Design, Synthesis, Characterization and Biological Evaluation of Some Novel Azetidin-2-One

DESIGN, SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME NOVEL AZETIDIN-2-ONE DERIVATIVES

M. Pharm. Dissertation Protocol Submitted to the Rajiv Gandhi University of Health Sciences, Karnataka. Bangalore.

By Mr. SIRAJ HUSSAIN ANSARI B. Pharm.

Under the guidance of Prof. G. SUDHEENDRA M Pharm. (Ph.D)

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY LUQMAN COLLEGE OF PHARMACY, GULBARGA

2014 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. NAME OF THE CANDIDATE AND Mr. SIRAJ HUSSAIN ANSARI ADDRESS LUQMAN COLLEGE OF PHARMACY, BEHIND P&T QUARTERS, OLD JEWARGI ROAD, GULBARGA-585102

2. NAME OF THE INSTITUTION LUQMAN COLLEGE OF PHARMACY, BEHIND P&T QUARTERS, OLD JEWARGI ROAD, GULBARGA-585102

3. COURSE OF STUDY AND SUBJECT M.PHARM

(PHARMACEUTICAL CHEMISTRY)

4. DATE OF ADMISSION OF COURSE 08-07-2013

5. TITLE OF THE TOPIC DESIGN, SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME NOVEL AZETIDIN-2-ONE DERIVATIVES 6. Brief Resume of the intended work:

6.1 Need for the study:

The search for the newer drug is an endless effort for which the researchers have always an

interesting field open for the discovery of new more efficacious drugs with reduced toxicity

profile. The synthesis of heterocyclic compounds has always drawn the attention of

medicinal chemists over the years mainly because of their diverse biological properties.

Azetidinones and Quinazolinones are the important classes of heterocycles which are being

explored constantly since many years because they are endowed with variety of biological

activities. In the present investigation, we have planned for the synthesis of some new

biological agents comprising the above two heterocycles linked to each other through an

appropriate substituted alkyl chain that would result in potent antimicrobial and

antitubercular agents.

AZETIDIN-2-ONES

Azetidin-2-ones, commonly known as β-lactams, are well-known heterocyclic

compounds among the organic and medicinal chemists mainly because of their antimicrobial

and diverse pharmacological activities. The β-lactam antibiotics are still the most prescribed

antibiotics used in medicine. They are considered as an important contribution of science to

humanity1,2. The most widely used antibiotics such as the Penicillins, Cephalosporins,

Carumonam, Aztreonam, Thienamycine and the Nocardicins contain β-lactam (azetidin-2-

one) rings3. The long-term use of β-lactam antibiotics exert selective pressure on bacteria and

permit the proliferation of resistant organisms4. A comparative study of current antibiotics

with those from previous decades shows an alarming increase in bacterial resistance to β-

lactam antibiotics5,6. The development of several synthetic and semi-synthetic β-lactam

antibiotics by the pharmaceutical industry was due to the growing resistance of bacteria

towards the β-lactam antibiotics and the need for medicines with a more specific

antibacterial activity7. A large number of antibiotics contain amide linkage. Several derivatives of amides were prepared and found to possess antimicrobial activities. Literature survey reveals that various drugs e.g. penicillin8 (antibacterial), pyrazinamide9 (antitubercular), indinavir10, ritonavir11. (Protease inhibitors as anti-AIDS) etc contain their particular activities due to the amide linkage present in their structure.

2-Azetidinones are the monocyclic β-lactams, are well-known heterocyclic compounds among the organic and medicinal chemists12,13. A large number of 3-chloro monocyclic β-lactams possess powerful antibacterial, antimicrobial, anti-inflammatory, anticonvulsant and antitubercular activities14. They also function as enzyme inhibitors and are effective on the central nervous system15. β-Lactams also serve as synthon for various biologically important classes of organic compounds16.

QUINAZOLIN-4-ONES

Quinazolin-4-one derivatives are versatile nitrogen heterocyclic compounds which have long been known as a promising class of biologically active compounds possessing wide variety of biological and pharmacological activities like antibacterial17, anthelmintic18, neuroleptic19, antitubercular20, platelet anti-aggregating21, antifungal22, anticancer23, anti- inflammatory24, antiviral25, CNS depressant activity26, antiparkinson27, bronchodilator28 etc. It is observed during the literature survey that, Quinazolinone system possesses the variable sites like position 2 and 3 which can be suitably modified to yield potent chemotherapeutic and pharmacotherapeutic agents21.

The literature survey also reveals that, the better drug molecules would be obtained by bringing changes in its biological behavior of the lead compound either by structure variation and/or combination of two or more biologically active moieties into one molecular framework.

Prompted by the above observations, here in we propose for the design and synthesis of some new structural hybrids of azetidin-2-ones to which another important class of heterocycles, substituted quinazoline-4-one is bridged appropriately through an amide linkage to yield the title compounds. And the various derivatives synthesized would be screened for their antimicrobial properties. This combination suggested is an attempt to investigate the influence of such hybridization and structure variation on the anticipated biological activities hoping the possibility that the target derivatives might be more efficacious as antimicrobial agents.

6.2 Objective of the study:

It is well established that various derivatives of azetidin-2-one and quinazoline-4-one exhibit broad spectrum of biological activities. Several derivatives of amides were prepared and found to possess antimicrobial activities; literature survey also reveals that, a large number of antibiotics contain amide linkage eg. penicillin (antibacterial), pyrazinamide

(antitubercular), indinavir, ritonavir (Protease inhibitors as anti-AIDS) etc contain their particular activities due to the amide linkage present in their structure.

Prompted by all the above observations, we have planned to prepare some new 2- azetidinone derivatives bridged through an amide linkage to suitably substituted quinazoline-

4-one nucleus and evaluate them for antimicrobial activities.

The present investigations includes the following:

 Substituted 1,3,4 benzoxazinone prepared are reacted with active hydrogen atoms of

amine group bearing moiety by conventional synthetic methods to form 2,3-

substituted quinazolinone nucleus following known methods. The hydrazide of which

is then reacted with different aryl aldehydes to yield Schiff bases following literature

methods. These are further cyclised to prepare azetidin-2-one derivatives by the

reaction with appropriate cyclising agent(s).

 The chemical structure of the compounds synthesized could be established on the

basis of elemental analysis and IR, 1HNMR and Mass spectral studies.

 The compounds of the above type containing different heterocyclic moieties would be

evaluated for their antimicrobial properties against a panel of gram positive and gram

negative bacteria as well as fungi.

 Few of the selected compounds would also be evaluated for their antitubercular

activity against Mycobacterium tuberculosis H37 RV. 6.3 Review of Literature:

A) AZETIDIN-2-ONES: Abundant literature is available that reveals the use of azetidin-2- one nucleus as synthon for the preparation of various types of derivatives and evaluation for their microbiological and pharmacological profiles. Few of the important literature of azetidin-2-ones are here as under:

 Bhagat T M et al., (2012)29 synthesized 2-azetidinone containing benzothizolyl

moiety and evaluated their antibacterial activity.

O R S H NH N Cl N Ar H Br

 Pramilla S et al., (2012)30 synthesized 2-azetidinones derived from benzimidazole

and evaluated their antimicrobial activity.

O O N N

N CH2 R N CH2 R N N

O O2S NH N O O2S NH N

O Cl O O

 Kokila P et al., (2012)31 synthesized novel 3-chloro- [1- (3,6-(diphenyl) [1,2,4]

triazolo [3,4b][1,3,4] thiadiazole)] -4-(3,4-diethoxy phenyl)-azetidin-2-one and

evaluated their antimicrobial activity.

 Meshram J S et al., (2011)32 performed an efficient synthesis of novel bioactive azetidinones and thiazolidinones of 1,5-dimethyl-2-phenyl-1H-pyrazole-3(2H)-one

and screened their antibacterial activity using bacterial strains (E. coli, B. subtilis,

Pseudomonas sp., Rhodococci, B. stearothermopelus) by measuring the zone of

inhibition on agar plates.

OH OH CH CH H3C 3 H3C 3

H3C N CH3 H3C N CH3 N N N N N N

R N N O R

O Cl S

(Azetidinone) (Thiazolidinone)

 Taj T et al., (2011)33 performed an expeditious green synthesis of Schiff bases and azetidinones derivatised with 1,2,4-triazoles and evaluated their antimicrobial and antitubercular activities. The antimicrobial activity was carried out by using the MIC (Minimum Inhibition Concentration) technique. O

H3C N N O CH R O Hx HB N Cl HA N N R' N H CH3

 Srivastava Y K et al., (2011)34 performed microwave induced synthesis of some

biologically active azetidinones. All the compounds were subjected to antibacterial

activity against E. coli , P. vulgaris . K. pneumoneae and S. aureus.

N N NH2 N

 Jubie S et al., (2009)35 synthesized some 2-azetidinone derivatives and evaluated

their antimicrobial activity. The synthesized compounds were subjected to antimicrobial screening by cup plate method for zone of inhibition. The antibacterial

activity was tested against various gram +ve bacteria (S. faecalis, S. aureus) and gram

–ve bacteria (P. aeruginosa, E. coli) and antifungal activity was tested against fungi

(C. albicans, A. niger).

 Toraskar M P et al., (2009)36 synthesized some azetidinones and evaluated their

antifungal activity. All the compounds were screened for invitro antifungal activity

against C.albicans using cup-plate agar diffusion method by measuring the zone of

inhibition.

CH2CONH

 Vijay Kumar M M J et al., (2009)37 synthesized new novel anti-inflammatory

agents as N-substituted-3-chloro-2-azetidinones.

H CO H3CO 3

HO HO Cl Cl

N N N N NH O NH O F S F S O O Cl Cl

 Bhat I K et al., (2007)38 synthesized azetidinone derivatives with the para-anisidine

moiety and evaluated their antimicrobial study. The bacterial strains employed were

Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. The fungal strain used was Candida albicans. This activity was assayed

using the cup-plate agar diffusion method by measuring the zone of inhibition.

HN CH2 C NH N

 Pai N R et al., (2007)39 synthesized N-substituted-3-chloro-2-azetidinones and

evaluated their biological activity. The compounds were tested for their antibacterial

activity against bacteria such as gm +ve (S. aureus, B. subtilis) and gm –ve

(P.aeruginosa, E.coli) and for their antifungal activity against fungi such as C.

tropicans, A. niger and F. heterosporium.

O Cl N O H NH CH2 NH N R HOOC S

 Mehta A G et al., (2006)40 synthesized azetidinone and thiazolidinone derivatives of

2-amino-6-(2-naphthalenyl)thiazolo[3,2-d]thiadiazole and evaluated their antifungal

activity. The synthesized compounds were screened for their antifungal activity

against various fungi such as Panicilium expansum, Botrydepladia thiobromine,

Nigrospora sp. and Trichothesium sp.

R N H N H R H N N S S Cl S O O

 Mehta A G et al., (2006)41 synthesized novel azetidinone and thiazoloidinones

derivatives and evaluated their antimicrobial activity. Antimicrobial activity of all the

compounds were studied against gram +ve bacteria (Bacillus Subtillies and

staphycoccus aureus) and gram -ve bacteria (E.Coli and salmonella typhi). N R N H H R H N N S S Cl S O O

 Guner V A et al., (2005)42 performed antimicrobial activity of 4-substituted-styryl-2-

azetidinones. Compounds were subjected to an antimicrobial screening procedure

against Gram(+) and Gram(-) strains of Staphylococcus aureus ATCC 25923;

Bacillus subtilis ATCC 6633; Escherichia coli ATCC 35218; Pseudomonas

aeruginosa ATCC 10145; Candida albicans ATCC 90028, Candida glabrata ATCC

90030.

R3 N O

B) QUINAZOLIN-4-ONES: The extensive literature survey revealed that the compounds containing Quinazolinone derivatives are reported to possess the wide range of biological activities. There are few important literatures for Quinazolinones as under.

 Shah R M et al., (2012)43 synthesized novel 2-thioxo-quinazolin-4-one derivatives

and their characterization.

R O Br N

 Haiyang T et al., (2012)44 performed Facile Synthesis and Herbicidal Evaluation of

4H-3,1-benzoxazin-4-ones and 3H-quinazolin-4-ones with 2-phenoxymethyl

substituent. O

O X N R

 Venkatesh P et al., (2011)45 designed and synthesized quinazolinone, benzothiazole

derivatives bearing guanidinopropanoic acid moiety and their Schiff bases as

cytotoxic and antimicrobial agents.

NH C NH CH2 S COOH R1

 Abbas S Y et al., (2011)46 synthesized some biologically active 4(3H)-

quinazolinones derived from 2,3-pyridine dicarboxylic anhydride. The synthesized

compounds were evaluated for their antifungal activity against fungi such as

Aspergillus ochraceus wilhelm and Penicillium chrysogenum Thom.

 Revanasiddappa H D et al., (2010)47 synthesized new Schiff bases containing

4(3H)-quinazolinone ring system and evaluated their biological activity. All the

synthesized compounds were tested against fungi such as Aspergillus Niger,

Aspergillus flavus and Alternaria solani by disc diffusion method.

 Reddy P S N et al., (2010)48 evaluated antibacterial, antifungal and antifeedant

activity of quinazolinonyl-b-lactams/quinazolinones and bis (quinazolinonyl-b-

lactams). The synthesized compounds were tested for antifungal activity against fungi

such as Fusarium oxisporium and Macrophomina sorgina. O

NH2 N X N N N CH3COHN X' O

 Rajasekaran S et al., (2010)49 synthesized of some 2-phenyl-3-substituted

quinazolin-4(3H)-ones and evaluated their antituberculor, antibacterial and

antioxidant activities. The compounds were evaluated their antituberculor activity

against mycobacterium tuberculosis by agar dilution method.

O NH NH N R O N

 Kaur P et al., (2009)50 developed new approachof quinazolinone peptides as potent

medicinal agents. The synthesized compounds were evaluated their antifungal

activity against Microsporam audouinii, Trichophyton mentagrophtes, Candida

albicans and Aspergillus Niger.

 Khairy A M et al., (2009)51 prepared novel 4-(3H)-quinazolinone containing

biologically active thiazole, pyrazole, 1,3-diathiazole, pyridine, chromene,

pyrazolopyrimidine and pyranochromene of expected biological activity. All the

synthesized compounds were evaluated for their antifungal activity against Aspergillus ochraceus Wilhelm and Fusarium oxysporium fungi.

H3C CH3 N N CH2 NH I NH N NHPh CH2 N CH3

 Al-Deeb A O et al., (2008)52 synthesized of some new 3H-quinazoli-4-one

derivatives as potential antitubercular agents. All the compounds were evaluated

against Mycobacterium tuberculosis.

I R1 N O N S R2 O

 Dahiya R et al., (2008)53 synthesized some peptide derivatives of iodoquinazolinones

and nitroimidazoles and evaluated their antimicrobial and anthelmintic activities.

They were evaluated their antimicrobial activity such as Bacillus subtilis (NCIM

2063), Staphylococcus aureus (NCIM 2079), Pseudomonas aeruginosa (NCIM 2034)

and Klebsiella pneumoniae (NCIM 2011) and fungal strains Microsporum audouinii

(MUCC 545), Trichophyton mentagrophytes (MUCC 665), Candida albicans

(MUCC 29) and Aspergillus Niger (MUCC 177).

O NH OH X OH O I N

 Desai A R et al ., (2005)54 performed Niementowski reaction that is microwave

induced and conventional synthesis of quinazolinones and 3-methyl-1H-5-

pyrazolones and their antimicrobial activity. All compounds were screened for their

antifungal against Candida albicans and Candida krusei and antibacterial against B.

subtilis, S.aureus as gram positive and E.coli, P. aeruginosa as gram negative bacteria.

CH Y X N 3 N N H

7. Materials and Methods:

7.1 Method of collection of data:

A. Synthesis of Target Molecules:

The synthesis of title compounds will be carried out following the given scheme for which

the collection of data is as below:

1. The homogeneity of the compounds is monitored by TLC technique and Rf values are

recorded.

2. Percentage of yield, physical constant, solubility and elemental analytical data for

each compound will be determined and recorded.

3. Spectroscopic data of new compounds i.e. I.R., NMR, Mass spectral data will be

recorded for structural confirmation of few synthesized compounds. IR spectra in

KBr (cm-1) would be recorded on a Schimadzu FTIR-8000 series spectrophotometer

1 and H NMR spectra (CDCl3/DMSO-d6) on EM 390 MHz spectrometer using TMS as

internal standard (Chemical shifts are expressed in δ ppm). Mass spectra would be

recorded on a Jeol JMSD-300 Mass Spectrometer operating at 70 eV.

B. Biological activity:

 Antimicrobial screening55,56:

Antibacterial activity of the compounds would be carried out against gram positive

and gram negative bacteria and antifungal activity against fungal strains by disc

diffusion or cup and plate method to determine zone of inhibition (in mm). During

the study, appropriate standard antibacterial and antifungal drugs, respectively, would be used to compare the activities.

 Antitubercular activity57:

Antitubercular activity would be carried out by Middle brook 7H9 agar medium

against Mycobacterium tuberculosis H37 RV strain. Middle brook 7H9 agar medium

containing different derivatives, standard drug as well as control is inoculated at 37oC

for four weeks. At the end of four weeks they are checked for growth and scaled for

growth inhibition.

7.2 Synthetic strategy:

All the compounds in the present study would be synthesized by following given scheme.

The starting material 1,3,4-benzoxazinone will be synthesized from anthranilic acid by known method. It is then reacted with active hydrogen atoms of amino group bearing moiety by conventional synthetic methods to form 2,3 disubstituted Quinazolinone nucleus. The hydrazide of which is then treated with different aryl aldehydes to yield Schiff bases which are further cyclized to prepare different azetidin-2-ones by the reaction with appropriate cyclising agent(s).

SCHEME O O

OH O Glycine N

N CH3 N CH3

(i) esterification (ii) NH2-NH2.H2O (99%) O

substituted benzaldehyde O derivatives

H N N N Ar

Appropriate cycling agent O

H Ar N N N

O N CH 3 O R TITLE COMPOUNDS

7.3 Source of data: 1. From available literature. 2. From library based books 3. Web sites - www.sciencedirect.com. - http://jgate-helinet.informindia.co.in - www.pubmed.com. - www.scirus.com . - www.herbmed.com.

7.3-1 Assessment of toxic effect: ------Not applicable ------7.3-2 Screening of Statistical analysis: ------

7.3-3 Does the study require any investigations or interventions to be conducted on patients or humans or animals? If so, please describe briefly. ------No------

7.3-4 Has ethical clearance been obtained from your institution in case of 7.4? ------Not applicable------8. List of References: 1. Southgate R. The synthesis of natural β-lactam antibiotics. Contemp. Org. Synth.

1994, 1, 417-431.

2. Morin R B, Gorman M. Chemistry and Biology of β-Lactam Antibiotics. Academic

Press, New York, 1982.

3. Mata E G, Fraga M A, Delpiccolo C M L. An efficient stereo selective solid-phase

synthesis of β-lactams using Mukaiyama’s Salt for the Staudinger Reaction. J Comb

Chem. 2003, 5, 208-210.

4. Page E I. The Chemistry of β-Lactams. Blackie Academic and Professional. New

York, 1992.

5. Niccolai D, Trasi L, Thomas R J. The renewed challenge of antibacterial

chemotherapy. Chem Commun. 1997, 2333-2342.

6. Chu D T W, Plattner J I, Katz L. New Directions in Antibacterial Research. J Med

Chem. 1996, 39, 3853-3874.

7. Van der Steen F H, Van Koten G. Synthesis of 3-amino-2-azetidinones: A literature

survey. Tetrahedron, 1991, 47, 7503-7524.

8. Abraham E P and Florey H W. Lancent II, 1941,177.

9. Emmerson A M, David. Green Wood’s Antimicrobial Chemotherapy, 1995,3,306.

10. Clereq D. Clin Microbial Rev.1997, 10, 674.

11. Alterman M and Samuelsson B. J Med Chem, 1998,41, 3782.

12. Alcaide B, Almendros P, Aragoncillo C. β-Lactams: Versatile building blocks for the

stereoselective synthesis of non-β-lactam products. Chem Rev. 107, 11, 4437-4492

13. Bhalla A, Madan S, Venugopalan P, Bari S S. C-3 β-lactam carbocation equivalents:

versatile synthons for C-3 substituted β-lactams. Tetrahedron 62 (21): 5054-5063

(2006).

14. Chavan A A, Pai N R. Synthesis and Biological Activity of N-Substituted-3-chloro- 2-azetidinones. Molecules 12 (11): 2467-2477 (2007).

15. Jocoby G A. Extended-spectrum β-lactamases and other enzymes providing

resistance to oxyimino-β-lactams. Infect Dis Clin North Am. 11 (4): 875-887 (1997).

16. Conte L J. Fluorine Chem. 1995, 70, 175.

17. Singh V K S, Gulati A and Shankar K. Antiparkinsonian agents from quinazolinyl

thiazolidinones and azetidinones. Indian Journal of Chemistry. 1987; 26:652-656.

18. Gupta D P, Ahmad S, Kumar A and Shankar K. Newer quinazolinone derivatives as

anthelmintic agents. Indian Journal of Chemistry. 1988; 27(B):1060-1062.

19. Mukherji D D, Nautiyal S R, Prasad C R and Dhawan B N. CNS-depressant activity

of some newly synthesized 4(3H)-quinazolones. Indian Journal of Medical Research.

1980; 71:480-482.

20. Joshi V, Chaudhari R P. Synthesis, characterization and antibacterial activity of some

new 2,3,6-trisubstituted quinazolin-4(3H)-ones. Indian Journal Chemistry. 1987;

26(B):602.

21. Desai AR and Desai K. Niementowski reaction: microwave induced and

conventional synthesis of quinazolinones and 3-methyl-1H-5-pyrazolones and their

antimicrobial activity. ARKIVOC. 2005 (xiii) 98-108

22. Chaurasia M R, Sharma S K. The synthesis of 6,8-disubstituted-2-phenyl-3-

(substituted benzothiozol-2-yl)-4-(3H)-quinazolinones and their antifungal activity.

Journal Indian Chemical Soc. 1972; 49:370.

23. Pandey V K and Lohani H C. The anti-tumour activity of 2-aryl/alkyl-3(2-amino

ethyl-1, 3, 4-thiadiazol-5-yl) quinazolin-4(3H) ones. Journal Indian Chemical Soc.

1979; 56:415.

24. Ravi S, Devender R A, Malla R V and Sattur P B. The synthesis of new N4-(N-(6,8-

dibromo-2-methyl-3-quinazolin-4(3H)-one)acetamido)-N1-substituted

sulfanilamides. Current Science. 1984; 53:1069.

25. Mishra V S and Sunita D. The synthesis of 2-phenyl-3-benzimidazolyl-alkyl/aryl-6- bromoquinazoline-4(3H)-ones. Journal Indian Chemical Society. 1978; 55:172.

26. Kumar R, Gupta T K and Surendra S. The synthesis of quinazolone azomethines for

CNS depressant activity. Indian Journal Pharm. 1970; 33:108.

27. Tiwari S S and Pandey V K. The synthesis of some new benzoxinones and their corresponding quinazolinones. Journal Indian Chemical Society. 1975; 52:736. 28. Raghu R A and Rajesh H B. The synthesis and bronchodilator activity of benzimidazo (1, 2,-c) quinazolines .Indian Journal Chemistry. 1999; 38(B):434.

29. Bhagat TM, Rathod SP, Swamy DK, Kuberka SV. Synthesis and antibacterial

activity of 2-azetidinone containing benzothiazolyl moiety. International Journal of

ChemTech Research. 2012;4(1):272-276.

30. Manu S, Pramilla S. Synthesis and antimicrobial activity of 2-azetidinones derived

from benzimidazole. Journal of Chemical and Pharmaceutical Research.

2012;4(1):146-153.

31. Kokila P, Rekha P, Sarju P, Sejal J, Rinku P. Synthesis and antimicrobial activity of

novel 3-chloro- [1- (3,6-(diphenyl) [1,2,4] triazolo [3,4b][1,3,4] thiadiazole)] -4-(3,4-

diethoxy phenyl)-azetidin-2-one and their derivatives. Journal of Applied

Pharmaceutical Science. 2012;2(1):114-118.

32. Meshram J S, Chopde H N, Pagadala R, Jetti V. An efficient synthesis of novel

bioactive azetidinones and thiazolidinones. International Journal of Pharma and Bio

Sciences. 2011; 02:6299.

33. Taj T, Kamble R R, Gireesh T, Badami B V. An expeditious green synthesis of

Schiff bases and azetidinones derivatised with 1,2,4-triazoles. J. Chem. Sci. 2011;

123:657.

34. Srivastava Y K, Malhotra G, Gothwal P. Microwave induced synthesis of some

biologically active azetidinones. Der Chemica Sinica. 2011; 2(3):47.

35. Jubie S, Gowrwmma B, Muthal N K, Kalirajan R, Gomathi S, Elango K. Synthesis and antimicrobial evaluation of some 2-azetidinone derivatives. International journal

of Chem Tech Research. 2009; 1(2):153-157.

36. Toraskar M P, Kadam V J, Kulkarni V M. Synthesis and antifungal activity of some

azetidinones. International Journal of Chem Tech Research. 2009; 1(4):1194-1199.

37. Vijay Kumar M M J, Nagaraja T S, Shameer H, Jayachandra E, Sreenivasa G M. N-

substituted-3-chloro-2-azetidinones: Synthesis and characterization of new novel

anti-inflammatory agents. Journal of Pharmaceutical Sciences and Research. 2009;

1(2):83-92.

38. Bhat I K, Chaithanya S K, Satyanarayana P D, Kalluraya B. The synthesis and

antimicrobial study of some azetidinone derivatives with the para-anisidine moiety. J.

Serb. Chem. Soc. 2007; 72(5):437-442.

39. Chavan A A, Pai N R. Synthesis and biological activity of N-substituted-3-chloro-2-

azetidinones. Molecules. 2007; 12:2467-2477.

40. Patel K H and Mehta A G. Synthesis and antifungal activity of azetidinone and

thiazolidinone derivatives of 2-amino-6-(2-naphthalenyl)thiazolo[3,2-d]thiadiazole.

E-Journal of chemistry. 2006; 3(13):267-273.

41. Patel K H, Mehta A G. Synthesis of novel azetidinone and thiazolidinones

derivatives and evaluation of their antimicrobial efficacy. E-Journal of chemistry.

2006; 3(11):103-109.

42. Tan S, Guner V A, Ergene A. Antimicrobial activity of 4-substituted-styryl-2-

azetidinones. Turkish J. Pharm. Sci. 2005; 2(1):11-15.

43. Shah RM, Prajapati NK, Patel PS. Synthesis and characterization of novel 2-thioxo-

quinazolin-4-one derivatives. International Journal of Science Innovations and

Discoveries. 2012;2 (1):90-93.

44. Zumuretiguli A, Yufeng W, Haiyang T, Xiaoting H, Aidong Z. Facile Synthesis and

Herbicidal Evaluation of 4H-3,1-benzoxazin-4-ones and 3H-quinazolin-4-ones with

2-phenoxymethyl substituent. Molecules. 2012;17:3181-3201 45. Venkatesh P, Tiwari VS. Design and synthesis of Quinazolinone, Benzothiazole

derivatives bearing guanidinopropanoic acid moiety and their Schiff bases as

cytotoxic and antimicrobial agents. Arabian Journal of Chemistry, King Saud

University. (2011).

46. Abbas S Y, Ammar Y A, Mohamed El-sharief A M, El-gaby M S A. Synthesis of

some biologically active 4-(3H)-quinazolinones derived from 2,3-pyridine

dicarboxylic anhydride. Chemical Sciences Journal. 2011; CSJ-15:1-10.

47. Revanasiddappa H D, Prasad K S, Shiva K L, Jayalakshmi B. Synthesis and

biological activity of new Schiff base containing 4-(3H)-quinazolinone ring system.

International Journal of Chem Tech Research. 2010; 2(2):1344-1349.

48. Reddy P S N, Mittapelli V, Reddy V D. Antibacterial, antifungal and antifeedant

activity of quinazolinoyl-β-lactams/quinazolinones and bis (quinazolinoyl-β-

lactams). Rasayan J. Chem. 2010; 3:635-640.

49. Rajasekaran S, Rao G, Sanjay P P N. 2D QSAR studies of some novel quinazolinone

derivatives as antitubercular agents. J. Comput. Method. Mol. Design. 2011; 1(3):69-

50. Kaur P, Kaur A, Kaur R, Kaur K. quinazolinone peptides: new approach as potent

medicinal agents. Journal of global pharma technology. 2010; 2(4):35-39.

51. Khairy A M, El B, Aly M M, Mohamed Y A, Basyouni W M, Abbas S Y. Novel

4(3H)-quinazolinone containing biologically active thiazole, pyrazole, 1, 3-

dithiazole, pyridine, chromene, pyrazolopyrimidine and pyranochromene of expected

biological activity. World Journal of Chemistry. 2009; 4(2):161-170.

52. Alu-deeb A O, Alafeefy A M. Synthesis of some new 3H-quinazoline-4-one

derivatives as potential antitubercular agents. World Applied Sciences Journal. 2008;

5(1):94-99.

53. Dahiya R, Anil K, Yadav R. Synthesis and biological activity of peptide derivatives

of iodoquinazolinnones/nitroimidazoles. M D P I. 2008; 13:958-976. 54. Desai A R, Desai K. Niementowski reaction: Microwave induced and conventional

synthesis of quinazolinones and 3-methyl-1H-5-pyrazolones and their antimicrobial

activity. ARKIVOC. 2005; xiii: 98-108.

55. Sadana A K, Miraza Y, Aneja K R, Prakash O. Hypervalent iodine mediated

synthesis of 1-aryl/ hetryl-1,2,4-triazole [4,3-a] pyridines and 1-aryl/ hetryl 5-methyl-

1,2,4-triazole [4,3-a]quinolines as antibacterial agents. Eur J Med Chem. 2003; 38:

533-536.

56. Greenwood D, Snack R, Peurtherer J. Medical microbiology: A guide to microbial

infections: Pathogenesis, immunity, laboratory diagnosis and control. 15th ed. 1997.

57. Elmer WK, Stephen DA, William MJ, Paul CS and Washing CW. Text book of

Diagnostic Microbiology, 5th Edn (Lippincot and Pubmed), 2002. 9. SIGNATURE OF CANDIDATE

(Mr. SIRAJ HUSSAIN ANSARI) 10. REMARKS OF THE GUIDE The work is highly justifiable, would yield significant data for researchers and is feasible to work in this institution. 11. NAME AND DESIGNATION OF Prof. G. SUDHEENDRA M Pharm. (Ph.D) 11.1 GUIDE PROFESSOR & HEAD 11.2 SIGNATURE

11.5 HEAD OF DEPARTMENT Prof. G. SUDHEENDRA M Pharm. (Ph.D)

11.6 SIGNATURE

12. REMARKS OF THE CHAIRMAN AND PRINCIPAL

Recommended and Forwarded

12.1 SIGNATURE

(Principal)