I= SYNTHESIS AND CHARACTERIZATION OF POTENTIALLY BIOACTIVE NUCLEOSIDES BEARING DIFFERENT HETEROCYCLIC MOIETIES
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Title of Thesis
SYNTHESIS AND CHARACTERIZATION OF POTENTIALLY BIOACTIVE NUCLEOSIDES BEARING DIFFERENT HETEROCYCLIC MOIETIES

Author(s)
Humaira Akhtar
Institute/University/Department Details
Department of Chemistry/ Quaid-i-Azam University Islamabad
Session
2006
Subject
Organic Chemistry
Number of Pages
321
Keywords (Extracted from title, table of contents and abstract of thesis)
heterocyclic moieties, nucleosides, carboxylic acid hydrazides, triazoles, oxadiazoles, benzimidazoles, nucleosides, triazole nucleosides, oxadiazole nucleosides, benzimidazole nucleosides

Abstract
The work presented in this thesis consists of synthesis, reactions, characterization of five membered heterocyclic compounds and their corresponding nucleosides. The heterocyclic bases which were prepared included 4,5-disubstihled-1,2,4-triazole-3-thiones, 4-amino-5-substituted-l ,2,4-triazole-3-thiones, 5-substituted-l,3,4-oxadiazole-3-thiols and 2-substituted benzimidazoles. Firstly, thirteen substituted carboxylic acid hydrazides were prepared, which were condensed with eight isothiocyanates to yield 1,4-disubstituted thiosemicarbazides which were used to synthesize 4,5-disubstituted-1 ,2,4-triazole-3-thiones. These hydrazides were also condensed with carbon disulfide in presence of base to the corresponding 5-substituted-l,3,4-oxadiazole-2-thiols. These oxadiazoles were used as starting materials for the synthesis of 4-amino-5-substituted-1,2,4-triazole-3-thiones. Also the synthesized carboxylic acid hydrazides were fused with 1,2-phenylene diamine to yield corresponding 2-arylsubstituted benzimidazoles.

In another series some substituted phenoxyalkyl carboxylic acids were synthesized. These carboxylic acids were used as starting materials for the synthesis of different heterocyclic bases, e.g., these phenoxyalkyl carboxylic acids were subjected to fusion reaction with thiocarbohydrazide and the corresponding 5-substituted phenoxyalkyl-4-amino-l,2,4-triazole-3-thiones were obtained. The reaction of hydrazine hydrate (80%) with these phenoxyalkyl carboxylic acids was used to give corresponding hydrazides which were subjected to condensation reaction with carbon disulfide in presence of base to furnish 5-phenoxyalkyl substituted-l,3,4-oxadiazole-2-thiols. These phenoxyalkyl carboxylic acids were also used for the synthesis of 2-substituted phenoxyalkyl benzimidazoles, by reaction with 1,2-phenylene diamine. All these synthesized heterocyclic bases were then subjected to coupling reaction with acetobromosugar in presence of mercuric cyanide and molecular sieves using nitromethane as solvent. The method gave exclusively β-nucleosides regioselectivity. The acetylated products were then subjected to deacetylation in methanolic ammonia to yield de protected nucleosides. Since the deacetylated nucleosides get decomposed readily, therefore, all the acetylaed glycosides could not be de protected due to decomposition of products during the reaction. All the synthesized heterocyclic bases and the corresponding nucleosides were characterized by their IR, 1H-NMR, 13C-NMR and mass spectral data in almost all cases. In addition in some cases, elemental analysis was also carried out. All the desired compounds were isolated in pure form. Some was nucleosides especially the deprotected nucleosides wee purified by column chromatography. The purity in each case was established with the help of TLC in different solvent systems. Complete 1H-NMR, 13C-NMR and mass spectral data of each type of compounds is included and discussed. The plausible fragmentation patterns of some representative compounds of each series are also included. Some of the synthesized nucleosides were also screened for their antibacterial, antifungal and phytotoxic activities. The results of these antibacterial, antifungal activities are also reported and discussed, e.g., the results of antibacterial screening of thirty different compounds as minimum inhibition concentration (MIC) against two gram negative and four gram positive bacteria are included and discussed. Seven nucleosides were also checked for their phytotoxic activities but the compounds were not found very active. The results show that nucleosides show good antibacterial activity as compared to their antifungal and phytotoxic activities.

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S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
435.66 KB
2 1 Introduction 1
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  1.1 Triazoles 1
  1.2 Oxadiazoles 6
  1.3 Benzimidazoles 13
  1.4 Nucleosides 20
  1.5 Triazole Nucleosides 34
  1.6 Oxadiazole Nucleosides 43
  1.7 Benzimidazole Nucleosides 45
  1.8 Aim Of The Present Work 50
  1.9 Plan Of Work 51
3 2 Experimental 63-170
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  2.1 Substrates And Reagents 63
  2.2 Synthesis Of Carboxylic Acid Hydrazides 64
  2.3 Isothiocyanates 171 (A-H ) 65
  2.4 1 ,4 -Disubstituted Thiosemicarbazide 173-179(A-G), 180(B-D) 65
  2.5 2 ,4 - Dihydro-4,5-Disubstituted- 3 H-1 ,2,4-Triazo Le- 3-Thiones (181-187a-G),188(B-D) 71
  2.6 General Procedure For The Sysnthesis Of 5-Substituted-4-Amino- 1 ,2,4 -Triazole-3-Thiones 206(A-J) 80
  2.7 Preparation Of Thiocarbohydrazide 209 84
  2.8 Synthesis Of 4-Amino-5-(Substituted Phenoxymethyl )- 1 ,2,4 - Triazole-3-Thiones 210(A-J,I) 84
  2.9 General Procedure For The Synthesis Of 5-(Substituted)- 1 ,3,4 - Oxadiazole-2-Thiols 205(A-Q) 86
  2.10 Synthesis Of 2-(Substituted )Phenoxyalky1carboxylic Acids 215(A-O) 88
  2.11 Synthesis Of Substituted Phenoxycarboxylic Acid Hydrazides 216(A-F ,J -O) 90
  2.12 Synthesis Of 5-(Substituted Phenoxyalkyl)- 1 ,3,4 -Oxadiazole-3- Thiols 217(A-F,J-O) 92
  2.13 General Procedure For The Synthesis Of 2-( Arylsubstitu -Ted) Benzimidazoles 220(A-I ) 95
  2.14 General Procedure For The Synthesis Of 2-(Substituted Phenoxymethyl )Benzimidazoles 223(A-J) 97
  2.15 Synthesis Of Acetylated Nucleosides Bearing 4 ,5 -Disubstituted-1,2,4-Triazole-3-Thiones 100
  2.16 General Procedure For The Deacetylation Of Protected Nucleosides 126
  2.17 Synthesis Of Nucleosides Bearing 5-(Substituted)-4-Amino-1 ,2,4 -Triazole-3-Thiones 136
  2.18 Deprotection Of Acetylated Amino- Triazole Nucleosides 145
  2.19 Synthesis Of Nucleosides Bearing 1 ,3,4 -0xadiazole Moiety 147
  2.20 Deprotection Of Acetylated Oxadiazole Nucleosides 159
  2.21 Synthesis Of Nucleosides Bearing 2-Substituted Benzimidazole Moiety 163
  2.22 Antibacterial Studies Screening 169
  2.23 Antifungal Screening 170
  2.24 Phytotoxic Activity Screening 170
4 3 Results And Discussion 171-300
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  3.1 Isothiocyanates 172
  3.2 Carboxy Lic Acid Hydrazides 172(A-O ) 172
  3.3 1 ,4 -Disubstituted Thiosemicarbazides 173-180(A-G) 174
  3.4 4 ,5 -Disubstituted-3h-L ,2,4-Triazole-3-Thiones 181-187(A-G), 188(B-D) 175
  3.5 N-(2€™ ,3€™,4€™ ,6€™ - Tetra-O-Acetyl- ’ -D- Glucopyronasyl )-4,5-(Substituted)- 3 H-L ,2,4-Triazole- 3-Thiones 189-195 (A-G), 196(B-D) 179
  3.6 N-( ’-D- Glucopyranosyl )-4,5-(Substituted)-3h-L ,2,4-Triazole-3- Thiones 197(A-C,E), 198(B,C,H), 199(A,C,-E), 201(A,B,D,E,G) And204(B-D) 214
  3.7 4- ( Amino )- 5-( Substituted)-L ,2,4- Triazole - 3-Thiones 206( A- J) 223
  3.8 N-(2€™ ,3€™,4€™ ,6€™ - Tetra-O- Acety - ’-D- Glucopyranosy 1)-4-Amino- 5-(Substituted)-L ,2,4-Triazole-3-Thiones 207(A-J) 228
  3.9 N- ( ’ - D- Glucopyranosy 1)-4-Amino- 5-Substituted-L ,2, 4-Triazo Le-3-Thiones 208(B-C,G,H) 236
  3.10 4-Amino-5-(Substituted Phenoxymethyl )- L ,2,4 -Triazole-3- Thiones 210(A-J,I) 238
  3.11 N-( 2€™ ,3€™,4€™ ,6€™ - Tetra-O-Acetyl- ’-D- Galactopyranosyl )-4-Amino-5-( Substitutedphenoxymethyl -L ,2,4-Triazole-3-Thiones 210(A-G,I) 239
  3.12 5-(Substituted)- 1 ,3,4 -Oxadiazole-2-Thiols 205(A-Q) 248
  3.13 N-(2€™ ,3€™,4€™ ,6€™ - Tetra-O-Acetyl- ’ -D- Gluco/Galactopyranosyl )-S- Substituted-1 ,3,4-Oxadiazole-2-Thiones 213(A-Q) 249
  3.14 N- ( ’ - D- Gluco/Galactopyranosyl )-5-Substituted-L,3 ,4- Oxadiazole-2-Thiols 214(A,B,F,I-K,O-Q) 264
  3.15 2-( Substitutedphenoxyalkyl )Carboxylic Acids 215(A-O) And Their Hydrazides 216(A-F,J-O) 268
  3.16 5-( Substitutedphenoxyalky 1)-1 ,3 ,4-Oxadiazole-2-Thiols217(A-F,J-O) 269
  3.17 N-(2€™ ,3€™,4€™ ,6€™ - Tetra-O-Acetyl- ’ -D- Glucopyranosyl )-5-( Substi - Tuted Phenoxymethy 1)-1,3 ,4-Oxadiazole-2-Thiones 218( A-F) 274
  3.18 2-Aryl Benzimidazoles 220(A-J ) 280
  3.19 N-(2€™ ,3€™ ,4€™ ,6€™- Tetra-O-Acetyl- ’ -D- Glucopyranosyl )-2-(Substituted)Benzimidazoles 221(A-D) 281
  3.20 2-( Phenoxymethyl )- 1 ,3 -Benzimidazoles 223(A-I) 285
  3.21 N-( 2€™ ,3€™,4€™ ,6€™- Tetra-O-Acetyl-‘-D- Glucopyranosyl )-2-( Phenoxymethyl )Benzimidazoles 224(A-H) 286
  3.22 Antibacterial Screening Of Synthesized Compounds 290
  3.23 Antifungal Studies 291
  3.24 Phytotoxic Activity Screening 292
  3.24 Conclusions 301-303
  3.25 References 304-320
  3.26 List Of Publications 321