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Mrunmayee Toraskar et al. / Journal of Pharmacy Research 2010, 3(1),169-173 Review Article ISSN: 0974-6943 Available online through http://jprsolutions.info Azetidinone : A bioactive moiety Mrunmayee Toraskar*1, Vithal Kulkarni2, Vilasrao Kadam1 Bharati Vidyapeeth’s College of Pharmacy,Department of Pharmaceutical Chemistry, Sec-8,C.B.D. Belapur, Navi Mumbai 400614,India 2 poona College of Pharmacy, Erandwane, Pune-38,India Received on: 20-09-2009; Revised on: 14-10-2009; Accepted on:18-12-2009 1 ABSTRACT 2-Azetidinone is a ß-lactam cyclic amide with four atoms in a ring. Traditionally ß-lactam is a part of structure of broad spectrum antibiotic class of drugs – penicillins and cephalosporins .The ring ultimately is proven to be a generic descriptor for penicillin family. These molecules operate by forming a covalent adducts with membrane bound bacterial transpeptidases which are also known as penicillin binding proteins (PBPs), involved in the biosynthesis of cell walls.Cycloaddition of monochloracetylchloride with imine (Schiff base) result in formation of 2azetidinone(ß-lactam).Present work is an attempt to review chemistry, synthesis, spectral studies and applications of 2-azetidinones. Keywords: 2-Azetidinone, ß-lactam, Cyclic amide, Antibacterial INTRODUCTION The chemistry of ß-lactams has taken an important place in organic chemistry since the discovery of Penicillin by Sir Alexander Fleming in 1928 and shortly thereafter Cephalosporin which were both used as successful antibiotics. Even now the research in this area is stimulated because of development of bacterial resistance to widely used antibiotics of this type1. There is a need for functionalized ß- lactams or for new active principles in ß- lactam series. Apart from antibiotic activity ß- lactam also possess cholesterol inhibition, antithrombotic, antiviral and antifungal activities.The 2-azetitinone (ß- lactams) ring is a common structural feature of a number of broad spectrum ß-lactam antibiotics including penicillins, cephalosporins, carbapenems, nocardicin and monobactams which have been widely used as chemotherapeutic agents to treat bacterial infection and microbial diseases.2,3 These molecules operate by forming a covalent adduct with membrane bound bacterial transpeptidases which are also known as penicillin binding proteins (PBPs) involved in the biosynthesis of cell wall.4 These mechanism based inhibitors prevent the construction of cell wall and eventually lead to cell lysis and death. Moreover due to their ß- lactamase inhibitory action 2-azetidinones based heterocycles represent an attractive target of contemporary organic synthesis.5 It has been reported that introduction of different substituents to four membered ß-lactam nucleus tend to exert profound influence in conferring promising biological activities.We have recently reported synthesis and antimicrobial screening of 2-(1Hbenzotriazol-1-yl)-N-[3-chloro-2-(substituted phenyl)-4-oxoazetidin1-yl] acetamide6. Ezetimibe, 1-(4-fluorophenyl)-3(R)-(3-(4-fluorophenyl) 3(S)hydroxypropyl)-4(S)-(4-hydroxyphenyl)-2-azetidinone, is a selective cholesterol absorption inhibitor that effectively blocks intestinal absorption of cholesterol. Such drugs prevent the absorption of cholesterol, by inhibiting the passage of dietary and biliary cholesterol across the intestinal wall. These drugs represent a new class of pharmaceutical agents that can be used to treat patients with hypercholesterolemia. Ezetimibe alone, or in combination with statins, effectively reduce LDL-C concentrations. It also increases high-density lipoprotein cholesterol (HDL-C), and may reduce elevated triglyceride (TG) concentrations. CHEMISTRY OFAZETIDINONES The name lactam is given to cyclic amides.In older nomenclature second carbon in an aliphatic carboxylic acid was designated as α ,the third as ß and so on.Thus a ß- lactam is a cyclic amide with four atoms in its ring.The contemporary name for this ring system is azetidinone. ß- lactam came to be a generic descriptor for penicillin family.The ring ultimately proved to be the main component of the pharmacophore. So the term possesses medicinal as well as chemical significance. N O H SPECTROSCOPIC STUDIES *Corresponding author. Mrunmayee Toraskar Bharati Vidyapeeth’s College of Pharmacy,Department of Pharmaceutical Chemistry,Sec-8,C.B.D. Belapur, Navi Mumbai 400614,India Tel.: + 91-9867715334 E-mail:. [email protected];[email protected] I.R.Study The carbonyl C=O group shows a strong stretching absorption in the region of 1870-1640 cm-1. High intensity and freedom from Journal of Pharmacy Research Vol.3.Issue 1.January 2010 169-173 Mrunmayee Toraskar et al. / Journal of Pharmacy Research 2010, 3(1),169-173 interfering bands make it the easiest band to recognize in IR spectra. Also, the position is affected by factors such as electronic and mass effect of neighbouring substituents, conjugation, hydrogen bonding and ring strain.7 N.M.R.Study The chemical shift of the protons at C3 and C4 explains the effect of the substituents which are attached to these carbons. Electronegative substituents, such as chloro and azido attached to C3 reduce the electron density around the proton attached to C3 resulting in strong deshielding effect on this proton. The greater the electronegativity of the substituent, the more it deshields the proton adjacent to it, and hence, the greater the chemical shift of this proton8. 2. Wasserman Cyclization Roger Joyeau et al10 studied the stability of 2-azetidinones to enzymatic ring opening by ß-lactamases. They suggested that a halogen ß- to the carbonyl would increase the IR absorption of the C=O, one of the criteria of the reactivity of the ß-lactam in this aspect. Fluorine substitution, which will not introduce a large steric hindrance, is particularly interesting for a possible biological effect and possible stability towards ß -lactamase. ß -Bromopropionamide derivative (2) was prepared, which can be cyclized by wasserman procedure using sodium hydride to give the N-(3-carboxy-6-methylphenyl) 3- difluoro-2azetidinone (3). F SF4 BrCH2CF2COOEt BrCH2COCOOEt ClSO3H Br H2NAr F Cl SYNTHETIC METHODS OFAZETIDINONES O F The recent and the advanced increase in both the spectrum of ß – lactam antibiotics and the number of the known producing organisms is due to the development of new and more sensitive screening techniques. Further progress had been added by continuous synthetic derivatization to those monocyclic ß -lactam compounds. Many methods had been reported in the literature. Some of those methods were listed in this study. Br F F N CH3 NaH F O CH3 H N O 3 2 HOOC HOOC Scheme 2 1. Ketene-imine Cycloaddition 3. Synthesis of ß-Lactams from Imidates The ketene-imine cycloaddition was reported by Staudinger9 to be a smooth well-documented route to the synthesis of substituted ß lactam derivatives. In an effort to investigate a suitably substituted monocyclic ß -lactam as a minimum requirement for biological activity, many scientists reported the trans stereoselective synthesis of butadienyl azetidinones and their Diels-Alder cycloaddition. This included the preparation of a series of Schiff’s bases and their reaction with dienylketene to produce a trans azetidinone .This involved the in situ formation of the ketene and its subsequent addition to the imine. Cardellini and his group11 reported the synthesis of alkoxy ß -lactams via acid chloride imine route. Imidates (4) such as substituted Nphenyl formimidate, were reacted with acid chlorides to produce ß lactam (6). The major feature of this synthesis is its high stereoselectivity, only trans -4-alkoxy- ß -lactams were formed. H TEA RO-CH=N-C6H5 + H OR X X-CH2-COCl N CH2Cl2 O 4 R R O O TEA Cl + CH2Cl2 H H R1 Scheme 1 6 N N R1 Scheme 3 4. ß -Lactam Formation Using Microwave Irradiation Formation of 2-azetidinones by the reaction of an acid chloride, Schiff’s base and a triethylamine seems to involve multiple pathways, some of which are very fast at higher temperatures. When it is conducted in open vessels in unmodified domestic microwave ovens, high level irradiation leads to preferential formation of trans ß -lactams in several cases when the Schiff’s base is derived from an aryl aldehyde rather than glyceraldehydes acetonide.12 MW PhCH2O-CH2COCl + PhCH2O PhCH=N-CH2Ph N Chlorobenzene O Journal of Pharmacy Research Vol.3.Issue 1.January 2010 Ph PhCH2O + CH2Ph Ph N O 169-173 CH2Ph Mrunmayee Toraskar et al. / Journal of Pharmacy Research 2010, 3(1),169-173 5. Acid Chloride Addition Reaction Bose et al13has applied a method to prepare ß-lactams which involved the reaction between benzylideneaniline and few selected acid . carbohydrazide with chloroacetyl chloride and triethylamine.The compounds were screened in-vitro for their antimicrobial activity against S.aureus,P.aeruginosa, A.niger and C.albicans.15 R2 R1 R3 XCH CHR 2 C H 2X CH R R Cl NAr CO Cl O C NA r H N O N N O Cl O X H C CH R O C NAr E t3 N H 2C CH R O C NAr Cl X Cl 3.Anand K.Halve,Deepti Bhadauria and Rakesh Dubey studied synthesis and antimicrobial activity of 3 chloro-4-(3-methoxy-4-acetyl oxyphenyl)-1-[3-oxo-3-(phenylamino) propanamido] azetidin 2-ones and 3 chloro–4-[2-hydroxy-5- ( nitro substituted phenylazo) phenyl ]16 1- phenylazetidin 2- ones. X R2 Cl H C CH R O C N X Ar CH O C H 2R 2 O C N O O Ar NH O NH N N R Scheme 5 H H Cl BIOLOGICALACTIVITIES OFAZETIDINONES H3C Antibacterial activity. H H Cl N N O O O2N 1. Ameya A.Chavan , and Nandini R. Pai reported synthesis of 2{2-[3-chloro-2-(aryl)-4- oxoazetidin-1-ylamino] acetylamino} benzothiazole-6-carboxylic acid. 2- amino aminobenzothiazole -6 carboxylic acid on condensation with chloroacetyl chloride yielded 2- ( 2-chloroacetyl amino) benzothiazole-6- carboxylic acid which on amination with hydrazine hydrate gave 2- ( 2hydrazinoacetyl amino) benzothiazole-6- carboxylic acid.These subjected to Schiff reaction in presence of glacial acetic acid with various aromatic aldehydes.The Schiff’s bases obtained ,upondehydrative annulation in presence of chloroacetyl chloride and triethylamine yielded 2-{2-[3-chloro-2-(aryl)-4- oxo azetidin-1-ylamino] acetylamino} benzothiazole-6-carboxylic acid. The compounds were screened for antibacterial activity against S.aureus, B.subtilis, P.aeruginosa and E.coli14. O NH HOOC N N H Cl O Cl H O N N N NH Ar O Cl O N 4. N.C Desai , M.D Shah & A.M Bhavsar prepared N- ( 3-Chloro-2oxo-4 arylazetidinyl) {4-[5 oxo-2 phenyl- 4- ( phenylmethylene) ( 2imidazolinyl] phenyl} carboxamides and N (3-chloro-2-oxo-4arylazetidin-1-yl)-2-(4-chlorophenyl) acetamides and evaluated for their antibacterial activity against E.coli and S. aureus in terms of minimum inhibitory concentration.Also QSAR studies for the compounds were done for structural and physicochemical parameters.17 R H Ar O O S Cl N 2.Gundibasappa K. Nagaraja,Gowdara K. Prakash,Marlingaplara N. Kumaraswamy,Vijayavittala P.Vaidya and Kittappa M. Mahadevan have synthesized N-[3- chloro-2- (2- chloroquinolin-3-yl)-4 oxoazetidin-1-yl] naphtho [2, 1-b] furan -2-carboxamide as antimicrobial agents by reacting Schiff’s bases of naphtho [2,1-b] furan– N Journal of Pharmacy Research Vol.3.Issue 1.January 2010 169-173 Mrunmayee Toraskar et al. / Journal of Pharmacy Research 2010, 3(1),169-173 5.N.C Desai,Dipika Dave,M.D. Shah and G. D Vyas have investigated the synthesis and antibacterial activity of Methyl 2-{2-[3-chloro-4-oxo1-(4-nitrophenylcarbonylamino)azetidin-2yl]phenoxy}-acetate against S.aureus and Salmonella typhi.18 O O S Cl N O N N R O 9. (15) K.M Thakar , V.V Kachhadia and H.S Joshi have synthesized 4-Aryl-3-chloro-1-(3’,5’-dichloro-2’benzo (b) thio phenoylamino)-2azetidinones and evaluated their antimicrobial activity against E.coli, S.aureus, P.vulgaris and A.niger .Also the compounds were tested for their antitubercular activity against M.tuberculosis H37Rv.22 O O O Ar N N H Cl Cl Cl O O N S N Cl R Cl H O Anticonvulsant activity 10. S.K Srivastava, S.Srivatsava & S.D Srivastava synthesized 1- [5’(N9- Carbazolylmethyl) - 1’, 3’, 4’- thiadiazole- 2-yl)]- 4-substituted -3 chloro-2 oxo- azetidines.The compounds were screened for their anticonvulsant activity and anti-inflammatory activity at 50 mg/kg 23 R O H N N H S 6. 4,4’-Bis(3-chloro-4-(4-methyl phenyl)-2-oxo-azetidin-1-yl)diphenyl sulphone have been synthesized and screened for in-vitro antifungal and antitubercular activity by P.D.Mehta, N.P.S.Sengar et al 19 R O Cl O O O N N Antitubercular activity Ar N S 7.4 Aryl-3-chloro-1- (benzimidazole-2yl-benzamido)-2- azetidinones were studied by Preeti Kaythara, Tejas Upadhayay, Rajeev Doshi and H.H Parel and tested in-vitro for their antitubercular activity against M.tuberculosisH37Rv.20 N O Cl Anticancer activity 11.Robert M. Adlington, Jack E. Baldwin, Gerald W. Becker, Beining Chen, Leifeng Cheng, Stephen L. Cooper, Robert B. Hermann, Trevor J. Howe, William McCoull, Ann M. McNulty, Blake L. Neubauer, and Gareth J. Pritchard synthesized and studied prostate specific antigen inhibiting activity of 2-azetidinones.24 N N H O R N H O N Cl 8. Khyati A Parikh, Paresh S.Oza , SB Bhatt and A.R Parikh studied synthesis of 4- aryl -1-(4’-a-methoxyimino-carbmethoxy methyl thiazol-2’-yl)-3-chloro- 2- azetidinones and evaluated the compounds for their antitubercular activity against M. tuberculosisH37Rv.21 Journal of Pharmacy Research Vol.3.Issue 1.January 2010 169-173 Mrunmayee Toraskar et al. / Journal of Pharmacy Research 2010, 3(1),169-173 Antiviral activity 12. Alan D. Borthwick, Gordon Weingarten, Terry M. Haley, Mirek Tomaszewski , Wei Wang , Zhouhan Hu Jean Bedard , Haloun Jin , Leonard Yuen , Tarek S. Mansour studied design and synthesis of monocyclic ß-lactams as mechanism based inhibitors of human cytomegalovirus protease which have been shown to acylate the viral enzyme in a time dependant manner.25 R1 8. 9. 10. 11. 12. OAc R2 7. 13. N NHR4 O 14. O 15. C.N.S.Activity 16. 13.Rajesh K Goel, Amanpreet Singh, Pattipati S Naidu, Mohinder P Mahajan, Shrinivas K Kulkarni studied some azetidin-2-ones as C.N.S modulating agents which were previously synthesized and evaluated for hypolipidemic and antihyperglycemic activity based on the predictions made by the computer software “Prediction of Activity Spectra for Substances (PASS)”.26 17. 18. CONCLUSION 19. ß-lactams are still the most prescribed antibiotics in medicine.The activity of famous antibiotics such as penicillin,cephalosporins and carbapenems are attributed to the presence of 2-azetidinone ring in them. The literature confirms that the 2-azetidinone moiety have diverse biological activities such as antimicrobial, antiviral, anticancer, cholesterol absorption inhibition and enzyme inhibition. 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Desai, N.C ,Dave, D.,Shah M.D. and Vyas G.D , Synthesis and antibacterial activity of some novel 4 oxo- 1,3 thiazolidines, 2 oxo azetidines and 5 oxoimidazolines, Part vi, Indian Journal of Chemistry, Vol 39B, April 2000 ,277-282 Mehta P.D., Sengar N.P.S. ,Subramaniyam E.V.S. and Satyanarayana D.,Synthesis and biological activity studies of some thiazolidinones and azetidinones.,Indian Journal of Pharmaceutical Sciences, JanFeb 2006, 103-106 Kaythara P, Upadhayay T,Doshi R and Parel. H.H, Synthesis of some 2-azetidinones as a potential anti- tubercular agents, Indian Journal of Heterocyclic Chemistry, Vol 10, July- Sep 2000, 09-12. Parikh Khyati A , Oza P. S , Bhatt S.B and Parikh A.R, Synthesis of some new 2-azetidinones as potential anti tubercular agents. Indian Journal of Chemistry, Vol 39 B,September 2000, 716-718. Thakar K.M, Kachhadia V.V and Joshi H.S, Synthesis of 4thiazolidinones and 2-azetidinones bearing benzo (b) thiophene nucleus as potential antitubercular and antimicrobial agents, Indian Journal of Chemistry, Vol 42B. June 2003, 1544-1547. Srivastava S.K, Srivatsava S. and Srivastava S.D, Synthesis of new carbazolyl –thiadiazol -2-oxo- azetidines , Indian Journal of Chemistry, Vol Feb-1999, 183-187. Adlington R. M., Baldwin J. E., Becker G. W., Chen B, Cheng L, Cooper S. L.,etal.;Design, Synthesis, and Proposed Active Site Binding Analysis of Monocyclic 2-Azetidinone Inhibitors of Prostate Specific Antigen, J. Med. Chem., 2001, 44 (10), 1491–1508 Borthwick A. D., Weingarten G, Haley T. M., Tomaszewski M, Wang Wei et alDesign and synthesis of monocyclic ß-lactams as mechanism based inhibitors of human cytomegalovirus protease.. Bioorganic & Medicinal Chemistry Letters, 8 (1998) 365-370 Goel R. K, Singh A, Naidu P. S, Mahajan M. P, Kulkarni S. K ;PASS assisted search and evaluation of some azetidin-2-ones as C.N.S. active agents.;J Pharm Pharmaceut Sci (www.cspscanada.org) 8(2):182- 189, 2005 Source of support: Nil, Conflict of interest: None Declared Journal of Pharmacy Research Vol.3.Issue 1.January 2010 169-173