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Saurashtra University e Accredited Grade B by AAC (CGPA 2.93) Upadhyay, Kuldip D., 2006, Studies on Some Bioactive eterocyclic Moieties, thesis PhD, Saurashtra University
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Saurashtra University e Accredited Grade B by AAC (CGPA 2.93) Upadhyay, Kuldip D., 2006, Studies on Some Bioactive eterocyclic Moieties, thesis PhD, Saurashtra University Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Saurashtra University Theses Service The Author STUDIES SME BIACTIVE ETECYCLIC MIETIES A TESIS SUBMITTED T TE SAUASTA UIVESITY I TE FACULTY F SCIECE F TE DEGEE F Doctor of Philosophy I CEMISTY BY KULDIP D. UPADYAY Supervisor Prof. AAMIK SA Department of Chemistry Saurashtra University ajkot (India) SEPTEMBE Statement under.ph.d. 7 of Saurashtra University The work included in the thesis is my own work under the supervision of Prof. Anamik Shah and leads to some contribution in the field of synthetic Chemistry and is supported by recent references. Date: 18th September 2006 Place: ajkot Kuldip D. Upadhyay CETIFICATE This is to certify that present work submitted for the Ph.D. Degree of Saurashtra University by Mr. Kuldip D. Upadhyay has been the result of work carried out under my supervision and is a good contribution in field of Chemistry of Triazolotriazinoindoles, 1,5-Benzothiazepines, Pyrano quinolones, Pyrroles, Styryl coumarins and related heterocycles with a special emphasis on biological activities. Date: 18th September 2006 Place: ajkot Prof. Anamik Shah Department of Chemistry Saurashtra University ajkot ACKWLEDGEMETS At the outset, I would like to extol Prof. Anamik Shah for his advice during my doctoral research endeavor during the yester years. As my supervisor, he constantly encouraged me to remain focused on achieving my goal. is observation and comments helped me to establish the overall direction of the research and to move forward expeditiously with investigation in depth. I thank him for providing me the opportunity to work with numerous local and global peers. I am greatful to Dr. P..Parsania, Prof. and ead, Department of Chemistry and Prof...Parekh for providing all the necessary facilities in carrying out my research work. My gratitude is also due to the teaching and non teaching staff of my department for their constant help. My thesis bears imprint of many people. My seniors and associates at the Saurashtra University continued to have an important impact on my thanking: Dr. A.G.Dave, Dr..J.Bhayani, Dr. Dharmendra Thakar, Dr. Sudhir Joshi, Dr. Ashok Sarvani, Dr.Yogesh aliapara, Dr. Vipul Vora, Dr. Mausmi Chavda, Dr. Kartik Ladva, Dr. Bhavik Desai, Dr. Denish Karia, Dr. Bharat Varu, Dr. imish Mungra, Dr. Vishal arodia, Dr. ajesh Loriya, Dr. Kinnari Dholariya, Dr. Jignesh Patel, Dr. Gautam Patel, Dr. arsukh Gavariya and Dr. Alpesh Parecha, Every great and worthwhile in human life is an accumulation of hundreds and sometimes thousands of tiny efforts and sacrifices that nobody ever sees or appreciates. Thus I want to acknowledge how much I have learned from working with my colleagues: Dr. Priti Adlakha, Dr. Kena aval, Dr. Anjana Shah, Dr. itarth Acharya, Dr. Dinesh Manvar, Dr. rishikesh Acharya, Dr. Arun Mishra, Dr. Chintan Dholakiya, Mr. Jitendar Bariwal, Mr. Vijay Virsodiya, Mr. ikhil Vekariya, Mr. Atul Manvar, Mr. upesh Khunt, Ms. Jalpa Trivedi, Mr. aval Kapuriya, Mr. ajesh Kakadiya, Mr. Dhaval Joshipura, Mr. Bhavin Thanki, Mr. iral Mehta, Mr. Bhavin Shukla, Mr. andlal Sekhda, Mr. Vishal Sankharva, Ms. imisha Joshi, Ms. Arti Pandya, Ms. Mira Merthak, Mr. Sunil Mavani, Mr. okad Sunil, Mr. itesh Mathukiya, Mr. Janak Surani, Mr. Mayur Joshi, Mr. Mahesh Ladani, Mr. Jignesh Akbari, Mr. Paresh Vasoya, Mr. Viren Akbari, Mr. Pankaj Kachhadiya, Mr. ikunj Kachhadiya, Mr. ajesh Chavda. My sincere thanks extended to Dr. anjan Shah and Aditya for making me feel homely throughout my research tenure. I am indebted to the following organizations that helped me in the spectral and elemental analysis: Sophisticated Analysis Instrumentation Facilities, Punjab University, Chandigarh. M.S. University, Vadodara Central Drug esearch Institute(CDI), Lucknow. I am also indebted to the following Institutes and Scientists for their generous support in evaluating the antimicrobial and antitubercular activities. Tuberculosis Antimicrobial Acquisition and Coordinating Facility(TAACF), Albama, USA. Dr. Virendra Pandey, ew Jersey Medical School, USA. Mrs. Chetna Upadhyay, Department of Biosciences, Saurashtra University, ajkot Prof. Arthur Smenia, Universitydad Federal de Santa Catrina, Brazil. My overriding debt continues to my parents and family members who provided me with time, support and inspiration needed to prepare this thesis. Kuldip D. Upadhyay CTETS Chapter-1: Synthesis and Characterization of Some ovel 1- (Un)substituted phenyl-10-[1,2,4]-triazolo[3,4 :3,4][1,2,4] triazino[5,6-b]indoles...1 Introduction...2 Pharmacology...4 Synthetic Approaches and Chemistry...27 Current Work...42 eaction Scheme...44 eaction Mechanism...45 Experimental Protocols...48 Experimental...49 Physical Constants...50 Spectral Characterization...53 I Spectral Study M Spectral Study...58 Mass Spectral Study...63 Chapter-2: Synthesis and Characterization of Some 4-ydroxy-3- (2(un)substituted phenyl-2,3-dihydro-1,4-benzothiazepine-4-yl)- 2-chromen-2-ones...66 Introduction...67 Pharmacology...71 Some 1,5-Benzothiazepine Drugs and Derivatives Under Preclinical or Phase clinical trials Synthetic Approaches Current Work...133 eaction Scheme eaction Mechanism Experimental Protocols Experimental Physical Constants Spectral Characterization I Spectral Study M Spectral Study Mass Spectral Study Chapter-3: Synthesis and Characterization of Some 2-Amino-6- alkyl/alkylaryl-5-oxo-4-substituted phenyl-5,6-dihydro-4pyrano[3,2-c]quinoline-3-carbonitriles Introduction Pharmacology Synthetic Approaches Work Done At ur Laboratory eaction Scheme eaction Mechanism Experimental Protocols Experimental Physical Constants Spectral Characterization I Spectral Study M Spectral Study Mass Spectral Study...231 Chapter-4: Synthesis and Characterization of Some 1-[2,4-Dimethyl-5-(5-(un)substituted phenyl-1,3,4-oxadiazol-2-yl)-1-pyrrol- 3-yl]ethanones Part-A. 1,3,4-xadiazole Introduction Pharmacology Some xadiazole Drugs and Derivatives Under Preclinicalor Phase clinical trials Synthetic Approaches Part-B. Pyrrole Introduction Pharmacology Some Pyrrole Drugs and Derivatives Under Preclinical or Phase clinical trials Synthetic Approaches Work Done At ur Laboratory and Current Work Plan eaction Scheme eaction Mechanism Experimental Protocols Experimental Physical Constants Spectral Characterization I Spectral Study M Spectral Study Mass Spectral Study...323 Chapter-5: Synthesis and Characterization of Some 6-Chloro-2oxo- 4-[(E)-2-phenylethyl]-2-chromene-3-carbonitriles Introduction Pharmacology Synthetic Approaches Work Done At ur Laboratory eaction Scheme eaction Mechanism Experimental Protocols Experimental Physical Constants Spectral Characterization I Spectral Study M Spectral Study Mass Spectral Study Chapter-6: Antitubercular and Antibacterial Study of ewly SynthesizedCompounds Introduction Antitubercular Screening Assay Protocols Antibacterial Screening Protocols Antitubercular and Antibacterial Activity DataTables esults and Discussion List of Paper Presentation in ational & International Conferences: Conferences/ Workshops Attended...397 1 CAPTE-1 Synthesis and Characterization of Some ovel 1-(Un)substituted phenyl-10-[1,2,4]-triazolo [3,4 :3,4][1,2,4]triazino[5,6-b]indoles 2 Introduction Azoles and azines are well known for their diversed biological activities. It is also known that fusion of the heterocyclic nuclei enhances the pharmacological activities more than its parent nucleus. The importance of the indole nucleus is well established in pharmaceutical chemistry as it s corresponding derivatives are used as antipyretic, anticonvulsant, antianalgesic and antidepresant agents 1. A few naturally occurring members of this class of compounds, pyridindolol 2,3 and the two antibiotics CV-1 4 and gualamycin 5-7, have been isolated from different species of Streptomyces. Valuable biological activities are known to be associated with the 1,2,4-triazolo[4,3 :2,3]-1,2,4-triazino[5,6- b]indole skeleton. 3-hydrazino-1,2,4-triazino[5,6-b]indoles show antihypertensive 8,9, antiviral 8, blood-platelet aggregation inhibitory 9,10, analgesic 11, and antibacterial activities 12. ydrazone derivatives of 3-hydrazino-1,2,4- triazino[5,6-b]indoles have been found to possess antiumor activity against P388 lymphocytic leukemia in mice 13 and antibacterial activity 14,15. In addition, 1,2,4-triazolo[3,4 :3,4]- and -[4,3 :2,3]-1,2,4-triazino[5,6-b]indoles exhibit antiviral and antibacterial properties Pyridindol Gualamycin 1(a).M.Bell, A.Zalay,.esterlin, S.Clemans, D.Dum, J.Bradford, J.ozitis, J.Med.Chem., 22, 537(1977) (b).f.popp, J.eterocycl.Chem., 21, 1641(1984) (c).k.joshi, V.Pathak, S. Jain, Pharmazie, 35, 677(1980) 2.T.Aoyagi, M.Kumagai, T.azato, M.amada, T.Takeuchi,.Umezawa, J. Antibiot., 28,555(1975) 3.M.Kumagai,. aganawa, T. Aoyagi,.Umezawa,.akamura, Y.Iitaka, J. Antibiot.,28,876(1975) 4.T.Yasuzawa, M. Yoshida, M. Ichimura, K. Shirahata,. Sano, J. Antibiot.,40, 727(1987) 5.K.Tsuchiya, S. Kobayashi, T.arada, T.Kurokawa, T.akagawa,. Shimada, K. Kobayashi, J. Antibiot.,48, 626(1995) 3 ' 1,2,4-triazino[5,6-b]indole-3-hydrazones 1,2,4-Triazolo[3,4 :2,3]- 1,2,4-triazino[5,6-b]indoles 1,2,4-Triazolo[4,3 :2,3]- 1,2,4-triazino[5,6-b]indoles Polycyclic fused heteroaromatics of functionalized isatin derivatives are of interest because of their potential biological activity in analogy to the antiviral drug VP and the DA-intercalating drug/da topoisomerase II inhibitor CA C 3 S C 3 3 C VP32947 C 3 CA0424 Polycyclic fused heteroaromatics with established biological activies 6.K.Tsuchiya, S. Kobayashi,T. Kurokawa, T. akagawa,.shimada,. akamura, Y. Iitaka, M. Kitagawa, K.Tatsuta, J. Antibiot., 48, 630(1995) 7.K.Tatsuta, M.Kitagawa, T. oriuchi, K.Tsuchiya,.Shimada, J.Antibiot., 48, 741(1995) 8.D.Kaminsky, US Patent 3: , Chem Abstr. 79, (1973) 9. A.Monge, J.Palop, C.amirez, E.Fernandez-Alvarez, Acta Farm Bonaerense, 6, 157(1987), Chem Abstr.,109, (1988) 10.A.Monge, J.Palop, C. amirez, M. Font, E.Fernandez-Alvarez, Eur J Med Chem 26, 179(1991) 11. A.Tomchin, M. Ignat eva, G. Masyuta, Khim-Farm Zh, 6, 23(1972), Chem Abstr 77,43170(1972) 12.A.Dave, K.Bhatt,.Undavia, P.Trivedi, J Indian Chem Soc 66, 246(1989) 13..Eshba,. Salama, I.Labouta, A. mar, Pharmazie, 42, 664(1987) 14. K.Joshi, S. Jain, A. Jain, Curr Sci, 51, 346(1982), Chem Abstr., 97, (1982) 15.B.olla, K. Udupa, J Indian Chem Soc., 65, 524(1988) 16.J.Gladych, J.unt, D.Jack,. aff, J.Boyle, C.Stewart,.Ferlauto, ature, 221,286(1969) 17. J.Gwaltney, J Proc Soc Exp Biol Med, 133, 1148(1970) 18.J.Boyle, W. aupp, F.Stanfield,.aff, E.Dick, D. D Alessio, C. Dick, Ann Y Acad Sci, 173, 477(1970) 19. E.Katz, E.Margalith, Antimicrob Agents Chemother.,25, 195(1984), Chem Abstr 100,132158(1984) 20. F.Abdel-Latif,.Shaker, S. Mahgoub, M. Badr, J eterocycl Chem, 26, 769(1989) 21.S.Baginski, D.Pevear, M.Seipel, S. Sun, C. Benetatos, S. Chunduru, C.ice, M. Collett, Proc. atl. Acad. Sci. U.S.A.,97, 7981(2000) 22.K.irata, J. Araya, S.akaike, K. Kitamura, T. Ishida,,Chem. Pharm. Bull.,49, 44(2001) 23.V.am, Arch.Pharm.,313,108(1980) 24.J.Gladych,.ornby, J.unt, D. Jack, J. Boyle,.Ferlauto, C.Kormendy, F.Stanfield,.Stewart, J.Med.Chem., 15(3), 277(1972) 4 The triazino[5,6-b]indole derivatives have aroused considerable interest as a result of their broad spectrum of antibacterial, antifungal and antiparasitic activities 23. The majority of the 5-as-triazino[5,6-b]indoles are active in vitro against a variety of viruses including several strains of rhinovirus 24. Since they are purine analogues, it is expected that they should exert their pharmacological effects by interfering with DA metabolism. Pharmacology Triazino[5,6-b]indole derivatives are Purine analogues and exhibit diversed pharmacological activities. They have been described to have activity against A.niger and when provided as seed dressing, they protected sorghum seeds from infection with this organism 25. The modes of action of these drugs are not known. Some triazinoindoles have antiviral properties. SK&F was active against picornavirus in vitro and A synthesis was inhibited 26, while SK&F had activity against herpes simplex virus, in which DA synthesis was suppressed 27. Triazinoindoles were also shown to have antihypertensive properties 28 and inhibit thromboxane synthetase in rats. Some triazinoindoles are also mutagenic 29. The literature survey reviewed on pharmacological profile of Triazino[5,6-b]indole- and- Triazolotriazino[5,6-b] derivatives highlighed the following classification of the major therapeutic activity as per mention below. Antiviral activity Antifungal Activity Anticancer Activity Antimalarial activity Antihypertensive and Platelet aggregation Inhibitors / Thromboxine synthetase Inhibitors Antibacterial activity 25.. Abdel ahman, Z. El Gendy, M.Mahmoud. Ind. J. Chem., 29B, (1990) 26..aff, W.Flagg, J.Gallo, J.oover, J.Miller, C.Pinto, J.Pagano., Proc. Soc. Exp. Biol.Med., 141, 475(1972) 27.E.Katz, E. Margalith, Antimicrob. Agents Chemother., 25,195(1984) 28.A.Monge, J. Palop, C. amirez, M. Font, E. Fernandez-Alvarez.,Eur. J. Med. Chem., 26,179(1991) 29.A.Lopez-de-Cerain, E. Garcia, A. Gullon.Mutagenesis, 7,37(1992) 30.T.Ueda, I.akata, Yakugaku Zasshi, 80, 1068(1960), Chem.Abst.,55,562(1961) 31.D.Bauer, F.Sheffield, ature, 184,1496(1959) 32..Thompson, A. Minton, S.Jun, J.fficer, G. itchings,, J. Immunol., 70, 229 (1953). 5 Antiviral activity The antiviral activity of as-triazines 30 and clinical efficacy of methisazone 31 were well documented. The action of isatin-3-thiosemicarbazone is known to have antiviral activity against certain poxviruses 32,33. The antiviral spectrum of 1-methylisatin 3-thiosemicarbazone, which reportedly extends to adenoviruses, may be rather broader but is still limited to several groups of DA viruses 33,34. It was therefore an unexpected finding that these compounds are also active against certain rhinoviruses. J.M.Z.Gladych 35 and co-workers have studied Isatin thiosemicarbazone analogues among which two compounds were found to have activity against all rhinovirus strains used so far. uman rhinovirus (V) is a primary cause of mild upper respiratory infection in humans 36. Although rhinovirus infection, as the common cold is known to spread easily throughout human populations, only higher primates are susceptible 37,38 ; thus, the virus possesses a narrow host range. This narrow host range is reflected in tissue culture in that the V replicates only in cells of primate origin. In vitro testing of the 5-triazino[5,6-b]indoles shown a broad spectrum antiviral activity against both DA and A viruses. A notable feature of the series is the wide spread action against several strains of rhinovirus which is most consistently shown by compounds containing hydroxyalkylamino substituents at C-3. 1 CS 2 Isatin-3-thiosemicarbozones = C 3 Methisazone or (1-methylisatin-3-thiosemicarbazone) as-triazino[5,6-b]indoles 1 =,Cl, 2, Me, Pr,, Me 2 =, Me, C 6 5 (C 2 ) 2, C 6 5 C 2 3 = (C 2 ) 2, (C 2 ) 3, 2, Me 2, Morphonyl, Me 2 C(C 2 ) 2, Me(C 2 ) 11, C 3 (C 2 ) 17, C 2 C()C 2, (C 2 ) 4, Me(C 2 ) 3, (C 2 ) 2 (C 2 ) 2, Me 2 (C 2 ) 3, (C 2 ) 6 etc. 33.D.Bauer, P. Sadler, Brit. J. Pharmacol. Chemother., 15, 101 (1960). 34.D.Bauer, K. Apostolov, Science, 154, 796 (1966). 35.J.Gladych, J.unt, D. Jack,.aff, J.Boyle,.Stewart,.Ferlauto, ature, 221, 286(1969) 36.D.Tyrrell, M.Bynoe,Lancet i,76(1966) 37.E.Dick, Proc. Soc. Exp.Biol. Med.,127,1079(1968) 38.C.Pinto,.uff,ature (London), 224,1310(1969) 6 The search for effective antirhinovirus agents has yielded a wealth of compounds belonging to widely varying chemical classes: thiosemicarbazones 35, isoquinolines 39,40, triazinoindoles 41, guanidines 42, benzoates 43, furanyls 44, benzimidazoles 45, thiourea 46, diketones 47,48,49, flavans 50,51, flavones 52, chalcones 53, nitrobenzenes 54,55, and isoxazoles 56,57. The most recently developed antirhinovirus compounds 50, 56, 53, 57 reach their MICs within the range of to 0.01 µg/ml. A wide variety of purine nucleoside (mainly tubercidin and adenosine) analogs, which had previously been shown to inhibit the replication of a broad spectrum of A viruses, were evaluated for their antirhinovirus activity in human diploid (WI-38) fibroblasts 58. Among the 5- or 6-substituted tubercidin analogs, several derivatives, i.e., tubercidin, sangivamycin, toyocamycin, 5-(1-hydroxyethyl)tubercidin, and 5-(2-buten-1-yl)tubercidin (the later being a mixture of E and Z isomers at a 2:1 ratio)(figure-1), inhibited the cytopathogenicity of rhinovirus types 1A, 1B and 9 at concentrations well below 1µg/ml, the most potent being tubercidin itself with an MIC 50 of 0.03 µg/mi. f the sugar-modified tubercidin analogs, only 2'-deoxytoyocamycin exhibited an MIC 50 of 1 µg/ml (against rhinovirus types 1B and 9). f the carbocyclic adenosine analogs, carbocyclic 7- deazaadenosine proved the most potent, with an MIC 50 of 2 µg/ml (against rhinovirus types 1B and 9). Acyclic adenosine analogs were totally ineffective as antirhinovirus agents, and from the miscellaneous reference compounds formycin A, pyrazofurin, and 3-deazaguanine showed the lowest MIC 50 s (within the range of 5 to 25 µg/ml). 39.S.eed, M.Bynoe. J. Med.Microbiol.,3,346(1970). 40.A.Zerial, G.Werner,.Philipotts, J.Wilmann, P.iggins, D.Tyrrell, Antimicrob. Agents Chemother.,27,846(1985) 41.S.Matsumoto, F.Stanfield, M.Goore,.aff, Proc. Soc. Exp. Biol.Med.,139,455(1972). 42..Bucknall, D.Swallow,. Moores, J. arrad,ature (London), 246,144(1973) 43..hnishi, K. Yamaguchi, S. Shimada, S. imuro, Y. Suzuki. Antimicrob. Agents Chernother.,22,250(1982) 44..Ash,.Parker, A.agan, G.Mayer, Antimicrob. Agents Chemother.,16,301(1979). 45.D.DeLong, S.eed, J.Infect. Dis., 141,87(1980). 46.A.Galabov, E.Velichkova, G.Vassilev, Chemotherapy,23,81(1977). 47.G.Diana, P.Carabateas,. Johnson, G.Williams, F. Pancic, J.Collins,J. Med. Chem., 21,889(1978). 48.G.Diana, U.Salvador, E.Zalay, P.Carabateas, G.Williams, J.Collins, F. Pancic, J. Med.Chem., 20,757(1977). 7 Despite their higher potency as antirhinovirus compounds, tubercidin, 5-(1- hydroxyethyl)tubercidin, 5-(2-buten-1-yl)tubercidin, sangivamycin, and toyocamycin did not display much selectivity in their antirhinovirus action. Their selectivity indexes fell in the range of 3 to 30 (index A) and 1.3 to 4 (index B). f the sugar-modified tubercidin analogs, only the ara analog of sangivamycin showed some selectivity (index A = 8.6; index B = 3.1). f the carbocyclic and acyclic adenosine analogs, none proved to be a selective inhibitor of rhinovirus; and of the miscellaneous group of compounds, 3- deazaguanine showed the highest selectivity (index A = 50; index B = 33) or 6-substituted tubercidin analogues) 2 eplanocin(carbocyclic adenisine analogues) 49.G.Diana, U.Salvador, E.Zalay,.Johnson, J.Collins, W.Johnson, W. inshaw,. Lorenz, W.Thielking, F. Pancic, J. Med. Chem., 20,750(1977). 50.D.Bauer, J.Selway, J.Batchelor, M. Tisdale, I.Caldwell, D.Young, ature (London),292,369(1981). 51..Phillpotts, J. Wallace, D.Tyrrell, D.Freestone, W.Shepherd, Arch. Virol.,75,115(1983). 52..Ishitsuka, C. hsawa, T. hiwa, I. Umeda, Y. Suhara,Antimicrob. Agents Chemother., 22,611(1982). 53..Ishitsuka,Y. inomiya, C. hsawa, M. Fujiu, Y. Suhara.Antimicrob. Agents Chemother., 22,617(1982). 54..Powers, J.Gwaltney,F.
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