Received: 31 August 2021 Accepted: 15 September 2021

DOI: 10.1002/jhet.4366

ARTICLE

Synthesis, biological evaluation, and molecular docking

study of thiophene-, piperazine-, and thiazolidinone-based
hybrids as potential antimicrobial agents

Nisheeth C. Desai1 | Yogesh M. Rupala1 | Ashvinkumar G. Khasiya1 |

Keyur N. Shah1 | Unnat P. Pandit2 | Vijay M. Khedkar3

1
Division of Medicinal Chemistry,
Department of Chemistry, Mahatma
Abstract
Gandhi Campus, Maharaja Antibiotic resistance in bacteria exacerbates the issue of antimicrobial resis-
Krishnakumarsinhji Bhavnagar tance. Bacteria that cause common or serious infections have evolved resis-
University, Bhavnagar, India
2 tance to every new antibiotic that has been introduced into the market, to
Special Centre for Systems Medicine,
Jawaharlal Nehru University, New Delhi, varying degrees, over several decades. Faced with this reality, one of society's
India most urgent needs is for new antimicrobial drugs with novel mechanisms of
3
School of Pharmacy, Vishwakarma action. With this objective, we describe here the development of a novel set of
University, Pune, India
compounds including piperazine- and thiophene-based thiazolidinones (5a–i)
Correspondence and thiophene-thiazolidinones (6a–i). Compounds (5a–i) and (6a–i) were
Nisheeth C. Desai, Division of Medicinal
developed, synthesized, and tested for their antimicrobial activity, and their
Chemistry, Department of Chemistry,
(UGC NON-SAP & DST-FIST Sponsored), structures were elucidated with the help of various analytical techniques.
Mahatma Gandhi Campus, Maharaja Compounds 5a and 5d showed excellent antibacterial efficacy against Pseudo-
Krishnakumarsinhji Bhavnagar
monas aeruginosa, with MICs of 50 μg/ml, whereas compounds 6c and 6e
University, Bhavnagar, 364002, Gujarat,
India. showed similar potency against Staphylococcus aureus and Escherichia coli,
Email: dnisheeth@rediffmail.com respectively. The antifungal efficacy of compounds 5e and 6i against Candida

Funding information
Department of Science and Technology;
University Grants Commission (UGC)
albicans was outstanding (MIC = 50 μg/ml). The only compound that had
excellent antifungal efficacy against Aspergillus niger was compound 5e
(MIC = 50 μg/ml). The chemico-in silico-biology approach could provide valu-
able insights into the potential of this novel hybridized scaffold for the devel-
opment of promising antimicrobial agents.

1 | INTRODUCTION antimicrobial agents [2]. To address the problem of

Every day, 50,000 people suffer from microbial illnesses
globally, according to the World Health Organization [1].
In recent years, the death rate from microbial diseases
has been dropping slowly. One of the primary causes of
rising microbial diseases is the world's growing popula-
tion. The current emphasis on the creation of antimicro-
bial agents has fallen short of expectations because of
excessive toxicity and poor antibacterial action, as well as
microbial resistance, prompting a quest for innovative
multidrug resistance, several synthetic techniques based
on a hybrid molecular approach have been devel-
oped [3,4].
A distinguishing characteristic of the hybrid molecu-
lar method is the generation of prospective leads to com-
bat microbial resistance [5,6]. In molecular hybridization,
more than one active pharmacophore is combined to pro-
duce desirable hybrids. When two or more active scaf-
folds are implanted in a single entity, its biological
activity changes. This idea is important for developing

J Heterocyclic Chem. 2021;1–13. wileyonlinelibrary.com/journal/jhet © 2021 Wiley Periodicals LLC. 1

2 DESAI ET AL.
novel antimicrobial agents with novel modes of action to
combat antimicrobial resistance. As a result, hybrid mol-
ecules can lower the probability of multidrug resistance
as well as drug–drug interactions, potentially assisting in
combating microbial resistance and mortality.
The goal of purposefully selecting rhodanine hybrids
was to provide a wide range of pharmacological activities.
Antibacterial [7], antifungal [8], antiviral [9], antimalar-
ial [10], anti-inflammatory [11], and anticancer proper-
ties have been linked to rhodanine-based analogues
[12,13]. The analogues of rhodanine with
2,4-thiazolidinedione have a five-membered heterocyclic
core with >C═O group on the fourth carbon and have
demonstrated a wide range of therapeutic effects [14].
This piques researchers' interest in studying and strategi-
cally designing molecular modifications, as well as evalu-
ating their pharmacological behavior.
Thiophene is another heterocyclic molecule that
has drawn the attention of medicinal and chemical
biologists. Thiophene derivatives have been shown to
have a variety of biological properties, including
antibacterial [15,16], analgesic, anti-inflammatory [17],
antiviral [18], antitumor [19], and antioxidant. It is also
linked to antibacterial and antifungal agents [20–22],
antidepressants [23], antihistamines [24], and antima-
larial agents [25].
Shalke et al. [26] reported their findings on
2-((5-benzylidene-4-oxo-4,5-dihydrothiazol-2-yl)-substituted
amino acids as antibacterial and anticancer agents in 2019.
Among the substances studied, 2-((5-benzylidene-4-oxo-4,-
5-dihydrothiazol-2-yl)amino)-3-hydroxypropanoic acid
demonstrated a positive outcome with minimum inhibitory
concentration (MIC) values of 15 and 12.5 μg/ml against
B. subtilis and Staphylococcus aureus, respectively. Pansare
et al. [27] described the synthesis of 2-((4-oxo-5-(thiophen-
2-ylmethylene)-4,5-dihydrothiazol-2-yl)amino)-substituted
acids, which were then used to generate effective
F I G U R E 1 Hybrid motifs based on thiophene, arylidene, and thiazolidinone, which have emerged as effective antibacterial agents due
to their rational creation
antibacterial drugs. Jadhav et al. [28], on the other hand,
synthesized 5-arylidine-2-(methylthio)-thiazolone deriva-
tives as a key precursor in the synthesis of antibacterial
drugs. Kalaria et al. [29] prepared several thiazol-4(5H)-
one derivatives, including 2-(50 -(1H-benzo[d]imidazol-
1-yl)-30 -methyl-10 -phenyl-5-(thiophen-2-yl)-3,4-dihydro-10 H,
2H-[3,40 -bipyrazol]-2-yl)-5-(thiophen-2-ylmethylene)thiazol-
4(5H)-one, which was found to be the most effective com-
pound against E. coli with the IC50 value 9.1 μM. The target
compounds were made by replacing the substituted 30 -
methyl-10 -phenyl-5-(thiophen-2-yl)-3,4-dihydro-10 H,2H-
[3,40 -bipyrazole]-2-carbothioamide at the C2 position of
thiazol-4(5H)-one ring by substituted piperazines and
aryl/alkyl amines. Insuasty et al. [30] developed
5-arylidene-2-dimethylamino-1,3-thiazol-4-ones, which
showed antifungal activity against 10 different fungus
strains. The thiophene ring was introduced at C5, and dif-
ferent substituted piperazines and aryl/alkyl amines were
introduced at the C2 position of the thiazol-4(5H)-one ring
to construct the target compounds. Nemr et al. [31] syn-
thesized numerous thiazolone–benzenesulfonamide
derivatives, including 4-(5-(5-allyl-2-hydroxy-3-meth-
oxybenzylidene)-4-oxo-4,5-dihydrothiazol-2-ylamino)
benzenesulfonamide, 4-(5-(4-nitrobenzylidene)-4-oxo-4,-
5-dihydrothiazol-2-ylamino) benzenesulfonamide, and
4-(5-(4-hydroxy-3-methoxybenzylidene)-4-oxo-4,5-dihydrothiazol-
2-ylamino)benzenesulfonamide as effective motifs against
S. aureus, with activity indices of 80.69%, 69.74%, and
68.30%, respectively. The rational architecture of the
recently published work is shown in Figure 1.
The strategic re-design of hybrid heterocyclic com-
pounds (5a-i) and (6a-i) based on commercially available
drug-like Rosiglitazone and Pioglitazone is accomplished
by reconstructing thiazolidinedione and inserting
substituted piperazines and various alkyl/aryl amines, as
shown in Figure 2. Changes in the structure of thiazole
from nitazoxanide, as well as the addition of substituted
DESAI ET AL. 3

F I G U R E 2 Novelty,
NO2
correlation of targeted compounds, O O S
O
and commercially available drugs
N N
for the purpose of work strategy H

Nitazoxanide

Structure alteration of thiazole

O O
and introduction of substituted
HN piperazines and alkyl/aryl
O N amines for enhancing potency
S
Pioglitazone

S S
Structural modifications in the
O O Modification of
thiazolidinedione moiety and N
substituents on
introduction of substituted
S N S N piperazine ring for
piperazines and different N
magnifying
alkyl/aryl amines N N
R R' antimicrobial profile
Targeted N
molecules X
O O
HN N N Cinnarizine
O
S Introducing thiophene ring at
Rosiglitazone 5th position in the targeted molecules
and replacement of chloride
group by hybrid motif
Cl
S
O
N
Cl N

Cl
Tioconazole

piperazines and alkyl/aryl amines, improved its
pharmacophoric ability. Cinnarizine's antibacterial pro-
file is enhanced by modified substituents on its pipera-
zine ring. The installation of the active pharmacophore
thiophene at the 5-position in the targeted molecules
derived from tioconazole, as well as the substitution of
the chloride group with a hybrid motif, improves
antibacterial activity.
The in silico approach of molecular docking has
evolved as one of the most useful techniques to gain
insight into the plausible mechanism of action for the
compounds exhibiting promising levels of activity in the
in vitro cell-based assay. This predictive modeling
approach not only helps to gauge the binding affinity of a
molecule to the biological target but also sheds light on
the various thermodynamic interactions that influence
the mechanical interlocking of the molecule at the active
site of the receptor [32,33].
Our research group has been attempting to solve the
issue of microbial resistance through a hybrid molecular
approach [34–36]. Our work plan is to search for diverse
therapeutic entities by fusing more than one active
pharmacophore, which could serve as a starting point for
the development of heterocyclic scaffolds for antimicro-
bial agents [37–39]. Using this approach, we created
thiazolidinone clubbed thiophene hybrids and have eval-
uated their antimicrobial potency. Furthermore molecu-
lar docking study was performed against critical bacterial
target- DNA gyrase to gauze their binding modes and the
thermodynamic interactions governing their binding
affinities.
2 | RESULTS A ND DISCUSSION
2.1 | Chemistry
Products 5a–i and 6a–i were synthesized using the reac-
tions shown in Scheme 1. Rhodanine was synthesized by
a procedure reported in the literature [40]. Condensation
of thiophene-2-carboxyaldehyde (1) with rhodanine (2)
in the presence of sodium acetate produced the
corresponding Schiff's base 5-(thiophen-2-ylmethylene)-
2-thioxothiazolidin-4-ones (3). Compound (3) and
2-(methylthio)-5-(thiophen-2-ylmethylene)thiazolidin-
4-one (4) intermediates were produced in a basic
4 DESAI ET AL.
SCHEME 1 Preparation of alkyl/aryl piperazinyl and dialkyl/aryl amino derivatives
medium of triethylamine (TEA) by activating the sulfur
atom by refluxing at 0–5 C followed by the addition of
methyl iodide. The piperazine and aryl/alkyl amine deriv-
atives were added by the reaction with (4) in ethanol
(95%), leading to the formation of the titled compounds
2-(4-(alkyl/aryl)(piperazininyl)-5-(thiophen-2-ylmethylene)
thiazol-4(5H)-ones (5a–i) and 2-(dialkyl/arylamino)-
5-(thiophen-2-ylmethylene)thiazol-4(5H)-ones (6a–i) at
room temperature.
The distinctive bands of >C═O, >C═N, >C═C<, and
C N were seen in the IR spectrum of compound 5a at
1693, 1598, 1388, and 1284 cm1, respectively. The 1H
NMR spectrum of 5a showed two singlet signals at 1.7
and 8.4 ppm, indicating –NH and >C═CH protons,
respectively. In addition, three multiplets were seen at
2.8, 3.6, and 7.3–8.1, which were attributed to the methy-
lene groups of eight piperazines and the protons of thio-
phene. Apart from the connection of the thiophene ring
to rhodanine, the carbons of the >C═C resonated at
153.11 ppm in 13C NMR spectrum. The presence of meth-
ylene group carbons in the piperazine ring was suggested
by signals at 47.16 and 51.45 ppm. The mass spectrum
compound 5a revealed peaks at m/z = 280.05, which cor-
responded to the molecular ion peak. Spectral analysis
revealed the chemical structure of 2-(dialkyl/arylamino)-
5-(thiophen-2-ylmethylene)thiazol-4(5H)-ones (6a–i).
The 1H NMR spectrum of compound 6a showed only one
singlet at 8.41 ppm, which corresponds to the unsatu-
rated proton. Two multiplets at 3.15 and 7.30–7.95 ppm,
on the other hand, suggest the presence of nitrogen with
two methyl groups and thiophene protons. Meanwhile,
the mass spectrum indicated a molecular ion peak at m/
z = 238.02, which was consistent with the compound's
structure.
2.2 | Biological evaluation
In vitro tests were performed on the title compounds
against Gram-negative bacteria Escherichia coli (MTCC-
443) and Pseudomonas aeruginosa (MTCC-1688); Gram-
positive bacteria Staphylococcus aureus (MTCC-96) and
Streptococcus pyogenes (MTCC-442); and the fungi Can-
dida albicans (MTCC-227) and Aspergillus niger (MTCC-
282). Ampicillin and nystatin were used as standard
drugs to compare the antimicrobial effect of the titled
compounds. The National Committee for Clinical Labo-
ratory Standards procedure was followed when carrying
out the broth dilution method. [41–43]
2.2.1 | Antibacterial activity
The newly synthesized compounds were evaluated
in vitro for antibacterial activity, and their MIC values
are listed in Table 1. Compounds 5a and 5d had excellent
antibacterial action against Gram-negative bacteria
P. aeruginosa (MIC = 50 μg/ml), whereas compound 6e
showed outstanding antibacterial activity against Gram-
negative bacteria E. coli (twofold more than the standard
antibiotic ampicillin). Compound 6e had considerable
antibacterial activity against P. aeruginosa (62.5 μg/ml),
DESAI ET AL. 5

T A B L E 1 Antibacterial and
Compound Log P (o/w)b EC PA SA SP CA AN
antifungal activities (minimum
inhibition concentration, μg/ml) of 5a 1.584 62.5 50 100 62.5 500 500
thiophene-thiazolidinone derivatives 5b 1.691 125 250 1000 125 250 500
(5a–i and 6a–i) against bacterial and 5c 2.086 500 100 500 500 500 500
fungal strainsa
5d 2.482 62.5 50 500 1000 200 500
5e 4.024 500 500 1000 500 50 50
5f 3.173 1000 1000 500 500 500 >1000
5g 3.539 1000 1000 500 500 500 250
5h 2.868 1000 500 250 250 100 125
5i 1.812 250 1000 500 500 250 >1000
6a 2.237 500 250 1000 250 500 >1000
6b 2.959 250 250 500 125 250 500
6c 3.495 500 125 50 62.5 250 500
6d 4.323 500 250 500 500 500 >1000
6e 3.739 50 62.5 500 500 250 >1000
6f 4.525 250 500 500 500 100 250
6g 3.617 125 250 1000 500 500 500
6h 3.971 500 250 500 500 500 500
6i 4.942 100 500 250 500 50 62.5
Ampicillin 100 100 250 100 — —
Nystatin — — — — 100 100
a
EC, Escherichia coli MTCC 443; PA, Pseudomonas aeruginosa MTCC 1688; SA, Staphylococcus aureus
MTCC 96; SP, Staphylococcus pyogenes MTCC 442; CA, Candida albicans MTCC 227; AN, Aspergillus niger
MTCC 282.
b
Column 2 gives the lipophilicity values (log P o/w) for the title compounds, which were found to follow
Lipinski's rule, indicating that they had drug-like characteristics. However, no direct correlation was
observed between the observed antimicrobial activity and lipophilicity. o/w is octanal–water partition
coefficient.

while compounds 5a and 5d had similar activity against
E. coli. The only molecule with excellent antibacterial
activity against Gram-positive bacteria S. aureus
(MIC = 50 μg/ml) was compound 6c. The hybrids 5a and
6c showed considerable activity against S. pyogenes
(MIC = 62.5 μg/ml).
2.2.2 | Antifungal activity
The in vitro antifungal activity was investigated against
C. albicans and A. niger, and the results were compared
with those of the standard medicine nystatin.The antifun-
gal activity of the targeted compounds is shown in
Table 1. Compound 5e was found to be effective against
C. albicans and A. niger (MIC = 50 μg/ml), whereas com-
pound 6i had excellent antifungal activity against
C. albicans (MIC = 50 μg/ml) and significant activity
against A. niger (MIC = 62.5 μg/ml). Compound 5e was
twofold more active than nystatin. Compounds 5h and 6f
had MIC values against C. albicans that were comparable
with the that of the standard drug nystatin.
Figure 3 shows the structure–activity relationship
(SAR) of the designed molecules, displaying the overall
scaffold as well as the influence of substitutions on the
activity of the designed molecules (e.g., the presence of
an alkyl group enhances activity or the presence of aryl
group in a particular position decreases its activity, in
comparison to the reported molecules related to the
designed scaffold). This will aid in the completion of the
work in a single figure that is indicative of the study, by
demonstrating how the alkyl, aryl, or dialky/aryl substi-
tutions alter the scaffold's effectiveness.
2.3 | Molecular docking studies
In order to rationalize the biological findings of the syn-
thesized rhodanine-bearing thiophene derivatives and
guide further SAR studies, we then looked at how the
6 DESAI ET AL.
F I G U R E 3 Structure–activity relationship of the target compounds influencing the biological activity of alkyl/aryl piperazine and
dialkyl/aryl amino substituents
most active compounds 5a, 5d, 6c, and 6e interacted with
the microbial target DNA gyrase (PDB code:1KZN).
Microbial DNA gyrase is found in almost all bacteria and
plays an important role in the transcription, replication,
and chromosome segregation processes [44]. Further-
more, a very low structural homology with human
topoisomerases but essential for the survival of bacteria
makes it a desired and plausible therapeutic target for the
identification of new antibacterial agents [45–47]. The
molecular docking calculations were performed using the
GLIDE program of the Small Drug Discovery Suite
(Schrödinger, LLC, New York, NY) [48,49], and the
resulting docking solutions were analyzed for per-residue
interactions to identify the significant thermodynamic
interactions with the receptor.
Results of the docking simulations showed that all
four molecules (5a, 5d, 6c, and 6e) could nicely bind to
the active site of DNA gyrase through several interactions
(bonded and nonbonded), producing docking scores of
7.34 (Glide binding energy: 45.8 kcal/mol), 7.31
(Glide binding energy: 43.639 kcal/mol), 7.17 (Glide
energy: 42.774 kcal/mol), and 7.41 (Glide binding
energy: 46.918 kcal/mol), respectively. Favorable van
der Waals interactions with Val43, Asn46, Ala47, Asp49,
Glu50, Arg76, Val71, Gly77, Ile78, Asp73, Pro79, Ile90,
Met91, Val167, Val120, and Thr165 were found to be the
most important thermodynamic interactions contributing
to the interlocking of these compounds into the active
site. The enhanced binding was also observed to be due
to significant electrostatic interactions with Asn46,
Asp49, Glu50, Asp73, Arg76, and Arg136 residues of the
active site. Furthermore, the enzyme–inhibitor complexes
also showed hydrogen bonding between 5a and Glu50
(1.795 Å), 5d and Gly77 (2.442 Å), Thr165 (2.323 Å), 6c
and Gly77 (2.684 Å), 6e and Gly77 (2.442 Å), Thr165
(2.302), which acts as an “anchor” for guiding their
DESAI ET AL. 7

orientation into the active site's 3D space. These in silico 3 | CONCLUSION

affinity results suggest that the synthesized rhodanine-
bearing thiophene derivatives could be subjected to Novel thiazolidinone-based compounds were synthesized in
structure-based optimization to arrive at potent mole- high yield and purity. Antibacterial and antifungal study of
cules with higher potency and selectivity (Figures 4–7). novel hybrids 2-(4-(alkyl/aryl)piperazininyl)-5-(thiophen-

FIGURE 4 Binding mode of substituted thiazolidinone 5a to the microbial DNA gyrase

FIGURE 5 Binding mode of substituted thiazolidinone 5d to the microbial DNA gyrase

FIGURE 6 Binding mode of substituted thiazolidinone 6c to the microbial DNA gyrase

8 DESAI ET AL.
FIGURE 7 Binding mode of substituted thiazolidinone 6e to the microbial DNA gyrase
2-ylmethylene)thiazol-4(5H)-ones (5a–i) and 2-(dialkyl/
arylamino)-5-(thiophen-2-ylmethylene)thiazol-4(5H)-ones
(6a–i) gave promising results.The antibacterial efficacy of
compounds 5a, 5d, 6c, and 6e against Gram-positive and
Gram-negative bacteria was remarkable. Compound 5a had
antibacterial efficacy against E. coli (MIC = 62.5 μg/ml),
P. aeruginosa (MIC = 50 μg/ml), and S. pyogenes
(MIC = 62.5 μg/ml). The antibacterial activity of compound
5a was superior to that of the antibiotic ampicillin. In com-
parison to the standard drug nystatin, compounds 5e and 6i
showed promising antifungal effectiveness against
C. albicans and A. niger. Molecular docking studies could
rationalize the antimicrobial activity and shed light on the
various thermodynamic interactions of the investigated mol-
ecules with the enzyme active site, which will now be uti-
lized to arrive at compounds with better potency and
specificity. The significant correlation observed between the
binding affinities of the most active molecules toward DNA
gyrase and their in vitro antibacterial activities provide the
confidence to strategically carry out a structure-based drug
design study to systematically modify this hybrid scaffold.
This will aid in identifying candidates with improved antimi-
crobial efficacy with selectivity toward to the target enzyme.
4 | EXPERIMENTAL
4.1 | Synthesis
4.1.1 | Preparation of
5-(2-thienylmethylene)-2-thioxo-1,3-thiazolidin-
4-one (3)
A blend of thiophene-2-carbaldehyde (1) (0.01 mol),
rhodanine (2) (0.01 mol), freshly fused sodium acetate
(0.01 mol), and 150 ml of ethanol is heated on a steam
bath with stirring for 3 h. After it attains room tempera-
ture, the reaction mixture was poured into crushed ice.
The solid formed was filtered and dried after a water
wash. Recrystallization was carried out by dry DMF.
4.1.2 | Preparation of 2-methylthio-
5-(2-thienylmethylene)-1,3-thiazolin-4-one (4)
A flat-bottom flask was set on a magnetic stirrer, and
compound (3) (0.01 mol) was dissolved in 20 ml of etha-
nol and held at a temperature of 0–5 C. Triethylamine
(0.015 mol) was added to the reaction mixture and agi-
tated for half an hour at a temperature below 5 C.
Between 0 and 5 C, methyl iodide was added dropwise to
the reaction mixture, which was then agitated for 4 h at
the same temperature. The reaction mixture was then
placed on crushed ice after it had reached room tempera-
ture. From rectified spirit, the separated solid was fil-
tered, washed with cold water, and recrystallized.
4.1.3 | Preparation of 2-(4-(alkyl/aryl)
(piperazininyl)-5-(thiophen-2-ylmethylene)
thiazol-4(5H)-ones (5a–i)
A flat-bottom flask was set on a magnetic stirrer, and
compound (4) (0.01 mol) was dissolved in 30 ml of etha-
nol. Methyl piperazine (0.01 mol) was added dropwise to
the reaction mass with stirring for 4 h at room tempera-
ture before the solvent was removed under reduced pres-
sure. The crystalline powder was then thoroughly
agitated in cold ether, filtered, rinsed in cold ethanol,
dried, and recrystallized from ethanol.
Description of 2-(piperazin-1-yl)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (5a)
Yield (73%); solid; m.p. 195–197 C; IR (KBr, cm1): 1693
(>C═O), 1598, 1527 ( C═N, C═C), 1284 ( C N),
800 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 1.76 (s,
DESAI ET AL.
1H, CH2 NH), 2.82 (m, 4H, CH2 NH CH2), 3.63
(m, 4H, CH2 N CH2), 7.31–8.15 (m, 3H, thiophene
ring), 8.44 (s, 1H, C═CH); 13C NMR (100 MHz, DMSO-
d6): δ = 47.16 (C3, C5 of piperazine ring), 51.45 (C2, C6 of
piperazine ring), 129.15 (C3 of thiophene ring), 129.79
(C2 of thiophene ring), 131.29 (C4 of thiophene ring),
136.98 (C5 of thiophene ring), 137.88 (C2 of
thiazolidinone ring), 151.11 ( C═C), 158.28 (C5 of
thiazolidinone ring), 169.02 (>C═O); MS (m/z): 280.05
(M+): Anal. Calcd. for C12H13N3OS2: C, 51.59; H, 4.69; N,
15.04: Found: C, 51.35; H, 4.14; N, 15.23%.
Description of 2-(4-methylpiperazin-1-yl)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (5b)
Yield (87%); solid; m.p. 188–190 C, IR (KBr, cm1): 1678
(>C═O), 1595, 1569 ( C═N, C═C), 1274 ( C N),
802 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 1.92
(m, 4H, CH2 N CH2), 2.24 (s, 3H, N CH3), 2.82 (m,
4H, CH2 N CH2), 7.25–7.87 (m, 3H, thiophene ring),
8.30 (s, 1H, C═CH); 13C NMR (100 MHz, DMSO-d6):
δ = 46.15 ( N CH3), 48.96 (C2, C6 of piperazine ring),
51.85 (C3, C5 of piperazine ring), 128.35 (C3 of thiophene
ring), 129.23 (C2 of thiophene ring), 130.59 (C4 of thio-
phene ring), 137.82 (C5 of thiophene ring), 138.66 (C2 of
thiazolidinone ring), 152.35 ( C═C), 158.41 (C5 of
thiazolidinone ring), 167.32 (>C═O); MS (m/z): 294.07
(M+): Anal. Calcd. for C13H15N3OS2: C, 53.22; H, 5.15; N,
14.32: Found: C, 53.35; H, 5.19; N, 14.41%.
Description of 2-(4-ethylpiperazin-1-yl)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (5c)
Yield (79%); solid; m.p. 193–195 C, IR (KBr, cm1):
1682 (>C═O), 1604, 1580 ( C═N, C═C), 1279
( C N), 794 ( C S); 1H NMR (400 MHz, DMSO-d6):
δ = 1.05 (t, J = 7.0 Hz, 3H, N CH2 CH3), 2.52 (m,
2H, N CH2 CH3), 3.24 (m, 4H, CH2 N CH2),
3.93 (m, 4H, CH2 N CH2), 7.30 (s, 1H, C═CH),
7.34–7.97 (m, 3H, thiophene ring); 13C NMR
(100 MHz, DMSO-d6): δ = 11.91 ( N CH2 CH3),
49.28 (C2, C6 of piperazine ring), 51.89
(N CH2 CH3), 52.47 (C3, C5 of piperazine ring),
122.89 (C3 of thiophene ring), 128.54 (C2 of thiophene
ring), 129.76 (C4 of thiophene ring), 132.02 (C5 of
thiophene ring), 138.72 (C2 of thiazolidinone ring),
153.16 ( C═C), 157.56 (C5 of thiazolidinone ring),
164.98 (>C═O); MS (m/z): 308.08 (M+): Anal. Calcd.
for C14H17N3OS2: C, 54.70; H, 5.57; N, 13.67:
Found: C, 54.78; H, 5.65; N, 13.82%.
Description of 2-(4-propylpiperazin-1-yl)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (5d)
Yield (68%); solid; m.p. 209–211 C, IR (KBr, cm1): 1676
(>C═O), 1591, 1562 ( C═N, C═C), 1267 ( C N),
9
795 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 0.82
(m, 3H, N CH2 CH2 CH3), 1.45 (m, 2H,
N CH2 CH2 CH3), 2.49–2.89 (m, 6H, CH2 N
(CH2)2), 3.85 (m, 4H, N (CH2)2), 7.19 (s, 1H, C═CH),
7.27–8.05 (m, 3H, thiophene ring); 13C NMR (100 MHz,
DMSO-d6): δ = 11.91 ( N CH2 CH2 CH3), 21.84
( N CH2 CH2 CH3), 49.28 (C2, C6 of piperazine ring),
52.47 (C3, C5 of piperazine ring), 58.84
( N CH2 CH2 CH3), 128.11 (C3 of thiophene ring),
129.85 (C2 of thiophene ring), 131.36 (C4 of thiophene
ring), 139.25 (C5 of thiophene ring), 139.82 (C2 of
thiazolidinone ring), 152.88 ( C═C), 158.85 (C5 of
thiazolidinone ring), 169.28 (>C═O), MS (m/z): 322.10
(M+): Anal. Calcd. for C15H19N3OS2: C, 56.05; H, 5.96; N,
13.07: Found: C, 56.15; H, 5.89; N, 13.19%.
Description of 2-(4-phenylpiperazin-1-yl)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (5e)
Yield (69%); solid; m.p. 144–146 C, IR (KBr, cm1): 1690
(>C═O), 1610, 1582 ( C═N, C═C), 1287 ( C N),
797 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 3.29
(m, 4H, CH2 N CH2), 3.75 (m, 4H, CH2 N CH2),
7.19 (s, 1H, C═CH), 722–8.19 (m, 8H, Ar-H, thiophene
ring); 13C NMR (100 MHz, DMSO-d6): δ = 48.27 (C2, C6
of piperazine ring), 52.37 (C3, C5 of piperazine ring),
114.35 (Ar-C), 124.05 (Ar-C), 125.15 (C3 of thiophene
ring), 128.96 (C2 of thiophene ring), 129.55 (Ar-C), 132.54
(C4 of thiophene ring), 138.12 (C5 of thiophene ring),
139.55 (C2 of thiazolidinone ring), 149.66 (Ar-C), 152.88
( C═C), 158.41 (C5 of thiazolidinone ring), 170.13
(>C═O), MS (m/z): 356.08 (M+): Anal. Calcd. for
C18H17N3OS2: C, 60.82; H, 4.82; N, 11.82: Found: C,
60.26; H, 4.63; N, 11.55%.
Description of 2-(4-cyclohexylpiperazin-1-yl)-
5-(thiophen-2-ylmethylene)thiazol-4(5H)-one (5f)
Yield (84%); solid; m.p. 161–163 C, IR (KBr, cm1): 1678
(>C═O), 1595, 1569 ( C═N, C═C), 1274 ( C N),
792 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 1.15–
1.65 (m, 10H, cyclohexyl ring), 2.51 (m, 4H,
CH2 N CH2), 2.62 (m, 1H, cyclohexyl ring), 3.65 (m,
4H, CH2 N CH2), 7.21–8.01 (m, 3H, thiophene ring),
7.45 (s, 1H, C CH); 13C NMR (100 MHz, DMSO-d6):
δ = 49.35 (C2, C6 of piperazine ring), 54.41 (C3, C5 of
piperazine ring), 127.35 (cyclohexyl ring), 128.15 (C3 of
thiophene ring), 128.05 (cyclohexyl ring), 128.09
(cyclohexyl ring), 129.56 (C2 of thiophene ring), 131.14
(C4 of thiophene ring), 137.62 (C5 of thiophene ring),
138.55 (C2 of thiazolidinone ring), 138.59 (cyclohexyl
ring), 152.88 ( C═C), 160.11 (C5 of thiazolidinone ring),
170.13 (>C═O), MS (m/z): 362.13 (M+): Anal. Calcd. for
C18H23N3OS2: C, 59.80; H, 6.41; N, 11.62: Found: C,
59.84; H, 6.43; N, 11.66%.
10
Description of 2-(4-benzylpiperazin-1-yl)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (5g)
Yield (66%); solid; m.p. 145–147 C, IR (KBr, cm1): 1682
(>C═O), 1616, 1588 ( C═N, C═C), 1297 ( C N),
798 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 2.27–
2.67 (m, 4H, CH2 N CH2 CH3), 3.35–3.60 (m, 4H,
CH2 N CH2), 3.65 (s, 2H, N CH2), 7.05 (s, 1H,
C═CH), 7.14–8.13 (m, 8H, Ar-H, thiophene ring); 13C
NMR (100 MHz, DMSO-d6): δ = 48.94 (C2, C6 of pipera-
zine ring), 53.16 (C3, C5 of piperazine ring), 64.58
(N CH2 Ar), 126.35 (Ar-C), 127.19 (Ar-C), 128.32 (Ar-
C), 129.10 (Ar-C), 130.36 (C3 of thiophene ring), 132.74
(C4 of thiophene ring), 133.55 (C2 of thiophene ring),
139.09 (C5 of thiophene ring), 140.85 (C2 of
thiazolidinone ring), 152.00 ( C═C), 159.58 (C5 of
thiazolidinone ring), 169.40 (>C═O); MS (m/z): 370.10
(M+): Anal. Calcd. for C19H19N3OS2: C, 61.70; H, 5.18; N,
11.37: Found: C, 61.75; H, 5.22; N, 11.43%.
Description of 5-(thiophen-2-ylmethylene)-
2-(4-(vinyloxy)piperazin-1-yl)thiazol-4(5H)-one (5h)
Yield (75%); solid; m.p. 182–184 C, IR (KBr, cm1): 1689
(>C═O), 1610, 1583 (-C═N, C═C), 1290 ( C N),
792 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 2.95 (m,
4H, CH2 N CH2), 3.74 (m, 4H, CH2 N CH2), 5.07 (t,
1H, J = 7.6 Hz, N O CH), 5.17 (d, 2H, J = 14.2 Hz,
O CH═CH2), 7.21 (s, 1H, C═CH), 7.45–7.99 (m, 3H,
thiophene ring), 13C NMR (100 MHz, DMSO-d6): δ = 47.15
(C2, C6 of piperazine ring), 54.11 (C3, C5 of piperazine ring),
92.36 (C═CH2), 127.32 (C3 of thiophene ring), 128.89 (C2 of
thiophene ring), 131.26 (C4 of thiophene ring), 137.26 (C5
of thiophene ring), 145.55 (C2 of thiazolidinone ring),
151.39 ( C═C), 158.32 (C5 of thiazolidinone ring), 164.13
(>C═O), 175.25 ( O CH); MS (m/z): 322.06 (M+): Anal.
Calcd. for C14H15N3O2S2: C, 52.32; H, 4.70; N, 13.07:
Found: C, 52.42; H, 4.95; N, 13.26%.
Description of 2-(4-ethoxypiperazin-1-yl)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (5i)
Yield (67%); solid; m.p. 262–264 C, IR (KBr, cm1): 1659
(>C═O), 1584, 1557 -(C═N, C═C), 1262 ( C N),
797 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 1.15 (t,
3H, J = 6.8 Hz, O CH2 CH3), 2.89 (m, 4H, (O N
(CH2)2, 3.54 (m, 2H, O CH2 CH3), 3.89 (m, 4H,
CH2 N CH2), 7.31 (s, 1H, C═CH), 7.80–8.26 (m, 3H,
thiophene ring); 13C NMR (100 MHz, DMSO-d6):
δ = 12.93 ( O CH2 CH3), 45.52 (C2, C6 of piperazine
ring), 55.96 (C3, C5 of piperazine ring), 64.82
(O CH2 CH3), 122.96 (C3 of thiophene ring), 128.05 (C2
of thiophene ring), 129.62 (C4 of thiophene ring), 132.05
(C5 of thiophene ring), 138.48 (C2 of thiazolidinone ring),
153.45 ( C═C), 159.63 (C5 of thiazolidinone ring), 163.23
(>C═O), MS (m/z): 324.08 (M+): Anal. Calcd. for
DESAI ET AL.
C14H17N3O2S2: C, 51.99; H, 5.30; N, 12.99: Found: C,
52.63; H, 5.41; N, 13.24%.
4.1.4 | General preparation of
2-(dimehtylamino)-5-(2-thienylmethylene)-
1,3-thiazolin-4-ones (6a–i)
In a flat-bottom flask on a magnetic stirrer, compound
(4) (0.01 mol) was dissolved in 30 ml of ethanol. Drops of
dimethylamine (0.01 mol) were added to the reaction
mass with stirring for 4 h at room temperature before the
solvent was extracted under reduced pressure. The crys-
talline powder was then thoroughly agitated in cold
ether, filtered, rinsed in cold ethanol, dried, and rec-
rystallized from ethanol.
Description of 2-(dimethylamino)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (6a)
Yield (70%); solid; m.p. 159–162 C, IR (KBr, cm1): 1663
(>C═O), 1613, 1574 ( C═N, C═C), 1322 ( C N),
757 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 3.15
(m, 6H, N (CH3)2), 7.30–8.13 (m, 3H, thiophene ring),
8.21 (s, 1H, C═CH), 13C NMR (100 MHz, DMSO-d6):
δ = 41.35 (N (CH3)2), 128.35 (C3 of thiophene ring),
129.29 (C2 of thiophene ring), 130.23 (C4 of thiophene
ring), 137.74 (C5 of thiophene ring), 138.88 (C2 of
thiazolidinone ring), 152.43 ( C═C), 158.49 (C5 of
thiazolidinone ring), 169.08 (>C═O); MS (m/z): 238.02
(M+): Anal. Calcd. for C10H10N2OS2: C, 50.40; H, 4.23; N,
11.75: Found: C, 50.95; H, 4.75; N, 11.89%.
Description of 2-(diethylamino)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (6b)
Yield (62%); solid; m.p. 186–188 C; IR (KBr, cm1): 1644
(>C═O), 1610, 1569 ( C═N, C═C), 1312 ( C N),
751 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 1.21
(m, 6H, N (CH2 CH3)2), 3.35 (m, 4H, N
(CH2 CH3)2), 7.35–8.01 (m, 3H, thiophene ring), 8.29 (s,
1H C═CH);13C NMR (100 MHz, DMSO-d6): δ = 12.75
( N (CH2 CH3)2), 43.92 ( N (CH2 CH3)2), 122.99
(C3 of thiophene ring), 127.85 (C2 of thiophene ring),
138.46 (C4 of thiophene ring), 132.66 (C5 of thiophene
ring), 138.13 (C2 of thiazolidinone ring), 150.55 ( C═C),
154.99 (C5 of thiazolidinone ring), 163.12 (>C═O); MS
(m/z): 266.05 (M+): Anal. Calcd. for C12H14N2OS2:
54.11; H, 5.30; N, 10.52: Found: 54.19; H, 5.43; N, 10.69%.
Description of 2-(diisopropylamino)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (6c)
Yield (62%); solid; m.p. 174–176 C; IR (KBr, cm1): 1616
(>C═O), 1584, 1544 ( C═N, C═C), 1343 ( C N),
745 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 1.28–
DESAI ET AL.
1.66 (m, 12H, [ CH3 CH CH3]2), 2.95 (s, 2H,
[ CH3 CH CH3]2), 7.35–8.01 (m, 3H, thiophene ring),
8.32 (s, 1H C═CH); 13C NMR (100 MHz, DMSO-d6):
δ = 21.35 ( CH3 CH CH3)2, 51.16 ( CH3 CH CH3)2,
128.15 (C3 of thiophene ring), 129.23 (C2 of thiophene
ring), 130.13 (C4 of thiophene ring), 139.62 (C5 of thio-
phene ring), 139.75 (C2 of thiazolidinone ring), 152.33
( C═C), 158.96 (C5 of thiazolidinone ring), 169.02
(>C═O); MS (m/z): 294.09 (M+): Anal. Calcd. for
C14H18N2OS2: C, 57.11; H, 6.16; N, 9.51: Found: C,
57.29; H, 6.36; N, 9.91%.
Description of 2-(diisobutylamino)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (6d)
Yield (59%); solid; m.p. 185–187 C, IR (KBr, cm1): 1689
(>C═O), 1573, 1513 ( C═N, C═C), 1354 ( C N),
751 (C S); 1H NMR (400 MHz, DMSO-d6): δ = 0.78 (d,
12H, J = 7.1 Hz, N (CH2 CH,[CH3]2)2),1.65 (m, 2H,
N (CH2 CH(CH3)2)2), 3.15 (d, 4H, J = 6.0 Hz, N
(CH2 CH(CH3)2)2), 7.46–8.05 (m, 3H, thiophene ring),
8.55 (s, 1H C═CH), 13C NMR (100 MHz, DMSO-d6):
δ = 12.62 ( N (CH2 CH(CH3)2)2), 17.85 ( N
(CH2 CH(CH3)2)2), 26.09 ( N (CH2 CH(CH3)2)2),
121.78 (C3 of thiophene ring), 127.65 (C2 of thiophene
ring), 129.23 (C4 of thiophene ring), 133.59 (C5 of thio-
phene ring), 138.46 (C2 of thiazolidinone ring), 158.95
( C═C), 158.95 (C5 of thiazolidinone ring), 167.13
(>C═O); MS (m/z): 322.12 (M+): Anal. Calcd. for
C16H22N2OS2: C, 59.59; H, 6.88; N, 8.69: Found: C,
59.79; H, 6.06; N, 8.98%.
Description of 2-(dipropylamino)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (6e)
Yield (69%); solid; m.p. 152–154 C; IR (KBr, cm1): 1645
(>C═O), 1587, 1533 ( C═N, C═C), 1357 ( C N),
750 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 0.89 (m,
6H, N [CH2 CH2,CH3]2), 1.61 (m, 4H, N 3H, J = 7.0 Hz,
(CH2 CH2 CH3)2), 3.56 (m, 4H, N N CH2 CH3), 6.59–7.82 (m, 8H, Ar-H, thiophene ring),
[CH2 CH2 CH3]2), 7.41–8.10 (m, 3H, thiophene ring),
8.29 (s, 1H C═CH); 13C NMR (100 MHz, DMSO-d6):
δ = 11.56 ( N [CH2 CH2 CH3]2), 20.85 ( N
(CH2 CH2 CH3)2), 51.44 ( N (CH2 CH2 (CH3)2),
128.75 (C3 of thiophene ring), 129.15 (C2 of thiophene ring),
130.05 (C4 of thiophene ring), 137.51 (C5 of thiophene ring),
138.66 (C2 of thiazolidinone ring), 152.43 ( C═C), 158.39
(C5 of thiazolidinone ring), 167.03 (>C═O); MS (m/z):
294.09 (M+): Anal. Calcd. for C14H18N2OS2: C, 57.11; H,
6.16; N, 9.51: Found: C, 57.56; H, 6.54; N, 9.93%.
Description of 2-(dibutylamino)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (6f)
Yield (73%); solid; m.p. 191–193 C; IR (KBr, cm1): 1655
(C═O), 1577, 1525 ( C═N, C═C), 1334 (C N),
11
753 (C S); 1H NMR (400 MHz, DMSO-d6): δ = 0.95 (m,
6H, N (CH2 CH2 CH2 CH3)2), 1.25 (m, 4H, N
(CH2 CH2 CH2 CH3)2), 1.50 (m, 4H, N (CH2
CH2 CH2 CH3)2), 3.31 (m, 4H, N (CH2 CH2 CH2
CH3)2), 7.31–8.00 (m, 3H, thiophene ring), 8.50 (s, 1H,
C═CH); 13C NMR (100 MHz, DMSO-d6): δ = 13.89
( N (CH2 CH2 CH2 CH3)2), 19.12 ( N (CH2 CH2
CH2 CH3)2), 30.55 ( N (CH2 CH2 CH2 CH3)2),
50.09 ( N (CH2 CH2 CH2 CH3)2), 122.99 (C3 of thio-
phene ring), 127.16 (C2 of thiophene ring), 128.86 (C4 of
thiophene ring), 132.19 (C5 of thiophene ring), 138.49 (C2
of thiazolidinone ring), 150.49 ( C═C), 153.48 (C5 of
thiazolidinone ring), 163.22 (>C═O); MS (m/z): 322.12
(M+): Anal. Calcd. for C16H22N2OS2: C, 59.59; H, 6.88; N,
8.69: Found: C, 59.75; H, 6.16; N, 8.99%.
Description of 2-(methyl(phenyl)amino)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (6g)
Yield (78%); solid; m.p. 166–168 C, IR (KBr, cm1): 1675
(>C═O), 1619, 1583 ( C═N, C═C), 1333 ( C N),
756 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 3.39 (s,
3H, N CH3), 6.29–8.02 (m, 8H, Ar-H, thiophene ring), 8.23
(s, 1H, C═CH), 13C NMR (100 MHz, DMSO-d6): δ = 36.56
( CH3), 118.25 (Ar-C), 122.41 (C3 of thiophene ring),
124.65 (Ar-C), 126.36 (C2 of thiophene ring), 128.95 (Ar-C),
129.51 (C4 of thiophene ring), 130.89 (C5 of thiophene ring),
136.36 (C2 of thiazolidinone ring), 143.46 ( C═C), 155.86
(C5 of thiazolidinone ring), 164.19 (>C═O); MS (m/z):
300.04 (M+): Anal. Calcd. for C15H12N2OS2: C, 59.98; H,
4.03; N, 9.33: Found: C, 59.79; H, 4.13; N, 9.29%.
Description of 2-(ethyl(phenyl)amino)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (6h)
Yield (66%); solid; m.p. 172–174 C, IR (KBr, cm1): 1674
(>C═O), 1622, 1580 ( C═N, C═C), 1329 ( C N),
748 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 1.31 (t,
N CH2 CH3), 4.05 (m, 2H,
8.26 (s, 1H, C═CH); 13C NMR (100 MHz, DMSO-d6):
δ = 13.62 ( N CH2 CH3), 43.56 ( N CH2 CH3),
117.45 (Ar-C), 120.49 (Ar-C), 122.39 (C3 of thiophene ring),
126.16 (C2 of thiophene ring), 127.64 (Ar-C), 130.59 (C4 of
thiophene ring), 132.59 (C5 of thiophene ring), 136.56 (C2
of thiazolidinone ring), 142.36 (Ar-C), 153.94 ( C═C),
155.54 (C5 of thiazolidinone ring), 164.17 (>C═O); MS (m/
z): 314.05 (M+): Anal. Calcd. for C16H14N2OS2: C, 61.12; H,
4.49; N, 8.91: Found: C, 61.26; H, 4.96; N, 9.05%.
Description of 2-(diphenylamino)-5-(thiophen-
2-ylmethylene)thiazol-4(5H)-one (6i)
Yield (70%); solid; m.p. 179–182 C, IR (KBr, cm1): 1657
(>C═O), 1606, 1561 ( C═N, C═C), 1317 ( C N),
752 ( C S); 1H NMR (400 MHz, DMSO-d6): δ = 7.05–
12
8.23 (m, 13H, Ar-H, thiophene ring), 8.49 (s, 1H C═CH),
13
C NMR (100 MHz, DMSO-d6): δ = 121.15 (Ar-C),
127.26 (Ar-C), 128.49 (C3 of thiophene ring), 129.26 (C2
of thiophene ring), 129.66 (Ar-C), 130.14 (C4 of thiophene
ring), 137.65 (C5 of thiophene ring), 138.49 (C2 of
thiazolidinone ring), 152.15 ( C═C), 158.26 (C5 of
thiazolidinone ring), 167.15 (>C═O); MS (m/z): 362.05
(M+): Anal. Calcd. for C20H14N2OS2: C, 66.27; H, 3.89; N,
7.73: Found: C, 66.36; H, 3.59; N, 7.83%.
A C K N O WL E D G M E N T S
Nisheeth C. Desai thanks the University Grants Commis-
sion (UGC), New Delhi, for the grant of the BSR Faculty
Fellowship 2019 [No. F. 18-1/2011(BSR)] and financial
help. The authors are extremely grateful to the UGC and
the Department of Science and Technology, Govt of
India, New Delhi, for providing the resources under the
NON-SAP and DST-FIST program, respectively. The
authors are also thankful to Schrodinger Inc. for the
GLIDE software for performing the computational stud-
ies. They wish to thank to Priyanka Desai, founder of
iScribblers, for language editing.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new
data were created or analyzed in this study.
ORCID
Nisheeth C. Desai https://orcid.org/0000-0001-6864-
8661
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SU PP O R TI N G I N F O RMA TI O N
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online version of the article at the publisher's website.
How to cite this article: N. C. Desai, Y.
M. Rupala, A. G. Khasiya, K. N. Shah, U. P. Pandit,
V. M. Khedkar, J. Heterocycl. Chem. 2021, 1.
https://doi.org/10.1002/jhet.4366