Name: Fathers name: Registration for: Name of Supervisor: Name of Institute: Biological Research Topic : Azetidinones.

Deenish Dabeer Sheikh Dabeer M.S./Ph.D. Prof.Dr.Khalid M.Khan H.E.J.Research Institute of International Centre For Chemical and sciences. University of Karachi,Karachi-75270,Pakistan. Synthesis of biologically active 4-Thiazolidinones and 2-

SUMMARY Thiazolidinone is a saturated form of thiazole with carbonyl group on fourth carbon,has been considered as a magic moiety(wonder nucleus)which posses several types of biological activities.Thaizolidine-4-one and its derivatives exhibit a broad range of biological activities like antifungal,antioxidant,cytotoxic,anti-inflammatory,analgesic,anti YFV(Yellow fever virus)activity, antitubercular, antimicrobial antibacterial, antiviral, anti HIV, antimalarial etc.Their biological activity is reported to be associated with their ability to assume a butterflylike conformation. The binding mode provided by thiazolidinones is similar to that provided by other non-nucleosides reverse transcriptase inhibitors[16].Thiazolidine-4-ones are derivatives of thiazolidine with carbonyl group at fourth position. 2-Azetidinones,commonly known as -Lactams are extremely important heterocyclic compounds.The most familiar classes of antibiotics such as cephalosporins, penicillins and monobactams, and carbapenems are attributed to the presence of 2-azetidinone moiety in them. Lactams also serve as synthons for many biologically significant classes of organic compounds. Their ability to act as powerful antibacterial, antimicrobial, antiinflammatory[17],anticonvulsant[18] and antitubercular has resulted in being used clinically for last few decades. Besides the antibacterial activity[19,20 ],recently ,some other significant biological activities of 2-azetidinone and its derivatives have also been reported like carbonic anhydrase inhibitors[21],local anesthetics[22]and hypoglycemic agent activity, Phospholipase enzyme inhibition[26].It has also been effective on the CNS(central nervous system)[23-25]. Our main objective is to synthesize a variety of known and unknown derivatives of 4thiazolidinones and 2-azetidinones.The synthesized library would be randomly screened for a range of in vitro and in vivo bioassays.The structure elucidations of these compounds and their derivatives would be carried out by various techniques like U.V., I.R., Mass Spectrometry and 1H-NMR studies. References: 1) Pathak AK, Chawala V, Saraf KS. E- J Chem, 2011; 8: 240-244. 2) Patel NB, Shaikh M, Faiyazalam. Saudui pharm J, 2010; 3: 129. 3) Srivastava SK, Srivastava S, Srivastava SD. Indian J Chem, 1999; 38: 183. 4) Chatrabhuji PM, Nimavat K S, Vyas K B, Undavia N K. RJPBCS , 2010;1: 1451. 5) Bhatt J J, Shah B R, Shah H P, Trivedi P B et al. Cheminform, 1994; 25: 189-192.

6) Mei-Hsiu Shih, Fang-Ying Ke. Bioorganic & Med Chem, 2004; 12: 4633 7) S.G.Kucukguzel, E.E.Orul, S.Rollas, F.Salin, A.Ozbek;\ Eur.J.Med.Chem., 37, 197-206 (2002).

8) G.S.Singh, B.J.Molotsi; Il Farmaco., 60, 727-730 (2005).

9) V. P. M.Rahman, S.Mukhtar, W. H.Ansari, G.Lemiere; Eur.J.Med.Chem., 40, 173-184 (2005).

10) D.S.Mehta, V.H.Shah; Indian.J.Heterocyc.Chem., 11,

(2001).

11) R.K.Rawal, Y.S.Prabhakar, S.B.Katti, E.DeClercq; Bioorg.Med.Chem., 13, 6771-6776 (2005). 12) M.G.Vigorita, R.Ottana, F.Monforte, R.Maccari, A. Trovato, M.T.Monforte, M.F.Taviano; Bioorg.Med. Chem.Lett., 11, 2791-2794 (2001). 13) R.Paramashivappa, P.P.Kumar, S.P.V.Rao, S.A.Rao; Bioorg.Med.Chem.Lett., 13, 657660 (2003). 14) B.Goel, T.Ram, R.Tyagi, E.Bansal, A.Kumar, D.Mukherjee, J.N.Sinha; Eur.J.Med.Chem., 34, 265-269 (1999). 15) M.A.Mahran, S.M.El-Nassry, S.R.Allam, L.A.El- Zawawy; Pharmazie., 58, 527-530 (2003). 16) Barreca, M. L.; Carotti, A.; Carrieri, A.; Chimirri, A.; Monforte, A. M.; Pellegrini Calace, M. L.; Rao, A. Bioorg. Med. Chem. 1997, 7, 2283 17) Sreenivasa Rao, D., Jayachandran, E.,Sreenivasa, G.M., Shivakumar, B.,Inhibition of albumin denaturation and anti-inflammatory activity of 2-[N-p-Tolyl sulphon hydrazino]6-fluoro-7- substituted (1,3) benzothiazoles,Oriental J. of Chemistry, 2005, 21(1),113116. 18) Abdel Ghany aly el-helby., Mohammed Hemeda abdel wahed., Acta Pharm.,2003, 53, 127- 138. 19)Kumar.A, Gurtu.S, Agrawal J.C, Sinha J.N, Bhargava K.P and Shanker K. Synthesis and cardiovascular activity of substituted 4-azetidinones, J. Indian Chem. Soc., 1983, LX, 608-609. 20) Patel R.B, Desai P.S and, Chikhalia K.H., Pyrimidinebased thiazolidinones and azetidinones: Antimicrobial and antitubercular agents, Indian J.Chem, 2006, Sec B, 773-

778. 21) Wollesdrof, O.W. Jr., Schwam, H.,Synthesis of 1-o-acyl derivatives of hydroxyl benzothiazol 2-sulfonamide as topically active carbonic-anhydrous inhibitors, Chem. Abstr., 1989, 111,194656 x. 22) Costakes, E., Tsatsas. G., Synthesis of 2- (alkylamino acyl imino) 3-methyl benzothiazolines for local anaesthetic activity, Chem. Abstr., 1979, 90, 203935 q. 23) Ameya A.Ch 19) Sreenivasa Rao, D., Jayachandran, E.,Sreenivasa, G.M., Shivakumar, B.,Inhibition of albumin denaturation and anti-inflammatory activity of 2-[N-p-Tolyl sulphon hydrazino]6-fluoro-7- substituted (1,3) benzothiazoles,Oriental J. of Chemistry, 2005, 21(1),113116. 20) Abdel Ghany aly el-helby., Mohammed Hemeda abdel wahed., Acta Pharm.,2003, 53, 127- 138. 19)Kumar.A, Gurtu.S, Agrawal J.C, Sinha J.N, Bhargava K.P and Shanker K. Synthesis and cardiovascular activity of substituted 4-azetidinones, J. Indian Chem. Soc., 1983, LX, 608-609. 20) Patel R.B, Desai P.S and, Chikhalia K.H., Pyrimidinebased thiazolidinones and azetidinones: Antimicrobial and antitubercular agents, Indian J.Chem, 2006, Sec B, 773778. 21) Wollesdrof, O.W. Jr., Schwam, H.,Synthesis of 1-o-acyl derivatives of hydroxyl benzothiazol 2-sulfonamide as topically active carbonic-anhydrous inhibitors, Chem. Abstr., 1989, 111,194656 x. 22) Costakes, E., Tsatsas. G., Synthesis of 2- (alkylamino acyl imino) 3-methyl benzothiazolines for local anaesthetic activity, Chem. Abstr., 1979, 90, 203935 q. 23) Ameya A.Chavan and Nandini R.Pai., Synthesis and biological Activity of N-substituted-3chloro-2-azetidinones, Molecules., 2007,12, 2467-2477. 24) Freddy H.Havaldar and Sushil Kumar J. Mishra., Synthesis of some azetidi-2-ones and thiazolidin-4-ones as potential antimicrobial Agents. Indian J. Heterocycl., Chem. 2004, 13, 197200. 25) Patel K.H and Mehta A.G., Synthesis and antifungal activity of azetidinones and thiazolidinones derivative of 2-amino-6- (2-naphthalenyl) thiazolo [3, 2-d] thiadiazole, E.J.Chem., 2006, 3(13), 267-273. 26) Anti-Tubercular and Anti-Inflammatory Activities of Azetidin-2-One Derivatives and Their Effects on the
Activity of Phospholipase A2. Mayur C. Yerigeri, Satish Kumar Murari, Kuntebommanahalli N. Thimmaiah, Shanta Kumar Sugur Math and Bannikuppe Sannanaik Vishwanath.Medicinal Chemistry,vol:4(2),2008,190193

Name: Fathers name: Registration for: Name of Supervisor: Name of Institute: Biological

Deenish Dabeer Sheikh Dabeer M.S./Ph.D. Prof.Dr.Khalid M.Khan H.E.J.Research Institute of International Centre For Chemical and

sciences. University of Karachi,Karachi-75270,Pakistan. Research Topic : Synthesis of biologically active 4-Thiazolidinones and 2Azetidinones. Biological activity: Medicinal chemistry deals with the design synthesis and production of molecules having therapeutic value.during the past few decades growth in areas like combinatorial chemistry and heterocyclic chemistry has lead to development of many privileged structures with proven utility in medicinal chemistry. Thiazolidine-4-ones are usually solids,often melting with decomposition but the attatchment of an alkyl group to the nitrogen lowers the melting point.thiazolidine-4-ones are derivatives of thiazolidine with carbonyl group at the fourth position.The carbonyl group of thiazolidine -4ones is highly unreactive.thiazolidine-4-ones are the derivatives,which belongs to important group of heterocyclic compounds containing sulphur and nitrogen in a five membered ring. A diversity of biological effects is associated with thiazolidine-4-one and its derivatives .their broad range of biological activities and pharmacological properties includes antifungal,antioxidant,cytotoxic,anti-inflammatory,analgesic,anti-YFV(yellow fever virus)activity,antitubercular,antimicrobial,antibacterial,. Thiazolidine-4-one derivatives possess different pharmacological and biological activities.Antimicrobial activity is the most potent activity of this moiety.Antibacterial activity is strongly dependent on the nature of substituent at C-2 and N-3 position. Thiazolidine-4-ones bearing 2,4-dichlorophenyl group , hydroxyl methoxyphenyl 4chlorophenyl group and dimethyl amino group at second position have showed good antitubercular activity. Thiazolidine-4-ones containing 2,4-dimethyl amino phenyl at second position shows good antitubercular activity in all the species. Unsubstituted phenyl group at fourth position of thiazolidine-4-one increases antioxidant activity. The presence of para-flourophenyl substituent decreased the cytotoxicity of thiazolidine4-one derivativesagainst DLA cells. The unsubstitutedphenyl ring at third position shows less activity against gram ve strains and moderately effective against gram +ve. The nitro group at meta and para position of the aryl ring respectively ,possess stronger antibacterial activity. Electron withdrawing moiety shows less activity compared to electron donating group e.g. OCH3,NMe2 etc. Neurodegenerative disorders like Alzheimers disease,stroke,multiple sclerosis and head trauma are treated with 5-[[{3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2imino-4-thiazolidinone. Novel thiazolidinone acetic acid derivatives showed diuretic properties when used as pharmaceuticals.

 Some other derivatives of thiazolidinone have valuable pharmacological activities including the ability to reduce blood glucose levels and blood lipid levels. Novel substituted 4-thiazolidinone derivatives showed cyclooxygenase and 5lipoxygenase inhibiting properties. In addition,these derivatives are topical anti anflammatory agents for inflamed conditions of the skin. Some derivatives of thiazolidinone are useful kemokine inhibitors. Substituted thiazolidinone carboxylic acid amide derivatives are known to be used particularly for treating or preventing cancer. 3-[4-(1-substituted-4-piperazinyl)butyl]-4-thiazolidinone compounds are useful as antipsychotic,analgesic,anticonvulsant and anxiolytic agents. Thiazolidinone compounds and compositions for angina pectoris comprising the compounds as an active ingredient. Novel 2-thiazolidinone derivatives show a cytoprotective and gastric acid secretioninhibiting effect and thus may be used in the therapy of gastric and duodenal ulcers. In addition,they exert a cytoprotective action against gastric laesions induced. 2-(carbamoyloximino)-4-thiazolidinone compounds have been found to exhibit miticidal,nematocidal or insecticidal activity. Secretory diarrhea is one of the leading cause of infant death in developing countries and major cause of morbidity in adults.T he cystic fibrosis trans membrane conductance regulator (CFTR)protein is required for fluid secretion in the intestine and airways and,when defective,causes the lethal genetic disease ,cystic fibrosis.50,000 chemically diverse compounds were screened for inhibition of cAMP/flavones- stimulated C1transport in epithelial cells expressing CFTR.Six CFTR inhibitors of the 2-thioxo-4thiazolidinone chemical class were identified.Thiazolidinone CFTR inhibitors may be useful in developing large-animal models for cystic fibrosis and in reducing intestinal fluid loss in cholera and other secretory diarrheas[26].

WORK PLAN: Due to the emerging medicinal importance of 4-thiazolidinone,2-azetidinone and their analogues, we are interested in synthesizing the 4-thiazolidinone, 2-azetidinone and their derivatives. The main objective is to develop new methodologies for the synthesis of 4-thiazolidinone,2azetidinone and their derivatives. In addition a variety of known and unknown derivatives would be synthesized with the enhancement of their therapeutic values, these compounds will be randomly checked for different in vitro and in vivo activities which are available in our institute eg:antibacterial,antifungal,antioxidant,antisecticidal,phototoxic,cytotoxic(brine shrimp lethality) bioassay ,anti-inflammatory, antiallergic, anti HIV ,anticancer ,antitumor, antidiabetic, antiurease, phosphodiesterase, -glucosidase, -glucoronidase, thymidine phosphorylase, antiglycation and their structure activity relationship will be established. The structure elucidations of these compounds and their derivatives would be determined by various techniques e.g: U.V., I.R., Mass Spectrometry and 1H-NMR studies. Following schemes would be used to synthesize 4-thiazolidinone,2-azetidinone,their analogues and derivatives.

SYNTHETIC STRATEGIES:

SCHEME 1:

SCHEME 2: SCHEME 3:

SCHEME 4:

SCHEME 5:

SCHEME 6:

SCHEME 7:

SCHEME 8:

SCHEME 9:

SCHEME 10:

SCHEME 11: SCHEME 12:

REFERENCES OF A AND B THIA PAPERS: 1) Pathak AK, Chawala V, Saraf KS. E- J Chem, 2011; 8: 240-244. 2) Patel NB, Shaikh M, Faiyazalam. Saudui pharm J, 2010; 3: 129. 3) Srivastava SK, Srivastava S, Srivastava SD. Indian J Chem, 1999; 38: 183. 4) Chatrabhuji PM, Nimavat K S, Vyas K B, Undavia N K. RJPBCS , 2010;1: 1451. 5) Bhatt J J, Shah B R, Shah H P, Trivedi P B et al. Cheminform, 1994; 25: 189-192. 6) Mei-Hsiu Shih, Fang-Ying Ke. Bioorganic & Med Chem, 2004; 12: 4633 7) S.G.Kucukguzel, E.E.Orul, S.Rollas, F.Salin, A.Ozbek;\ Eur.J.Med.Chem., 37, 197-206 (2002).

8) G.S.Singh, B.J.Molotsi; Il Farmaco., 60, 727-730 (2005).

9) V. P. M.Rahman, S.Mukhtar, W. H.Ansari, G.Lemiere; Eur.J.Med.Chem., 40, 173-184 (2005).

10) D.S.Mehta, V.H.Shah; Indian.J.Heterocyc.Chem., 11,

(2001).

11) R.K.Rawal, Y.S.Prabhakar, S.B.Katti, E.DeClercq; Bioorg.Med.Chem., 13, 6771-6776 (2005). 12) M.G.Vigorita, R.Ottana, F.Monforte, R.Maccari, A. Trovato, M.T.Monforte, M.F.Taviano; Bioorg.Med. Chem.Lett., 11, 2791-2794 (2001).

13) R.Paramashivappa, P.P.Kumar, S.P.V.Rao, S.A.Rao; Bioorg.Med.Chem.Lett., 13, 657660 (2003). 14) B.Goel, T.Ram, R.Tyagi, E.Bansal, A.Kumar, D.Mukherjee, J.N.Sinha; Eur.J.Med.Chem., 34, 265-269 (1999). 15) M.A.Mahran, S.M.El-Nassry, S.R.Allam, L.A.El- Zawawy; Pharmazie., 58, 527-530 (2003). 16) Barreca, M. L.; Carotti, A.; Carrieri, A.; Chimirri, A.; Monforte, A. M.; Pellegrini Calace, M. L.; Rao, A. Bioorg. Med. Chem. 1997, 7, 2283 17) Sreenivasa Rao, D., Jayachandran, E.,Sreenivasa, G.M., Shivakumar, B.,Inhibition of albumin denaturation and anti-inflammatory activity of 2-[N-p-Tolyl sulphon hydrazino]-6-fluoro-7substituted (1,3) benzothiazoles,Oriental J. of Chemistry, 2005, 21(1), 113-116. 18) Abdel Ghany aly el-helby., Mohammed Hemeda abdel wahed., Acta Pharm.,2003, 53, 127- 138. 19)Kumar.A, Gurtu.S, Agrawal J.C, Sinha J.N, Bhargava K.P and Shanker K. Synthesis and cardiovascular activity of substituted 4-azetidinones, J. Indian Chem. Soc., 1983, LX, 608-609. 20) Patel R.B, Desai P.S and, Chikhalia K.H., Pyrimidinebased thiazolidinones and azetidinones: Antimicrobial and antitubercular agents, Indian J.Chem, 2006, Sec B, 773-778. 21) Wollesdrof, O.W. Jr., Schwam, H.,Synthesis of 1-o-acyl derivatives of hydroxyl benzothiazol 2-sulfonamide as topically active carbonic-anhydrous inhibitors, Chem. Abstr., 1989, 111,194656 x. 22) Costakes, E., Tsatsas. G., Synthesis of 2- (alkylamino acyl imino) 3-methyl benzothiazolines for local anaesthetic activity, Chem. Abstr., 1979, 90, 203935 q.
23) Ameya A.Chavan and Nandini R.Pai., Synthesis and biological Activity of N-substituted-3-chloro-2azetidinones, Molecules., 2007,12, 2467-2477. 24) Freddy H.Havaldar and Sushil Kumar J. Mishra., Synthesis of some azetidi-2-ones and thiazolidin-4ones as potential antimicrobial Agents. Indian J. Heterocycl., Chem. 2004, 13, 197-200. 25) Patel K.H and Mehta A.G., Synthesis and antifungal activity of azetidinones and thiazolidinones derivative of 2-amino-6- (2-naphthalenyl) thiazolo [3, 2-d] thiadiazole, E.J.Chem., 2006, 3(13), 267-273.

26) Tonghui Ma,Jay R. Thiagarajah,Hong Yang,Nitin D. Sonawane,Chiara Folli,Luis J.V. Galietta, and A.S. Verkman. J. Clin. Invest. 110(11):16511658 (2002)