A REVIEW ON QUINOLONE DERIVATIVES

AS ANTIMICROBIAL AGENTS
A Project Report submitted to

In Partial fulfillment for the award of degree of

Bachelor of Pharmacy(2019-2023)

By- AASHISH

College Roll No :- 1901

University Roll No:- 968704

Under the supervision of

Dr.Rakesh Gupta

PROFESSOR(P’CEUTICAL CHEMISTRY)

VIPER, ROHTAK

VAISH INSTITUTE OF PHARMACEUTICAL EDUCATION AND

RESEARCH, ROHTAK(124001)

Pt.B.D.SHARMA UNIVERSITY OF HEALTH AND SCIENCE, ROHTAK

2023
 CERTIFICATE

This is to certify that detailed project work was carried out

byMr.Aashishstudying in B.pharmacy 8thsemester at VaishInstitute
ofPharmaceutical Education And Researchfor partial fulfillment
of subject project work code no. BP-812-TH.This work has been
carriedout under the guidance and supervision of Dr.Rakesh Gupta

SIGNATURE OF PRINCIPAL
DR. RakeshGupta
[Professor]
P’CEUTICAL CHEMISTRY
VIPER, ROHTAK

DATE:-
ACKNOWLEDGEMENT

I would like to express my special thanks of gratitude to my teacher

and our principal Dr.Rakesh Gupta who gaveme the golden opportunity
to do this project on the topic is “A Review on Quinolone derivatives as
antimicrobial agents”which also helpedme on doing a lot of research and I
came to know about a lot new thingsrelated to topic.

I am really thankful to my friends who helped me a lot in completion

especiallyAkshay.

Secondly , I would also like to thanks my Parents who helped me a lot in

finalizing this project within the limited time frame.
I am making this project not for marks but to also increase my knowledge
and skill.

AASHISH
 CONTENT
SERIAL NO. TITLE PAGE NO.

1 Certificate 2
2 Acknowledgment 3

3 Content 4
4 List of Table 5
5 Introduction 6-11

6 Aim & plan of work 12

7 Literature survey 13-19

8 Experimental work 20-25

9 Conclusion 26
10 References 27-29
 LIST OF TABLES
Sr.no. Title Page no.

1 Classification by generation 9

2 Literature survey of quinolone 13-19

derivative having antimicrobial
activity
3 Structure of selected of molecules 20-25
by chem draw ulta 12.0 software
Quinolones
A Family Of Broad Spectrum Antimicrobial Agents.
 Introduction:
In the early 20th century, infectious disease were the most common cause of human illness
leading to death, out of which bacterial infections accounted for about one thirdthese
infections. Quinolones are one of the most important families of the antimicrobial agents.
Today more than a dozen quinolones areactively prescribed. One example is
ciprofloxacin, a drug widely used to treat a variety of diseases caused by Gram-negative
and Gram-positive bacteria, including respiratory tract infections, urinary infections, and
several enteric diseases. As it is for other antibiotics, the use of quinolones is not absent
of problems. The routine use in the clinic and the sometimes unnecessary use or overuse
in animal production farms has propitiated the appearance of resistance to quinolones in
bacteria.The quinolone class of antimicrobials exerts its antimicrobial action through
inhibiting the DNA gyrase and topoisomerase IV which inhibits the synthesis of DNA
and RNA . Gram positive and gram negative have made the quinolones a good choice to
treat disease in both humans and animals. Finally,considerations for the use of quinolones
in human and veterinary medicine are discussed.

STRUCTURE:-

Fig.1 - Essential structure of all quinolone antibiotics: R is usually piperazine; if the

connection contains fluorine, it is a fluoroquinolone.
  Mode of action of Quinolones
Quinolones are bacteriocidal drugs, meaning that they kill bacteria. These antimicrobial
drugs inhibit the bacterial DNA gyrase enzyme which is necessary for DNA replication.
Since a copy of DNA must be made each time a cell divides, interfering with replication
makes it difficult for bacteria to multiply.

How DNA is packaged is very different in bacteria as opposed to eukaryotes. Bacteria

supercoil DNA using DNA gyrase, whereas eukaryotes coil DNA around histones protiens
because quinolones specifically target DNA gyrase, they do not interfere with human DNA.
Quinolone inhibition of bacterial DNA replication and bacterial killing may be dissociated
under some conditions, suggesting that events in addition to the initial interaction of the
quinolones with the topoisomerase-DNA complex may be required for cell killed.

Fig:- Mode of action of quinolones

 Adverse Effects of Quinolones

 Nausea
 Headache
 Diarrhea
 Vomiting
 Anxiety
 Insomnia
 Psychotic reactions
 Phototoxicity
 Liver enzyme abnormalities
  Arthropathy

 Types Of Quinolones:

Quinolones are a type of antibiotic and antmicrobial agents. Antibiotics kill or inhibit the
growth of bacteria. Nalidixic acid was the first quinolone discovered, but it has since been
discontinued.

There are five different quinolone classes. One of the classes, called fluoroquinolones, was
derived from quinolones by adding a fluorine atom to nalidixic acid. This enhanced its
activity against bacteria, and improved its absorption, metabolism, and excretion
characteristics. Although fluoroquinolones are still available, their side effects limit their use
and they are not usually used first-line. Common fluoroquinolones include:

 Delafloxacin
 Gemifloxacin
 Levofloxacin
 Ciprofloxacin
 Moxifloxacin
 Norfloxacin (discontinued)
 Ofloxacin.
Some people use the words quinolones and fluoroquinolones interchangeably, but
fluoroquinolones are the only class of quinolones still available. For this reason, the term
fluoroquinolones will be used from now on.

Fluoroquinolones detrimentally affect the function of two enzymes produced by bacteria,

topoisomerase IV and DNA gyrase, so that bacteria can no longer manufacture or repair their
own DNA. DNA gyrase is essential for bacterial growth and is not present in eukaryotic cells.
Fig.:-Some common fluoroquinolones which are derived from quinolones by
adding flourine atom
  CLASSIFICATION:-By GENERATION

GENERATION DRUGS NAME CLINICAL USES

1st
NORFLOXACIN Uncomplicated urinary
CIPROFLOXACIN tract infections

2nd
LEVOFLOXACIN Complicated UTI, GIT
FLEROXACIN infection

3rd
GATIFLOXACIN Sexually transmitted
SPARFLOXACIN disease, urinary tract
infection

4th
ALATROFLOXACIN Major system infections
ATROFLOXACIN [abdominal infections]

 Other Biological activites

Throughout this work we have mainly talked about the use of quinolones as
antimicrobials; however, various uses have been described that currently represent
an alternative in diverse therapies due to their broad mechanism of action. As the
quinolones keep homology and set its origin during the attempts to synthesize the
anti-malarial agent chloroquine, it is logical to explore the potential of quinolones as
antiparasitic agents. However, the efficacy of the FQ norfloxacin, as anti-malarial,
was accidentally discovered during treatment of patients suffering Salmonella Typhi
infection. Later, its efficacy was tested in patients suffering falciparum malaria

Table:-These are some other biological agents which shows their effects
AGENTS EFFECTS

[As Anti-Parasitic]
Florinated quinolone amides. Anti-parasitic, anti-trypanosomal.
Methyl quinolone derivatives. Antiparasitic

[As Antiviral]
Ofloxacin, Iprofloxacin.
Quinolone derivatives
molecules.
[As Anti-Fungal]
Quinolone derivative
molecules.
Clinafloxintriazole hybrids
Activity anti-hepatitis C virus
HIV 1 integrase inhibitors
Anti-Fungal activity
Antifungal activity against
C.mycoderma

[As Anti-Inflamatory]
Ciprofloxacin Anti-Inflamatory activity.
Livofloxacin Inhibition of microglia inflammatory
responce
[As Anti-Cancer/Anti-
Tumors]
Moxifloxacin Activity anti-tumor
Ciprofloxacin Anti-Cancer activity

[Quinolone Related
Molecules]
Quinazolinones related Anti-Convulsant
Compounds.
Quinolones Neuroprotective, Diuretic activity
CHAPTER 2:- AIM & PLAN OF WORK

AIM:-A review on Antimicrobial activity of quinolones derivatives and sketching of

selected molecule using Chem Draw Ultra ver.12.0 software.

PLAN OF WORK DONE:-

A) Literature review of the anti –microbial activity of the quinolone derivatives.

B) Sketching of the selected molecules using chem draw office 12.0 software.
LITERATURE SURVEY OF QUINOLONES :-
TABLE: Literature survey of quinolone derivatives having antimicrobial
activity

Sr.No. Literature survey Reference

Fu and coworkers reported a convenient and efficient method Fu and

through the selective cleavage of aromatic carbon–oxygen coworkers
1. (C–O) bonds under metal free and in the presence of a base
et al.,
to afford 4-quinolone derivatives in moderate yield
2021

Synthesis of N-substituted-4-quinolone derivatives via

cleavage of aromatic C–O bond

Janni and coworkers disclosed a new metal-free protocol to Janni and

2. prepare fused heterocycle quinolone derivatives from single
coworkers
S,N-acetal precursors through double hetero-annulation
under basic conditions et al.,

2016

Synthesis of 4-quinolone derivative using KOt Bu

(potassium tertbutoxide)

In 2015, Hu et al. designed a straight forward method for the

3. synthesis of numerous 2-aryl-4-quinolone derivatives from Huet al.,
Naryl methyl-2-aminophenyl ketones through a metal-free
oxidative intramolecular oxidative Mannich reaction, 2015
followed by C(sp3 )–H/C(sp3 )–H coupling and
aromatization using TEMPO as an oxidant and KOt Bu as
the base

TEMPO catalyzedintramolecular tandem oxidative C(sp3 )–

H/C(sp3 )–H coupling

In 2016, Zhou and coworkers reported a novel one-pot metal

4. free protocol for the synthesis of sulfone-containing 4- Zhou and
quinolones upon radical oxidative cyclization of o- coworkers
azidoarylacetylenic ketones and sulnic acids in the
et al.,
presence of radical initiators (TBHP) at 80 °C under Ar for
0.5 h affording phenyl-3- (phenylsulfonyl) quinolin-4(1H)- 2016
one

Metal-free synthesis of sulfone containing 4-quinolones.

Zhang's
5. group et al.,
Novel water-soluble antiproliferative agents, 4-quinolones , 2017
were synthesized by Zhang's group Zhang's group Heating
aniline with ethoxy methylene malonic ester at 100 °C
afforded Schiff bases, which was then cyclized to ethyl
4(1H)- quinolone-3-carboxylates using diphenyl ether under
refux conditions.

Synthesis of 4-quinolone using diphenyl ether

Recently, 3-cyano 4-quinolone derivatives were synthesized Jiang and

6. in good to excellent yields upon DABCO-mediated
coworkers
decarboxylative cyclization of isatoic anhydrides with active
methylene groups such as aryl/heteroaryl/ et al.,
alkoylacetonitriles, in CH3CN under microwave irradiation
at 80 °C for 30 min.
2019

Synthesis of 4-quinolone via one-pot DABCO-mediated

decarboxylative cyclization (1,4-diazabicyclo[2.2.2]octane)
 In 2017, Chen's group successfully synthesized 4-quinolone Chen's
7. derivatives 51 in one pot using a tandem procedure in good group et al.,
to excellent yields . The dihalo-substituted ketone substrates
converted to the corresponding quinolones in very good 2017
yields

Z= NH,NR, NOH

Synthesis of 4-quinolone through nucleophilic addition–

elimination-SNA reaction(nucleophilic aromatic substitution)

Similarly, Xie et al. recently synthesized tri-substituted 4- Xieet al.,

8. quinolone derivatives via a cascade reaction of Michael
addition and Truce–Smiles rearrangement between 2020
benzenesulfonamide derivatives and 1-(2-bromophenyl)-3-
phenyl prop-2-yn-1-ones in the presence of K2CO3 in DMF
at 100 ° C in excellent yield

Synthesis of 1,2,3-trisubstituted 4-quinolone derivatives

 In 2018, Kang's group reported the synthesis of 3-acyl-2-
9. substituted 4-quinolone via the Cu-catalyzedaza-Michael Kang's
addition of 2-aminobenzoates to b-substituted a,b- group et al.,
unsaturated ketones , followed by base-mediated cyclization
and oxidation 2018

Cu-catalyzed synthesis of 3-acyl-2-substituted 4-quinolone

derivatives

10. Wu et al. reported the synthesis of 1,2-disubstituted-4- Wu et al.,

quinolone 107 via gold-catalyzed cyclization of 1-(2′ -
azidoaryl) propynols in the presence of John Phos AuNTf2 2019
and DCE at 65 °C under N2

Gold-catalyzed synthesis of 1,2 disubstituted 4-quinolone

derivative
11. A straightforward method for the synthesis of 3-alkoxy-4- Huang's
quinolone derivatives via a gold-catalyzed 6-endo-dig azide- group et al.,
yne cyclization, followed by an intermolecular O–H insertion
cascade reaction of o-azidoacetylenic ketones 108 with 2021
alcohols at room temperature under an argon atmosphere,
was described by Huang's group

Gold(III)- catalyzed
synthesis of 3- alkoxy-4-
quinolone

12. Other metal-catalyzed synthesis of 4-quinolone. A one-pot Ji group et

method for the synthesis of 4-quinolones from indoles (N-
al.,
methylindole) in the presence of a Ru catalyst was
developed by Ji group in 2018 2018
 Synthesis of 4-quinolones via
photocatalysis using ruthenium
catalysis

Sonogashira coupling. 4-Quinolone derivative, which is the Sonogashira

13. key substructure of protease inhibitor BILN 2061, was
et al.,
synthesized and reported through carbonylativeSonogashira
coupling, followed by cyclization of 2-iodo-5- 2013
methoxyaniline derivative with thiazolylacetylene in the
presence of PdCl2 (dppf) as the catalyst in a good yield

Synthesis of 4-quinolone via carbonylativeSonogashira

coupling/cyclization

Shi and
14. In 2020, Shi and coworkers reported a condition-controlled
divergent synthesis strategy for constructing 1,2,3 coworkers
trisubstituted 4-quinolones et al.,

2020
 Synthesis of 1,2,3 tri-substituted 4-quinolones by C–H
activation

CHAPTER 3 EXPERIMENTAL WORK

COMPUTATIONAL WORK

MATERAL & METHODS:-

The hardware configuration was Intel®Pentium® N3540@ 2.16ghz, RAM

memory 4.0GB under 64 bit window operating system .

CHEM DRAW ULTRA 12.0:-

Quinolone derivatives selected by literature survey were designed by using

Chemdraw Ultra 12.0 software
CHAPTER 4 RESULT AND DISCUSSION

Sketching of the selected molecules of quinolones by literature survey using

Chem draw office 12.0 software.

A dataset of 10 molecules were selected and sketched by using chem.

Draw ultra 12.0 from reported work
Fig :- Structure of selected molecules by using chem draw ultra 12.0
software.

Sr.No. Sketched structure

1.
2.

3.
4.

5.

1-ethyl-6-fluoro-4-oxo-7-piperazin-1-yl-1N-quinoline-3-carboxylic acid

6.

8-Fluoro-3-methyl-9-(4-methyl-D3-piperazin-1-yl)-6-oxo-2,3-dihydro-6H-1-oxa-3a-
aza-phenalene-5-carboxylic acid
7.

1-Ethyl-6-fluoro 1,4-dihydro -4-oxo-7-[1-piperzinyl]-3- quinoline carboxylic acid

8.

8-Fluoro-3-methyl-9-(4-methyl-piperazin-1-yl)-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-
diaza-phenalene-5-carboxylic acid

9.

1-Cyclopropyl-6-fluoro-8-methoxy-7-[(4aS,7aS)-octahydropyrrolo[3,4-b]pyridin-6-
yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride
10.

1-Cyclopropyl-7-(4-ethylpiperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid

CHAPTER-5

Conclusion

From the literature survey, it is reviewed that the quinoloneclass of

antimicrobials has enjoyed a rich history of medicinal chemistryapplied
towards improving bacterial spectrum, pharmacokinetics, efficacy, and
adverse side effect profiles In the near future, quinolone resistance might
be stemmedby treating bacteria above their mutant prevention concen
-tration (MPC).Consequently,research and discovery of novel quinolo
-nesand inhibitors of DNA gyrase and topoisomerase IV will be necessary
tomeet current and future unmet clinical needs.
REFERENCES

 Armstrong, G.L., Conn, L.A., Pinner R.W., Trends in infectious disease mortality
in the united states during the 20th century. JAMA 1999.

 Cross R.M., Flanigan, D.L.,Monastyrskyi, A.; LaCrue, A.N., Saenz, F.E., Maignan,
J.R., Mutka, T.S., White, K.L., Shackleford, D.M., Bathurst, I. Orally bioavailable
6-chloro-7 –methoxy-4(1H)-quinolones efficacious against multiple stages of
plasmodium. J. Med. Chem. 2014,

 Wang F., Jin L.; Kong and X. Li.,Cobalt(III)- and rhodium(III)-catalyzed C-H
amidation and synthesis of 4- quinolones: C-H activation assisted by weakly
coordinating and functionalizableenaminone, Org. Lett., 2017, 19.
 Aldred K. J.,Mcpherson S. A., Turnbough C. L., Kerns R. J., Osheroff N. Nucleic
Acids Res. 2013.

 Samir, M.,Ramadan, M., M. H. Abdelrahman, M.,Abdel-Aziz and G. E.-D. A. Abuo-

Rahma, Recent Strategies in Design of Antitumor and Antibacterial
Fluoroquinolones, J. Adv. Biomed. Pharm. Sci., 2021.

 Klomp, F., Wenzel, C., Drozdzik, M., Oswald, S., Drug Interactions Involving
Intestinal and Hepatic CYP1A Enzymes. Pharmaceutics 2020,

 Berninger, M., Erk, C., Fuß, A., Skaf, J., Al-Momani, E., Israel, I.; Raschig, M.,
Güntzel, P., Samnick, S.,Holzgrabe, U. Fluorine Walk: The Impact of Fluorine in
Quinolone Amides on Their Activity against African Sleeping Sickness. Eur. J. Med.
Chem. 2018.

 Martins, D.A., Gouvea, L.R., Muniz, G.S.V.; Louro, S.R.W., Batista, D.d.G.J.,
Soeiro, M.d.N.C.,Teixeira, L.R. Norfloxacin and N-Donor Mixed-Ligand Copper(II)
Complexes: Synthesis, Albumin Interaction, and Anti-Trypanosomacruzi Activity.
Bioinorg. Chem. Appl. 2016, 2016.

 Kraus, J.M., Tatipaka, H.B., McGuffin, S.A., Chennamaneni, N.K., Karimi, M.,Arif,
J.,Verlinde, C.L.M.J.; Buckner, F.S., Gelb, M.H., Second Generation. Analogues of
the Cancer Drug Clinical Candidate Tipifarnib for Anti-Chagas Disease Drug
Discovery. J. Med. Chem. 2010.

 Khan, I.A.,Siddiqui, S., Rehmani, S., Kazmi, S.U., Ali, S.H.,Fluoroquinolones Inhibit
HCV by Targeting Its Helicase. Antivir. Ther. 2012.

 Xu, Z., Zhao, S.-J.,Lv, Z.-S., Gao, F., Wang, Y., Zhang, F., Bai, L., Deng, J.-L.
Fluoroquinolone-Isatin Hybrids and Their Biological Activities. Eur. J. Med. Chem.
2019.

 Sato, M.,Motomura, T., Aramaki, H.,Matsuda, T., Yamashita, M., Ito, Y., Kawakami,
H., Matsuzaki, Y.,Watanabe, W., Yamataka, K., et al. Novel HIV-1 Integrase
Inhibitors Derived from Quinolone Antibiotics. J. Med. Chem. 2006.

 Khamkhenshorngphanuch, T.,Kulkraisri, K., Janjamratsaeng, A., Plabutong, N.,

Thammahong, A., Manadee, K., Na Pombejra, S.,Khotavivattana, T. Synthesis and
Antimicrobial Activity of Novel 4-Hydroxy-2-Quinolone Analogs. Molecules 2020.

 Wang, Y.,Damu, G.L.V., Lv, J.-S., Geng, R.-X., Yang, D.-C., Zhou, C.-H. Design,
Synthesis andEvaluation of ClinafloxacinTriazoleHybrids as a New Type of
Antibacterial and Antifungal Agents. Bioorgan. Med. Chem. Lett. 2012.

 Zusso, M.,Lunardi, V., Franceschini, D.,Pagetta, A., Lo, R., Stifani, S., Frigo, A.C.,
Giusti, P., Moro, S. Ciprofloxacin and Levofloxacin Attenuate Microglia
Inflammatory Response via TLR4/NF-KB Pathway. J. Neuroinflamm. 2019.
 Araujo, F.G.,Slifer, T.L., Remington, J.S. Effect of Moxifloxacin on Secretion of
Cytokines by Human MonocytesStimulated with Lipopolysaccharide. Clin.
Microbiol. Infect. 2002.

 Shalit, I., Halperin, D., Haite, D., Levitov, A., Romano, J., Osherov, N.,Fabian, I. Anti
-Inflammatory Effects ofMoxifloxacin on IL-8, IL-1beta and TNF-Alpha Secretion
andNFkappaBand MAP-Kinase Activation in Human Monocytes Stimulated with
Aspergillusfumigatus. J. Antimicrob. Chemother. 2006.

 Fabian, I., Reuveni, D., Levitov, A., Halperin, D., Priel, E.,Shalit, I. Moxifloxacin
Enhances Anti - proliferative and Apoptotic Effects of Etoposidebut Inhibits Its
Proinflammatory Effects in THP-1 and Jurkat Cells. Br. J. Cancer 2006.

 Beberok, A.,Wrze´sniok, D.,Rok, J., Rzepka, Z., Respondek, M.,Buszman, E.

Ciprofloxacin Triggers the Apoptosis of Human Triple-Negative Breast Cancer
MDA-MB-231 Cells via the P53/Bax/Bcl-2 Signaling Pathway. Int. J. Oncol. 2018.

 Beberok, A.,Wrze´sniok, D.,Minecka, A., Rok, J., Delijewski, M., Rzepka, Z.,
Respondek, M.,Buszman, E. Ciprofloxacin-Mediated Induction of S-Phase Cell Cycle
Arrest and Apoptosis in COLO829 Melanoma Cells.Pharmacol. Rep. 2018

 Nishi. K., Kato, M., Sakurai, S., Matsumoto, A., Iwase, Y.,Yumita, N. Enoxacin with
UVA Irradiation Induces Apoptosis in the AsPC1 Human Pancreatic Cancer Cell Line
Through ROS Generation. Anticancer Res. 2017.

 Patitungkho, S., Adsule, S., Dandawate, P., Padhye, S., Ahmad, A.,Sarkar, F.H.,
Synthesis, Characterization and Anti-Tumor Activity of Moxifloxacin-Copper
Complexes against Breast Cancer Cell Lines. Bioorgan. Med. Chem. Lett. 2011.

 Kljun, J., Bytzek, A.K., Kandioller, W., Bartel, C., Jakupec, M.A., Hartinger,
C.G.,Keppler, B.K.; Turel, I.Physico - chemical Studies and Anticancer Potency of
Ruthenium H6-p-Cymene Complexes Containing Antibacterial Quinolones.
Organometallics 2011.

 Regmi, N.L.,Abd El-Aty, A.M.; Kubota, R., Shah, S.S.,Shimoda, M., Lack of
Inhibitory Effects of Several Fluoroquinolones on Cytochrome P-450 3A Activities at
Clinical Dosage in Dogs. J. Vet. Pharm. 2007.

 Zhang, H.-J., Jin, P., Wang, S.-B., Li, F.-N., Guan, L.-P.,Quan, Z.-S. Synthesis and
Anticonvulsant Activity Evaluation of 4-Phenyl-[1,2,4] Triazolo [4,3-a] Quinazolin-
5(4H)-One and Its Derivatives. Arch. Pharm. 2015.

 Wang. Z., Hu, J., Yang, X.,Feng, X., Li, X., Huang, L.,Chan, A.S.C. Design,
Synthesis, and Evaluation of Orally Bioavailable Quinoline–Indole Derivatives as
Innovative Multitarget-Directed Ligands: Promotion of Cell Proliferation in the Adult
Murine Hippocampus for the Treatment of Alzheimer’s Disease. J. Med. Chem. 2018.
 Ukrainets I.V., Bereznyakova, N.L.,Mospanova, E.V., 4-Hydroxy-2-Quinolones
121.Synthesis andBiological Properties of 1-Hydroxy-3-Oxo-5,6-Dihydro-3h-
Pyrrolo[3,2,1-Ij]Quino-Line-2-Carboxylic Acid Alkylamides. Chem. Heterocyclic
Compd. 2007.