SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITY OF QUINOLINE DERIVATIVES

M. Pharm. Dissertation Protocol Submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore – 560041

ByMr. Patel Niravkumar Ashokbhai B.Pharm

Under the Guidance of

Dr. S. D. JOSHI M. Pharm, Ph.D.

PROFESSOR & HEAD,

DEPT. OF PHARMACEUTICAL CHEMISTRY,

Department of Pharmaceutical Chemistry

SET’s College of Pharmacy,S. R. Nagar, Dharwad,

1

Karnataka – 580002.

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA

ANNEXURE –II

PROFORMA FOR REGISTRATION OF SUBJECT DISSERTATION

1. NAME OF THE CANDIDATE

AND ADDRESS

Mr. PATEL NIRAVKUMAR ASHOKBHAI

DEPT. OF PHARMA CHEMISTRY

SET’s COLLEGE OF PHARMACY

S.R.NAGAR,

DHARWAD – 580002.

2. NAME OF THE INSTITUTION SET’s COLLEGE OF PHARMACY

S.R.NAGAR,

DHARWAD – 580002.

3. COURSE OF STUDY AND

SUBJECT

MASTER OF PHARMACY IN

PHARMACEUTICAL CHEMISTRY

4. DATE OF ADMISSION TO THE

COURSE

JUNE - 2010

2

5. TITLE OF THE TOPIC

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL ACTIVITY OF QUINOLINE DERIVATIVES

6.0 Brief resume of the intended work

6.1 Need for study

The synthesis of heterocyclic derivatives has been an important part and is aimed in

modifying the action of drugs, particularly to reduce the side effects and to potentiate the

drug action. Today more than 60% drugs used in practice are synthesized derivatives and

day by day the scope of synthetic medicinal chemistry is increasing.

Quinoline is a heterocyclic scaffold. Several quinoline derivatives isolated from

natural resources or prepared synthetically are significant with respect to medicinal

chemistry and biomedical use. Indeed quinoline derivatives are some of the oldest

compounds which have been utilized for the treatment of a variety of diseases. Quinoline, a

distereoisomer of quinine was in the early 20th century acknowledged as the most potent of

the antiarrhythmic compounds isolated from the cinchona plant.1

The pyridine ring fused with the benzene nucleus in different ways with resultant

formation of quinoline, isoquinoline and quinolizinium salts. But quinoline has good

pharmacological attention. Quinoline ring structure is obtained by ortho condensation of

3

benzene ring with pyridine.2

Quinoline derivatives exhibiting variety of pharmacological properties like

antimalarial,3-5 antibacterial,6-9 antifungal,10-13 antitubercular,14-17 antileasimanial,18,19 anti-

HIV,20 antiviral,21 anti-convulsant,22,23 analgesic,24-26 anti-inflammatory, 24-26 anticancer 27,28

and antioxidant 29 activities.

Antimicrobial resistance has been an issue since the introduction into clinical use of the

first agents in the 1940s. Although the discovery and development of new classes of

antimicrobials through the 1960s presented an array of treatment options, these options for

some serious and life-threatening infectious diseases may now be more limited. 30

A numbers of recent clinical reports describe the increasing occurrence of methicillin-

resistant S. aureus and other antibiotic-resistant human pathogenic microorganisms in

world. Infections caused by those microorganisms pose a serious challenge to the medical

community and the need for an effective therapy has led to a search for novel antimicrobial

agents.

6.2 Review of literature

Anti-malarial activity: Charris JE et al.,3 have synthesized a series of 2-quinolinylmethylidene-5,7-dimethoxy

indanones which was prepared via base catalyzed Claisen-Schmidt condensation of 5,7-

dimethoxy-1-indanone with the appropriate 2-chloro-3-formylquinoline derivative.

Evaluation of their in vitro inhibition of β-hematin formation and hemoglobin

hydrolysis and in vivo efficacy in P. berghei suggest the antimalarial activity was

derived from inhibition of hemoglobinolytic proteases. Compounds 2-(2'-chloro-6'-

methoxy-3'-quinolinylmethylidene)-5,7- dimethoxy indanone.14

Comps R

9 H

10 6-CH3

12 8- CH3

14 6-OCH3

Meenakshi J et al.,4 have reported the synthesis of 2-substituted/2,5-disubstituted-8-

quinolinamines and some of their amino acid conjugates. Antimalarial evaluation was

4

carried out against drug-sensitive P. berghei strain and multi-drug resistant P. yoelii

nigeriensis strain and compound N 1-[4-(2-tert-butyl-6-methoxy-8-quinolylamino)-

pentyl]-(2S)-2,5-diaminopentamide & N1-[4-(2-tert-butyl-6-methoxy-8-

quinolylamino)pentyl]-(2S)-2-6-diaminohexanamide showed good antimalarial

activities.

Comps R

47 (CH2)3NH2

48 (CH2)4NH2

Peter BM et al.,5 have reported the synthesis of ring-substituted 4-aminoquinolines. The

entire compounds were further evaluated for their antimalarial activity and most of the

compound showed promising antimalarial activity against P. falciparum using a

fluorescent-active cell sorting (FACS) assay. It was found that all compounds were

more active against 3D7 and noted that the most active compounds had substituent’s

located at either the 6th or 7th position on the quinoline ring.

Antibacterial activity: Kidwai M et al.,6 have synthesized 7-(5'-Alkyl-1',3',4'-thiadiazol/oxadiazol-2'-yl-thio)-

6-fluoro-2,4-dimethylquinolines and 3-formyl-2-(2'-hydroxy-1',4'-naphthoquinon-3-yl)-

4-methyl/6-methyl/7-methyl/8-methylquinolines by the reaction of 5-alkyl-1,3,4-thia-

diazol/oxadiazol-2-thiols with 7-chloro-6-fluoro-2,4-dimethylquinoline. The

compounds were further screened for antibacterial activities. All compounds showed

promising antibacterial activity.

R X

C7H15 O

C11H23 S

5

Nandhakumar RN et al., 7 have reported Vilsmeier hack reaction on 4-

hydroxyquinolines lead to potential intermediate 4-chloro-3-formyl-2-(2-

hydroxyethene-1-yl)-quinolines. The intermediate was further utilized to prepare

quino[3,2-e][1,3]diazocines on treatment with phenylhydrazine hydrochloride. All the

synthesized diazepino quinoline derivatives were screened for their antibacterial and

antifungal as well as cytogenetic activities. Compounds showed good antibacterial and

antifungal activity against S. typhi and A. hydrophila respectively.

Comps R1 R2 R3 R4

8a H H H H

8b CH3 H H H

8c H CH3 H H

8d H H Cl H

8e CH3 H H CH3

Muhammad A et al.,8 have reported a series of quinoline-based chalcone by the

condensation of quinoline-3-carbaldehyde with acetophenone and N-substituted-3-

acetyl-4-hydroxy-2-quinoline with heterocyclic carbaldehyde. The prepared chalcones

were screen for antimicrobial activites against E. coli, P. aeruginosa, B. subtiles, K.

aerogens, S. albus, A. flavus, A. niger, R. rubera, L. lopofera and C. albicans. All the

prepared chalcones showed significant antimicrobial activities.

Kishor HC et al.,9 have synthesized some new substituted quinolinyl chalcones and

evaluated for antimicrobial activity against Gram positive and Gram negative strains

using a microdilution procedure. Synthesized compounds showed excellent activity

against S. aureus, B. subtillis, E. coli and S. typhosa microorganisms.

Antifungal activity: Carlos MG et al.,10 have diversed polyfunctionalized quinolines using Lewis acid-

catalyzed imino by Diels-Alder reactions between corresponding aldimines and tested

for antifungal properties. Among them, 4-pyridyl derivatives displayed the best

activities mainly against dermatophytes. The activity appears not be related neither to

6

the lipophilicity nor to the basicity of compounds.

Robert M et al.,11 have synthesized a variety of quinoline derivatives. All the prepared

derivatives were analyzed using the reversed-phase high performance liquid

chromatography (RP-HPLC) method for the lipophilicity measurement. The prepared

compounds were tested for their antifungal activity. 2-[(3-

hydroxyphenylimino)methyl]quinoline-8-ol(8),2-[(4-hydroxyphenylimino)

methyl]quinolin-8-ol (9) and 2-[(2,5-dichloro-4-nitrophenyl

amino)methoxy)methyl]quinolin-8-ol (10) showed antifungal activity comparable to or

higher than that of the standard fluconazole against strains Candida albicans ATCC

44859, Candida tropicalis 156 and Candida glabrata.

8 9 10

Rajendran SP et al.,12 have prepared some Schiff bases derived from 3-amino-2H-

pyrano[2,3-b]quinoline-2-one. 8-methyl-3-amino-2H-pyrano[2,3-b]quinoline-2-one

synthesized by reaction of 2-choro-3-formyl quinoline with ethyl glycinate

hydrochloride in pyridine at 120 ºC for 6 h. The compounds synthesized were screened

for their antifungal activities. Compound 3c, 3d and 3e showed good of antifungal

activity against Aspergillus niger.

Comps R1 R2 R3

3c H CH3 H

3d OCH3 H H

3e H OCH3 H

Gundibasappa KN et al.,13 synthesized N-[3-chloro-2-(2-chloroquinoline-3-yl)-4-

xoazetidin-1-yl]naphtho[2,1-b]furan-2-carboxamide derivatives. These synthesized

quioline derivatives were screened for antimicrobial activity. The compounds N-[2-(5-

methyl-2-chloroquinolin-3-yl)-3-chloro-4-oxoazetidin-1-yl] naphtho[2,1-b]furan-2-

7

carboxamide was found to be highly active as antibacterial agent against P. aerugenosa

and as antifungal agent against A. niger and C. albicans species.

Anti-tubercular activity: Alka M et al.,14 have studied the synthesis and characterization of some 4-amino

substituted 2,8-bis(trifluoromethyl)quinoline derivatives. All of the synthesized

compounds were primarily screened against Mycobacterium tuberculosis strain H37Rv

(ATCC 27294) at the single concentration of 6.25 μg/ml. The compound (2,8-bis-

trifluoromethylquinolin-4-yl)-(2-piperidin-1-yl-ethyl)amine showed good

antitubercular activity.

Marcus VN et al.,15 have synthesized series of 7-chloroquinoline derivatives and

evaluated for antibacterial activity against Mycobacterium tuberculosis H37Rv using

the Alamar Blue susceptibility test and the activity expressed as the minimum inhibitory

concentration (MIC) in µg/ml. Compounds N-(7-chloroquinolin-4-yl)octane-1,8-

diamine and N-(7-chloroquinolin-4-yl)decane-1,10-diamine exhibited a significant

activity at 6.25 and 3.12 µg/ml.

Ram Shankar U et al.,16 have carried out design, synthesis, molecular modelling and

characterization of 3-benzyl-6-bromo-2-methoxy-quinolines and amides of 2-[(6-

bromo-2-methoxy-quinolin-3-yl)-phenylmethyl]-malonic acid monomethyl ester. These

synthesized quinoline derivatives were screened for their antimycobacterial activity.

The compounds (±)6-bromo-3-(imidazol-1-yl-phenyl-methyl)-2-methoxy-quinoline(3),

6-bromo-2-methoxy-3-{phenyl-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-methyl}-

quinoline (8), (±)-6-bromo-2-methoxy-3-(phenyl-pyrazol-1-ylmethyl)-quinoline(17)

and (±)-6-{[(6-bromo -2-methoxy-quinolin-3-yl)-phenylmethyl]-amino}-chromen-2-

one(18) have shown 92–100% growth inhibition of mycobacterial activity with

minimum inhibitory concentration (MIC) of 6.25 µg/ml.

Comps R

3 Imidazolyl

8 1-(3-trifluoromethyl-phenyl)-piperazinyl

17 Pyrazolyl

18 6-amino-chromen-2-one

8

Sandra G et al.,17 have synthesized a series of 4-quinolylhydrazones and tested against

Mycobacterium tuberculosis at a concentration of 6.25 µg/ml. The synthesized

compounds bearing a methoxy group at C6 or C7 and 6, 7-methylendioxy substituent

quinoline derivatives showed a 100% inhibition of Mycobacterium tuberculosis growth

at a concentration of 6.25 µg/ml exhibited good anti-inflammatory activity.

Antileishmanial agent: Andre GT et al.,18 have synthesized novel quinoline derivatives and antileishmanial

efficacy determined in vitro against Leishmania chagasi, using extracellular and

intracellular parasite models. 2-methyl-3-[(2E)-3-phenylprop-2-enyl]quinolin-4-ol

demonstrated 8.3-fold greater activity than did the standard pentavalent antimony.

Nashira CV et al.,19 have reported the synthesis 2-n-propylquinoline (1), 2-

(2methoxyethenyl)quinoline (2) and 2-(2-hydroxyprop-2-enyl)quinoline (3) and

evaluated for antileishmanial activities.

Anti-HIV activity: Shuguang C et al.,20 have designed and synthesized thirty-two quinoline derivatives as

HIV-1 Tat–TAR interaction inhibitors. All the compounds showed high antiviral

activities by inhibiting the formation of SIV-induced syncytium in CEM174 cells.

Molecular modeling experiments indicated that these compounds may inhibit Tat–TAR

interaction by binding to Tat protein instead of TAR RNA.

Anti-Viral activity: Pramilla S et al.,21 have reported new series of quinoline derivarives prepared by

treating 2-methyl-4-chloroquinoline and 2-methyl-4-chloroacetyloxyquinoline with

sodium salts of 2-arylamino-5-mercapto-1,3,4-thiadiazoles to give 2-methyl-4-(2-

arylamino-1,3,4-thiadiazol-5-thio-yl)-quinoline and 2-methyl-4-(2-aryl-amino-1,3,4-

thiadiazol-5-thio-acetyloxy)-quinoline. The synthesized compounds evaluated for

antifungal activity against Helmintho sporum, antibacterial activity against Bacillus

subtilis and antiviral acivity against Tobacco mosaic virus.

Anticonvulsant activity: Xian-Yu Sun et al.,22 have synthesized a new series of 8-alkoxy-5,6-dihydro-

[1,2,4]triazino[4,3-a]quinolin-1-one derivatives. Their anticonvulsant activities were

evaluated by the Maximal Electro Shock (MES) test and their neurotoxicities were

evaluated by the rotarod neurotoxicity test. The results showed that 8-heptyloxy-5,6-

9

dihydro-[1,2,4]triazino[4,3-a]quinolin-1-one 5t was the most potent with median

effective dose (ED50) value of 11.4 mg/kg, median toxicity dose (TD50) of 114.1 mg/kg.

The o-chloro derivative 5g exhibited the most potent activity and o-bromo derivative 5j

exhibited weaker activity than 5g. The derivatives 5h and 5i containing two chlorine

groups did not exhibited better anticonvulsant activity than derivatives with single

chlorine group.

Nichols AC et al.,23 have synthesized some new quinoline derivatives and screened for

anticonvulsant activity by Maximal Electro Shock, Pentylenetetrazole (PTZ) and

Threshold tonic extension (TTE) test.

Anti-Inflammatory: Sandhya B et al.,24 have reported the anti-inflammatory activity and antimicrobial

activity of some of 8-methyl-tetrazolo[1,5-a]quinoline derivatives.

Ashraf HA et al.,25 have synthesized novel 4-substituted-7-trifluoromethylquinoline

derivatives with nitric oxide releasing properties and tested for their in vivo anti-

inflammatory, analgesic and ulcerogenic properties, as well as their in vitro nitric oxide

release ability.

Abdel-Rahman BA et al.,26 synthesized a series of some novel pyrimido[4,5-b]quinolin-

4-ones derivatives and also evaluated their analgesic, anti-inflammatory and

antimicrobial activity. Among all active compounds 5and 8 possess high activity toward

Comps R

5g –C6H4(o-Cl)

5h –C6H3(2,4-Cl2)

5i –C6H3(2,6-Cl2)

5j –C6H4(o-Br)

5t n-C7H15

10

the fungi as compared with the reference drug nystatinan and found to have significant

peripheral analgesic activity.

Compound 5 Compound 8

Anticancer activity: Deady LW et al.,27 have reported a series of 11-oxo-11H-indeno[1,2-b]quinolines

bearing a carboxamide-linked cationic side chain at various positions on the

chromophore. This was studied to determine structure-activity relationships between

cytotoxicity and the position of the side chain.

Yeh-Long Chen et al.,28 have synthesized a certain linear 4-anilinofuro[2,3-b]quinoline

and angular 4-anilinofuro[3,2-c]quinoline derivatives and evaluated in vitro against the

full panel of NCI’s 60 cancer cell lines.

Anti-oxidant activity:- Lhassane I et al.,29 have reported new hexahydropyrimido[5,4-c]quinoline-2,5-diones

and 2-thioxohexahydropyrimido[5,4-c]quinoline-5-ones which were prepared in two

steps from ethyl 4-phenyl-6-methyl-2-oxo tetrahydropyrimidine-5-carboxylates or 4-

phenyl-6-methyl-2-thioxotetrahydropyrimidine-5-carboxylates. Their antioxidant

properties were evaluated by two methods: scavenging effect on 2, 2-diphenyl-1-

picrylhydrazyl (DPPH) radicals and scavenging effect on hydroxyl radicals.

Compounds containing thiourea moiety have better activity.

6.3 Objectives of the study1. To synthesize some newer derivatives of quinoline.

11

2. To monitor the progress of the reactions by TLC.

3. To purify the compounds by recrystallization and column chromatography methods.

4. To characterize the synthesized compounds by different analytical techniques such

as IR, NMR and Mass spectral data.

5. To evaluate the antimicrobial activities of newly synthesized quinoline derivatives.

7.0 Materials and methods:

7.1 Sources of data Chemical Abstracts

Indian Journal of Chemistry

Indian Journal of Heterocyclic Chemistry

Journal of Medicinal Chemistry

Journal of Heterocyclic Chemistry

European Journal of Medicinal Chemistry

Bioorganic and Medicinal Chemistry

Word wide web

J-Gate@ Helinet etc.

7.2 Method of collection of Data

A) Synthesis of the compounds: Chemicals and other reagents required for synthesis will be procured from standard

company sources. Compounds will be synthesized by using standard techniques. The

reactions will be monitored by TLC and purification of the compounds will be achieved by

standard procedures like recrystallization.

B) Characterization of the compounds: The synthesized compounds will be characterized by preliminary laboratory techniques

such as melting point, boiling point etc. Compounds synthesized will be confirmed by

FTIR, Mass Spectroscopy and NMR spectral data. The Mass and NMR spectral data of the

synthesized compound will be collected by sending the compounds to research centres at

IISc, Bangalore.

C) Invitro evaluation of antibacterial activity:

12

The MIC determination of the tested compounds will be carried out in side-by-

side comparison with ciprofloxacin and norfloxacin against Gram-positive (Staphylococcus

aureus, Bacillus subtilis) and Gram-negative bacteria (Klebsiella pneumoniae, Escherichia

coli) by broth microdilution method.31 Serial dilutions of the test compounds and reference

drugs will be prepared in Mueller-Hinton agar. Drugs (10 mg) will be dissolved in

dimethylsulfoxide (DMSO, 1 ml). Further progressive dilutions with melted Mueller-

Hinton agar will be performed to obtain the required concentrations of 1, 2, 4, 8, 16, 31.25,

62.5, 125, 250 and 500 mg/ml. The tubes will be inoculated with 105 cfu/ml (colony

forming unit/ml) and incubated at 37 0C for 18 h. The MIC will be the lowest concentration

of the tested compound that yields no visible growth on the plate. To ensure that the solvent

will have no effect on the bacterial growth, a control will be performed with the test

medium supplemented with DMSO at the same dilutions as used in the experiments.

D) Invitro evaluation of antitubercular activity:

The preliminary antitubercular screening for test compounds will be obtained

for M. tuberculosis H37Rv, the MIC of each drug will be determined by broth dilution

assay31 and is defined as the lowest concentration of drug, which inhibits 99% of bacterial

population present at the beginning of the assay. A frozen culture in Middlebrook 7H9

broth will be supplemented with 10% albumine dextrose catalase and 0.2% glycerol will be

thawed and will be diluted in broth to 105 cfu/ml for M. tuberculosis and will be used as the

inoculum. In the assay U-tubes will be used to accommodate compounds in 1-500 mg/ml

dilutions. Each test compound will be dissolved in DMSO and then diluted in broth twice at

the desired concentration. The final concentration of DMSO in the assay medium will be

1.3%. Each U-tube will be then inoculated with 0.05 ml of standardized culture and then

will be incubated at 37 0C for 21 days. The growth in the U-tubes will be compared with

visibility against positive control (without drug), negative control (without drug and

inoculum) and with standard isoniazid.

7.3 Does the study require any investigation or interventions to be

Conducted on patients or other humans or animals?

NO

13

7.4 Has ethical clearance been obtained from your institution in case of

7.3?NA

8.0 REFERENCES:

1. Sudharshan M, Zehra T, Sanjay B. Advances in the syntheses of quinoline and

quinoline annulated ring systems. Current Org Chem 2008;12:1116-83.

2. Raj KB. Heterocyclic chemistry. 4th ed. New delhi(India): New age

international;2005. p. 366.

3. Charris JE, Lobo GM, Camacho J, Ferrer R, Barazarte A, Domínguez JN et al.

Synthesis and antimalarial activity of (E) 2-(2'-chloro-3'-quinolinylmethylidene)-

5,7-dimethoxyindanones. Letters Drug Design Discovery 2007;4: 49-54.

4. Meenakshi J, Suryanarayana V, Sandeep S, Rahul J. Synthesis and blood-

schizontocidal antimalarial activities of 2-substituted/2,5-disubstituted-8-

quinolinamines and some of their amino acid conjugates. Bioorg Med Chem

2004;12:1003-10.

5. Peter BM, John S, Ally PL, Jennifer LW, Joseph LD, Kiplin GR. Synthesis of

ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities.

Bioorg Med Chem Lett 2005;15:1015-8.

6. Kidwai M, Bhushan KR, Sapra P, Saxena RK, Gupta R. Alumina supported

synthesis of antibacterial quinolines using microwaves. Bioorg Med Chem

2000;8:69-72.

7. Nandhakumar R, Thangaraj S Palathurai SM. Isolation of 4-chloro-3-formyl-2-(2-

hydroxyethene-1-yl) quinolines by Vilsmeier haack reaction on

quinaldines:construction of diazepino quinoline heterocyclesand their

antimicrobial and cytogenetic studies. Acta Pharm. 2003(53):1-14.

8. Muhammad A, Munawar AM, Hamid LS. Antimicrobial activity and synthesis of

quinoline based chalcones. J Allplied Sci 2007;7(17):2485-9.

9. Kishor HC, Mayank JP, Dhaval BV. Design, synthesis and evaluation of novel

quinolyl chalcones as antibacterial agents. ARKIVOC 2008;(xii):189-97.

10. Carlos MG, Vladimir VK, Maximiliano AS, Sandra LÁ, Susana AZ. In vitro

antifungal activity of polyfunctionalized 2-(hetero)arylquinolines prepared through

14

imino diels–alder reactions. Bioorg Med Chem 2008;16:7908-20.

11. Robert M, Josef J, Vladimir B, Luis S, Halina N, Barbara P et al. Antifungal

properties of new series of quinoline derivatives. Bioorg Med Chem

2006;14:3592-8.

12. Rajendran SP, Karvembu. Synthesis and antifungal activities of Schiff bases

derived from 3-amino-2H-pyrano[2,3-b]quinoline-2-ones. Indian J Chem sec B

2002;41:222-4.

13. Gundibasappa KN, Gowdara KP, Marlingaplara NK, Vijayavittala PV, Kittappa

MM. Synthesis of novel nitrogen containing naphtho[2,1-b]furan derivatives and

investigation of their antimicrobial activities. Archive Org Chem 2006(xv):160-8.

14. Alka M, Villendra SN, Uma R. Synthesis and antimycobacterial activities of

certain trifluoromethyl-aminoquinoline derivatives. . Archive Org Chem

2006(x):220-7.

15. Marcus VN, Karla CP, Carlos RK, Mônica AP, Marcelle LF, Maria CSL.

Synthesis and in vitro antitubercular activity of a series of quinoline derivatives.

Bioorg Med Chem 2009;17:1474-80.

16. Ram SU, Jaya KV, Nageswara RV, Vivek S, Shailesh SD, Jyoti C. Design,

synthesis, biological evaluation and molecular modelling studies of novel

quinoline derivatives against Mycobacterium tuberculosis. Bioorg Med Chem

2009;17:2833-41.

17. Sandra G, Luisa S, Maria A, Pierangela T, Luisa C, Salvatore SC et al.

Development of antitubercular compounds based on a 4-quinolylhydrazone

scaffold. Further structure activity relationship studies. Bioorg Med Chem

2009;17:6063-72.

18. Andre GT, Ana Claudia MP, Carlos AB, Fernanda SM, Samanta ETB, Maria

Amelia BS et al. Synthesis and antileishmanial activities of novel 3-substituted

quinolines. Antimicrob Agents Chemother. 2005;49(3):1076-80.

19. Nashira CV, Christine H, Joel V, Alain F, Christian B, Bruno F et al. Selection of

the most promising 2-substituted quinoline as antileishmanial candidate for clinical

trials. Biomed Pharmacother 2008;62:684-9.

20. Shuguang C, Ran C, Meizi H, Ruifang P, Zhiwu T, Ming Y. Design, synthesis and

biological evaluation of novel quinoline derivatives as HIV-1 Tat–TAR interaction

inhibitors. Bioorg Med Chem 2009;17:1948-56.

21. Pramilla S, Garg SP, Nautiyal SR. Some new biologically active quinoline

15

analogues. Indian J Heterocycl Chem 1998;7:201-4.

22. Xian-Yu S, Lei Z, Cheng-Xi Wa, Hu-Ri P a, Zhe-Shan Q. Design, synthesis of 8-

alkoxy-5,6-dihydro-[1,2,4]triazino[4,3-a]quinolin-1-ones with anticonvulsant

activity. Eur J Med Chem 2009;44:1265-70.

23. Nicolas AC, Lemone LY. Quinoline acid derivatives. United States Patent. 1998

Jul 21;5783700.

24. Sandhya B, Suresh K. Synthesis of Schiff’s bases of 8-methyl-tetrazolo[1,5-

a]quinoline as apotential anti-inflammatory and antimicrobial agents. Indian J

Chem sec B 2009;48:142-5.

25. Ashraf HA, Hegazy GH, El-Zaher AA. Synthesis of novel 4-substituted-7-

trifluoromethylquinoline derivatives with nitric oxide releasing properties and their

evaluation as analgesic and anti-inflammatory agents. Bioorg Med Chem

2005;13:5759-65.

26. Abdel-Rahman BA, El-Enanyb MM, Mahmoud MN. Synthesis, analgesic, anti-

inflammatory and antimicrobial activity of some novel pyrimido[4,5-b]quinolin-4-

ones. Bioorg Med Chem 2008;16:3261-73.

27. Deady LW, Desneves J, Kaye AJ, Finly GJ, Baguley BC, Denny WA. Positioning

of the carboxamide side chain in 11-oxo-11H-indeno[1,2-b]quinoline carboxamide

anticancer agent effect on cytotoxicity. Bioorg Med Chem 2001;9:445-52.

28. Yeh-Long C, Chen IL, Tai-Chi W, Chein-Hwa H, Cherng-Chyi T. Synthesis and

anticancer evaluation of certain 4-anilinofuro[2,3-b]quinoline and 4-

anilinofuro[3,2-c]quinoline derivatives. Eur J Med Chem 2005;40:928-34.

29. Lhassane I, Arulraj N, Laurence N, Catherine G, Alain X, Robert JF. Synthesis

and antioxidant activity evaluation of new hexahydropyrimido[5,4-c]quinoline-

2,5-diones and 2-thioxohexahydropyrimido[5,4-c]quinoline-5-ones obtained by

biginelli reaction in two steps. Eur J Med Chem 2008;43:1270-5.

30. Kumar RN, Suresh T, Dhanabal T, Mohan PS. A novel approach to 12-chloro-3-

thio-4H-quinoline[3,2-e][ 1,3]diazocines via Vilsmeier hack reaction. Indian J

Chem sec B 2007;46:995-1000.

31. Talath S, Gadad AK. Synthesis, antibacterial and antitubercular activities of some

7-[4-(5-amino-[1,3,4]thiadiazole-2-sulfonyl)-piperazin-1-yl]fluoroquinolonic

derivatives. Eur J Med Chem 2006;41:918-24.

16

9. SIGNATURE OF THE

STUDENT

10. REMARK OF THE GUIDE

The above mentioned information and literature has been extensively investigated, verified

and was found to be correct. The present study will be carried out under my supervision

and guidance.

11. 11.1 NAME AND DESIGNATION

OF THE GUIDE

11.2 SIGNATURE

Dr. S. D. JOSHI M. Pharm, Ph.D.PROFESSOR & HEAD,DEPT. OF PHARMACEUTICAL CHEMISTRY,SET’s COLLEGE OF PHARMACY, S.R.NAGAR, DHARWAD – 580002.

11.3 NAME AND DESIGNATION

OF CO-GUIDE

11.4 SIGNATURE

------------------------

11.5 HEAD OF THE

DEPARTMENT

11.6 SIGNATURE

Dr. S. D. JOSHI M. Pharm, Ph.D.PROFESSOR & HEAD,DEPT. OF PHARMACEUTICAL CHEMISTRY,SET’s COLLEGE OF PHARMACY, S.R.NAGAR, DHARWAD – 580002.

12. 12.1 REMARK OF THE

PRINCIPAL

12.2 SIGNATURE

The above mentioned information is correct and I

recommend the same for approval.

Dr. V. H. KULKARNI M. Pharm, Ph.D.PROFESSOR & PRINCIPAL, SET’s COLLEGE OF PHARMACY,S.R.NAGAR, DHARWAD – 580002.

17