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Title of Thesis

Synthesis, Characterization and Biological Activities of Oxygen, Nitrogen and Sulphur Containing Heterocyclic Compounds

Author(s)

Ghulam Qadeer

Institute/University/Department Details
Department of Chemistry / Quaid-i-Azam University, Islamabad
Session
2009
Subject
Chemistry
Number of Pages
349
Keywords (Extracted from title, table of contents and abstract of thesis)
Activities, Characterization, Homophthalic, Synthesis, Nitrogen, Heterocyclic, Alkaline, Fascinating, Synthesized, Oxygen, Sulphur, Compounds, Biological

Abstract
The work presented in this thesis consists of the synthesis, characterization, and biological screening of heterocyclic compounds. For convenience, the work has been divided into two parts, part one is related to the compounds containing oxygen atom in the heterocyclic ring whereas part two refers to the compounds containing nitrogen and/ or sulphur atoms in the heterocyclic ring.
Part one of this thesis is related to the synthesis, characterization and biological activity of some heterocyclic compounds containing oxygen in the ring.These compounds include some naturally and unnaturally occurring substituted isocoumarins and 3,4-dihydroisocoumarins. The synthesis of naturally occurring isocoumarin Thunberginol B is reported, in which 3,5-dimethoxyhomophthalic acid is a key intermediate for the synthesis of Thunberginol B. It was synthesized efficiently in five steps from 3,5-dimethoxybenzaldehyde via a series of reactions including synthesis of 3,5-dimethoxycinnamic acid, 3-(3′,5′- dimethoxyphenyl)propionic acid, cyclization of 3-(3′,5′-dimethoxyphenyl)propionic acid to 5,7-dimethoxy-1-indanone and oxidative decomposition of methyl 2- hydroxy-2-(5,7-dimethyoxy-1-oxo-1H-inden-2(3H)-ylidene)acetate to 3,5- dimethoxyhomophthalic acid. 3,4-Dimethoxybenzoylchloride was prepared from 3,4-dimethoxybenzoic acid on reaction with thionyl chloride which on condensation with 3,5-dimethoxyhomophthalic acid afforded 3-(3',4'- dimethoxyphenyl)-6,8-dimethoxyisocoumarin. Complete demethylation of 3-(3',4'- dimethoxyphenyl)-6,8-dimethoxyisocoumarin with hydrobromic acid in acetic acid gave 3-(3',4'-dihydroxyphenyl)-6,8-dihydroxyisocoumarin (Thunberginol B).in addition to above, some unnaturally occurring halogenated isocoumarins and their 3,4-dihydrodrivatives were also synthesized. The difluorophenyl- and dichlorophenylisocoumarins by condensation of homophthalic acid with an appropriate acid chloride.Alkaline hydrolysis of the isocoumarins yielded corresponding keto-acids, which on reduction give the corresponding racemic hydroxy-acids. 3,4-Dihydroisocoumarins were obtained from these racemic hydroxy-acids by cyclodehydration using acetic anhydride.
All the synthesised compounds were identified using their IR, 1H NMR and mass spectral data. In many cases 13C NMR and elemental analysis data were employed to support the characterization. In each case, a plasible mass fragmentation pattern is suggested. The synthesized compounds were screened for their antifungal, antibacterial, herbicidal, insecticidal, fungicidal, antimetastatic, brine shrimp lethality, antioxidant, anti -inflammatory, antiviral, anti- HIV, anti-HBV and anticancer activities and in some cases, very fascinating results were obtained which were then published in different international journals.These synthetic schemes have tremendous potential for further synthesis of novel biological active compounds.
Part two of the thesis describes the synthesis and biological screening of some,hitherto unreported, isatin derivatives (Indolinones), 1,4-disubstituted thiosemicarbazides and their related 2,5-disubstituted-1,3,4-thiadiazoles and 4,5- disubstituted-3H-1,2,4-triazole-3-thiones. Indolinones were formed by the direct condensation of hydrazides with halogenated isatins. Triazoles were formed by intramolecular dehydrative cyclization of thiosemicarbazides in basic media while thiadiazoles were formed in acidic media, which is an intermediate during the synthesis of various heterocyclic compounds.Thiosemicarbazides were formed by aldol type condensation reaction of acid hydrazides and isothiocyanates. Isothiocyanates were formed by the reaction of anilines with carbon disulphide in ammonium hydroxide solution to yield ammonium dithiocarbamate, an intermediate which on oxidation with lead nitrate yield isothiocyanate.Acid hydrazides were formed by the reaction of esters of carboxylic acid with hydrazine hydrate and esters were formed by refluxing carboxylic acid in methanol in catalytic amount of carboxylic acids. As a result of these synthetic schemes, thirty new indolinones, ten disubstituted-1,3,4-thiadiazoles and twenty disubstituted 1,2,4-triazole-3-thiones were synthesized. The characterization of these synthesized compounds was carried out by IR, 1H NMR, 13C NMR, elemental analysis, Mass spectral data and XRD analysis. The synthesized compounds were screened for their antifungal, antibacterial, herbicidal, insecticidal, fungicidal, plant growth regulatory activity and antiviral activities.

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S. No. Chapter Title of the Chapters Page Size (KB)
1 0 CONTENTS

 

 
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2

1

INTRODUCTION

1.1 Nomenclature and structural types
1.2 Physical properties
1.3 Biological activities
1.4 Behavior towards human beings
1.5 Biosynthesis
1.6 Synthesis of isocoumarins and 3,4-dihydro-isocoumarins
1.7 Interconverision of isocoumarins and 3,4-dihydro- 34 isocumarins
1.8 Reactions of isocoumarins and 3,4-dihydtoisocoumarins
1.9 Plan of work

1
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3 2 SYNTHESIS OF NATRUAL ISOCOUMARIN

2.1 Synthesis of Naturally Occurring Thunberginol B

41
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4 3 SYNTHESIS OF UNNATRUAL ISOCOUMARINS AND 3,4-DIHYDROISOCOUMARINS

3.1 Synthesis of Dihalophenylisocouamrins
3.2 Synthesis of 3H-Furo[3,4-c]-isochromene-1,5-dione 85 (an unusal isocoumarin) and 3-(3′,4′,5′ trimethoxyphenyl)isocoumarin
 

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4

BIOLOGICAL ACTIVITIES

4.1 Antioxidant Studies
4.2 Anti-inflammatory Studies
4.3 Herbicide studies
4.4 Fungicide studies
4.5 Insecticide Studies
4.6 Antifungal studies
4.7 Antibacterial studies
4.8 Brine shrimp lethality (Artemia salina) studies
4.9 Antiviral studies against different Cel lCulture
4.10 Anti-HIV Studies
4.11 Anti-HBV studies
4.12 Anti-cancer studies
4.13 Antimetastatic studies

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6

5

INTRODUCTION

5.1 1,2,4-Triazole
5.2 Chemistry of 1,2,4-triazole
5.3 Spectroscopy of 1,2,4-triazoles
5.4 Applications and biological activities
5.5 Synthetic approaches towards 1,2,4-triazoles
5.6 1,3,4-Thiadiazoles
5.7 Applications
5.8 Synthetic approaches towards 1,3,4-thiadiazoles
5.9 Isatin derivatives-Indolinones
5.10 Plan of work

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6

RESULTS AND DISCUSSIONS

6.1 Synthesis of methyl / ethyl esters
6.2 Synthesis of hydrazides
6.3 Synthesis of isothiocyanates
6.4 Synthesis of thiosemicarbazides
6.5 Synthesis of substituted 1,2,4-triazol-3-thiones
6.6 Synthesis of 1,3,4-thiadiazoles
6.7 Synthesis of indolinones

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7

EXPERIMENTAL

7.1 Substrates and reagents
7.2 Purification of solvents
7.3 Instrumentation
7.4 General procedure for the synthesis of esters
7.5 General procedure for the synthesis of hydrazides
7.6 General procedure for the synthesis of isothiocyanate
7.7 General procedure for the synthesis of Thiosemicarbazides
7.8 General procedure for the synthesis of 1, 2, 4- triazol-3-thiones
7.9 General procedure for the Synthesis of 1,3,4-Thiadiazoles
7.10 General procedure for the synthesis of Indolinones

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8

BIOLOGICAL ACTIVITIES

8.1 Herbicide studies
8.2 Fungicide studies
8.3 Insecticide studies
8.4 Plant growth regulating studies
8.5 Antiviral studies against different cell cultures
8.6 Antifungal studies
8.7 Antibacterial studies

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9

REFERENCES

 

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