I= SYNTHESIS, CHARACTERIZATION AND ANTIMICROBIAL ACTIVITY OF SOME NOVEL SULFONAMIDES BEARING 1,3,4-OXADIAZOLE MOIETY
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Title of Thesis
SYNTHESIS, CHARACTERIZATION AND ANTIMICROBIAL ACTIVITY OF SOME NOVEL SULFONAMIDES BEARING 1,3,4-OXADIAZOLE MOIETY

Author(s)
Muhammad Zareef
Institute/University/Department Details
Department of Chemistry/ Quaid-i-Azam University Islamabad
Session
2006
Subject
Organic Chemistry
Number of Pages
346
Keywords (Extracted from title, table of contents and abstract of thesis)
sulfonamides, 1-3-4-oxadiazole moiety, carbonic anhydrase inhibitors, anticancer agents, anti-hiv agents, antiviral, antimalarial agents, erectile dysfunction

Abstract
The work presented in this thesis consists of synthesis, characterization, antibacterial, antifungal, anti-HIV, carbonic anhydrase inhibitory, antimalarial and luciferase studies of some' novel sulfonamides bearing 1,3,4-oxadiazole moiety. The sulfonamide and 1,3,4-oxadiazole moieties are crucial functionalities because of their wide variety of known pharmacological activities. Therefore, some novel chiral and achiral compounds were synthesized which contain both the sulfonamide and 1,3,4-oxadiazole entities in the same molecule. These compounds include: chiral and achiral 2-or 4-(4-substitutedphenylsuIfonamido)alkane hydrazides, their corresponding 4-substituted-N-[l- or 3-(5-mercapto-l ,3,4-oxadiazol-2-yl)alkylbenzenesulfonamides and their various derivatives. Some of these benzenesulfonamides have also been synthesized using microwave irradiation method (Schemes 1.2-1.4). It is worth noting here that reaction times have been reduced from hours to just few seconds under the microwave irradiation.

Synthetic strategies (Schemes 1.5-1.7) were employed to synthesize 5-substituted-2-mercapto-1,3,4-oxadiazoles, their. esters and amides. Thirty N-[(5-substitutedary 1)-1,3, 4-oxadiazo 1- 2- ylthio )methyl ]-4-substitutedbenzenesuIfonam ides and three camphor-10-sulfonamides were synthesized in two steps; first was the oxidative rearrangement of various amides to their corresponding amine hydro chlorides which were converted to their respective sulfonamides in the second step (Scheme 1.7). Eight novel chiral N-[ (5-substitutedaryl)-1,3 ,4-oxadiazol-2-ylthio )ethyl]-4-substitutedbenzene-sulfonamides were also synthesized (Scheme 1.8) using the same methodology as employed in Scheme 1.7. Reduction reaction with acyloxyborohydride on various amide derivatives of 5-substituted-2-mercapto-l,3,4-oxadiazole was attempted, where oxadiazole ring was found cleaved yielding novel benzenediazasulfonamides (Scheme 1.9).

Direct chorosulfonation of various 5-substitutedphenyl-2-mercapto/methylthio-1,3,4-oxadiazoles with chlorosulfonic acid provided twenty five novel chiral and achiral benzenesulfonamides bearing 1,3,4-oxadiazole moiety (Scheme 1.10). Thirty two S-[(5-substitutedpheny 1)-1,3 ,4-oxadiazol- 2-y 1)-2-( 4-substitutedphenylsulfonamido) alkanthioate were also synthesized using two different already reported methods (Schemes 1.11 and 1.12). Five N-substitutedpyrrolidin-2-ones were synthesized using a novel approach (Scheme 1.13). In this cyclization reaction polyphosphate ester (PPE) was used as dehydrating agent 4-Substituted-N-[ 4-(5-substitutedphenyl)-1 ,3,4-oxadiazol-2-yl)-phenyl]benzenesulfonamides and their counter part tertiary benzene-sulfonamides were also synthesized using a modified method in presence of triethylamine and 4-(N,N-dimethylamino)pyridine (DMAP) (Scheme 1.14).

All the synthesized compounds were characterized using IR, 1H NMR and mass spectral data. In addition, elemental analysis/HRMS in many cases and 13C NMR in some cases were also employed to support the characterization. A plausible mass fragmentation pattern of some representative compounds is also suggested. Single X-ray crystallography was performed on seven selected crystalline compounds in order to establish the exact geometry and enantiomeric purity (in case of chiral compounds). Some of the .synthesized compounds were evaluated for their antibacterial, antifungal, anti-HIV, carbonic anhydrase inhibitoty, antimalarial and luciferase activities. Some of them were found active and showed interesting results in various studies mentioned above. These data in comparison with the standard drugs, is presented and discussed.

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S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
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2 1 Introduction 1-52
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  1.1 Sulfonamides 1
  1.2 History Of Sulfonamides 2
  1.3 Classification Of Sulfonamides 4
  1.4 Antibacterial And Antifungal 6
  1.5 Carbonic Anhydrase Inhibitors 8
  1.6 Anticancer Agents 10
  1.7 Antiviral And Anti-HIV Agents 12
  1.8 Antimalarial Agents 13
  1.9 Male Erectile Dysfunction (ED ) 16
  1.10 Miscellaneous Applications 17
  1.11 Applications In Synthetic Organic Chemistry 18
  1.12 Methods Of Synthesis 21
  1.13 Concerning 2 ,5 -Disubstitued-1,3,4-Oxadiazoles And 5- Substitued-2-Mercapto-1,3 ,4-Oxadiazo Les 26
  1.14 General Methods Of Preparation 30
  1.15 Importance Of Compounds Having Thioester Entity 35
  1.16 Some Sulfonamide Drugs In Use 35
  1.17 Aim Of Work 37
  1.18 Plan Of Work 38
3 2 Experimental 53-172
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  2.1 Substrates And Reagents 53
  2.2 Solvents 53
  2.3 Instruments 53
  2.4 General Procedure For The Synthesis Of 2 Or 4- ( 4 -Substituted- Phenylsulfonamido ) Alkanoic Acids (35a-Z, 35a'-G') And Their Ethyl Esters (36a-Z, 36a'-G') 54
  2.5 General Procedure For The Synthesis Of 2 Or 4- ( 4 -Substituted- Phenylsulfonamido )Alky / Vphenyl Hydrazides (37a-Z, 37a'-G') 58
  2.6 General Procedure For The Synthesis Of 4-Subtituted-N-[3 Or 1-(5-Mercapto- L ,3,4 -Oxadiazol-2-Yl)Alky/ Vphenyl ] Benzenesulfonamides (38a-Z, 38a'-G') 65
  2.7 Synthesis Of 4-Methyvchloro-N-[1 Or 3-(5-Mercapto-L ,3,4 - Oxadiazol-2-Yl)Alkyl] Benzenesulfonamides (38) Under MWI 76
  2.8 General Procedure For The Synthesis Of Potassium-3-[2 Or 4-(4- Methyl/ Chlorophenylsulfonamido ) ] Alkanoyldithiocarbazinate (39) 76
  2.9 General Procedure For The Synthesis Of 4-Methyi/Chloro-N-[1 Or 3-(5-Mercapto- L ,3,4 -Oxadiazol-2-Yl)Alkyl] Benzenesulfonamides (38) 76
  2.10 General Procedure For The Synthesis Of N-[1 Or 4-(5-( Substitutedthio ) -1,3, 4-Oxadiazol-2-Yl)Alkyl]-4-Substitutedbenzene- Sulfonamides (40a-Z, 40a'-D') 77
  2.11 General Procedure For The Preparation Of Substituted Carboxylic Acid Hydrazides (43a-W ) 87
  2.12 General Procedure For The Preparation Of S-Substituted-2- Mercapto-1 ,3,4 -Oxadiazoles (44a-W) 87
  2.13 General Procedure For The Synthesis Of [5-(Aryl)-1 ,3,4 - Oxadiazol-2-Ylhio ] Esters (45a-W And 46a-I) 93
  2.14 General Procedure For The Preparation Of [5-(Alkyl)-1 ,3,4 - Oxadiazol-2-Ylthio ] Acetates 98
  2.15 General Procedure For The Synthesis Of [5-(Aryl)- L ,3,4 - Oxadiazol-2-Ylthio ] Propionate (46a-I) 99
  2.16 General Procedure For Synthesis Of [5-( Substitutedaryl )-1 ,3,4 - Oxadiazol-2-Ylthio ]Amides (47a-W) 101
  2.17 Chiral 2-[5-( Substitutedphenyl )- 1 ,3,4 -Oxadiazol-2-Ylthio]- Propionamide (48a-I) 107
  2.18 General Procedure For The Synthesis Of S-Substitute-2-Methyl/ Benzylthio-1 ,3,4 -Oxadiazole (49a-P) 110
  2.19 General Procedure For Synthesis Of N-[(5-Substituted-Aryl )- 1,3 ,4-Oxadiazol-2-Ylthio ]Methyl]-4-Substitutedbenzene- Sulfonamides (51a-Z, 51a'-D') 113
  2.20 General Procedure For The Preparation Of N-[(5-(Substituted- Phenyl)- L ,3,4 -Oxadiazol-2-Ylthio)Methyl]-Camphor-10- Sulfonamides (52a-C) 123
  2.21 General Procedure For The Synthesis Of N-[(S-Substituted- Phenyll2-Pyridyl)-1 ,3 ,4-Oxadiazol- 2-Ylthio ]Ethyl]-4-Substituted- Benzenesulfonamides (54a-H) 124
  2.22 General Procedure For The Synthesis Of N- Substitutedbenzoyl - N' -Methyl-N' -( 4-Substitutedbenzenesulfonyl) Hydrazines ( Benzenediazasulfonamides ) (56a-J) 127
  2.23 General Procedure For The Preparation Of Substituted-(4- Camphor-10-Sulfonyl ) Hydrazines ( Camphor-L0-Sulfonamides) (57 A-B) 131
  2.24 General Procedure For Synthesis Of Benzenesulfonamides Bearing 5-Mercapto/Methylthio-1 ,3,4 -Oxadiazole Moiety(59a-R) 132
  2.25 General Procedure For Synthesis Of Substituted-3-(5-Mercapto- 1 ,3,4 -Oxadiazol-2-Yl)-N-( L- Phenylethyl )-2-Substitutedbenzene- Sulfonamides (60a-G) 139
  2.26 General Procedure For Synthesis Of S-(5-(Substituted-Phenyl/4- Pyridyl )- L ,3,4 -Oxadiazol-2-Yl]-2-( 4-Substitutedphenylsulfona- Mido ) Alkanethioate (61a-Z, 61a'-F) 142
  2.27 General Procedure For Synthesis Of 1-(4-Substitutedphenyl )- Sulfonyl ]Pyrrolidin-2-Ones (63a-E) 155
  2.28 General Procedure For The Synthesis Of N ,N' - Diacylhydrazine (64a-I) 157
  2.29 General Procedure For The Preparation Of 2 ,5 -Disubstituted-1,3,4-Oxadiazoles (65a-I) 157
  2.30 General Procedure For The Synthesis Of 2-(4-Aminophenyl)-5- Substituted-L ,3,4 -Oxadiazoles (66a-I) 159
  2.31 General Procedure For Preparation Of 4-Substituted-N-(4-(5- Substitutedphenyl )-1 ,3,4-Oxadiazol-2-Yl)Phenyl]Benzene- Sulfonamides (67a-Q) And 4-Substituted-(N-(4-Substituted- Benzenesulfonyl )-N-( 5-Phenyl-L ,3,4-Oxadiazol-2-Yl) ]Benzene- Sulfonamides (68a-Q) 162
4 3 Results And Discussion 173-190
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  3.1 4-Substituted-N-(1 Or 3-(5-Mercapto- 1 ,3,4 -Oxadiazol-2-Yl)Alkyll 173
  3.2 N- ( 1 Or 3-(5-( Subsitutedthio )-1 ,3,4-Oxadiazol-2-Yl)Alkyl]-4- Subsitutedbenzenesulfonamide (40a-Z And 40a'-D') 189
  3.3 5-Substituted Carboxylic Acid Hydrazides (43a- W) 201
  3.4 5-Substituted-2-Mercapto-L ,3,4 -Oxadiazoles (44a-W) 201
  3.5 (5-(Substituted- L ,3,4 -Oxadiazol-2-Ylthio )]Esters (45a-W) 207
  3.6 Synthesis Of (S-( Substitutedaryl )- 1 ,3,4 -Oxadiazol-2-Ylthio]- Amides (47a-W) 213
  3.7 Methyllbenzylthio Derivatives (49a-P) Of 2-Mercapto- L ,3,4 - Oxadiazoles 222
  3.8 N-[ ( 5 -Substitutedaryl)-1 ,3,4-Oxadiazol-2-Ylthio )Alkyl]-4- Substitutedbenzenesulfonamides (5la-Z) (51a'-D') (54a-H) 222
  3.9 Camphor-10-Sulfonamides Bearing S-Substituted- L ,3,4 - Oxadiazole Moiety (52a-C) 226
  3.10 N-Substitutedbenzoyl-N' -Methyl- N' -( 4-Substitutedbenzene- Sulfonyl ) Hydrazines ( Benzendiazasulfonamides ) (56a-J) 234
  3.11 Camphor-10-Diazasulfonamides (57 A-B ) 238
  3.12 Substitutea-(5-Mercapto/Methylthio-L ,3 ,4-Oxadiazol-2- Ylthio ) Substitutedbenzenesulfonamides (59a-R) (60a-G) 242
  3.13 S- [ 5 -Substitutedphenyl/ 4-Pyridyl] -1,3 ,4-Oxadiazol- 2-Yl] -2-(4- Substitutedphenylsulfonamido ) Alkanethioate (61 A-Z) (61a' -F) 248
  3.14 1- [ ( 4-Substitutedphenyl) Sulfonyl ]Pyrrolidin-2-Ones (63 A-E) 254
  3.15 2 ,5 -Disubstituted-1,3,4-Oxadiazoles (65a-J) And 2-(4-Amino- Phenyl)-5-Substituted-L ,3,4-Oxadiazole (66a-I) 259
  3.16 4-Substituted-N-[ 4-(5-Phenyl-L ,3,4-Oxadiazol-2-Ylthio)- Phenyl] Benzenesulfonamides (67a-Q) And 4-Substituted-[N-( 4-Substitutedbenzenesulfonyl)]-N-(5-Phenyl-L ,3,4- Oxadiazol-2-Yl) Benzenesulfonamides (68a-Q) 260
  3.17 X-Ray Crystallography 270
5 4 Biological Activity 291-329
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  4.1 In Vitro Antibacterial Activity 291
  4.2 2 Or 4-Substituted- ( 4 -Substitutedsulfonamido ) Alkanehydrazides (37) 292
  4.3 4-Substituted-N-[1 Or 3-(5-Mercapto- 1 ,3,4 -Oxadiazol-2- Yl )Alkyl] Benzenesulfonamides (38) And Their Derivatives (40) 292
  4.4 2-Mercapto-5-Substituted-L ,3,4 -Oxadiazoles (44) And Their Amide Derivatives (47) 292
  4.5 N-[5-( Substitutedaryl )- 1 ,3,4 -Oxadiazol-2-Ylthio ]Methyl-4- Substituted Benzenesulfonamids (51) And N-Substituted- Benzoyl -N' -( 4-Substitutedbenzenesulfonyl) Hydrazines (56) ( Benzenediazasulfonamides ) 293
  4.6 Benzenesulfonamides Bearing 5-Mercapto/Methylthio- 1 ,3,4 - Oxadiazole Moiety (59 & 60) 293
  4.7 1-[(N- Substitutedphenyl ) Sulfonyl ]Pyrrolidin-2-One (63) 293
  4.8 4-Substituted-N- [ 4 -( 5-Substituted Phenyl-L,3,4-Oxadiazole-2- Yl )Phenyl] Benzenesulfonamides (67) 294
  4.9 In Vitro Antifungal Bioassay 294
  4.10 Conclusion 295
  4.11 Antibacterial Bioassay ( Mic ) Of 4-Substituted-N-[1 Or 3-(5- Mercapto-L ,3 ,4-Oxadiazol-2-Yl)Alkyl] Benzenesulfonamides (38) And Benzenesulfonamides Bearing 2,5-Disubstituted-L ,3,4- Oxadiazoles 295
  4.12 Anti-Hiv Activity 313
  4.13 Carbonic Anhydrase Inhibition Of Human Tumor-Associated Isozymes Ix And Cytosolic Isozymes I And Ii With Some 2 Or 4-(4-Substitutedphenylsulfonamido ) Alkane Hydrazides And 4- Substituted-N-[1 Or 3-(5-Mercapto-L ,3,4-Oxadiazol-2-Yl)- Alkyl]Benzenesulfonamides 317
  4.14 Antimalarial Bioassay Of 2 Or 4-(4-Substitutedphenyl- Sulfonamido ) Alkane Hydrazides (37) And 4-Substituted-N-[1 Or3-( 5- Mercapto-L,3 ,4-Oxadiazol- 2-Yl)Alkyl] Benzenesulfona-Mides (38) 321
  4.15 Methods 325
  4.16 Luciferase Activity 327
  4.17 References 330-343
  4.18 List Of Publications 344-346