected
with the malignant cells each year. The number of these cancer cases has been increasing day
17
by day. Therefore, an serious attention needed for the development of latest and new anti-
cancer agents has been arising. Dithiocarbamic compounds show extensive variety of
biological activities. 2(5H)-furanone derivatives widely occur in the naturally occuring
products which already using widely in the cancer therapy due to its prominent biological
activity. Wei et al. synthesized the series of latest and new dithiocarbamates derivative which
contain the 2(5H)-furanone-piperazine as a attachéd molecule. The reaction proceeds in
reflux by mixing the rectanct in CS 2, alongwith the addition of allyl bromide. The reaction
completed in 1.5 – 3.5 hour and obtained yield was 75%. The product formed showed good
cytoxic activity in vitro. The product showed the greatest inhibitory activity in the against of
Hela cell lines (IC50 = 0.06 ± 0.01 μM) for the 72 hours and against the cell lines of SMMC-
7721 (IC50 = 0.006 ± 0.04 μM) for 72 hours. But showed lower level of toxicity against the
LO2 cell lines (IC50 = 4.56 ± 0.01 μM) (Wei et al., 2018).
Scheme 2.6: Synthesis of 2(5H)-furanone dithiocarbamate derivative

Due to significances of dithiocarbamate in medicinal field and the day-by-day increasing
demand of it made it more interested for the researchers. A highly effectual C-S cross
coupling between aryl iodide and tetraalkylthiuran disulfide provides dithiocarbamate in a
very good yields. Q.Cao et al. expressed the synthesis by using CuCl 2 (1mol %) as catalyst
using zinc powder as reductant and potassium carbonate (K 2CO3) was employed as base. This
approach proved helpful for the synthesis of dithiocarbamate with the use of less addition of
the catalyst and without using any ligand. This method was not noly improved in showing
performance and economical but also required the easily available reactants along with all
these features also provided better yield. (Q. Cao, Peng, Cheng, & Dong, 2018).
18
Scheme 2.7: Synthesis of dithiocarbamate in the presence of catalyst
The acetylation and the de-acetylation of histone have an important role in the gene
expression of epigenetic regulation. The histone acetylation and de-acetylation help in
balancing the activities of the histone by HDACs (histone de-acetylases) and HATs (acetyl-
transferases). HDACs have the recognition in the various kinds of cancer cell-lines which
catalyze by removing the Ac-groups from the histones and resulting in the condensation of
chromatin along with the suspension of tumor gene. HDACs have been proven as the
objective for the treatment of cancer by inhibiting the selected the cells in apoptosis, cell
cycle and differentiation. The family of HDAC made up of 18 iso-forms and these 18 iso-
forms further classified into the four sub-classes. The classes have sub-families on the basis
of their catalytic mechanism and the sequence homology. There are different types of HDAC
inhibitors like Tacedinaline which under clinical tribunal for treatment of the diverse kinds of
the cancer cells. Generally, HDAC inhibitors are having three domains. Xie’s group
presented the convenient path way to get the desired product using oone-pot method. They
treated the carbon disulfide with the amines and the 4-(BrCH 3) benzoic acid. Then added the
benzene-1,2-diamine in the existence of K 3PO4, ET3N and DMF at room temperature. The
synthesized compound showed the effective anti-cancer and anti-tumor activity against the
different cell lines with the lowest IC 50 value (IC50 = 0.54 ~ 2.49 μM) as compared to MS275
and CS055. HDACs have selective inhibitors such as M133, M122 and M101 and these
inhibitors inhibit the colonial formation of the human hepato-cellular carcinoma cell-lines
(SMMC7721). Apart from this M133 and M101 founded very operational against the
SMMC7721 cancer cell-line by arresting the cycle of cancer cell at the G2/M phase. This also
displayed that the introduction of the 2-aminobenzeamide improve the anti-tumor activity as
well as the inhibitory activity of HDAC (Xie, Li, Tang, & Yuan, 2018).
19
Scheme 2.8: Synthesis of histone dithiocarbamate derivative
Quinazoline derivatives having side chain at C 5 and C6 position possess effective anti-tumor
activity. In spite of this, Ding et al. proposed the synthesis of quinazoline-4-(3H)-one based
dithiocarbamate derivative. This reaction needed 5,10-CH 2THF which donate the –CH3 and
oxidized the 7,8-DHF. DHFR used as a catalyst which converted the7,8-DHF into 5,6,7,8-
THF in the presence of NADPH which acted as a reductant. The prepared compound
evaluated their anti-cancer activity against MCF-7, HCT-116, HeLa and A549 cell-lines of
human with the IC50 = 5.53 μM (Ding et al., 2016).
Scheme 2.9: Synthesis of quinazoline dithiocarbamate derivative

The metal-enzyme CA plays as significant role in the CO 2 hydration into the bicarbonate.
Carbonic anhydrase are associated in many important cellular processes like pH homeostasis,
respiration, bone resorption, electrolyte secretion and biosynthetic and organs process e.g;
gluconeogenesis, lipogenesis and ureagenesis which need bicarbonate as the substrate. These
enzymes plays a significant role in the inhibition and management of many disorders like
acid-base dis-equilibria, glaucoma, epilepsy and many other altitude sickness etc. Apart from
them the carbonic anhydrase enzyme uses as an inhibitors in the treatment of the hypoxic
tumors. Altintop et al. reprted the synthesis of dithiocarbamate derivatives of benzodioxole
based by the reaction of N-(1,3-benzodioxol-5-ylmethyl)-2-chloroacetamide with the Na salt

of the N,N-disubstituted dithiocarbamates. The synthesized derivatives evaluated for the
cytotoxicity activity against the A549 and many other human cell lines. The compound found
very effective against the HCA-1 with the IC 50 value ranges from the 0.346 nM to 0.288 nM
and HCA-11 with the IC50 value ranges from 0.287 to 0.338 nM (Altintop et al., 2013).
20
Scheme 2.10: Synthesis of N,N-disubstituted dithiocarbamate
Regardless of that considerable development has been completed in the cancer treatment but
cancer is static a main health problem and it distresses medicinal municipal all over the
world. Yan et all. Reported the reaction between heterocyclic methylamines and carbon
disulfide followed by the 3-bromopropionitrile. The product obtained showed the good
proliferative activity. It showed anti-cancer activity against the MDA-MB-468 lines of cell.
1,3,4-oxadiaole derivative showed the enhanced inhibitory activity (IC 50 = 1.23 μM) against
the BeL-7402 cel lines. Apart from this oxadiazoles also showed activity against MDA-MB-
68 (IC50 = 4.29 μM) and SK-BR-3 (IC50 = 0.58 μM). Due to its exhibiting better inhibitory
activity widely use in drug molecules (Y.-B. Li et al., 2016).
Scheme 2.11: Synthesis of oxadiazole dithiocarbamate derivative

Malignant cancer considered one of utmost life-threatening ailments. Regardless of major
breakdown through in numerous areas of current medicine, still persist substantial challenges
in the discovery of successful treatment for the cancer. Therefore, there is still vital to
discover the new and advance anti-cancer drugs of innovative chemical entity. To investigate
anti-cancer effect dithiocarbamates derivatives, Li et all. synthesized the dual
dithiocarbamates and evaluated their anti-cancer activities in vitro on human cell lines. The
reaction occurred when paraformaldehyde reacted with dimethyl hydrochloride in reflux. The
formed intermediate further reacted treated with the carbon disulfide and CH 2NCl. The
reaction performed using solvent and base. The DMF used as a solvent and K 2CO3 as a base.
The novel product investigated against the various cell lines of human like the MCF-7,
HepG2, H522, SW480, MDA-MB-453, A375, H1299, COLO205 and PC3. This showed
inhibiting activity against nine different types of tumor cell with IC 50 << 1 μM. It showed IC50
= 54 nM against hepG2 cell lines and IC 50 = 23 nM against the MCF-7. This also exhibited
many folds decrease of cytotoxicity against the cell line of hepatic (R.-D. Li et al., 2015).
21
Scheme 2.12: Synthesis of dithiocarbamate using DMF as a solvent
Diseases like STIs are diabolic and insidious that would not be ignored. Every year, more
than 340 million cases of STIs reported. Different drugs designed to deal with STIs but these
drugs have to face many challenges from FDA. Kumar et al. synthesized the derivatives of
piperidine substituted based ditiocarbamate. They become able to synthesized almost 13
drugs and these drugs many times more effective than the already available drugs. These
drugs have been proved potently spermicidal and microbicidal (Kumar et al., 2012).
Sch
eme 2.13: Synthesis of piperidine based dithiocarbamate drug
A small set of collection of the derivatives of dithiocarbamate ester synthesized through the
derivatiation of N2O position of the emetine. These compounds have anti-cancer evaluation,
show positive LNCaP value in the androgen receptor and negative PC 3 in androgen receptor.
Akinboye et al. represented the derivatives dithiocarbamate ester study showed that these
compounds have appreciable effectiveness against all cell lines of cancer and having
cytotoxicity value ranges from IC50 = 1.312 ± 0.031 IM value to the 5.201 ± 0.125 IM by the
treatment of varius days. The alkylation at S of the compound leads to more stables
derivatives of dithiocarbamate esters (Akinboye et al., 2015).
22
Scheme 2.14: Synthesis of S-alkylated dithiocarbamate
From the last many years researchers are trying to discover the usefulness of MBH (Moritae-
Baylise-Hillman) chemistry in the heterocyclic scaffolds synthesis with the biological
effectiveness in the medicine field. Dighe et al. become able to synthesize the thiazines based
derivatives of dithiocarbamate using allyl amine. Thiazines core belong to anti-biotic class of
cephalosporin. They preceded the reaction in water and not got any reasonable results. Then,
they treated the thiazines with CS2 and phenylmethanamine using K2CO3 and MeOH at room
temperature with constant stirring for 13 hours. The obtained product exhibited anti-
hyperglycemic activity against the PPARϪ at the transcription level (Dighe et al., 2014).
Scheme 2.15: Synthsis of heterocyclic scaffolds dithiocarbamate

Triazole and its derivatives have been used widely in pharmaceutical industry and in many
others field due to its potential properties. Due to this many triazoles and its derivatives
synthesized. The triazole compounds are synthesized by reacting alkynes with azides. The
reaction is usually occurred at high temperatures and in the presences of some reagents.
Li et al. reported the synthesis of 1,2,3-triazoles group containing dithiocarbamates expressed
the synthesis using catalyst. The reaction happened between the benzoyl bromide and alkyne
followed by the reaction with NaN 3. The CuBr used as a catalyst and reaction proceeded at
70oC temperature. The 1,2,3-triazoles tested in vitro against anti-tumor. It showed excellent
growth inhibitory results against the CDC25B (Q.-H. Li, Ding, & Huang, 2014).
23
Sc
heme 2.16: Synthesis of 1,2,3-triazole dithiocarbamate
Azoles like voriconazole, fluconazole, posaconazole and itraconazole are the commonly used,
fungicides. These drugs inhibit the (CYP51) an enzyme which encoded the ERG11 gene. The
CYP51 inhibition involved the H-bonding (hydrophilic region), the spilited hydrophobic
region and coordinated iron bond of the Heme-group. This inhibition occurs when the N-atom
of azlole ring attach with Fe-atom of Heme group of enzyme. As a result, the toxic
compounds synthesized which are difficult to replace or remove successfully. Therefore,
keeping in mind these toxic compounds the need of developing new anti-fungal drugs arises
which have lower toxicities and show broad spectrum. Other hand, dithiocarbamates attracted
attention due to its bilgical activity against fungal and many other diseases. So, in the
development of new anti-fungal drugs, the reactions between dithiocarbamates and azoles
designed to synthesize and evaluated their anti-funagl activites. Zou et al. represented the
synthesis by the reaction of dithioic acid with oxirane using carbon disulfide. The obtained
product showed higher anti-fungal activities against the A. Fumi than the fluconazole. It also
exhibited better activity against the C. neoformans with the value MIC 80 < 0.125 mg/ml (Zou
et al., 2014).
Scheme 2.17: Synthesis of oxirane dithiocarbamate derivative

DNA is consider the vital pharmacological target for many drugs specially in the clinical
usage. The small molecules which can bind to DNA has proved to be very operative agents
against viral, bacterial and cancer diseases. Small molecules interact with the DNA through
different binding means. In the anti-cancer therapy DNA intercalators is consider as a most
important drugs class. Kamal et al. synthesized the series of the new β-carboline
24
dithiocarbamates derivatives which have different substitution at their different positions. The
precursors and their synthesized derivatives evaluated in the vitro cyto-toxic activity against
the cancer in human cell line. The synthesized compound showed the cytotoxic activity IC 50 =
1.34 to 0.79 μM (Kamal et al., 2015).
Scheme 2.18: Synthesis of derivatives of β-carboline dithiocarbamate

Dithiocarbamates are known as pharmacophore due to its lipophilicity. Medicinal
researchers studied the dithiocarbamates broadly because it has the ability to replace its
carbamate group with any compounds and can synthesize new compounds by simply the
bio-isosteric replacement. Pyrazolines have been able to attain quite attention due to its
synthetic and medicinal importance in pharmaceutical industry. Derivatives of pyrazoline
exhibited the broad spectrum of the biological activities including the anti-cholinesterase
activity. Bala et al. synthesized the derivatives of the N-substituted pyrazoline and evaluated
as cholinesterase inhibitors and MAO-B which shown favorable results against the
Parkinson’s and Alzhmeimer’s diseases. The synthesized compound also investigated for the
cytotoxic effects (Bala, Gupta, & L Sharma, 2014).
Scheme 2.19: Synthesis of pyrazoline based dithiocarbamate derivatives

Multi-component reactions are the reactions which utilize three or more than three starting
reactants combine together in a flask to generate a single product. In the combinatorial
chemistry, the MCRs ensure that the reaction would be highly economical and generated
product exhibited potential value. As the part of interest, Azizi et al. has become able to
25
establish such green reaction means which help to synthesize many useful compounds. In
this search, the researcher become able to develop one-pot method for the synthesis of
dithiocarbamates using four components i.e; CS 2, alkyl halides and amines without catalytic
conditions. The reaction proved advantageous with high efficiency, good yield and easily
commercially available starting materials. The synthesized derivatives of dithiocarbamate
compounds showed different biological activities like anti-bacterial, anti-tumor, anti-
microbial, anti-cancer, anti-fungal and anti-inflammatory etc (Najmedin Azizi, Khajeh,
Hasani, & Dezfooli, 2013).
Scheme 2.20: Synthesis of Dithiocarbamate using four component one-pot method

Medication resistance to renowned antifungals like azole derivatives is pouring the increase
in worldwide mortality because of the fungal infection. The identification of the new
molecular substances structurally distinct to these which may be representative of the valid
strategy has the ability to overcome the resistance according to the currently available
medicines. In determination to develop highly effective anti-fungal drugs, Chauhan et al.
reported the dithiocarbamate compounds which contain pyridine moiety and these
compounds shown good anti-fungal activity against the Candida albicansstrain. Furthermore,
these drugs did not shown any kind of toxicity level up to MIC 51 = 3.12 μM mL-1 at the cell
line (L929) against mammals (Chauhan et al., 2012).
Scheme 2.21: Synthesis of pyridine based dithiocarbamate derivative

Dithiocarbamates have the capability to form coordination complexes with the metals with
different modes of bindings. These coordinated complexes have the ability to show broad
spectrum against different biological activities bactericidal and fungicidal. Dithiocarbamates
26
contain sulfur atom with which metal ions bind in different fashion either in mono-dentate
way or bi-dentate way. The nitrogen functionalized in different ways which help metal
complex to enhance its physical and chemical properties. M–S2CNR2 is the dithiocarbamate
core in which M = metal and R = Alkyl/Aryl and it proved of great importance due to its
synthetic utility. Husain et al. reported the synthesis of Ni(diethyldithiocarbamate) 2 by the
reaction of sodium diethyldithiocarbamate with NiL(ClO 4)2. He also refined its crystal
structure from R = 10.6% to R = 2.99%. The anti-fungal and anti-bacterial activity of
prepared complex determined against different bacterial strains such as Pseudomonas
aeruginosa, Escherichia coli and Bacillus thuringiensiso and against fungal strain such as
Fusarium oxysporum, Penicilliumchrysogenum and Aspergillus nigrus. The coordinated
complex Ni(dithiocarbamate)2 shown better anti-fungal and anti-bacterial activity than
slandered antibiotics (Husain, Nami, Singh, Oves, & Siddiqi, 2011).
Sc
heme 2.22: Synthesis of dithiocarbamate complexes with metal
From many other objectives the main objective of the organic and the medicinal chemistry is
to design, synthesize and the evaluation of the molecules as the human healing agents. From
the last many years, many dithiocarbamates and its derivatives has been synthesized. The
synthesized compounds evaluated and shown many biological activities due to which it
attain the attention of the researchers from the field of the medicines. Like the brassinin,
sulforamate and butenolids obtained from different natural resources and these are exhibited
various biological activities. Butenolide having compounds which consider as the effective
anticancer agent, fungicides and bactericides etc. Due to butenolides benefits researchers
found interest in the combining of the dithiocarbamate with the butenolide. Wang et al.
synthesized and evaluated the butenolide containing dithiocarbamate. They treated the 3-
bromomethyl butenolide with the CS2 in the presence of amine and Na3PO4.11H2O in
acetone. The synthesized compound has shown anti-tumor activity and anti-cancer activity.
The compounds evaluated against the different human cell-lines and it exhibited IC 50 < 30
IM against the cancer (X.-J. Wang et al., 2011).
27
Scheme 2.23: Synthesis of derivatives of butenolide dithiocarbamate
Tuberculosis cases reported more than the 9.4 million every year and about 1.7 million
people die every year. But the rate of new TB cases is increasing day by day in the whole
world. Both types of TB infection are the main reason of death in the entire world. The not
properly availability of TB drugs make this situation even more badly and becomes a
problem of worldwide. It had been forty years for the development of the anti-TB drug. Now
there is need to develop new and advanced compounds. Recently, Horita et al. reported the
synthesis of dithiocarbamate derivative by treating 5-acetamido-2-(acetoxymethyl)-6-
chlorotetrahydro-2H-pyran-3,4-diyl with ammonium 1-pyrrolidinethiocarbamate in the
presence of dimethyl carbonate with constant stirring whole night. They synthesized
dithiocarbamate based drug for the treatment of TB which is OCT313, it exhibited the
effective antimycobacterial activity. The structural development of the compound has also
been done by the group at C positions by the replacement of DMDC with the PDTC. The
synthesized derivative evaluated and exhibited the antimycobacterial activity against MTB.
OCT313HK and GIc-NAc-PDTC showed the most effective anti-TB activity having the
MIC value of 6.25-12.5l g/ml. OCT313HK were also potent against the MTB clinical-
isolates such as MDR and XDR. It employed the prime bacterial activity and also displayed
bacteriolytic activity even at very high absorptions. Collectively, the study showed that
OCT313HK is novel and effective drug against the MTB (Horita et al., 2011).
Scheme 2.24: Synthesis of dithiocarbamate based TB drug

MCRs are also known as the multicomponent reactions which have the ability to produce a
28
variety of composites and afford the effective method for combinatorial synthesis which in
result structurally varied compounds. By using the method the compounds formed having
molecular complexity due to combing of multiple steps for the synthesis of one substance
and it is not the demand and need of synthetic design. So, the method of MCRs with the
green conditions attracted the attention of researchers of different working groups. A highly
efficient, one pot reaction using three components; amines and CS 2 with the alkyl vinyl
ethers via Markovnik addition reaction, was showed by Halimehani et al. This reaction was
performed under a mild and greener conditions. This provides exceptional yield and
regiospecific product. It has shown highly efficient, environment friendly and facile method
without using any basic and toxic organic solvent (DMF, DMSO). Water played dual rule of
solvent and as well as promoter and this method given excellent yield in green conditions
(Halimehjani, Marjani, & Ashouri, 2010).
Scheme 2.25: Synthesis of dithiocarbamate via Markovnik addition reaction

The incorporation of the lipo-philic as the side chain into benzene ring of the quinazoline has
directed to the development of many potent anti-cancer like Trimetrexate. In the search of
quinazoline based dithiocarbamate derivatives which may exhibit anti-cancer activities,
different researcher do work. Cao et al. synthesized the quinazoline dithiocarbamates and
evaluated for cytotoxic activity. The compound inhibited anti-cancer against MCF-7(IC 50 =
7.15 mM), A549 (IC50 = 5.44 mM), HCT-116 (IC50 = 11.44 mM) and HeLa (IC50 = 12.16
mM) cell lines. They treated the quinazoline with CS 2 and halo-hydrocarbon along with the
anhydrous K3PO4 at room temperature with constant stirring for the 2 to 12 hours (S.-L. Cao
et al., 2010).
29
Scheme 2.26: Synthesis of quinazoline dithiocarbamate derivative
Dithiocarbamate and its derivatives synthesized by different researchers due to its biological
importance. The solvent was implied for the synthesis of dithiocarbamate derivatives.
Researchers shown the interest to synthesize the dithiocarbamate and its derivative without
using solvent to make the dithiocabarmate more potent. By keeping this point in mind
different researchers designed the synthesis of dithiocarbamate. In this way, Chaturvedi et al.
represented a minor, appropriate and one pot method provides dithiocarbamates in
exceptional yields by the mixing of amines, carbon disulfide and a Michael acceptor,
provided solvent-less conditions at room temperature (Chaturvedi, Mishra, & Mishra, 2007).
Scheme 2.27: Synthesis of dithiocarbamate in solvent less-conditions

From the last few years, the central objective of scientists to develop an economic and
greener process for the synthesis of drugs which also has the abilities to shown biological
activities. For this Azizi et al. reported the reaction between amines, carbon disulfide and
alkyl halide at room temperature. This one pot reaction is a most efficient and easiest way of
the synthesis of dithiocarbamate and products afforded in 68-97% yield. This reaction
occurred in solvent-less and neat conditions due to which there is no side product and pure
product isolated by simply extracted method. By using this method many drugs has been
synthesized which has been implied for different biological activities (Najmodin Azizi,
Torkiyan, & Saidi, 2006).
Scheme 2.28: Synthesis of dithiocarbamate drug in greener conditions

Regardless of many advancement and discoveries in various drugs in the field of medicine
since many years, successfully treatment of many diseases like cancer is still an important
task from the start of 21st century. For the reason challenging to determine new drugs which
act actively to kill the tumor cell and inhibit the spread of anti-cancer without general
30
toxicity. Class of dithiocarbamic acid is one of the classes of the organic molecules which
exhibit the variety of the biological activities. Recently, Hou et al. synthesized the many 4- N
substituted derivatives and evaluated in vitro for anti-cancer activities. The synthesized
compound was found very active anti-cancer agent having IC 50 = 5.3 IM for HL-60 and
against Bel-7402 the IC50 = 11.5 IM. The introduction of the suitable R-group at the 4-N
made the compound favorable and improvement in the activity (Hou et al., 2006).
Scheme 2.29: Synthesis of 4-N-substituted derivative of dithiocarbamate

Structure amendment of the folic acid directed to discovery of many anti-folates as the
efficient anti-cancer drug. For example a Brassinin consider as the dithiocarbamate and
isolated from the cabbage. Another example Sulforamate used to synthesize many
dithiocarbamate compounds and exhibited in vivo and in vitro anti-tumor activity.
Researchers were interested to synthesized anti-folates which act as anti-tumor agents with
the combination of dithiocarbamate with the 4(3H)-quinazolinone. Cao et al. reported the
synthesis of the derivatives of the 4(3H)-quinazolinone with the side chain of
dithiocarbamate. They reacted the 6-bromomethyl-2-methyl-4(3H)-quinazolinone with
carbon disulfide using the anhydrous K3PO4. The obtained product estimated for the anti-
tumor activity against the human K562 cells in myelogenus leukemia. It showed inhibitory
activity with the IC50 value 0.51 M against the K562 cells (S.-L. Cao et al., 2005).
Scheme 2.30: Synthesis of 4(3H)-quinazolinone dithiocarbamate derivative
31
32
CHAPTER 3
MATERIALS AND METHODS
All the research work performed at the laboratories of the Department of Chemistry Riphah
International University Faisalabad and Department of Chemistry Government College
University Faisalabad. All the chemicals and solvents which have been utilize, bought from
the E. Merck Germany and use them after distilled at least once.
3.1Chemicals/ Reagents
● Morpholine
● Substituted piperazine
● Carbon disulfide
● Heterocyclic amine
● Ethanol
● Methanol
● DMF
● DCM
● Distilled water
● n-hexane
● Ethyl acetate
● Potassium carbonate
3.2 Equipments
● Sonicator
● Sonicator tube
● Beakers
● Funnels
● Separating funnel
● Pipette
● Thermometer
● Round bottom flask
● Conical flasks
● Glass rod
● Spatula
● Hot plate
● Magnetic stirrer
● Capillaries
33
● TLC plate
● Micro pipette
3.3 Instruments
● Weighing balance
● UV-Lamp
● Electric oven
● Melting point Apparatus
● Spectrophotometer
3.4 General Information
All the glass wares were being firstly dried in oven at 100 oC and then performed all the
reactions. All the reagents and chemicals which were in liquid state had been transferred with
the help of disposable syringes. Anhydrous sodium sulfate was used for drying purpose such
as the drying of the organic layer.
1
H-NMR-spectra were measured on a 500 MHz nuclear magnetic resonance spectrometer
(model AV-400).
13
C-NMR-spectra were also measured on a frequency of 100 MHz on a nuclear
magnetic resonance spectrometer (model AV-500).
Solvents = CDCl3, DMSO, MeOD
Solvent peak calibrated at 7.26 ppm
PC-software MestRe-C used for the interpretation of spectra
Abbreviations implied for the interpretation of the NMR spectra are as the following;
● Singlet (s),
● Doublet (d),
● Doublet of doublet (dd),
● Triplet (t),
● Quartet (q),
● Multiplet (m)
Chemical shifts (δ-values) measured in ppm.
Preparative flash column chromatography was performed by using columns packed with
the silica gel grade 60 (35-70 µm) which bought from the Macherey-Nagel.
Thin layer chromatography has been done by using commercially available pre-coated
polygram® SIL-G/UV 254 plates which was bought from the company fluka. The spot was
detected using UV-lamp.
Different solvents like DCM, DMF, n-hexane, Acetonitrile, Sulphuric acid and ethyl acetate
were used for analytical grading. Commercially available solvents like ethyl acetate and
34
petroleum ether were distilled before using.
3.5 General Experimental Procedures (GPS)
GP 01: Synthesis of Mesyl substituted piperazine
Substituted piperazine was synthesized by treating the piperazine with alkyl sulfonyl halide in
DCM at room temperature with constant stirring for 24-48 hours. The reaction was checked
by using TLC. When the reaction got completed, product was afforded with filtration. Crude
product was purified by the recrystallization with the warm water and n-hexane.
GP 02: Synthesis of tert-butoxycarbonyl substituted N-piperazine
The starting precursor substituted piperazine was prepared by treating the anhydrous
piperazine with tert-butoxycarbonyl using base K2CO3 and employing DMF as a solvent.
Reaction medium was allowed to stand under reflux for 6-8 hours and accomplishment of
reaction monitored by performing TLC. Product was purified by column chromatography.
Crude product afforded by extraction using ethyl acetate and water in three washes (ethyl
acetate : water = 30 : 10).
GP 03: Synthesis of Aryl dithiocarbamate derivatives using conventional method
Substituted heterocyclic amines were allowed to react with various aryl halides using carbon
disulphide and using ethanol as solvent under constant stirring at room temperature for 24-48
hours. The headway of the reaction was monitored by the TLC. Upon the completion of
reaction, the solvent evaporated and the deposit was collected. After collecting the residue
then washed it with water and dried over the anhydrous sodium sulfate. The final product was
collected after evaporation of the solvent. Then lastly, the product was purified with column
chromatography.
GP 04: Synthesis of Aryl dithiocarbamate substituted piperazine using ultrasonic
method
Substituted piperazine treated with the various alkyl and allyl halides using carbon disulfide
and solvent like ethanol under ultrasonic conditions at 70-80oC. The mixture was kept in
sonicator until the precipitation was completed which approximately taken 60-90 minutes. At
different intervals of time the TLC was performed to monitor the reaction progress. When the
reaction got completed the excessive solvent was evaporated under reduced pressure. The
residue was collected and purified to obtain the desired aryl dithiocarbamate derivatives.
GP 05: Synthesis of Aryl dithiocarbamate substituted morpholine using ultrasonic
method
Morpholine reacted with the various alkyl and allyl halides in the presence of solvent ethanol
and carbon disulfide under ultrasonic conditions. The reaction performed at temperature 90-
35
120oC and about taken 80-100 minutes for the completion of reaction. The TLC used to
monitor the reaction by using different ratio of solutions (n-hexane / ethyl acetate). When
reaction got completed the solvent was removed under the reduced pressure and obtained
product washed dried and purified.
3.6 Synthesis of Compounds
3.6.1 Synthesis of 1-(methylsulfonyl)piperazine 108
According to GP 01, 1-(methylsulfonyl)piperazine 108 was synthesized by treating the
piperazine 106 (0.41g, 4.8 mmol) with methylsulfonyl chloride 107 (0.1g, 0.8 mmol) in DCM
(05 mL) at room temperature with constant stirring for 24-48 hours. The reaction was
monitored by the TLC. After the completion of reaction, product was afforded with filtration.
Crude product was purified by the recrystallization with the warm water and n-hexane.
TLC: [Dichloromethane : methanol = 7 : 3, Rf = 0.3].
Scheme 3.1: Synthesis of 1-(methylsulfonyl)piperazine 108

3.6.2 Synthesis of tert-butyl piperazine-1-carboxylate 110
According to GP 02, the starting precursor tert-butyl piperazine-1-carboxylate 110 was
prepared by treating the anhydrous piperazine 106 (86.14g, 4.8 mmol) with tert-butyl
carbonochloridate 109 (0.1g, 0.7 mmol) in the presence of base potassium carbonate and
DMF (05 mL) employed as a solvent. Reaction medium was allowed to stand under reflux for
6-8 hours and completion of reaction was monitored by performing TLC. Crude product
afforded by extraction using ethyl acetate and water in three washes [Dichloromethane :
water = 30 : 10]. Purification was carried out by coloumn chromatography in
[Dichloromethane : methanol = 9 : 1].
Scheme 3.2: Synthesis of tert-butyl piperazine-1-carboxylate 110
36
3.6.3 Synthesis of benzyl 4-(methylsulfonyl)piperazine-1-carbodithioate 112a
According to GP 04, to a mixture corresponding 1-(methanesulfonyl)piperazine 108 (0.01g,
0.60 mmol) and (chloromethyl)benzene 111a (0.05g, 0.60 mmol) were added to the Sonicator
containing (05mL) of ethanol. The CS2 (0.09g, 1.2 mmol) was added to the reaction mixture
and kept in sonicator for 60-90 minutes at 70-80oC. TLC was performed to monitor the
completion of reaction. After the completion of reaction, the product was extracted with ethyl
acetate and water. The organic layer washed with water and then with the 05% solution of
NaOH. The washed and cleaned organic layer collected. The collected product dried over the
Na2SO4 and solvent was removed through evaporation.
S
cheme 3.3: Synthesis of benzyl 4-(methylsulfonyl)piperazine-1-carbodithioate 112a
White powder; 106oC; FT-IR: (C=O); 1650 cm-1, (C-N); 1100 cm-1, (C=S); 800 cm-1, (C-C);
600 cm-1. 1H NMR (δ): 500 MHz, CDCl3; 7.40 (2H, d, j = 10 Hz), 7.33 (2H, dd, jA = jB = 8
Hz), 7.26 (1H, d, j = 8 Hz), 4.43 (2H, s), 2.81 (t, 4H, j = 10 Hz), 2.95 (3H, s), 2.7 (t, 4H, j =
10 Hz). 13CNMR, 196 (C=S), 128.7, 128.7, 127.1, 127.7, 127.7, 136.0 (ph), 47.7, 52.4 (P,P),
40.1 (CH3).
3.6.4 Synthesis of 4-(tert-butyl)benzyl 4-(methylsulfonyl)piperazine-1-carbodithioate
112b
According to GP 04, for the synthesis of 4-(tert-butyl)benzyl 4-(methylsulfonyl)piperazine-1-
carbodithioate 112b, 1-(methylsulfonyl)piperazine 108 and 1-(tert-butyl)-4-
(chloromethyl)benzene 111b added in the ethanol (05 mL). To the mixture the CS 2 added, the
reaction is performed under ultrasonic conditions so kept it in sonicator for 60-90 minutes at
70-80oC. Progress of the reaction was monitored by the TLC. Upon the completion of
reaction, the residue was separated and solvent was removed through evaporation. The crude
product was washed with water and dried over the anhydrous Na 2SO4 and purified with the
column chromatography.
37
Scheme 3.4: 4-(tert-butyl)benzyl 4-(methylsulfonyl)piperazine-1-carbodithioate 112b
600 cm-1. 1H NMR (δ): 500 MHz, CDCl3; 7.34 (2H, d, j = 10 Hz), 7.15 (2H, dd, jA = jB = 8
Hz), 4.43 (s, 2H), 2.81 (t, 4H, j = 10 Hz), 2.95 (s, 3H), 1.35 (s, 9H). 13CNMR, 196 (C=S),
138.9, 133.0, 133.1, 44.7, 16.0, 124.6 (ph), 47.7, 52.4 (P,P), 40.1 (CH 3), 31.1 (C(CH3), 29.9,
29.9, 29.9 (CH3).
3.6.5 Synthesis of 2-cyanobenzyl 4-(methylsulfonyl)piperazine-1-carbodithioate 112c
According to GP 04, 2-cyanobenzyl 4-(methylsulfonyl)piperazine-1-carbodithioate 112c
synthesized by adding 1-(methylsulfonyl)piperazine 108 and 2-(chloromethyl)benzonitrile
111c along with the CS2 in ethanol which employed as a solvent. The reaction was performed
under ultrasonic conditions. To check the completion of reaction TLC was performed with
different concentrations of solvents at different intervals of time. The reaction mixture was
kept in sonicator for 60-90 minutes at 70-80oC until the desired product formed and
precipitation got completed. The solvent was allowed to remove by evaporation and crude
product was separated. The crude product washed, dried and purified through the filtration.
Scheme 3.5: Synthesis of 2-cyanobenzyl 4-(methylsulfonyl)piperazine-1-carbodithioate 112c

600 cm-1. 1H NMR (δ): 500 MHz, CDCl3; 7.61 (1H, t, j = 10 Hz), 7.52 (1H, d, j = 8 Hz), 7.44
(1H, d, j = 10 Hz), 7.41 (1H, d, j = 10 Hz), 4.59 (2H, s), 2.95 (s, 3H), 2.81 (4H, t, j = 10 Hz),
2.47 (4H, t, j = 10 Hz). 13CNMR, 196 (C=S), 115.8 (C≡N), 144.5, 128.4, 133.0, 127.8, 132.2,
112.0 (ph), 52.4, 47.7 (P,P), 40.7 (CH2), 40.1, 40.1, 40.1(CH3).
3.6.6 Synthesis of tert-butyl 4-(benzythio)carbonothioyl)piperazine-1-carboxylate 114a
According to GP 04, to the mixture tert-butyl piperazine-1-carboxylate 110 (0.10 g, 01
mmol), chloromethyl benzene 111a (0.07 g, 0.53 mmol) and carbon disulfide (0.02 g, 0.53
38
mmol) added in the ethanol (05 mL). Then the mixture allowed to react in sonicator for 60-90
minutes at 70-80oC. The reaction conditions were monitored by the use of TLC. On the
completion of reaction, the solvent was removed under the reduced pressure. The obtained
product 114a was extracted by using dichloromethane, washed with water and then dried.
Lastly, the residue purified with the column chromatography in 9:1 solution of n-hexane and
ethyl acetate.
Scheme 3.6: Synthesis of tert-butyl 4-(benzythio)carbonothioyl)piperazine-1-carboxylate

114a
600 cm-1. 1H NMR (δ): 500 MHz, CDCl3; 7.26 (2H, d, j = 10 Hz), 7.3 3 (2H, dd, jA = jB = 8
Hz), 7.26 (1H, d, j = 8 Hz), 4.43 (s, 1H), 3.22 (t, 4H, j = 10 Hz), 2.95 (t, 4H, j = 10 Hz), 1.38
(s, 9H). 13CNMR, 196 (C=S), 154.7 (C=O), 128.7, 128.7, 127.1, 127.7, 127.7, 136.0 (ph),
79.8 (C(CH3)3), 50.2, 53.2 (P,P), 28.4, 28.4, 28.4 (CH3).
3.6.7 Synthesis of tert-butyl 4-(((4-tert-butyl)thio)carbonothioyl) piperazine-1-
carboxylate 114b
According to GP 04, to a corresponding mixture tert-butyl piperazine-1-carboxylate 110
(0.10 g, 0.53 mmol) and CS2 (0.40 g, 0.53 mmol ) was added in ethanol (05 mL). After 10
min, 1-(tert-butyl)-4-(chloromethyl)benzene 111b (0.90 g, 0.53 mmol) was added. The
mixture was allowed to react under ultrasonic conditions at 70-80 o C for 60-90 minutes. The
reaction was monitored by the TLC (Dichloromethane : methanol = 7:3), solvent was
removed under pressure and then the residue extracted with the ethyl acetate. The organic
layer was combined which dried over the Na 2SO4, concentrated under the vacuum and
purified by the column chromatography the silica gel or recrystallization to obtain the product
114b.
39
Scheme 3.7: Synthesis of tert-butyl 4-(((4-tert-butyl)thio)carbonothioyl) piperazine-1-
carboxylate 114b
600 cm-1. 1H NMR (δ): 500 MHz, CDCl3; 7.34 (2H, d, j = 10 Hz), 7.15 (2H, d, j = 10 Hz), 4.43
(1H, s), 3.22 (4H, t, j = 10 Hz), 2.95 (4H, t, j = 10 Hz), 1.38 (9H, s). 13CNMR, 196 (C=S),
154.7 (C=O), 132.9, 128.7, 128.5, 125.0, 149.7, 125.0, 128.5 (ph), 79.8 (C(CH 3)3), 50.2, 53.2
(P,P), 44.0 (CH2), 28.4, 28.4, 28.4 (CH3).
3.6.8 Synthesis of tert-butyl –(((2-cyanobenzyl)thio)carbonothiyl)piperaizine-1-
carboxylate 114c
According to GP 04, the general procedure for the synthesis of compound tert-butyl –(((2-
cyanobenzyl)thio)carbonothiyl)piperaizine-1-carboxylate 112c was based on the addition of
2-(chloromethyl) benzonitrile 111c (0.10 g, 0.70 mmol) and CS2 (0.05 g, 0.70 mmol) in
solvent ethanol (05 mL). Sequentially, substituted heterocyclic amine like tert-butyl
piperazine-1-carboxylate 110 was added. The reaction mixture was allowed to react in
sonicator for 60-90 minutes at 70-80o C temperature and monitored the progress of reaction
by the TLC (n-Hexane / ethyl acetate, 9 : 1) until the conversion of starting materials was
satisfactory. After the completion of reaction, the mixture was extracted with the ethyl
acetate. The collected organic phase was dried and solvent was removed under vacuum to
provide the desired product.
40
Scheme 3.8: Synthesis of tert-butyl –(((2-cyanobenzyl)thio)carbonothiyl)piperaizine-1-
carboxylate 114c
600 cm-1. 1H NMR (δ): 500 MHz, CDCl3; 7.61(2H, t, j = 10 Hz), 7.52 (2H, d, j = 8 Hz), 7.44
(2H, t, j = 10 Hz), 7.41 (1H, s), 4.59 (2H, s), 2.95 (4H, t, , j = 10 Hz), 1.38 (9H, s).
13
CNMR, 196 (C=S), 154 (C=O), 115.8 (C≡N), 144.5, 128.4, 133.0, 127.8, 132.2, 112.0 (ph),
79.8 (C(CH3)3), 50.2, 53.2 (P,P), 40.7 (CH2), 28.4, 28.4, 28.4 (CH3).
3.6.9 Synthesis of benzyl morpholine-4-carbodithioate 115a
According to GP 05, a mixture of benzyl chloride 111a (0.14 g, 1 mmol), morpholine 113
(0.1 g, 01 mmol) in ethanol (05 mL) and CS2 was stirred. The whole mixture was left in
sonicator for 80-100 minutes at 90-120oC. The TLC was used to check the progress of the
reaction. When the reaction got completed, the mixture was extracted with using the ethyl
acetate. The combined organic layer was washed with water, dried over anhydrous Na 2SO4
and concentrated under vacuum to afford the crude product. The crude product was purified
by the recrystallization from the mixture solvents of n-hexane and ether to afford the pure
product 115a.
Scheme 3.9: Synthesis of benzyl Morpholine-4-carbodithioate 115a

600 cm-1. 1H NMR (δ): 500 MHz, CDCl 3; 7.40(2H, d, j = 10 Hz), 7.33 (2H, d, j = 10 Hz),
7.26(1H, d, j = 10 Hz), 4.43 (2H, s), 4.13 (4H, d, j = 10 Hz), 3.65 (4H, t, , j = 10 Hz).
13
CNMR, 196 (C=S), 136.0, 127.7, 128.7, 127.1, 128.7, 127.7 (ph), 65.5, 51.9 (P,P),
44.0(CH2).
3.6.10 Synthesis of 4-(tert-butyl)benzyl Morpholine-4-carbodithioate 115b
According to GP 05, the morpholine 113 (0.1 g, 1 mmol ), 1-(tert-butyl)-4-
(chloromethyl)benzene (0.2 g, 0.1 mmol) 111b and carbon disulfide (0.07g, 0.53 mmol)
added in the ethanol (05 mL). Then the mixture was kept in sonicator and allowed to react
under ultrasonic condition for 80-100 minutes at the 90-120 o C. The reaction monitored by
the TLC. On the completion of reaction, the solvent was removed under the reduced pressure.
The obtained product 115b extracted by using dichloromethane, washed with water and then
41
dried. Lastly, the obtained product was purified with the column chromatography in the
solution of dichloromethane and methanol.
Scheme 3.10: Synthesis of 4-(tert-butyl)benzyl morpholine-4-carbodithioate 115b

600 cm-1. 1H NMR (δ): 500 MHz, CDCl3; 7.34 (2H, d, j = 10 Hz), 7.15 (2H, d, j = 10 Hz),
4.43 (1H, s), 4.13 (4H, t, j = 10 Hz), 3.65 (4H, t, j = 10 Hz). 13CNMR, 196 (C=S), 133.3,
128.6, 126.1, 126.1, 128.6 (ph), 146.8 (C(CH3)3), 65.5, 51.9 (P,P), 44.0 (CH2), 23.3, 33.2,
23.3 (CH3).
3.6.11 Synthesis of 2-cyanobenzyl Morpholine-4-carbodithioate 115c
According to GP 05, to a corresponding mixture of 2-(chloromethyl)benzonitrile 111c (0.10
g, 0.70 mmol), morpholine 113 (0.06 g, 0.60 mmol) and CS2 (0.40 g, 0.53 mmol) were added
in ethanol (05 mL). The reaction was performed under ultrasonic conditions, kept the mixture
in sonicator for 80-100 minutes at 90-120 oC. The reaction was monitored by the TLC
(Dichloromethane / methanol, 7:3), solvent was removed under pressure and then the residue
extracted with the ethyl acetate. The organic layer was combined which dried over the
Na2SO4, concentrated under the vacuum and purified by the column chromatography over the
silica gel and recrystallization to obtain the product 115c.
Scheme 3.11: Synthesis of 2-cyanobenzyl Morpholine-4-carbodithioate 115c

600 cm-1. 1H NMR (δ): 500 MHz, CDCl3; 7.61(1H, d, j = 10 Hz), 7.52 (1H, d, j = 10 Hz), 7.44
(1H, d, j = 10 Hz), 7.41 (1H, t, j = 10 Hz), 4.59 (2H, s), 4.13 (4H, t, j = 10 Hz), 3.65 (4H, t, j
42
= 10 Hz). 13CNMR, 196 (C=S), 115.8 (C≡N), 144.5, 128.4, 133.0, 127.8, 132.2, 112.0 (ph),
65.5, 51.9 (P,P), 44.7 (CH2).
3.7 Biological Evaluation

3.7.1 Antibacterial activity
Bacterial infection (air, water, and surfaces) is a serious problem and concern of the people of
the world. Anti-bacterial drugs have been using against bacterial diseases and showed quite
satisfactory results (Zhang et al., 2021). Heterocyclic substituted piperazine based drugs
shown good anti-bacterial applications in last few years. Aryl dithiocarbamates has also
ability to work against the bacterial infections (Kharb, Bansal, & Sharma, 2012).
Disc method was used to evaluate the antibacterial activity of the compounds. Approximately
100 μL of suspensions of the microorganisms were allowed to pour onto the nutrient of agar
media using the sterilized loop. Precise and specified concentration of solution of the
compound which (05 mg/100 μL) in the chloroform which was used to infused on the discs of
the filter paper, the sterilized disc used for infusion. On the other hand, ciprofloxacin was
dumped onto the agar plates which have already been inoculated with the bacterial cells. The
prepared plates were stored at 4oC for the 60 minutes, which were allowed to incubated for 24
hours at the 37oC. The antibacterial potential has been evaluated by measuring inhibition zone
which has been measured in mm.
Minimum Inhibitory Concentration (MIC)
The failed treatments and increasing resistance of the bacteria against the antibiotics required
to need the identification of cause of the problem and finding the ways which may help to
develop the improved and effective treatments. The main reason behind this problem is the
dosage of antibiotics against the bacterial infection, so it is important to use the antibiotics
dose according to the bacterial infection which proves as an effective treatment. There were
many parameters introduced and among those microbiological parameters MIC of
antimicrobial known since long time. MIC is lowest concentration of the antibacterial drug
which is expressed in the mg/L. The MIC value which usually have been determined by the
culturing of the microorganisms at the liquid or solid media. The lower the MIC value lesser
the drug require for inhibition and the drugs with lower MIC values are more effective for
inhibiting the growth of organisms. Resazurin microtiter-plate analyze was used for the
calculation of the MIC values of all the compounds. For the assay, 10 mg/mL and 100 mg/mL
(w/v) concentrations of the standard antibiotics and compounds containing solution of
approximately 100 µL prepared which used for assay in the 10 % DMSO. The prepared
43
solution was added in all the available 96 plates in the first row (50 µL test compounds) and
rest of the plates filled with the 50 µL of the nutrient broth. After this, 10 µL of each of the
indicator resazurin and microbial suspensions added to all the well plates. The column of well
plates which containing solutions of compounds, 10% DMSO
( -ve control), ciprofloxacin ( +ve control) and the microbial solutions containing broth
incubated for the 24 hours at 37 oC. Laterly, the temperature decreased from 37 oC to 25oC for
the 48 hours. The changing in color of the solutions in well plates helped to evaluate the MIC
values.
Statistical analysis
All the experimental work were performed in the triplicate and the statistical analysis was
carried out using Microsoft Excel 2010. The obtained results expressed as mean ± SD.
44
CHAPTER 4
RESULTS AND DISCUSSION
The dithiocarbamates are known as the class of the compounds that has the ability to show
many biological applications due to its chemical versatility. Due to this, many biological
activities have already been recognized to these dithiocarbamate compounds, like anti-
bacterial, anti-viral, anti-cancer, anti-fungal, anti-malarial, anti-tumor and many others .
Heterocyclic compounds containing Nitrogen moiety occurred abundantly in nature and their
structural sub-units existence in many naturally occurring products like hormones, antibiotics,
vitamins, alkaloids, dyes and pharmaceutical among many others made N-heterocyclic
compounds of great significance to life (Saini, Kumar, Dwivedi, & Singh, 2013). N-
heterocyclic compounds considered as the building block for the synthesis of biological and
medicinal important compounds. As the many other heterocyclic compounds occurred in
nature but N-heterocyclic compounds are the most abundant than the oxygen or sulfur
containing heterocyclic compounds. N-heterocyclic containing organic compounds showed
better biological activity than the non-nitrogen containing compounds (Shaabani, Nazeri, &
Afshari, 2019). The analogous of N-heterocyclic containing organic compounds occupied a
vital position in the synthesis of drugs in the medicinal chemistry. N-heterocyclic compounds
have attained much attention worldwide due to possessing wide medicinal activities such as
anti-biotics, anti-bacterial, anti-tumor, cytotoxic, anti-tubercular, anti-inflammatory and many
more effects among these. About 90% of the new synthesized drugs contain heterocyclic
compounds which exhibited considerable biological effects (Heravi & Zadsirjan, 2020). Drug
approved by FDA and currently available in markets are more than 75% are N-heterocyclic
containing moieties. Many new N-heterocyclic containing compounds have been designed
which have quite significant physiological and promising medicinal applications is ever
growing (Kerru, Gummidi, Maddila, Gangu, & Jonnalagadda, 2020). In the coming years,
much more interest in new nitrogen containing pharmaceuticals is expected. The aim of this
work was to synthesize different aryl dithiocarbamate derivatives and then evaluation of the
biological activities of these synthesized derivatives. The work was started from these N-
heterocyclic derivatives.
Figure 4.1: Structure of N-heterocycles
45
General scheme for the synthesis of aryl dithiocarbamate derivatives 112a-c from 107.
Figure 4.2: Outline for the synthesis of series of derivatives 112a-c

46

4.1 Synthesis of aryl dithiocarbamate derivatives 112a-c
4.1.1 Synthesis of 1-(methylsulfonyl)piperazine 108
The synthesis of the series of aryl dithiocarbamate derivative 112a-c started from the 1-
47
(methylsulfonyl)piperazine 108. For the synthesis of 1-(methylsulfonyl)piperazine 108, the
piperazine 106 were allowed to treated with methanesulfonyl chloride 107 in DCM at room
temperature with constant stirring for 24-48 hours. The reaction was monitored by the TLC.
The reaction proceeded smoothly and 1-(methylsulfonyl)piperazine 108 was obtained in 90%
yield. The results are summarized in table 4.1.
Table 4.1: Synthesis of 1-(methylsulfonyl)piperazine 108 in different conditions
Sr. # Conditions Solvent Time (hr) Temperature (oC) Yield (%)
1. Stirring Ethanol 24 Room temperature Failed
2. Stirring Ethyl acetate 24 Room temperature Failed
3. Stirring DCM 12 Room temperature 20
4. Stirring DCM 48 Room temperature 90
48
49
The reaction between piperazine 106 and methanesulfonyl chloride 107 were performed by
employing ethanol as a solvent and at room temperature with constant stirring for 24 hours.
The reaction did not proceed to afford 1-(methylsulfonyl)piperazine 108 as a desired product
(Table 4.1, entry 1). The same reaction was performed by treating piperazine 106 with
methanesulfonyl chloride 107 using ethyl acetate as a solvent at room temperature for 24
hours with constant stirring. In ethyl acetate, again did not any reaction took place and 1-
(methylsulfonyl)piperazine 108 product did not formed, reaction failed (Table 4.1, entry 2).
After these attempts, in order to achieve product, piperazine 106 and methanesulfonyl
chloride 107 were allowed to react in the presence of DCM which employed as a solvent with
stirring for 12 hours at room temperature. Piperazine 106 and methanesulfonyl chloride 107
reacted and formed 1-(methylsulfonyl)piperazine 108 as a product. But the afforded yield of
1-(methylsulfonyl)piperazine 108 was very less which was only 20% , as the reaction was not
completed (Table 4.1, entry 3). As the reaction has been occurred by using DCM as a solvent
but the yield was less. To improve and get better yield, the reaction between piperazine 106
and methanesulfonyl chloride 107 performed in the presence of DCM by increasing reaction
time from 12 to 48 hours with constant stirring at room temperature. The isolated yield of 1-
(methylsulfonyl)piperazine 108 product was satisfactory which was afforded 90%% (Table
4.1, entry 4).
4.1.2 Synthesis of Aryl dithiocarbamate derivatives 112a-c from
methylsulfonyl piperazine 108
For the synthesis of series of aryl dithiocarbamate derivatives 112a-c, under ultrasonic
conditions methylsulfonyl piperazine 108 treated with aryl halides and carbon disulfide under
ultrasonic conditions. The synthesized aryl dithiocarbamate derivatives 112a-c were afforded
yield in 86 to 95% yield. The results are summarized in table 4.2.
50
51
Table 4.2: Synthesis of aryl dithiocarbamate derivatives 112a-c in different conditions
Sr. Reactant Condition Solvent Time Temper Product Yield

# s ature
Room
1. Stirring Methanol 10 hr. temp. Failed
111a
112a
Room
2. Stirring Ethanol 10 hr. temp. Failed
112a
111a
Room
3. Stirring Ethanol 48 hr temp. 28%
111a
112a
Incom
4. Sonicator Ethanol 30 min 40oC plete
reactio
111a
112a n
5. Sonicator Ethanol 80 120oC 86%

mins
111a
112a
Room
6. Stirring Ethanol 12 hr Temp. Failed
111b
52
112b
Room
7. Stirring Methanol 20 hr temp. Failed
111b
112b
Room
8. Stirring Ethanol 48 hr temp. 49%
111b
112b
Sonicator Ethanol 30 50oC Incom

9. mins plete
reactio
111b
n
112b
10. Sonicator Ethanol 80 120oC 91%

mins
111b
112b
53
Room
11. Stirring Ethanol 10 hr temp. Failed
112c
111c
Room
Stirring Methanol 12 hr temp. Failed
12.
112c
111c
Room
Stirring Ethanol 48 hr temp. 25%
13.
112c
111c
Incom
o
14. Sonicator Ethanol 30 50 C plete
mins reactio
112c
111c n
15.
Sonicator Ethanol 90 120oC 95%
mins
111c 112c
54
The reaction between 1-(methylsulfonyl)piperazine 108 and (chloromethyl)benzene 111a
took place in round bottom flask in the presence of carbon disulfide and using methanol as a
solvent. The reaction occurred at room temperature with constant stirring for 10 hours. By
treating the reactants 1-(methylsulfonyl)piperazine 108, (chloromethyl)benzene 111a and
carbon disulfide not any reaction occurred using methanol as a result desired product benzyl
4-(methylsulfonyl)piperazine-1-carbodithioate 112a could not formed, the reaction failed
(Table 4.2, entry 1). 1-(methylsulfonyl)piperazine 108 treated with (chloromethyl)benzene
111a and carbon disulfide in ethanol at room temperature with constant stirring for 10 hours.
The reaction did not proceeded and benzyl 4-(methylsulfonyl)piperazine-1-carbodithioate
112a did not formed, the reaction failed (Table 4.2, entry 2). 1-(methylsulfonyl)piperazine
108 and (chloromethyl)benzene 111a are allowed to react in the presence of carbon disulfide
and employing ethanol as a solvent. The reaction was performed at room temperature with
constant stirring for 48 hours. The benzyl 4-(methylsulfonyl)piperazine-1-carbodithioate
112a was formed as a product but afforded only 28% yield (Table 4.2, entry 3). 1-
(methylsulfonyl)piperazine 108 treated with (chloromethyl)benzene 111a and carbon
disulfide in ethanol under ultrasonic conditions at 40oC for 30 minutes. The incompleted
reaction occurred between the reactants (Table 4.2, entry 4). When 1-
(methylsulfonyl)piperazine 108 treated with (chloromethyl)benzene 111a and carbon
disulfide in ethanol under ultrasonic conditions, the little bit reaction was occurred. To
complete the reaction, time as well as temperature increased. The reaction occurred at 120 oC
for 80 minutes and obtained the product benzyl 4-(methylsulfonyl)piperazine-1-
carbodithioate 112a in 86% yield (Table 4.2, entry 5).
The reaction was performed between 1-(methylsulfonyl)piperazine 108 and 1-(tert-butyl)-4-
(chloromethyl)benzene 111b in the presence of carbon disulfide and employing ethanol as a
solvent at room temperature with constant stirring for 12 hours. The desired product 4-(tert-
butyl)benzyl 4-(methylsulfonyl)piperazine-1-carbodithioate 112b could not formed and
reaction failed (Table 4.2, entry 6). The reaction between 1-(methylsulfonyl)piperazine 108
and 1-(tert-butyl)-4-(chloromethyl)benzene 111b took place in round bottom flask in the
presence of carbon disulfide and using methanol as a solvent. The reaction occurred at room
temperature with constant stirring for 20 hours. By treating the reactants 1-
(methylsulfonyl)piperazine 108, 1-(tert-butyl)-4-(chloromethyl)benzene 111b and carbon
disulfide not any reaction occurred using methanol as a result desired product 4-(tert-
butyl)benzyl 4-(methylsulfonyl)piperazine-1-carbodithioate 112b could not formed, the
reaction failed (Table 4.2, entry 7). 1-(methylsulfonyl)piperazine 108 treated with 1-(tert-
butyl)-4-(chloromethyl)benzene 111b and carbon disulfide to obtain 4-(tert-butyl)benzyl 4-
55
(methylsulfonyl)piperazine-1-carbodithioate 112b. The reaction was occurred in ethanol at
room temperature with constant stirring for 48 hours. 4-(tert-butyl)benzyl 4-
(methylsulfonyl)piperazine-1-carbodithioate 112b was formed with afforded yield 49%
(Table 4.2, entry 8). To increase the product yield the reaction between 1-
(methylsulfonyl)piperazine 108, 1-(tert-butyl)-4-(chloromethyl)benzene 111b and carbon
disulfide occurred in sonicator at 50oC for 30 minutes. The reaction proceeded but found
incompleted (Table 4.2, entry 9). To accomplish the reaction, 1-(methylsulfonyl)piperazine
108, 1-(tert-butyl)-4-(chloromethyl)benzene 111b and carbon disulfide reacted in sonicator at
120oC for 80 minutes. The obtained product was 4-(tert-butyl)benzyl 4-
(methylsulfonyl)piperazine-1-carbodithioate 112b and afforded yield was 91% (Table 4.2,
entry 10).
By treating the reactants 1-(methylsulfonyl)piperazine 108, 2-(chloromethyl)benzonitrile
111c and carbon disulfide using ethanol as a solvent at room temperature with constant
stirring for 10 hours. The desired product 2-cyanobenzyl 4-(methylsulfonyl)piperazine-1-
carbodithioate 112c could not formed, the reaction failed (Table 4.2, entry 11). 1-
(methylsulfonyl)piperazine 108 treated with 2-(chloromethyl)benzonitrile 111c and carbon
disulfide to obtain product 2-cyanobenzyl 4-(methylsulfonyl)piperazine-1-carbodithioate
112c. The reaction was occurred in methanol at room temperature with constant stirring for
12 hours. 2-cyanobenzyl 4-(methylsulfonyl)piperazine-1-carbodithioate 112c was not formed
and reaction could not formed (Table 4.2, entry 12). To the corresponding reaction mixture 1-
(methylsulfonyl)piperazine 108, 2-(chloromethyl)benzonitrile 111c and carbon disulfide are
reacted in ethanol at room temperature with constant stirring for 48 hours. 2-cyanobenzyl 4-
(methylsulfonyl)piperazine-1-carbodithioate 112c did not obtained and reaction failed (Table
4.2, entry 13). 1-(methylsulfonyl)piperazine 108 and 2-(chloromethyl)benzonitrile 111c are
allowed to react in the presence of carbon disulfide in ethanol under ultrasonic conditions.
The reaction was performed at 50 oC for 30 minutes in Sonicator. The reaction found
incomplete and needed more time along with higher temperature (Table 4.2, entry 14). The
reaction was occurred in sonicator between
1-(methylsulfonyl)piperazine 108 and 2-(chloromethyl)benzonitrile 111c in the presence of
carbon disulfide in ethanol at 120oC under ultrasonic conditions for 90 minutes. 2-
cyanobenzyl 4-(methylsulfonyl)piperazine-1-carbodithioate 112c was formed and afforded
yield 95% (Table 4.2, entry 15).
4.2 Synthesis of aryl dithiocarbamate derivatives 114a-c from 110

4.2.1 Synthesis of tert-butyl piperazine-1-carboxylate 110
56
To synthesize tert-butyl piperazine-1-carboxylate 110 the anhydrous piperazine 106 treated
with tert-butyl carbonochloridate 109 in the presence of base potassium carbonate and
refluxing conditions in DMF for 8 hours. The desired product tert-butyl piperazine-1-
carboxylate 110 was obtained in 50%. The results are summarized in (Table 4.3).
Table 4.3: Synthesis of tert-butyl piperazine-1-carboxylate 110 under different conditions
Sr. # Conditions Solvent Time (hr) Temperature Yield (%)
1. Stirring Ethanol 6 Room temperature Failed
2. Reflux DCM 4 Room temperature Failed
3. Reflux DMF 4 Room temperature 6
4. Reflux DMF 8 Room temperature 50
57
The reaction between piperazine 106 and tert-butyl carbonochloridate 109 were performed by
employing ethanol as a solvent and at room temperature with constant stirring for 6 hours.
The reaction did not proceed and could formed and tert-butyl piperazine-1-carboxylate 110 as
a desired product. The reaction was failed to yield product (Table 4.1, entry 1). The reaction
was performed by treating piperazine 106 with tert-butyl carbonochloridate 109 using DCM
as a solvent at room temperature for 4 hours under reflux. In DCM, again did not any reaction
took place and tert-butyl piperazine-1-carboxylate 110 product did not formed, reaction failed
(Table 4.1, entry 2). Piperazine 106 and tert-butyl carbonochloridate 109 were allowed to
react in DMF which employed as a solvent under reflux for 4 hours at room temperature.
Piperazine 106 and tert-butyl carbonochloridate 109 reacted and formed as a product. But the
afforded yield of tert-butyl piperazine-1-carboxylate 110 was very less which was only 6%
(Table 4.1, entry 3). As the reaction has been occurred by using DMF as a solvent but the
yield was less. To improve and get better yield, the reaction between piperazine 106 and tert-
butyl carbonochloridate 109 performed in the presence of DMF by increasing reaction time
from 4 to 8 hours under reflux at room temperature. The isolated yield of product tert-butyl
piperazine-1-carboxylate 110 was satisfactory which was afforded 50% (Table 4.1, entry 4).
4.2.2 Synthesis of Aryl dithiocarbamate derivatives 114a-c from tert-
Butoxycarbonyl substituted N-piperazine 110
Substituted tert-butoxycarbonyl N-piperazine 110 treated with aryl halides 114a-c under
ultrasonic conditions to afford product in 89-92%. The results are summarized in table 4.4.
O S
O Cl N N
+ Conditions O S
O N R
NH R
110 111a-c 114a-c, 89-92%
111a, R = H
111b, R = 2-t-butyl
111c, R = 4-CN
58
Table 4.4: Synthesis of aryl dithiocarbamate derivatives 114a-c under different conditions
Sr. Reactant Condition Solvent Time Tempera Product Yield %

o
# s ture ( C)
Room
1. Stirring Methanol 10hr. temp. Failed
111a 114a
Room
2. Stirring Ethanol 10hr. temp. Failed
111a
114a
Room
3. Stirring Ethanol 48hr temp. 28
111a 114a
Incomple
4. Sonicator Ethanol 30min 40 te
114a reaction
111a
5. Sonicator Ethanol 80mins 120 89
111a 114a
Room
6. Stirring Ethanol 12hr Temp. Failed
111b 114b
59
Room
7. Stirring Methanl 20hr temp. Failed
114b
111b
Room
8. Stirring Ethanol 48hr temp. 49
114b
111b
Sonicator Ethanol 30mins 50 Incomple

9. te
114b
reaction
111b
10. Sonicator Ethanol 80mins 120 90
114b
111b
Room
11. Stirring Ethanol 10hr temp. Failed
60
111c
114c
Room
12. Stirring Methanol 12hr temp. Failed
111c 114c
Room
Stirring Ethanol 48hr temp. 25
13.
111c 114c
Incomple
14. Sonicator Ethanol 30mins 50 te
reaction
111c 114c
15.
Sonicator Ethanol 90mins 120 92
111c 114c
To the mixture of tert-butyl piperazine-1-carboxylate 110 in methanol was treated with
61
chloromethyl benzene 111a and carbon disulfide at room temperature with constant stirring
for 10 hours. The reaction failed and could not obtained the tert-butyl 4-
(benzythio)carbonothioyl)piperazine-1-carboxylate 114a as a desired product (Table 4.1,
entry 1). The same reaction had been proceeded using ethanol instead of methanol under
same conditions and again reaction failed (Table 4.1, entry 2). The reaction was occurred by
increasing the time from 10 hours to 48 hours, the tert-butyl 4-
(benzythio)carbonothioyl)piperazine-1-carboxylate 114a was afforded 28% (Table 4.1, entry
3). To obtain the better yield the chloromethyl benzene 111a was treated with tert-butyl
piperazine-1-carboxylate 110 and carbon disulfide under ultrasonic conditions at 40 oC for 30
minutes. The reaction was not got completed and needed more time to obtained tert-butyl 4-
(benzythio)carbonothioyl)piperazine-1-carboxylate 114a (Table 4.1, entry 4). The reaction
was occurred by increasing time 30 to 80 minutes and temperature to 40 to 100 oC, the product
tert-butyl 4-(benzythio)carbonothioyl)piperazine-1-carboxylate 114a afforded 89% (Table
4.1, entry 5).
To a corresponding mixture tert-butyl piperazine-1-carboxylate 110, 1-(tert-butyl)-4-
(chloromethyl)benzene 111b and carbon disulfide was added in ethanol, reaction took place
at room temperature for 12 hours with constant stirring. The product tert-butyl 4-(((4-tert-
butyl)thio)carbonothioyl) piperazine-1-carboxylate 114b was not obtained and reaction failed
(Table 4.1, entry 6). The same reaction occurred at room temperature by increasing time to 20
hours and changing solvent to methanol, tert-butyl 4-(((4-tert-butyl)thio)carbonothioyl)
piperazine-1-carboxylate 114b was not formed and reaction failed (Table 4.1, entry 7). The
reaction proceeded at room temperature with constant stirring for 48 hours and 40% yield of
tert-butyl 4-(((4-tert-butyl)thio)carbonothioyl) piperazine-1-carboxylate 114b obtained
(Table 4.1, entry 8). To increase yield the same reactants treated under ultrasonic conditions
at 50oC for 30 minutes, the reaction could not accomplished (Table 4.1, entry 9). The reaction
proceeded under ultrasonic conditions at 120oC for 80 minutes and afforded 90% yield of
tert-butyl 4-(((4-tert-butyl)thio)carbonothioyl) piperazine-1-carboxylate 114b (Table 4.1,
entry 10).
2-(chloromethyl) benzonitrile 111c was allowed to react with tert-butyl piperazine-1-
carboxylate 110 and carbon disulfide in the presence of ethanol at room temperature with
constant stirring for 10 hours. The desired product tert-butyl(((2-
cyanobenzyl)thio)carbonothiyl)piperaizine-1-carboxylate 114c was not formed and reaction
failed (Table 4.1, entry 11). The reaction occurred between the same reactants in the presence
of methanol at room temperature for 12 hours with constant stirring. The reaction did not
accomplish and could not obtain product (Table 4.1, entry 12). To obtain the tert-butyl –(((2-
62
cyanobenzyl)thio)carbonothiyl)piperaizine-1-carboxylate 114c, the reaction occurred in
ethanol at room temperature with constant stirring for 48 hours and afforded 25% yield
(Table 4.1, entry 13). The reactants 2-(chloromethyl) benzonitrile 111c, tert-butyl piperazine-
1-carboxylate 110 and carbon disulfide reacted under ultrasonic conditions at 50 oC for 30
minutes. The showed incomplete and did not yield tert-butyl –(((2-
cyanobenzyl)thio)carbonothiyl)piperaizine-1-carboxylate 114c (Table 4.1, entry 14). The
reaction occurred under ultrasonic conditions at 120 oC for 90 minutes and afforded 92% yield
of tert-butyl –(((2-cyanobenzyl)thio)carbonothiyl)piperaizine-1-carboxylate 114c (Table 4.1,
entry 15).
4.3 Synthesis of aryl dithiocarbamate derivatives 115a-c from 113
Morpholine 113 allowed to react with the aryl halide in the presence of carbon disulfide and
under ultrasonic conditions. The aryl dithiocarbamate derivatives 115a-c obtained in 81-90%
yield (scheme: 4.2). The results are summarized in table 4.5.
Tabl
e 4.5: Synthesis of aryl dithiocarbamate 115a-c under different conditions
Sr. # Reactant Condition Solvent Time Temperat Product Yield

o
s ure ( C) (%)
Room
1. Stirring Methanol 10 hr. temp. Failed
111a 115a
Room
2. Stirring Ethanol 10 hr. temp. Failed
111a 115a
63
Room
3. Stirring Ethanol 48 hr temp. 28
111a 115a
Incomple
4. Sonicator Ethanol 30 min 40 te
reaction
111a 115a
5. Sonicator Ethanol 80 120 81

mins
111a 115a
Room
6. Stirring Ethanol 12 hr Temp. Failed
111b
115b
Room
111b
115b
64
Room
8. Stirring Ethanol 48 hr temp. 49
111b
115b
Sonicator Ethanol 30 50 Incomple

9. mins te
reaction
111b
115b
10. Sonicator Ethanol 80 120 85

mins
111b
115b
Room
11. Stirring Ethanol 10 hr temp. Failed
111c 115c
65
Room
111c 115c
Room
Stirring Ethanol 48 hr temp. 25
13.
111c 115c
Incomple
14. Sonicator Ethanol 30 50 te
mins reaction
111c 115c
15.
Sonicator Ethanol 90 120 90
mins
111c 115c
66
To the mixture morpholine 113 was treated with benzyl chloride 111a and carbon disulfide in
the presence of methanol at room temperature with constant stirring for 10 hours. The
reaction failed and could not obtain benzyl Morpholine-4-carbodithioate 115a as a desired
product (Table 4.2, entry 1). The same reaction had been proceeded using ethanol instead of
methanol under same conditions and again reaction failed (Table 4.2, entry 2). The reaction
was occurred by increasing the time from 10 hours to 48 hours, the benzyl Morpholine-4-
carbodithioate 115a was afforded 28% (Table 4.2, entry 3). To obtain the better yield the
chloromethyl benzene 111a was treated with morpholine 113 and carbon disulfide under
ultrasonic conditions at 40oC for 30 minutes. The reaction did not got completed and needed
more time to obtained benzyl Morpholine-4-carbodithioate 115a (Table 4.2, entry 4). The
reaction was occurred by increasing time 30 to 80 minutes and temperature to 40 to 100 oC,
the product benzyl Morpholine-4-carbodithioate 115a afforded 81% (Table 4.2, entry 5).
1-(tert-butyl)-4-(chloromethyl)benzene 111b was allowed to react with morpholine 113 and
carbon disulfide in the presence of ethanol at room temperature with constant stirring for 12
hours. The desired product 4-(tert-butyl)benzyl Morpholine-4-carbodithioate 115b did not
formed and reaction failed (Table 4.2, entry 6). The reaction occurred between the same
reactants in the presence of methanol at room temperature for 20 hours with constant stirring.
The reaction did not accomplish and could not obtain product (Table 4.2, entry 7). To obtain
the 4-(tert-butyl)benzyl Morpholine-4-carbodithioate 115b, the reaction occurred in ethanol
at room temperature with constant stirring for 48 hours and afforded 28% yield (Table 4.2,
entry 8). The reactants 2-(chloromethyl) benzonitrile 111c, morpholine 113 and carbon
disulfide reacted under ultrasonic conditions at 50 oC for 30 minutes. The showed incomplete
and did not yield 4-(tert-butyl)benzyl Morpholine-4-carbodithioate 115b (Table 4.1, entry 9).
The reaction occurred under ultrasonic conditions at 120 oC for 80 minutes and afforded 85%
yield of 4-(tert-butyl)benzyl Morpholine-4-carbodithioate 115b (Table 4.2, entry 10).
To a corresponding mixture morpholine 113, 2-(chloromethyl)benzonitrile 111c and carbon
disulfide was added in ethanol, reaction took place at room temperature for 10 hours with
constant stirring. The product 2-cyanobenzyl Morpholine-4-carbodithioate 115c not obtained
and reaction failed (Table 4.2, entry 11). The same reaction occurred at room temperature by
increasing time to 12 hours and changing solvent to methanol, 2-cyanobenzyl Morpholine-4-
carbodithioate 115c was not formed and reaction failed (Table 4.2, entry 12). The reaction
proceeded at room temperature with constant stirring for 48 hours and 25% yield 2-
cyanobenzyl Morpholine-4-carbodithioate 115c obtained (Table 4.2, entry 13). To increase
yield the same reactants treated under ultrasonic conditions at 50 oC for 30 minutes, the
67
reaction could not accomplished (Table 4.2, entry 14). The reaction proceeded under
ultrasonic conditions at 120oC for 90 minutes and afforded 90% yield of 2-cyanobenzyl
Morpholine-4-carbodithioate 115c (Table 4.2, entry 15).
68
Biological evaluation
Antibacterial activity
Aryl dithiocarbamates have been used against bacterial infections since long. Heterocyclic
substituted piperazine based drugs used against bacterial infections from many years. The
aryl dithiocarbamate substituted piperazine synthesized and evaluate biological application.
Antibacterial activities of the synthesized aryl dithiocarbamate derivatives 112a-c, 114a-c
and 115a-c have been scrutinized against Bacillus subtilis and Escherichia coli. The zone of
inhibition (ZI) and minimum inhibitory concentration (MIC) values have shown in Table 4.3.
Ampicillin and ibuprofen were used as standard drugs while ciprofloxacin used as positive
control.
Table 4.6: Antibacterial activity results of compounds 112a-c, 114a-c and 115a-c
Compound Cd Baaillus subtilis Escherichia coli
ZI (mm) MIC (mg/mL) ZI (mm) MIC (mg/mL)
112a 23 ±0.75 2.4 ± 0.00 21 ± 1.45 3.0 ± 0.45
112b 20 ±0.34 3.3 ± 0.01 13 ± 1.25 2.0 ± 1.5
112c 42 ± 0.25 4.0 ± 0.00 32 ± 1.5 1.5 ±0.25
114a 22 ± 1.90 0.9 ± 0.25 16 ± 1.50 1.5 ± 0.75
114b 31 ± 0.25 2.5 ± 0.00 11 ± 1.50 0.9 ±1.008
114c 32 ±0.32 3.5 ± 0.00 12 ± 1.25 1.0 ± 0.80
115a 39 ±0.31 0.2 ± 0.24 44.0 ± 1.24 0.9 ± 0.50
115b 27 ±0.24 0.11 ± 0.31 30.0 ± 0.31 0.10 ± 0.31
115c 25 ±0.24 0.9 ± 0.31 30.0 ± 0.31 0.9 ±0.31
Ampicillin 18 ± 1.0 9.0 ± 1.1 12 ± 0.6 16 ± 1.1
Iburofen 15 ± 0.9 14.0 ± 1.0 11 ± 0.5 21 ± 1.4
Ciprofloxacin 29.3 ± 1.0 0.3 ± 0.0 31.1 ± 1.2 2.2 ± 0.1
Results have indicated that all the synthesized compounds exhibited significant antibacterial
activity especially against Bacillus subtilis. A compound 112c have exhibited maximum zone
of inhibition value (42mm) as compared to the standard drugs and positive control (29.3mm).
However, compounds 114b, 114c and 115b depicted ZI values (31mm, 32mm and 27mm
respectively) closure to ciprofloxacin. While no zone area was observed in case of 112b and
114a. 115a, 114a and 115c (0.2mm, 0.9mm and 0.9mm respectively) showed good anti-
bacterial activity. In case of Escherichia coli, only compound 115a showed maximum ne of
inhibition value (44mm) as compared to standard drugs. 112c, 115b and 115c displayed
antibacterial activity almost similar to ciprofloxacin by depicting ZI value 32mm, 30mm and
69
30mm. While 112a, 112b, 112c and 114a showed poor activity as compared to positive
control and no zone was observed for compounds 114b and 114c.
70
CHAPTER 5
SUMMARY
With the increasing demand of the discovery of new drugs with significant biological profile
for the treatment of the various diseases is continuously increasing in medicinal market. In
this consequences, dithiocarbamate and its derivatives have acknowledge as a versatile
entities and have attained attention of researchers due to having extensive therapeutic profile
like anti-bacterial, anti-microbial, anti-cancer, anti-malarial, anti-fungal, anti-viral, anti-
inflammatory and anti-tumor etc. By keeping in mind the biological importance and
significance of dithiocarbamate derivatives, the presented work was the successful effort for
the synthesis of series of aryl dithiocarbamate derivatives 112a-c, 114a-c and 115a-c using
ultrasonic conditions.
1-(methylsulfonyl)piperazine 108, tert-butyl piperazine-1-carboxylate 110 and morpholine
113 used as substituted N-heterocyclic amines which were treated with the alkyl halides using
carbon disulfide at 70o-120o C for 60-100 minutes under ultrasonic conditions.
Figure 5.1: Structures of used N-heterocyclic amines

The series of 112a-c, 114a-c and 115a-c compounds were synthesized using convenient and
slight modified method which was employed to acquire the targeted products. The purity of
each synthesized compounds was ascertained by TLC on silica plates by using different
solvent systems. Aryl dithiocarbamate derivatives 112a-c synthesized when methane sulfonyl
substituted piperazine reacted with alkyl halides. The synthesized aryl dithiocarbamate
derivatives 112a-c were afforded yield in 86 to 95% yield.
S
cheme 5.1: Synthesis of aryl dithiocarbamate derivatives 112a-c
Benzyl 4-(methylsulfonyl)piperazine-1-carbodithioate 112a, benzyl 4-
71
(methylsulfonyl)piperazine-1-carbodithioate 112b and 2-cyanobenzyl 4-
(methylsulfonyl)piperazine-1-carbodithioate 112c obtained as the products when 1-
(methylsulfonyl)piperazine 108 reacted with (chloromethyl)benzene 111a, 1-(tert-butyl)-4-
(chloromethyl)benzene 111b and 2-(chloromethyl)benzonitrile 111c respectively.
Figure 5.2: Structures of synthesized 112a-c aryl dithiocarbamate derivatives

Aryl dithiocarbamate derivatives 114a-c synthesized by treating tert-butyl piperazine with
alkyl halides under ultrasonic conditions afforded 114a-c derivatives in 89-92% yield.
Scheme 5.2: Synthesis of aryl dithiocarbamate derivatives 114a-c

When tert-butyl piperazine-1-carbonochloridate 110 with the (chloromethyl)benzene 111a, 1-
(tert-butyl)-4-(chloromethyl)benzene 111b and 2-(chloromethyl)benzonitrile 111c then
obtained tert-butyl 4-(benzythio)carbonothioyl)piperazine-1-carboxylate 114a, tert-butyl 4-
(((4-tert-butyl)thio)carbonothioyl) piperazine-1-carboxylate 114b and tert-butyl –(((2-
cyanobenzyl)thio)carbonothiyl)piperaizine-1-carboxylate 114c as a product respectively.
72
Figure 5.3: Structures of synthesized aryl dithiocarbamate 114a-c derivatives
Aryl dithiocarbamate derivatives 115a-c synthesized when Morpholine reacted with the aryl
halides in Sonicator using carbon disulfide as a solvent. The aryl dithiocarbamate derivatives
115a-c obtained in 81-90% yield.
Scheme 5.3: Synthesis of aryl dithiocarbamate derivatives 115a-c

Benzyl Morpholine-4-carbodithioate 115a synthesized by treating morpholine with
(chloromethyl)benzene 111a, 4-(tert-butyl)benzyl Morpholine-4-carbodithioate 115b formed
when morpholine reacted with 1-(tert-butyl)-4-(chloromethyl)benzene 111b and 2-
cyanobenzyl Morpholine-4-carbodithioate 115c obtained by reacting morpholine with 2-
(chloromethyl)benzonitrile 111c.
73
Figure 5.4: Structures of synthesized aryl dithiocarbamate 115a-c derivatives
The synthesized chemical entities were characterized on the basis of IR and NMR data. The
detail of these data of compounds was illustrated in the experimental section. Further, the
synthesized compounds were then subjected to antibacterial activities for calculating the
potential of these compounds against bacteria. Bacterial strains used for this study were
Escherichia coli (-) and Bacillis subtilis (+). Ampicillin and ibuprofen were used as standard
drugs while ciprofloxacin used as positive control.
74
Figure 5.5: Synthesized structures with their biological activity values
Synthesized compound showed anti-bacterial activities, as compound 115b exhibited MIC
values 0.1mg/mL against Bacillis subtilis and Escherichia coli. A compound 112c displayed
maximum zone of inhibition by depicting ZI value 42mm and 115a shown ZI value 44mm.
Future Prespective
This work might be the little effort for providing data about the future drug candidates and
further structural modification for more promising activities. As the dithiocarbamates are
gaining researcher’s interest due to having and demonstrated their health promoting
activities. They have been seen as a valuable source of biological active compound which can
sustain human health and preventing for many diseases due to its anti-cancer, anti-viral and
anti-inflammatory activities. A future interest is to work on finding the other biological
activities of aryl dithiocarbamates.
75
REFERENCES
Abu-El-Halawa, R., & Zabin, S. A. (2017). Removal efficiency of Pb, Cd, Cu and Zn from
polluted water using dithiocarbamate ligands. Journal of Taibah University for
Science, 11(1), 57-65.
Abulnaja, K. O., & Harwood, J. (1991). Thiocarbamate herbicides inhibit fatty acid
elongation in a variety of monocotyledons. Phytochemistry, 30(5), 1445-1447.
Adeyemi, J. O., & Onwudiwe, D. C. (2018). Organotin (IV) dithiocarbamate complexes:
Chemistry and biological activity. Molecules, 23(10), 2571.
Adeyemi, J. O., & Onwudiwe, D. C. (2020a). Chemistry and some biological potential of
bismuth and antimony dithiocarbamate complexes. Molecules, 25(2), 305.
Adeyemi, J. O., & Onwudiwe, D. C. (2020b). The mechanisms of action involving
dithiocarbamate complexes in biological systems. Inorganica Chimica Acta, 511,
119809.
Adokoh, C. K. (2020). Therapeutic potential of dithiocarbamate supported gold compounds.
RSC advances, 10(5), 2975-2988.
Aghbash, K. O., Alamgholiloo, H., Pesyan, N. N., Khaksar, S., & Rostamnia, S. (2021). Gold
nanoparticle stabilized dithiocarbamate functionalized magnetite carbon as promise
clean nanocatalyst for A3-coupling organic transformation. Molecular Catalysis, 499,
111252.
Ajiboye, T. O., Ajiboye, T. T., Marzouki, R., & Onwudiwe, D. C. (2022). The Versatility in
the Applications of Dithiocarbamates. International Journal of Molecular Sciences,
23(3), 1317.
Ajiboye, T. O., Babalola, S. O., & Onwudiwe, D. C. (2021). Photocatalytic Inactivation as a
Method of Elimination of E. coli from Drinking Water. Applied Sciences, 11(3), 1313.
Ajiboye, T. O., Oladoye, P. O., Olanrewaju, C. A., & Akinsola, G. O. (2022).
Organophosphorus pesticides: Impacts, detection and removal strategies.
Environmental Nanotechnology, Monitoring & Management, 17, 100655.
Ajiboye, T. O., Oyewo, O. A., & Onwudiwe, D. C. (2021a). Adsorption and photocatalytic
removal of Rhodamine B from wastewater using carbon-based materials. FlatChem,
29, 100277.
Ajiboye, T. O., Oyewo, O. A., & Onwudiwe, D. C. (2021b). Photocatalytic removal of
parabens and halogenated products in wastewater: a review. Environmental Chemistry
Letters, 19(5), 3789-3819.
Ajiboye, T. O., Oyewo, O. A., & Onwudiwe, D. C. (2021c). Simultaneous removal of
76
organics and heavy metals from industrial wastewater: A review. Chemosphere, 262,
128379.
Akinboye, E. S., Bamji, Z. D., Kwabi-Addo, B., Ejeh, D., Copeland, R. L., Denmeade, S. R.,
& Bakare, O. (2015). Design, synthesis and cytotoxicity studies of dithiocarbamate
ester derivatives of emetine in prostate cancer cell lines. Bioorganic & medicinal
chemistry, 23(17), 5839-5845.
Ali, A., Shen, H., & Yin, X. (1998). Simultaneous determination of trace amounts of nickel,
copper and mercury by liquid chromatography coupled with flow-injection on-line
derivatization and preconcentration. Analytica chimica acta, 369(3), 215-223.
Altintop, M. D., Özdemir, A., Kaplancikli, Z. A., Turan ‐Zitouni, G., Temel, H. E., & Çiftçi,
G. A. (2013). Synthesis and biological evaluation of some pyrazoline derivatives
bearing a dithiocarbamate moiety as new cholinesterase inhibitors. Archiv der
Pharmazie, 346(3), 189-199.
Asadi, M., Ebrahimi, M., Mohammadi‐Khanaposhtani, M., Azizian, H., Sepehri, S., Nadri,
H., . . . Mirzazadeh, R. (2019). Design, Synthesis, Molecular Docking, and
Cholinesterase Inhibitory Potential of Phthalimide‐Dithiocarbamate Hybrids as New
Agents for Treatment of Alzheimer's Disease. Chemistry & Biodiversity, 16(11),
e1900370.
Aspatwar, A., Parvathaneni, N. K., Barker, H., Anduran, E., Supuran, C. T., Dubois, L., . . .
Winum, J.-Y. (2020). Design, synthesis, in vitro inhibition and toxicological
evaluation of human carbonic anhydrases I, II and IX inhibitors in 5-nitroimidazole
series. Journal of enzyme inhibition and medicinal chemistry, 35(1), 109-117.
Ayalew, Z. M., Zhang, X., Guo, X., Ullah, S., Leng, S., Luo, X., & Ma, N. (2020). Removal
of Cu, Ni and Zn directly from acidic electroplating wastewater by Oligo-
Ethyleneamine dithiocarbamate (OEDTC). Separation and Purification Technology,
248, 117114.
Azizi, N., & Alipour, M. (2018). Synthesis of carboxylic dithiocarbamic anhydride and
substituted thiourea derivatives in water. Environmental Chemistry Letters, 16(4),
1415-1421.
Azizi, N., Khajeh, M., Hasani, M., & Dezfooli, S. (2013). An efficient four-component
synthesis of dithiocarbamate derivatives. Tetrahedron Letters, 54(39), 5407-5410.
Azizi, N., Torkiyan, L., & Saidi, M. R. (2006). Highly efficient one-pot three-component
Mannich reaction in water catalyzed by heteropoly acids. Organic Letters, 8(10),
2079-2082.
Badawy, M. E., & Rabea, E. I. (2016). Chitosan and its derivatives as active ingredients
77
against plant pests and diseases. In Chitosan in the preservation of agricultural
commodities (pp. 179-219): Elsevier.
Bakthavatsalam, S., Wiangnak, P., George, D. J., Zhang, T., & Franz, K. J. (2020).
Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate
cancer. Bioorganic & medicinal chemistry letters, 30(11), 127148.
Bala, V., Gupta, G., & L Sharma, V. (2014). Chemical and medicinal versatility of
dithiocarbamates: an overview. Mini reviews in medicinal chemistry, 14(12), 1021-
1032.
Bhalla, Y., Gupta, V. K., & Jaitak, V. (2013). Anticancer activity of essential oils: a review.
Journal of the Science of Food and Agriculture, 93(15), 3643-3653.
Bond, A., & Wallace, G. (1984). Preparation of metal dithiocarbamate complexes for
chromatographic separation and multi-element determinations. Analytica chimica
acta, 164, 223-232.
Cao, Q., Peng, H.-Y., Cheng, Y., & Dong, Z.-B. (2018). A Highly Efficient CuCl2-Catalyzed
C–S Coupling of Aryl Iodides with Tetraalkylthiuram Disulfides: Synthesis of Aryl
Dithiocarbamates. Synthesis, 50(07), 1527-1534.
Cao, S.-L., Feng, Y.-P., Jiang, Y.-Y., Liu, S.-Y., Ding, G.-Y., & Li, R.-T. (2005). Synthesis
and in vitro antitumor activity of 4 (3H)-quinazolinone derivatives with
dithiocarbamate side chains. Bioorganic & medicinal chemistry letters, 15(7), 1915-
1917.
Cao, S.-L., Wang, Y., Zhu, L., Liao, J., Guo, Y.-W., Chen, L.-L., . . . Xu, X. (2010).
Synthesis and cytotoxic activity of N-((2-methyl-4 (3H)-quinazolinon-6-yl) methyl)
dithiocarbamates. European Journal of Medicinal Chemistry, 45(9), 3850-3857.
Chaturvedi, D., Mishra, N., & Mishra, V. (2007). An efficient, basic resin mediated, one-pot,
synthesis of dithiocarbamates by Michael addition of dithiocarbamate anion to α, β-
unsaturated compounds. Journal of Sulfur Chemistry, 28(1), 39-44.
Chauhan, K., Sharma, M., Singh, P., Kumar, V., Shukla, P. K., Siddiqi, M. I., & Chauhan, P.
M. (2012). Discovery of a new class of dithiocarbamates and rhodanine scaffolds as
potent antifungal agents: synthesis, biology and molecular docking. MedChemComm,
3(9), 1104-1110.
Chen, N., Zhong, X., Li, P., & Xu, J. (2015). A Mild Radical Method for the Dimerzation of
Dithiocarbamates. European Journal of Organic Chemistry, 2015(4), 802-809.
Chen, Q. M., Li, Z., Tian, G. X., Chen, Y., & Wu, X. H. (2021). 1, 2, 3-triazole-
dithiocarbamate-naphthalimides: Synthesis, characterization, and biological
evaluation. Journal of Chemical Research, 45(3-4), 258-264.
78
Chia-Fu, Y., Sun-Dsong, C., Wei-Shi, C., Jia-Der, F., & Chuen-Ying, L. (1993). Application
of dithiocarbamate resin-metal complexes as stationary phases in gas chromatography.
Journal of Chromatography A, 630(1-2), 275-285.
Cihlar, T., & Fordyce, M. (2016). Current status and prospects of HIV treatment. Current
opinion in virology, 18, 50-56.
Cuzzocrea, S., Chatterjee, P. K., Mazzon, E., Dugo, L., Serraino, I., Britti, D., . . .
Thiemermann, C. (2002). Pyrrolidine dithiocarbamate attenuates the development of
acute and chronic inflammation. British journal of pharmacology, 135(2), 496-510.
Cvek, B., & Dvorak, Z. (2007). Targeting of nuclear factor-κB and proteasome by
dithiocarbamate complexes with metals. Current pharmaceutical design, 13(30),
3155-3167.
Dighe, S. U., Yadav, V. D., Srivastava, R., Mishra, A., Gautam, S., Srivastava, A. K., . . .
Batra, S. (2014). Reinvestigations into synthesis of allyldithiocarbamates and their
intramolecular cyclization: synthesis and antihyperglycemic activity of 2-
thioxothiazolidine-4-alkanoates. Tetrahedron, 70(38), 6841-6850.
Dinarello, C. A. (2010). Anti-inflammatory agents: present and future. Cell, 140(6), 935-950.
Ding, P.-P., Gao, M., Mao, B.-B., Cao, S.-L., Liu, C.-H., Yang, C.-R., . . . Li, Z. (2016).
Synthesis and biological evaluation of quinazolin-4 (3H)-one derivatives bearing
dithiocarbamate side chain at C2-position as potential antitumor agents. European
Journal of Medicinal Chemistry, 108, 364-373.
Ejelonu, B. C., Olagboye, S. A., Oyeneyin, O. E., Ebiesuwa, O. A., & Bada, O. E. (2018).
Synthesis, characterization and antimicrobial activities of sulfadiazine Schiff base and
phenyl dithiocarbamate mixed ligand metal complexes. Open Journal of Applied
Sciences, 8(08), 346.
El-Aarag, B. Y., Kasai, T., Zahran, M. A., Zakhary, N. I., Shigehiro, T., Sekhar, S. C., . . .
Kakuta, H. (2014). In vitro anti-proliferative and anti-angiogenic activities of
thalidomide dithiocarbamate analogs. International immunopharmacology, 21(2),
283-292.
Elahabaadi, E., Salarian, A. A., & Nassireslami, E. (2021). Design, synthesis, and molecular
docking of novel hybrids of coumarin-dithiocarbamate alpha-glucosidase inhibitors
targeting type 2 diabetes mellitus. Polycyclic Aromatic Compounds, 1-11.
Eng, G., Song, X., Duong, Q., Strickman, D., Glass, J., & May, L. (2003). Synthesis,
structure characterization and insecticidal activity of some triorganotin
dithiocarbamates. Applied organometallic chemistry, 17(4), 218-225.
Fan, Z., Qin, Y., Liu, S., Xing, R., Yu, H., Chen, X., . . . Li, P. (2019). The bioactivity of new
79
chitin oligosaccharide dithiocarbamate derivatives evaluated against nematode disease
(Meloidogyne incognita). Carbohydrate polymers, 224, 115155.
Fanaru, A., Les, A., Creanga, D., Dorohoi, D.-O., & Sacarescu, L. (2022). Magnetic
nanoparticles interactions with wastewater pollutants. Molecular Crystals and Liquid
Crystals, 1-14.
Ferraz, C. R., Manchope, M. F., Andrade, K. C., Saraiva-Santos, T., Franciosi, A., Zaninelli,
T. H., . . . Knysak, I. (2021). Peripheral mechanisms involved in Tityus bahiensis
venom-induced pain. Toxicon, 200, 3-12.
Ferreira, I., De Lima, G., Paniago, E., Takahashi, J., & Pinheiro, C. (2014). Synthesis,
characterization and antifungal activity of new dithiocarbamate-based complexes of
Ni (II), Pd (II) and Pt (II). Inorganica Chimica Acta, 423, 443-449.
Fu, D.-J., Li, J.-H., Yang, J.-J., Li, P., Zhang, Y.-B., Liu, S., . . . Zhang, S.-Y. (2019).
Discovery of novel chalcone-dithiocarbamates as ROS-mediated apoptosis inducers
by inhibiting catalase. Bioorganic chemistry, 86, 375-385.
Fu, D.-J., Li, J.-H., Yang, J.-J., Li, P., Zhang, Y.-B., Liu, S., . . . Zhang, S.-Y. (2019).
Discovery of novel chalcone-dithiocarbamates as ROS-mediated apoptosis inducers
by inhibiting catalase. Bioorganic chemistry, 86, 375-385.
Fu, W., & Huang, Z. (2018). Magnetic dithiocarbamate functionalized reduced graphene
oxide for the removal of Cu (II), Cd (II), Pb (II), and Hg (II) ions from aqueous
solution: Synthesis, adsorption, and regeneration. Chemosphere, 209, 449-456.
Fu, Z., Yuan, W., Chen, N., Yang, Z., & Xu, J. (2018). Na 2 S 2 O 8-mediated efficient
synthesis of isothiocyanates from primary amines in water. Green Chemistry, 20(19),
4484-4491.
Gao, Y., Li, L., Liu, Y., Li, W., Wang, Z., Shou, S., & Chai, Y. (2020). Effect of semaphorin-
3A on the cellular stability of CD4+ CD25+ regulatory T cells induced by
lipopolysaccharide. Zhonghua wei Zhong Bing ji jiu yi xue, 32(12), 1454-1460.
Ge, Y., Xu, L.-W., Liu, Y., Sun, L.-Y., Gao, H., Li, J.-Q., & Yang, K. (2019).
Dithiocarbamate as a valuable scaffold for the inhibition of metallo-β-lactmases.
Biomolecules, 9(11), 699.
Guan, S., Zhong, Z., Li, J., Xu, Y., Ding, L., Huang, Y., & Liu, L. (2021). Preparation of in-
situ grown carbon nanotubes via dithiocarbamate in composites with excellent
microstructure and mechanical performance. Composites Science and Technology,
203, 108569.
Halimehjani, A. Z., Marjani, K., & Ashouri, A. (2010). Synthesis of dithiocarbamate by
Markovnikov addition reaction in aqueous medium. Green Chemistry, 12(7), 1306-
80
1310.
Hao, S., Ding, S., Wu, Z., Bi, H., Bai, F., Yang, X., . . . Zhao, M. (2021). An Efficient
Synthesis of Alkyl Dithiocarbamates through Michael‐type Addition of
Tetraalkylthiuram Disulfides to Electrophilic Alkenes. Asian Journal of Organic
Chemistry, 10(10), 2521-2524.
He, W., Ding, Y., Tu, J., Que, C., Yang, Z., & Xu, J. (2018). Thermal conversion of primary
alcohols to disulfides via xanthate intermediates: an extension to the Chugaev
elimination. Organic & Biomolecular Chemistry, 16(10), 1659-1666.
Heravi, M. M., & Zadsirjan, V. (2020). Prescribed drugs containing nitrogen heterocycles: an
overview. RSC advances, 10(72), 44247-44311.
Hogarth, G., Ebony-Jewel, C.-R., & Richards, I. (2009). Functionalised dithiocarbamate
complexes: Synthesis and molecular structures of bis (2-methoxyethyl)
dithiocarbamate complexes [M {S2CN (CH2CH2OMe) 2} 2](M= Ni, Cu, Zn) and
[Cu {S2CN (CH2CH2OMe) 2} 2][ClO4]. Inorganica Chimica Acta, 362(4), 1361-
1364.
Hogarth, G., Ebony-Jewel, C.-R., Kabir, S. E., Richards, I., Wilton-Ely, J. D., & Zhang, Q.
(2009). Functionalised dithiocarbamate complexes: Synthesis and molecular
structures of 2-diethylaminoethyl and 3-dimethylaminopropyl dithiocarbamate
complexes [M {S2CN (CH2CH2NEt2) 2} n] and [M {S2CN (CH2CH2CH2NMe2)
2} n](n= 2, M= Ni, Cu, Zn, Pd; n= 3, M= Co). Inorganica Chimica Acta, 362(6),
2020-2026.
Horita, Y., Takii, T., Kuroishi, R., Chiba, T., Ogawa, K., Kremer, L., . . . Onozaki, K. (2011).
Synthesis and evaluation of anti-tubercular activity of new dithiocarbamate sugar
derivatives. Bioorganic & medicinal chemistry letters, 21(3), 899-903.
Hou, X., Ge, Z., Wang, T., Guo, W., Cui, J., Cheng, T., . . . Li, R. (2006). Dithiocarbamic
acid esters as anticancer agent. Part 1: 4-Substituted-piperazine-1-carbodithioic acid
3-cyano-3, 3-diphenyl-propyl esters. Bioorganic & medicinal chemistry letters,
16(16), 4214-4219.
Husain, A., Nami, S. A., Singh, S. P., Oves, M., & Siddiqi, K. (2011). Anagostic interactions,
revisiting the crystal structure of nickel dithiocarbamate complex and its antibacterial
and antifungal studies. Polyhedron, 30(1), 33-40.
Hussain, A., Pu, H., Hu, B., & Sun, D.-W. (2021). Au@ Ag-TGANPs based SERS for facile
screening of thiabendazole and ferbam in liquid milk. Spectrochimica Acta Part A:
Molecular and Biomolecular Spectroscopy, 245, 118908.
J Berry, D., Torres Martin de Rosales, R., Charoenphun, P., & J Blower, P. (2012).
81
Dithiocarbamate complexes as radiopharmaceuticals for medical imaging. Mini
reviews in medicinal chemistry, 12(12), 1174-1183.
Kamal, A., Sathish, M., Nayak, V. L., Srinivasulu, V., Kavitha, B., Tangella, Y., . . . Nagesh,
N. (2015). Design and synthesis of dithiocarbamate linked β-carboline derivatives:
DNA topoisomerase II inhibition with DNA binding and apoptosis inducing ability.
Bioorganic & medicinal chemistry, 23(17), 5511-5526.
Kanchi, S., Singh, P., & Bisetty, K. (2014). Dithiocarbamates as hazardous remediation
agent: A critical review on progress in environmental chemistry for inorganic species
studies of 20th century. Arabian Journal of Chemistry, 7(1), 11-25.
Kane, S., Lazo, P., Ylli, F., Stafilov, T., Qarri, F., & Marku, E. (2016). Separation of heavy
metal from water samples—The study of the synthesis of complex compounds of
heavy metal with dithiocarbamates. Journal of Environmental Science and Health,
Part A, 51(4), 335-340.
Kaufman, D. D. (1967). Degradation of carbamate herbicides in soil. Journal of Agricultural
and Food Chemistry, 15(4), 582-591.
Kaul, L., SŘss, R., Zannettino, A., & Richter, K. (2021). The revival of dithiocarbamates:
from pesticides to innovative medical treatments. IScience, 24(2), 102092.
Kerru, N., Gummidi, L., Maddila, S., Gangu, K. K., & Jonnalagadda, S. B. (2020). A review
on recent advances in nitrogen-containing molecules and their biological applications.
Molecules, 25(8), 1909.
Kumar, L., Jain, A., Lal, N., Sarswat, A., Jangir, S., Kumar, L., . . . Maikhuri, J. P. (2012).
Potentiating metronidazole scaffold against resistant trichomonas: design, synthesis,
biology and 3D–QSAR analysis. ACS medicinal chemistry letters, 3(2), 83-87.
Lamkanfi, M. (2011). Emerging inflammasome effector mechanisms. Nature Reviews
Immunology, 11(3), 213-220.
Lawal, M. M., Lawal, I. A., Klink, M. J., Tolufashe, G. F., Ndagi, U., & Kumalo, H. M.
(2020). Density functional theory study of gold (III)-dithiocarbamate complexes with
characteristic anticancer potentials. Journal of Inorganic Biochemistry, 206, 111044.
Li, C.-W., Chen, Z.-W., Wu, X.-L., Ning, Z.-X., Su, Z.-Q., Li, Y.-C., . . . Lai, X.-P. (2015). A
standardized Traditional Chinese Medicine preparation named Yejuhua Capsule
ameliorates lipopolysaccharide-induced acute lung injury in mice via downregulating
Toll-like receptor 4/nuclear factor-κB. Evidence-Based Complementary and
Alternative Medicine, 2015.
Li, Q.-H., Ding, Y., & Huang, N.-W. (2014). Synthesis and biological activities of
dithiocarbamates containing 1, 2, 3-triazoles group. Chinese Chemical Letters, 25(11),
82
1469-1472.
Li, R.-D., Wang, H.-L., Li, Y.-B., Wang, Z.-Q., Wang, X., Wang, Y.-T., . . . Li, R.-T. (2015).
Discovery and optimization of novel dual dithiocarbamates as potent anticancer
agents. European Journal of Medicinal Chemistry, 93, 381-391.
Li, Y.-B., Yan, X., Li, R.-D., Liu, P., Sun, S.-Q., Wang, X., . . . Li, R.-T. (2016). Discovery
of novel heteroarylmethylcarbamodithioates as potent anticancer agents: Synthesis,
structure-activity relationship analysis and biological evaluation. European Journal of
Medicinal Chemistry, 112, 217-230.
Liu, B., Yuan, X., Xu, B., Zhang, H., Li, R., Wang, X., . . . Li, R. (2019). Synthesis of novel
7-azaindole derivatives containing pyridin-3-ylmethyl dithiocarbamate moiety as
potent PKM2 activators and PKM2 nucleus translocation inhibitors. European
Journal of Medicinal Chemistry, 170, 1-15.
Lu, Y., Pan, Q., Gao, W., Pu, Y., Luo, K., He, B., & Gu, Z. (2022). Leveraging disulfiram to
treat cancer: Mechanisms of action, delivery strategies, and treatment regimens.
Biomaterials, 281, 121335.
Manoussakis, G., Bolos, C., Ecateriniadou, L., & Sarris, C. (1987). Synthesis,
characterization and anti-bacterial studies of mixed-ligand complexes of
dithiocarbamato—thiocyanato and iron (III), nickel (II), copper (II) and zinc (II).
European Journal of Medicinal Chemistry, 22(5), 421-425.
Menezes, D., Vieira, F., de Lima, G., Porto, A., Cortés, M., Ardisson, J., & Albrecht-Schmitt,
T. (2005). Tin (IV) complexes of pyrrolidinedithiocarbamate: synthesis,
characterisation and antifungal activity. European Journal of Medicinal Chemistry,
40(12), 1277-1282.
Menezes, D., Vieira, F., De Lima, G., Wardell, J., Cortés, M., Ferreira, M. P., . . . Vilas Boas,
A. (2008). The in vitro antifungal activity of some dithiocarbamate organotin (IV)
compounds on Candida albicans—A model for biological interaction of organotin
complexes. Applied organometallic chemistry, 22(4), 221-226.
Milacic, V., Chen, D., Giovagnini, L., Diez, A., Fregona, D., & Dou, Q. P. (2008).
Pyrrolidine dithiocarbamate-zinc (II) and-copper (II) complexes induce apoptosis in
tumor cells by inhibiting the proteasomal activity. Toxicology and applied
pharmacology, 231(1), 24-33.
Mohammed, M. H., & Leelon, A. A. (2021). Synthesis, characterization of isatin
dithiocarbamate derivatives with expected biological activities. Int. J. Drug Deliv.
Technol, 11, 209-212.
Mollazadeh, M., Mohammadi-Khanaposhtani, M., Valizadeh, Y., Zonouzi, A., Faramarzi, M.
83
A., Kiani, M., . . . Mahdavi, M. (2021). Novel coumarin containing dithiocarbamate
derivatives as potent α-glucosidase inhibitors for management of type 2 diabetes.
Medicinal Chemistry, 17(3), 264-272.
Morita, F., Nakakubo, K., Yunoshita, K., Endo, M., Biswas, F. B., Nishimura, T., . . . Maeda,
K. (2020). Dithiocarbamate-modified cellulose-based sorbents with high storage
stability for selective removal of arsenite and hazardous heavy metals. RSC advances,
10(50), 30238-30244.
Morrison, B. W., Doudican, N. A., Patel, K. R., & Orlow, S. J. (2010). Disulfiram induces
copper-dependent stimulation of reactive oxygen species and activation of the
extrinsic apoptotic pathway in melanoma. Melanoma research, 20(1), 11-20.
Nabipour, H., Ghammamy, S., Ashuri, S., & Aghbolaghc, Z. S. (2010). Synthesis of a new
dithiocarbamate compound and Study of Its biological properties. J. Org. Chem, 2,
75-80.
Oladipo, S. D., Tolufashe, G. F., Mocktar, C., & Omondi, B. (2021). Ag (I) symmetrical N, N
′-diarylformamidine dithiocarbamate PPh3 complexes: Synthesis, structural
characterization, quantum chemical calculations and in vitro biological studies.
Inorganica Chimica Acta, 520, 120316.
Omar, A.-M. M., AboulWafa, O. M., El-Shoukrofy, M. S., & Amr, M. E. (2020).
Benzoxazole derivatives as new generation of anti-breast cancer agents. Bioorganic
chemistry, 96, 103593.
Pastrana-Dávila, A., Amaya-Flórez, A., Aranaga, C., Ellena, J., Macías, M., Flórez-López, E.,
& D'Vries, R. F. (2021). Synthesis, characterization, and antibacterial activity of
dibenzildithiocarbamate derivates and Ni (II)–Cu (II) coordination compounds.
Journal of Molecular Structure, 1245, 131109.
Pitchaimani, P., Lo, K. M., & Elango, K. P. (2015). Synthesis, crystal structures,
luminescence properties and catalytic application of lanthanide (III) piperidine
dithiocarbamate complexes. Polyhedron, 93, 8-16.
Qin, Y., Liu, S., Xing, R., Yu, H., Li, K., Meng, X., . . . Li, P. (2012). Synthesis and
characterization of dithiocarbamate chitosan derivatives with enhanced antifungal
activity. Carbohydrate polymers, 89(2), 388-393.
Raffa, C. M., & Chiampo, F. (2021). Bioremediation of agricultural soils polluted with
pesticides: A review. Bioengineering, 8(7), 92.
Raina-Fulton, R. (2014). A review of methods for the analysis of orphan and difficult
pesticides: Glyphosate, glufosinate, quaternary ammonium and phenoxy acid
herbicides, and dithiocarbamate and phthalimide fungicides. Journal of AOAC
84
International, 97(4), 965-977.
Reddy, L., Odhav, B., & Bhoola, K. (2003). Natural products for cancer prevention: a global
perspective. Pharmacology & therapeutics, 99(1), 1-13.
Rogachev, I., Kampel, V., Gusis, V., Cohen, N., Gressel, J., & Warshawsky, A. (1998).
Synthesis, properties, and use of copper-chelating amphiphilic dithiocarbamates as
synergists of oxidant-generating herbicides. Pesticide Biochemistry and Physiology,
60(3), 133-145.
Runkle, J., Flocks, J., Economos, J., & Dunlop, A. L. (2017). A systematic review of
Mancozeb as a reproductive and developmental hazard. Environment International,
99, 29-42.
Sağlık, B. N., Osmaniye, D., Cevik, U. A., Levent, S., Çavuşoğlu, B. K., Büyükemir, O., . . .
Koparal, A. S. (2020). Synthesis, characterization and carbonic anhydrase I and II
inhibitory evaluation of new sulfonamide derivatives bearing dithiocarbamate.
European Journal of Medicinal Chemistry, 198, 112392.
Saini, M. S., Kumar, A., Dwivedi, J., & Singh, R. (2013). A review: biological significances
of heterocyclic compounds. Int. J. Pharm. Sci. Res, 4(3), 66-77.
Shaabani, A., Nazeri, M. T., & Afshari, R. (2019). 5-Amino-pyrazoles: potent reagents in
organic and medicinal synthesis. Molecular Diversity, 23(3), 751-807.
Shepherd, R. E. (2003). Chromatographic and related electrophoretic methods in the
separation of transition metal complexes or their ligands. Coordination chemistry
reviews, 247(1-2), 159-196.
Shinde, S. D., Sakla, A. P., & Shankaraiah, N. (2020). An insight into medicinal attributes of
dithiocarbamates: Bird’s eye view. Bioorganic chemistry, 105, 104346.
Song, Z., Zhou, Y., Zhang, W., Zhan, L., Yu, Y., Chen, Y., . . . Zhang, Y. (2019). Base
promoted synthesis of novel indole-dithiocarbamate compounds as potential anti-
inflammatory therapeutic agents for treatment of acute lung injury. European Journal
of Medicinal Chemistry, 171, 54-65.
Song, Z., Zhou, Y., Zhang, W., Zhan, L., Yu, Y., Chen, Y., . . . Zhang, Y. (2019). Base
promoted synthesis of novel indole-dithiocarbamate compounds as potential anti-
inflammatory therapeutic agents for treatment of acute lung injury. European Journal
Syed Annuar, S. N., Kamaludin, N. F., Awang, N., & Chan, K. M. (2021). Cellular basis of
organotin (IV) derivatives as anticancer metallodrugs: a review. Frontiers in
chemistry, 522.
Szolar, O. (2007). Environmental and pharmaceutical analysis of dithiocarbamates. Analytica
85
chimica acta, 582(2), 191-200.
Topping, R., & Jones, M. (1988). Optimal dithiocarbamate structure for immunomodulator
action. Medical hypotheses, 27(1), 55-57.
Vale, J. A., Faustino, W. M., Menezes, P. H., & de Sá, G. F. (2006). Eu (III) dithiocarbamate
complex and Np-tolylsulfonylphenylalanine as a novel chiral catalyst for the
asymmetric synthesis of cyanohydrins. Chemical communications(31), 3340-3342.
Vane, J., & Botting, R. (2003). The mechanism of action of aspirin. Thrombosis research,
110(5-6), 255-258.
Wang, H., Wei, J., Jiang, H., Zhang, Y., Jiang, C., & Ma, X. (2021). Design, synthesis and
pharmacological evaluation of three novel dehydroabietyl piperazine dithiocarbamate
ruthenium (II) polypyridyl complexes as potential antitumor agents: DNA damage,
cell cycle arrest and apoptosis induction. Molecules, 26(5), 1453.
Wang, X.-J., Xu, H.-W., Guo, L.-L., Zheng, J.-X., Xu, B., Guo, X., . . . Liu, H.-M. (2011).
Synthesis and in vitro antitumor activity of new butenolide-containing
dithiocarbamates. Bioorganic & medicinal chemistry letters, 21(10), 3074-3077.
Wang, Z., Yang, L., Ye, X., Huang, C., Yang, W., Zhang, L., . . . Fu, F. (2020). Multicolor
visual screening of total dithiocarbamate pesticides in foods based on sulfydryl-
mediated growth of gold nanobipyramids. Analytica chimica acta, 1139, 59-67.
Wei, M.-X., Zhang, J., Ma, F.-L., Li, M., Yu, J.-Y., Luo, W., & Li, X.-Q. (2018). Synthesis
and biological activities of dithiocarbamates containing 2 (5H)-furanone-piperazine.
European Journal of Medicinal Chemistry, 155, 165-170.
Xie, R., Li, Y., Tang, P., & Yuan, Q. (2018). Design, synthesis and biological evaluation of
novel 2-aminobenzamides containing dithiocarbamate moiety as histone deacetylase
inhibitors and potent antitumor agents. European Journal of Medicinal Chemistry,
143, 320-333.
Yu, J.-Y., Li, X.-Q., & Wei, M.-X. (2019). Synthesis and biological activities of artemisinin-
piperazine-dithiocarbamate derivatives. European Journal of Medicinal Chemistry,
169, 21-28.
Zhai, Z., Li, R., Bai, X., Ning, X., Lin, Z., Zhao, X., . . . Yin, Y. (2019). Design, synthesis
and biological evaluation of novel dithiocarbamate-substituted
diphenylaminopyrimidine derivatives as BTK inhibitors. Bioorganic & medicinal
chemistry, 27(18), 4124-4142.
Zhong, X., Chen, N., & Xu, J. (2018). A concise synthesis of cyclobrassinin and its analogues
via a thiyl radical aromatic substitution. New Journal of Chemistry, 42(16), 13549-
13557.
86
Zhou, H., Wu, B., Dekanovsky, L., Wei, S., Khezri, B., Hartman, T., . . . Sofer, Z. (2021).
Integration of BiOI nanosheets into bubble-propelled micromotors for efficient water
purification. FlatChem, 30, 100294.
Zou, Y., Yu, S., Li, R., Zhao, Q., Li, X., Wu, M., . . . Wu, Q. (2014). Synthesis, antifungal
activities and molecular docking studies of novel 2-(2, 4-difluorophenyl)-2-hydroxy-
3-(1H-1, 2, 4-triazol-1-yl) propyl dithiocarbamates. European Journal of Medicinal
Chemistry, 74, 366-374.
Abu-El-Halawa, R., & Zabin, S. A. (2017). Removal efficiency of Pb, Cd, Cu and Zn from polluted water
using dithiocarbamate ligands. Journal of Taibah University for Science, 11(1), 57-65.
Abulnaja, K. O., & Harwood, J. (1991). Thiocarbamate herbicides inhibit fatty acid elongation in a
variety of monocotyledons. Phytochemistry, 30(5), 1445-1447.
Adeyemi, J. O., & Onwudiwe, D. C. (2018). Organotin (IV) dithiocarbamate complexes: Chemistry and
biological activity. Molecules, 23(10), 2571.
Adeyemi, J. O., & Onwudiwe, D. C. (2020a). Chemistry and some biological potential of bismuth and
antimony dithiocarbamate complexes. Molecules, 25(2), 305.
Adeyemi, J. O., & Onwudiwe, D. C. (2020b). The mechanisms of action involving dithiocarbamate
complexes in biological systems. Inorganica Chimica Acta, 511, 119809.
Adokoh, C. K. (2020). Therapeutic potential of dithiocarbamate supported gold compounds. RSC
advances, 10(5), 2975-2988.
Aghbash, K. O., Alamgholiloo, H., Pesyan, N. N., Khaksar, S., & Rostamnia, S. (2021). Gold
nanoparticle stabilized dithiocarbamate functionalized magnetite carbon as promise clean
nanocatalyst for A3-coupling organic transformation. Molecular Catalysis, 499, 111252.
Ajiboye, T. O., Ajiboye, T. T., Marzouki, R., & Onwudiwe, D. C. (2022). The Versatility in the
Applications of Dithiocarbamates. International Journal of Molecular Sciences, 23(3), 1317.
Ajiboye, T. O., Babalola, S. O., & Onwudiwe, D. C. (2021). Photocatalytic Inactivation as a Method of
Elimination of E. coli from Drinking Water. Applied Sciences, 11(3), 1313.
Ajiboye, T. O., Oladoye, P. O., Olanrewaju, C. A., & Akinsola, G. O. (2022). Organophosphorus
pesticides: Impacts, detection and removal strategies. Environmental Nanotechnology,
Monitoring & Management, 17, 100655.
Ajiboye, T. O., Oyewo, O. A., & Onwudiwe, D. C. (2021a). Adsorption and photocatalytic removal of
Rhodamine B from wastewater using carbon-based materials. FlatChem, 29, 100277.
Ajiboye, T. O., Oyewo, O. A., & Onwudiwe, D. C. (2021b). Photocatalytic removal of parabens and
halogenated products in wastewater: a review. Environmental Chemistry Letters, 19(5),
3789-3819.
Ajiboye, T. O., Oyewo, O. A., & Onwudiwe, D. C. (2021c). Simultaneous removal of organics and
heavy metals from industrial wastewater: A review. Chemosphere, 262, 128379.
Akinboye, E. S., Bamji, Z. D., Kwabi-Addo, B., Ejeh, D., Copeland, R. L., Denmeade, S. R., & Bakare, O.
(2015). Design, synthesis and cytotoxicity studies of dithiocarbamate ester derivatives of
emetine in prostate cancer cell lines. Bioorganic & Medicinal Chemistry, 23(17), 5839-5845.
Ali, A., Shen, H., & Yin, X. (1998). Simultaneous determination of trace amounts of nickel, copper and
mercury by liquid chromatography coupled with flow-injection on-line derivatization and
preconcentration. Analytica Chimica Acta, 369(3), 215-223.
Altintop, M. D., Özdemir, A., Kaplancikli, Z. A., Turan‐Zitouni, G., Temel, H. E., & Çiftçi, G. A. (2013).
Synthesis and biological evaluation of some pyrazoline derivatives bearing a dithiocarbamate
moiety as new cholinesterase inhibitors. Archiv der Pharmazie, 346(3), 189-199.
87
Asadi, M., Ebrahimi, M., Mohammadi‐Khanaposhtani, M., Azizian, H., Sepehri, S., Nadri, H., . . .
Mirzazadeh, R. (2019). Design, Synthesis, Molecular Docking, and Cholinesterase Inhibitory
Potential of Phthalimide‐Dithiocarbamate Hybrids as New Agents for Treatment of
Alzheimer's Disease. Chemistry & Biodiversity, 16(11), e1900370.
Aspatwar, A., Parvathaneni, N. K., Barker, H., Anduran, E., Supuran, C. T., Dubois, L., . . . Winum, J.-Y.
(2020). Design, synthesis, in vitro inhibition and toxicological evaluation of human carbonic
anhydrases I, II and IX inhibitors in 5-nitroimidazole series. Journal of enzyme inhibition and
medicinal chemistry, 35(1), 109-117.
Ayalew, Z. M., Zhang, X., Guo, X., Ullah, S., Leng, S., Luo, X., & Ma, N. (2020). Removal of Cu, Ni and
Zn directly from acidic electroplating wastewater by Oligo-Ethyleneamine dithiocarbamate
(OEDTC). Separation and Purification Technology, 248, 117114.
Azizi, N., & Alipour, M. (2018). Synthesis of carboxylic dithiocarbamic anhydride and substituted
thiourea derivatives in water. Environmental Chemistry Letters, 16(4), 1415-1421.
Azizi, N., Khajeh, M., Hasani, M., & Dezfooli, S. (2013). An efficient four-component synthesis of
dithiocarbamate derivatives. Tetrahedron Letters, 54(39), 5407-5410.
Azizi, N., Torkiyan, L., & Saidi, M. R. (2006). Highly efficient one-pot three-component Mannich
reaction in water catalyzed by heteropoly acids. Organic Letters, 8(10), 2079-2082.
Badawy, M. E., & Rabea, E. I. (2016). Chitosan and its derivatives as active ingredients against plant
pests and diseases. In Chitosan in the preservation of agricultural commodities (pp. 179-219):
Elsevier.
Bakthavatsalam, S., Wiangnak, P., George, D. J., Zhang, T., & Franz, K. J. (2020). Dithiocarbamate
prodrugs activated by prostate specific antigen to target prostate cancer. Bioorganic &
medicinal chemistry letters, 30(11), 127148.
Bala, V., Gupta, G., & L Sharma, V. (2014). Chemical and medicinal versatility of dithiocarbamates: an
overview. Mini reviews in medicinal chemistry, 14(12), 1021-1032.
Bhalla, Y., Gupta, V. K., & Jaitak, V. (2013). Anticancer activity of essential oils: a review. Journal of
the Science of Food and Agriculture, 93(15), 3643-3653.
Bond, A., & Wallace, G. (1984). Preparation of metal dithiocarbamate complexes for
chromatographic separation and multi-element determinations. Analytica Chimica Acta, 164,
223-232.
Cao, Q., Peng, H.-Y., Cheng, Y., & Dong, Z.-B. (2018). A Highly Efficient CuCl2-Catalyzed C–S Coupling
of Aryl Iodides with Tetraalkylthiuram Disulfides: Synthesis of Aryl Dithiocarbamates.
Synthesis, 50(07), 1527-1534.
Cao, S.-L., Feng, Y.-P., Jiang, Y.-Y., Liu, S.-Y., Ding, G.-Y., & Li, R.-T. (2005). Synthesis and in vitro
antitumor activity of 4 (3H)-quinazolinone derivatives with dithiocarbamate side chains.
Bioorganic & medicinal chemistry letters, 15(7), 1915-1917.
Cao, S.-L., Wang, Y., Zhu, L., Liao, J., Guo, Y.-W., Chen, L.-L., . . . Xu, X. (2010). Synthesis and cytotoxic
activity of N-((2-methyl-4 (3H)-quinazolinon-6-yl) methyl) dithiocarbamates. European
Journal of Medicinal Chemistry, 45(9), 3850-3857.
Chaturvedi, D., Mishra, N., & Mishra, V. (2007). An efficient, basic resin mediated, one-pot, synthesis
of dithiocarbamates by Michael addition of dithiocarbamate anion to α, β-unsaturated
compounds. Journal of Sulfur Chemistry, 28(1), 39-44.
Chauhan, K., Sharma, M., Singh, P., Kumar, V., Shukla, P. K., Siddiqi, M. I., & Chauhan, P. M. (2012).
Discovery of a new class of dithiocarbamates and rhodanine scaffolds as potent antifungal
agents: synthesis, biology and molecular docking. MedChemComm, 3(9), 1104-1110.
Chen, N., Zhong, X., Li, P., & Xu, J. (2015). A Mild Radical Method for the Dimerzation of
Dithiocarbamates. European Journal of Organic Chemistry, 2015(4), 802-809.
Chen, Q. M., Li, Z., Tian, G. X., Chen, Y., & Wu, X. H. (2021). 1, 2, 3-triazole-dithiocarbamate-
naphthalimides: Synthesis, characterization, and biological evaluation. Journal of Chemical
Research, 45(3-4), 258-264.
Chia-Fu, Y., Sun-Dsong, C., Wei-Shi, C., Jia-Der, F., & Chuen-Ying, L. (1993). Application of
dithiocarbamate resin-metal complexes as stationary phases in gas chromatography. Journal
of Chromatography A, 630(1-2), 275-285.
88
Cihlar, T., & Fordyce, M. (2016). Current status and prospects of HIV treatment. Current opinion in
virology, 18, 50-56.
Cuzzocrea, S., Chatterjee, P. K., Mazzon, E., Dugo, L., Serraino, I., Britti, D., . . . Thiemermann, C.
(2002). Pyrrolidine dithiocarbamate attenuates the development of acute and chronic
inflammation. British journal of pharmacology, 135(2), 496-510.
Cvek, B., & Dvorak, Z. (2007). Targeting of nuclear factor-κB and proteasome by dithiocarbamate
complexes with metals. Current pharmaceutical design, 13(30), 3155-3167.
Dighe, S. U., Yadav, V. D., Srivastava, R., Mishra, A., Gautam, S., Srivastava, A. K., . . . Batra, S. (2014).
Reinvestigations into synthesis of allyldithiocarbamates and their intramolecular cyclization:
synthesis and antihyperglycemic activity of 2-thioxothiazolidine-4-alkanoates. Tetrahedron,
70(38), 6841-6850.
Dinarello, C. A. (2010). Anti-inflammatory agents: present and future. Cell, 140(6), 935-950.
Ding, P.-P., Gao, M., Mao, B.-B., Cao, S.-L., Liu, C.-H., Yang, C.-R., . . . Li, Z. (2016). Synthesis and
biological evaluation of quinazolin-4 (3H)-one derivatives bearing dithiocarbamate side chain
at C2-position as potential antitumor agents. European Journal of Medicinal Chemistry, 108,
364-373.
Ejelonu, B. C., Olagboye, S. A., Oyeneyin, O. E., Ebiesuwa, O. A., & Bada, O. E. (2018). Synthesis,
characterization and antimicrobial activities of sulfadiazine Schiff base and phenyl
dithiocarbamate mixed ligand metal complexes. Open Journal of Applied Sciences, 8(08),
346.
El-Aarag, B. Y., Kasai, T., Zahran, M. A., Zakhary, N. I., Shigehiro, T., Sekhar, S. C., . . . Kakuta, H.
(2014). In vitro anti-proliferative and anti-angiogenic activities of thalidomide
dithiocarbamate analogs. International immunopharmacology, 21(2), 283-292.
Elahabaadi, E., Salarian, A. A., & Nassireslami, E. (2021). Design, synthesis, and molecular docking of
novel hybrids of coumarin-dithiocarbamate alpha-glucosidase inhibitors targeting type 2
diabetes mellitus. Polycyclic Aromatic Compounds, 1-11.
Eng, G., Song, X., Duong, Q., Strickman, D., Glass, J., & May, L. (2003). Synthesis, structure
characterization and insecticidal activity of some triorganotin dithiocarbamates. Applied
organometallic chemistry, 17(4), 218-225.
Fan, Z., Qin, Y., Liu, S., Xing, R., Yu, H., Chen, X., . . . Li, P. (2019). The bioactivity of new chitin
oligosaccharide dithiocarbamate derivatives evaluated against nematode disease
(Meloidogyne incognita). Carbohydrate polymers, 224, 115155.
Fanaru, A., Les, A., Creanga, D., Dorohoi, D.-O., & Sacarescu, L. (2022). Magnetic nanoparticles
interactions with wastewater pollutants. Molecular Crystals and Liquid Crystals, 1-14.
Ferraz, C. R., Manchope, M. F., Andrade, K. C., Saraiva-Santos, T., Franciosi, A., Zaninelli, T. H., . . .
Knysak, I. (2021). Peripheral mechanisms involved in Tityus bahiensis venom-induced pain.
Toxicon, 200, 3-12.
Ferreira, I., De Lima, G., Paniago, E., Takahashi, J., & Pinheiro, C. (2014). Synthesis, characterization
and antifungal activity of new dithiocarbamate-based complexes of Ni (II), Pd (II) and Pt (II).
Inorganica Chimica Acta, 423, 443-449.
Fu, D.-J., Li, J.-H., Yang, J.-J., Li, P., Zhang, Y.-B., Liu, S., . . . Zhang, S.-Y. (2019). Discovery of novel
chalcone-dithiocarbamates as ROS-mediated apoptosis inducers by inhibiting catalase.
Bioorganic Chemistry, 86, 375-385.
Fu, W., & Huang, Z. (2018). Magnetic dithiocarbamate functionalized reduced graphene oxide for the
removal of Cu (II), Cd (II), Pb (II), and Hg (II) ions from aqueous solution: Synthesis,
adsorption, and regeneration. Chemosphere, 209, 449-456.
Fu, Z., Yuan, W., Chen, N., Yang, Z., & Xu, J. (2018). Na 2 S 2 O 8-mediated efficient synthesis of
isothiocyanates from primary amines in water. Green Chemistry, 20(19), 4484-4491.
Gao, Y., Li, L., Liu, Y., Li, W., Wang, Z., Shou, S., & Chai, Y. (2020). Effect of semaphorin-3A on the
cellular stability of CD4+ CD25+ regulatory T cells induced by lipopolysaccharide. Zhonghua
wei Zhong Bing ji jiu yi xue, 32(12), 1454-1460.
Ge, Y., Xu, L.-W., Liu, Y., Sun, L.-Y., Gao, H., Li, J.-Q., & Yang, K. (2019). Dithiocarbamate as a valuable
scaffold for the inhibition of metallo-β-lactmases. Biomolecules, 9(11), 699.
89
Guan, S., Zhong, Z., Li, J., Xu, Y., Ding, L., Huang, Y., & Liu, L. (2021). Preparation of in-situ grown
carbon nanotubes via dithiocarbamate in composites with excellent microstructure and
mechanical performance. Composites Science and Technology, 203, 108569.
Hafeez, F., Zahoor, A. F., Rasul, A., Ahmad, S., & Mansha, A. (2021). Synthesis and anticancer
evaluation of 2-oxo-2-(arylamino) ethyl 4-phenylpiperazine-1-carbodithioates. Pak. J. Pharm.
Sci, 34(1), 353-357.
Hafeez, F., Zahoor, A. F., Rasul, A., Mansha, A., Noreen, R., Raza, Z., . . . El-Hiti, G. A. (2022).
Ultrasound-Assisted Synthesis and In Silico Modeling of Methanesulfonyl-Piperazine-Based
Dithiocarbamates as Potential Anticancer, Thrombolytic, and Hemolytic Structural Motifs.
Molecules, 27(15), 4776.
Halimehjani, A. Z., Marjani, K., & Ashouri, A. (2010). Synthesis of dithiocarbamate by Markovnikov
addition reaction in aqueous medium. Green Chemistry, 12(7), 1306-1310.
Hao, S., Ding, S., Wu, Z., Bi, H., Bai, F., Yang, X., . . . Zhao, M. (2021). An Efficient Synthesis of Alkyl
Dithiocarbamates through Michael‐type Addition of Tetraalkylthiuram Disulfides to
Electrophilic Alkenes. Asian Journal of Organic Chemistry, 10(10), 2521-2524.
He, W., Ding, Y., Tu, J., Que, C., Yang, Z., & Xu, J. (2018). Thermal conversion of primary alcohols to
disulfides via xanthate intermediates: an extension to the Chugaev elimination. Organic &
Biomolecular Chemistry, 16(10), 1659-1666.
Heravi, M. M., & Zadsirjan, V. (2020). Prescribed drugs containing nitrogen heterocycles: an
overview. RSC advances, 10(72), 44247-44311.
Hogarth, G., Ebony-Jewel, C.-R., Kabir, S. E., Richards, I., Wilton-Ely, J. D., & Zhang, Q. (2009).
Functionalised dithiocarbamate complexes: Synthesis and molecular structures of 2-
diethylaminoethyl and 3-dimethylaminopropyl dithiocarbamate complexes [M {S2CN
(CH2CH2NEt2) 2} n] and [M {S2CN (CH2CH2CH2NMe2) 2} n](n= 2, M= Ni, Cu, Zn, Pd; n= 3,
M= Co). Inorganica Chimica Acta, 362(6), 2020-2026.
Hogarth, G., Ebony-Jewel, C.-R., & Richards, I. (2009). Functionalised dithiocarbamate complexes:
Synthesis and molecular structures of bis (2-methoxyethyl) dithiocarbamate complexes [M
{S2CN (CH2CH2OMe) 2} 2](M= Ni, Cu, Zn) and [Cu {S2CN (CH2CH2OMe) 2} 2][ClO4].
Inorganica Chimica Acta, 362(4), 1361-1364.
Horita, Y., Takii, T., Kuroishi, R., Chiba, T., Ogawa, K., Kremer, L., . . . Onozaki, K. (2011). Synthesis and
evaluation of anti-tubercular activity of new dithiocarbamate sugar derivatives. Bioorganic &
medicinal chemistry letters, 21(3), 899-903.
Hou, X., Ge, Z., Wang, T., Guo, W., Cui, J., Cheng, T., . . . Li, R. (2006). Dithiocarbamic acid esters as
anticancer agent. Part 1: 4-Substituted-piperazine-1-carbodithioic acid 3-cyano-3, 3-
diphenyl-propyl esters. Bioorganic & medicinal chemistry letters, 16(16), 4214-4219.
Husain, A., Nami, S. A., Singh, S. P., Oves, M., & Siddiqi, K. (2011). Anagostic interactions, revisiting
the crystal structure of nickel dithiocarbamate complex and its antibacterial and antifungal
studies. Polyhedron, 30(1), 33-40.
Hussain, A., Pu, H., Hu, B., & Sun, D.-W. (2021). Au@ Ag-TGANPs based SERS for facile screening of
thiabendazole and ferbam in liquid milk. Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy, 245, 118908.
J Berry, D., Torres Martin de Rosales, R., Charoenphun, P., & J Blower, P. (2012). Dithiocarbamate
complexes as radiopharmaceuticals for medical imaging. Mini reviews in medicinal chemistry,
12(12), 1174-1183.
Kamal, A., Sathish, M., Nayak, V. L., Srinivasulu, V., Kavitha, B., Tangella, Y., . . . Nagesh, N. (2015).
Design and synthesis of dithiocarbamate linked β-carboline derivatives: DNA topoisomerase
II inhibition with DNA binding and apoptosis inducing ability. Bioorganic & Medicinal
Chemistry, 23(17), 5511-5526.
Kanchi, S., Singh, P., & Bisetty, K. (2014). Dithiocarbamates as hazardous remediation agent: A critical
review on progress in environmental chemistry for inorganic species studies of 20th century.
Arabian Journal of Chemistry, 7(1), 11-25.
Kane, S., Lazo, P., Ylli, F., Stafilov, T., Qarri, F., & Marku, E. (2016). Separation of heavy metal from
water samples—The study of the synthesis of complex compounds of heavy metal with
dithiocarbamates. Journal of Environmental Science and Health, Part A, 51(4), 335-340.
90
Kaufman, D. D. (1967). Degradation of carbamate herbicides in soil. Journal of Agricultural and Food
Chemistry, 15(4), 582-591.
Kaul, L., SŘss, R., Zannettino, A., & Richter, K. (2021). The revival of dithiocarbamates: from pesticides
to innovative medical treatments. IScience, 24(2), 102092.
Kerru, N., Gummidi, L., Maddila, S., Gangu, K. K., & Jonnalagadda, S. B. (2020). A review on recent
advances in nitrogen-containing molecules and their biological applications. Molecules,
25(8), 1909.
Kharb, R., Bansal, K., & Sharma, A. K. (2012). A valuable insight into recent advances on antimicrobial
activity of piperazine derivatives. Der Pharma Chemica, 4(6), 2470-2488.
Kumar, L., Jain, A., Lal, N., Sarswat, A., Jangir, S., Kumar, L., . . . Maikhuri, J. P. (2012). Potentiating
metronidazole scaffold against resistant trichomonas: design, synthesis, biology and 3D–
QSAR analysis. ACS medicinal chemistry letters, 3(2), 83-87.
Lamkanfi, M. (2011). Emerging inflammasome effector mechanisms. Nature Reviews Immunology,
11(3), 213-220.
Lawal, M. M., Lawal, I. A., Klink, M. J., Tolufashe, G. F., Ndagi, U., & Kumalo, H. M. (2020). Density
functional theory study of gold (III)-dithiocarbamate complexes with characteristic
anticancer potentials. Journal of Inorganic Biochemistry, 206, 111044.
Li, C.-W., Chen, Z.-W., Wu, X.-L., Ning, Z.-X., Su, Z.-Q., Li, Y.-C., . . . Lai, X.-P. (2015). A standardized
Traditional Chinese Medicine preparation named Yejuhua Capsule ameliorates
lipopolysaccharide-induced acute lung injury in mice via downregulating Toll-like receptor
4/nuclear factor-κB. Evidence-Based Complementary and Alternative Medicine, 2015.
Li, Q.-H., Ding, Y., & Huang, N.-W. (2014). Synthesis and biological activities of dithiocarbamates
containing 1, 2, 3-triazoles group. Chinese Chemical Letters, 25(11), 1469-1472.
Li, R.-D., Wang, H.-L., Li, Y.-B., Wang, Z.-Q., Wang, X., Wang, Y.-T., . . . Li, R.-T. (2015). Discovery and
optimization of novel dual dithiocarbamates as potent anticancer agents. European Journal
Li, Y.-B., Yan, X., Li, R.-D., Liu, P., Sun, S.-Q., Wang, X., . . . Li, R.-T. (2016). Discovery of novel
heteroarylmethylcarbamodithioates as potent anticancer agents: Synthesis, structure-
activity relationship analysis and biological evaluation. European Journal of Medicinal
Chemistry, 112, 217-230.
Liu, B., Yuan, X., Xu, B., Zhang, H., Li, R., Wang, X., . . . Li, R. (2019). Synthesis of novel 7-azaindole
derivatives containing pyridin-3-ylmethyl dithiocarbamate moiety as potent PKM2 activators
and PKM2 nucleus translocation inhibitors. European Journal of Medicinal Chemistry, 170, 1-
15.
Lu, Y., Pan, Q., Gao, W., Pu, Y., Luo, K., He, B., & Gu, Z. (2022). Leveraging disulfiram to treat cancer:
Mechanisms of action, delivery strategies, and treatment regimens. Biomaterials, 281,
121335.
Manoussakis, G., Bolos, C., Ecateriniadou, L., & Sarris, C. (1987). Synthesis, characterization and anti-
bacterial studies of mixed-ligand complexes of dithiocarbamato—thiocyanato and iron (III),
nickel (II), copper (II) and zinc (II). European Journal of Medicinal Chemistry, 22(5), 421-425.
Menezes, D., Vieira, F., de Lima, G., Porto, A., Cortés, M., Ardisson, J., & Albrecht-Schmitt, T. (2005).
Tin (IV) complexes of pyrrolidinedithiocarbamate: synthesis, characterisation and antifungal
activity. European Journal of Medicinal Chemistry, 40(12), 1277-1282.
Menezes, D., Vieira, F., De Lima, G., Wardell, J., Cortés, M., Ferreira, M. P., . . . Vilas Boas, A. (2008).
The in vitro antifungal activity of some dithiocarbamate organotin (IV) compounds on
Candida albicans—A model for biological interaction of organotin complexes. Applied
organometallic chemistry, 22(4), 221-226.
Milacic, V., Chen, D., Giovagnini, L., Diez, A., Fregona, D., & Dou, Q. P. (2008). Pyrrolidine
dithiocarbamate-zinc (II) and-copper (II) complexes induce apoptosis in tumor cells by
inhibiting the proteasomal activity. Toxicology and applied pharmacology, 231(1), 24-33.
Mohammed, M. H., & Leelon, A. A. (2021). Synthesis, characterization of isatin dithiocarbamate
derivatives with expected biological activities. Int. J. Drug Deliv. Technol, 11, 209-212.
Mollazadeh, M., Mohammadi-Khanaposhtani, M., Valizadeh, Y., Zonouzi, A., Faramarzi, M. A., Kiani,
M., . . . Mahdavi, M. (2021). Novel coumarin containing dithiocarbamate derivatives as
91
potent α-glucosidase inhibitors for management of type 2 diabetes. Medicinal Chemistry,
17(3), 264-272.
Morita, F., Nakakubo, K., Yunoshita, K., Endo, M., Biswas, F. B., Nishimura, T., . . . Maeda, K. (2020).
Dithiocarbamate-modified cellulose-based sorbents with high storage stability for selective
removal of arsenite and hazardous heavy metals. RSC advances, 10(50), 30238-30244.
Morrison, B. W., Doudican, N. A., Patel, K. R., & Orlow, S. J. (2010). Disulfiram induces copper-
dependent stimulation of reactive oxygen species and activation of the extrinsic apoptotic
pathway in melanoma. Melanoma research, 20(1), 11-20.
Nabipour, H., Ghammamy, S., Ashuri, S., & Aghbolaghc, Z. S. (2010). Synthesis of a new
dithiocarbamate compound and Study of Its biological properties. J. Org. Chem, 2, 75-80.
Oladipo, S. D., Tolufashe, G. F., Mocktar, C., & Omondi, B. (2021). Ag (I) symmetrical N, N′-
diarylformamidine dithiocarbamate PPh3 complexes: Synthesis, structural characterization,
quantum chemical calculations and in vitro biological studies. Inorganica Chimica Acta, 520,
120316.
Omar, A.-M. M., AboulWafa, O. M., El-Shoukrofy, M. S., & Amr, M. E. (2020). Benzoxazole derivatives
as new generation of anti-breast cancer agents. Bioorganic Chemistry, 96, 103593.
Pastrana-Dávila, A., Amaya-Flórez, A., Aranaga, C., Ellena, J., Macías, M., Flórez-López, E., & D'Vries,
R. F. (2021). Synthesis, characterization, and antibacterial activity of dibenzildithiocarbamate
derivates and Ni (II)–Cu (II) coordination compounds. Journal of Molecular Structure, 1245,
131109.
Pitchaimani, P., Lo, K. M., & Elango, K. P. (2015). Synthesis, crystal structures, luminescence
properties and catalytic application of lanthanide (III) piperidine dithiocarbamate complexes.
Polyhedron, 93, 8-16.
Qin, Y., Liu, S., Xing, R., Yu, H., Li, K., Meng, X., . . . Li, P. (2012). Synthesis and characterization of
dithiocarbamate chitosan derivatives with enhanced antifungal activity. Carbohydrate
polymers, 89(2), 388-393.
Raffa, C. M., & Chiampo, F. (2021). Bioremediation of agricultural soils polluted with pesticides: A
review. Bioengineering, 8(7), 92.
Raina-Fulton, R. (2014). A review of methods for the analysis of orphan and difficult pesticides:
Glyphosate, glufosinate, quaternary ammonium and phenoxy acid herbicides, and
dithiocarbamate and phthalimide fungicides. Journal of AOAC International, 97(4), 965-977.
Reddy, L., Odhav, B., & Bhoola, K. (2003). Natural products for cancer prevention: a global
perspective. Pharmacology & therapeutics, 99(1), 1-13.
Rogachev, I., Kampel, V., Gusis, V., Cohen, N., Gressel, J., & Warshawsky, A. (1998). Synthesis,
properties, and use of copper-chelating amphiphilic dithiocarbamates as synergists of
oxidant-generating herbicides. Pesticide Biochemistry and Physiology, 60(3), 133-145.
Runkle, J., Flocks, J., Economos, J., & Dunlop, A. L. (2017). A systematic review of Mancozeb as a
reproductive and developmental hazard. Environment International, 99, 29-42.
Sağlık, B. N., Osmaniye, D., Cevik, U. A., Levent, S., Çavuşoğlu, B. K., Büyükemir, O., . . . Koparal, A. S.
(2020). Synthesis, characterization and carbonic anhydrase I and II inhibitory evaluation of
new sulfonamide derivatives bearing dithiocarbamate. European Journal of Medicinal
Chemistry, 198, 112392.
Saini, M. S., Kumar, A., Dwivedi, J., & Singh, R. (2013). A review: biological significances of
heterocyclic compounds. Int. J. Pharm. Sci. Res, 4(3), 66-77.
Shaabani, A., Nazeri, M. T., & Afshari, R. (2019). 5-Amino-pyrazoles: potent reagents in organic and
medicinal synthesis. Molecular Diversity, 23(3), 751-807.
Shepherd, R. E. (2003). Chromatographic and related electrophoretic methods in the separation of
transition metal complexes or their ligands. Coordination chemistry reviews, 247(1-2), 159-
196.
Shinde, S. D., Sakla, A. P., & Shankaraiah, N. (2020). An insight into medicinal attributes of
dithiocarbamates: Bird’s eye view. Bioorganic Chemistry, 105, 104346.
Song, Z., Zhou, Y., Zhang, W., Zhan, L., Yu, Y., Chen, Y., . . . Zhang, Y. (2019). Base promoted synthesis
of novel indole-dithiocarbamate compounds as potential anti-inflammatory therapeutic
92
agents for treatment of acute lung injury. European Journal of Medicinal Chemistry, 171, 54-
65.
Syed Annuar, S. N., Kamaludin, N. F., Awang, N., & Chan, K. M. (2021). Cellular basis of organotin (IV)
derivatives as anticancer metallodrugs: a review. Frontiers in chemistry, 522.
Szolar, O. (2007). Environmental and pharmaceutical analysis of dithiocarbamates. Analytica Chimica
Acta, 582(2), 191-200.
Topping, R., & Jones, M. (1988). Optimal dithiocarbamate structure for immunomodulator action.
Medical hypotheses, 27(1), 55-57.
Vale, J. A., Faustino, W. M., Menezes, P. H., & de Sá, G. F. (2006). Eu (III) dithiocarbamate complex
and Np-tolylsulfonylphenylalanine as a novel chiral catalyst for the asymmetric synthesis of
cyanohydrins. Chemical communications(31), 3340-3342.
Vane, J., & Botting, R. (2003). The mechanism of action of aspirin. Thrombosis research, 110(5-6),
255-258.
Wang, H., Wei, J., Jiang, H., Zhang, Y., Jiang, C., & Ma, X. (2021). Design, synthesis and
pharmacological evaluation of three novel dehydroabietyl piperazine dithiocarbamate
ruthenium (II) polypyridyl complexes as potential antitumor agents: DNA damage, cell cycle
arrest and apoptosis induction. Molecules, 26(5), 1453.
Wang, X.-J., Xu, H.-W., Guo, L.-L., Zheng, J.-X., Xu, B., Guo, X., . . . Liu, H.-M. (2011). Synthesis and in
vitro antitumor activity of new butenolide-containing dithiocarbamates. Bioorganic &
medicinal chemistry letters, 21(10), 3074-3077.
Wang, Z., Yang, L., Ye, X., Huang, C., Yang, W., Zhang, L., . . . Fu, F. (2020). Multicolor visual screening
of total dithiocarbamate pesticides in foods based on sulfydryl-mediated growth of gold
nanobipyramids. Analytica Chimica Acta, 1139, 59-67.
Wei, M.-X., Zhang, J., Ma, F.-L., Li, M., Yu, J.-Y., Luo, W., & Li, X.-Q. (2018). Synthesis and biological
activities of dithiocarbamates containing 2 (5H)-furanone-piperazine. European Journal of
Medicinal Chemistry, 155, 165-170.
Xie, R., Li, Y., Tang, P., & Yuan, Q. (2018). Design, synthesis and biological evaluation of novel 2-
aminobenzamides containing dithiocarbamate moiety as histone deacetylase inhibitors and
potent antitumor agents. European Journal of Medicinal Chemistry, 143, 320-333.
Yu, J.-Y., Li, X.-Q., & Wei, M.-X. (2019). Synthesis and biological activities of artemisinin-piperazine-
dithiocarbamate derivatives. European Journal of Medicinal Chemistry, 169, 21-28.
Zhai, Z., Li, R., Bai, X., Ning, X., Lin, Z., Zhao, X., . . . Yin, Y. (2019). Design, synthesis and biological
evaluation of novel dithiocarbamate-substituted diphenylaminopyrimidine derivatives as
BTK inhibitors. Bioorganic & Medicinal Chemistry, 27(18), 4124-4142.
Zhang, M., Wang, Y., Zeng, G., Yang, S., Liao, X., & Sun, D. (2021). Antibacterial activity and
mechanism of piperazine polymer. Journal of Applied Polymer Science, 138(20), 50451.
Zhong, X., Chen, N., & Xu, J. (2018). A concise synthesis of cyclobrassinin and its analogues via a thiyl
radical aromatic substitution. New Journal of Chemistry, 42(16), 13549-13557.
Zhou, H., Wu, B., Dekanovsky, L., Wei, S., Khezri, B., Hartman, T., . . . Sofer, Z. (2021). Integration of
BiOI nanosheets into bubble-propelled micromotors for efficient water purification.
FlatChem, 30, 100294.
Zou, Y., Yu, S., Li, R., Zhao, Q., Li, X., Wu, M., . . . Wu, Q. (2014). Synthesis, antifungal activities and
molecular docking studies of novel 2-(2, 4-difluorophenyl)-2-hydroxy-3-(1H-1, 2, 4-triazol-1-
yl) propyl dithiocarbamates. European Journal of Medicinal Chemistry, 74, 366-374.
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Aryl Dithiocarbamate Thesis 25-10-22

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Aryl Dithiocarbamate Thesis 25-10-22

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ABSTRACT

Figure 1.1: General structure of dithiocarbamate

Figure 1.2: General reaction of dithiocarbamate

1.3 Applications of aryl dithiocarbamates

Figure 1.6: Applications of aryl dithiocarbamates

Figure 1.7: Classes of DTFs and examples from each class

Figure 1.8: Some common examples aryl dithiocarbamates based herbicides

1.3.2 Application of aryl dithiocarbamates as an enzyme inhibitor

Figure 1.9: Biological active aryl dithiocarbamates based drugs

Figure 1.11: Examples of some anti-bacterial aryl dithiocarbamate agents

Figure 1.13: Examples of anti-inflammatory aryl dithiocarbamate agents

Scheme 2.1: Synthesis of the derivatives of artemisinin piperazine dithiocarbamate

Scheme 2.2: Synthesis of derivative of diphenylaminopyrimidine dithiocarbamate

Scheme 2.3: Synthesis of derivatives of indole dithiocarbamate

Scheme 2.5: Synthesis of indole dithiocarbamate derivative

Scheme 2.6: Synthesis of 2(5H)-furanone dithiocarbamate derivative

Scheme 2.9: Synthesis of quinazoline dithiocarbamate derivative

based by the reaction of N-(1,3-benzodioxol-5-ylmethyl)-2-chloroacetamide with the Na salt

Scheme 2.11: Synthesis of oxadiazole dithiocarbamate derivative

Scheme 2.15: Synthsis of heterocyclic scaffolds dithiocarbamate

Scheme 2.17: Synthesis of oxirane dithiocarbamate derivative

Scheme 2.18: Synthesis of derivatives of β-carboline dithiocarbamate

Scheme 2.19: Synthesis of pyrazoline based dithiocarbamate derivatives

Scheme 2.20: Synthesis of Dithiocarbamate using four component one-pot method

Scheme 2.21: Synthesis of pyridine based dithiocarbamate derivative

Scheme 2.24: Synthesis of dithiocarbamate based TB drug

Scheme 2.25: Synthesis of dithiocarbamate via Markovnik addition reaction

Scheme 2.27: Synthesis of dithiocarbamate in solvent less-conditions

Scheme 2.28: Synthesis of dithiocarbamate drug in greener conditions

Scheme 2.29: Synthesis of 4-N-substituted derivative of dithiocarbamate

Scheme 2.30: Synthesis of 4(3H)-quinazolinone dithiocarbamate derivative

Scheme 3.1: Synthesis of 1-(methylsulfonyl)piperazine 108

Scheme 3.2: Synthesis of tert-butyl piperazine-1-carboxylate 110

Scheme 3.5: Synthesis of 2-cyanobenzyl 4-(methylsulfonyl)piperazine-1-carbodithioate 112c

Scheme 3.6: Synthesis of tert-butyl 4-(benzythio)carbonothioyl)piperazine-1-carboxylate

Scheme 3.9: Synthesis of benzyl Morpholine-4-carbodithioate 115a

Scheme 3.10: Synthesis of 4-(tert-butyl)benzyl morpholine-4-carbodithioate 115b

Scheme 3.11: Synthesis of 2-cyanobenzyl Morpholine-4-carbodithioate 115c

3.7 Biological Evaluation

Figure 4.1: Structure of N-heterocycles

Figure 4.2: Outline for the synthesis of series of derivatives 112a-c

Figure 4.4: Outline for the synthesis of series of derivatives 115a-c

Table 4.1: Synthesis of 1-(methylsulfonyl)piperazine 108 in different conditions

Sr. # Conditions Solvent Time (hr) Temperature (oC) Yield (%)

1. Stirring Ethanol 24 Room temperature Failed

2. Stirring Ethyl acetate 24 Room temperature Failed

3. Stirring DCM 12 Room temperature 20

4. Stirring DCM 48 Room temperature 90

Sr. Reactant Condition Solvent Time Temper Product Yield

5. Sonicator Ethanol 80 120oC 86%

Sonicator Ethanol 30 50oC Incom

10. Sonicator Ethanol 80 120oC 91%

4.2 Synthesis of aryl dithiocarbamate derivatives 114a-c from 110

Table 4.3: Synthesis of tert-butyl piperazine-1-carboxylate 110 under different conditions

Sr. # Conditions Solvent Time (hr) Temperature Yield (%)

1. Stirring Ethanol 6 Room temperature Failed

2. Reflux DCM 4 Room temperature Failed

3. Reflux DMF 4 Room temperature 6

4. Reflux DMF 8 Room temperature 50

110 111a-c 114a-c, 89-92%

Sr. Reactant Condition Solvent Time Tempera Product Yield %

5. Sonicator Ethanol 80mins 120 89

Sonicator Ethanol 30mins 50 Incomple