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

DESIGN, SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF SOME NOVEL AZETIDIN-2-ONE DERIVATIVESM. 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, GULBARGA2014 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALOREANNEXURE IIPROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION1. NAME OF THE CANDIDATE AND Mr. SIRAJ HUSSAIN ANSARI ADDRESS LUQMAN COLLEGE OF PHARMACY, BEHIND P&T QUARTERS, OLD JEWARGI ROAD, GULBARGA-5851022. NAME OF THE INSTITUTION LUQMAN COLLEGE OF PHARMACY, BEHIND P&T QUARTERS, OLD JEWARGI ROAD, GULBARGA-5851023. COURSE OF STUDY AND SUBJECT M.PHARM(PHARMACEUTICAL CHEMISTRY)4. DATE OF ADMISSION OF COURSE 08-07-20135. 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-ONESAzetidin-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-ONESQuinazolin-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 NN CH2 R N CH2 R N NO O2S NH N O O2S NH NO Cl O OCl 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 3H3C N CH3 H3C N CH3 N N N N N NR N N O RO 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. OH3C 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.RN N NH2 NCl O 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).H3COR NO Cl 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.N NN RCH2CONHO Cl 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 3HO HO Cl ClN 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 wereBacillus 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.O RHN CH2 C NH NO ClOCH3 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 of2-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(Azetidinone) (Thiazolidinone) 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(Azetidinone) (Thiazolidinone) 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 ATCC90030.R1 R3R3 N OR2B) 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.OR O Br NN S H Haiyang T et al., (2012)44 performed Facile Synthesis and Herbicidal Evaluation of4H-3,1-benzoxazin-4-ones and 3H-quinazolin-4-ones with 2-phenoxymethyl substituent. OO 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.N HNNH 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 asAspergillus ochraceus wilhelm and Penicillium chrysogenum Thom.ONH2 NN N Revanasiddappa H D et al., (2010)47 synthesized new Schiff bases containing4(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.N CH3N NCH2 R 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. ONH2 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.NO N H 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.OI 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 (NCIM2063), 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 NN CH3 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.O OCH Y X N 3 N N HO N R7. 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 inKBr (cm-1) would be recorded on a Schimadzu FTIR-8000 series spectrophotometer1 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 OOH O Glycine NON CH3 N CH3(i) esterification (ii) NH2-NH2.H2O (99%) OH NN NH2ON CH3 substituted benzaldehyde O derivativesH N N N ArON CH3Appropriate cycling agent OH Ar N N NO N CH 3 O R TITLE COMPOUNDS7.3 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. 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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 SIGNATURE11.5 HEAD OF DEPARTMENT Prof. G. SUDHEENDRA M Pharm. (Ph.D)11.6 SIGNATURE12. REMARKS OF THE CHAIRMAN AND PRINCIPALRecommended and Forwarded12.1 SIGNATURE (Principal)

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

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