ABSTRACT

The synthesis of N-heteroaryl substituted benzene sulphonamides and evaluation of their biological activities are reported. Synthesis was achieved by the reaction of benzene sulphonyl chloride and substituted amino heterocycle in dry pyridine. The structures of synthesized compounds were assigned by spectroscopic methods. The eight (8) synthesized compounds were evaluated for antibacterial and antifungal activities. The results showed that some of the new compounds exhibited activities comparable to ciprofloxacin and ketoconazole. Acute toxicity (LD50) of the synthesized samples was carried out. Malaria parasitaemia was inoculated in the mice using parasitized blood from infected mice. The synthesized compounds were used at dose 2000 mg/kg body weight of mice. The antioxidant effects were determined using the antioxidant enzymes: superoxide dismutase (SOD), catalase and glutathione. Some of the new compounds displayed significant antioxidant properties. The parameters; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes activities were used for liver function test while serum urea and creatinine tests were used as markers for renal function. The results of the activities of the synthesized compounds showed appreciable inhibition of the growth of test organism. The liver and kidney function tests showed improved activity when compared with the positive control.

TABLES OFCONTENT

Title page i

Certification ii

Dedication iii

Acknowledgement iv

Abstract v

Table of content vi

List of the Tables x

List of the Schemes xi

List of the Figures xii

List of the Abbreviations xv

CHAPTER ONE

1.1 Introduction 1

1.2 background of study 2

1.2.0 Classification of Sulphonamides 7

1.2.1 Short Acting Sulphonamides 7

1.2.2 Intermediate or Moderate Acting Sulphonamides 8

1.2.3 Long Acting Sulphonamides 8

1.3 Statement of the problem 9

1.4 Objectives of the study 10

1.5 Justification of the study 10

CHAPTER TWO

2.1 Literature review 12

2.2.1 Synthesis of sulphonamides 12

2.2.2 Sulphonamides from sulphonyl chlorides 13

2.2.3 Sulphonamides from sulphonic acids 14

2.2.4 Sulphonamides from sulphenamides 16

2.2.5 Sulphonamides from sulphonate esters 17

2.2.6 Sulphonamides from N-arylation 21

2.3.1 Applications of the Sulphonamides 23

2.3.2 Sulphonamides as Drugs 25

2.2.2 Sulphonamides as antibacterial agents 25

2.2.3 Sulphonamides as HIV inhibitors 26

2.2.4 Sulphonamides as cysteine protease inhibitors 28

2.2.5 Sulphonamides as COX – II specific 32

2.2.6 Sulphonamides as carbonic anhydrase 33

CHAPER THREE

3.0 Experimental 37

3.1 General 37

3.2 General Procedures 37

3.3 Determination of the Antimicrobial Activity 37

3.4.1 Sensitivity Testing of Compounds. 38

3.4.2 Minimum Inhibitory Concentration (MIC) Testing of Compounds. 38

3.5.1 Acute Toxicity Studies (LD50) 39

3.5.2 Experimental protocol for Acute Toxicity Studies 39

3.5.3 Experimental Design 39

3.6.1 Inoculation of Parasitaemia 40

3.6.2 Determination of the Malaria parasite (Mp+) 41

3.7.0 Determination of the Antioxidant activity: 41

3.7.1 Determination of the Superoxide Dismutase (SOD) 41

3.7.2 Determination of the Catalase 41

3.7.3 Determination of the Glutathione 42

3.8.0 Determination of the Liver Function Test activity: 42

3.8.1 Determination of the Aspartate Aminotransferase (AST) Activity 42

3.8.2 Determination of the Alanine Aminotrasferase (ALT) Activity 43

3.9.0 Determination of the Kidney Function Test activity: 44

3.9.1 Determination of the Urea 44

3.9.2 Determination of the Creatinine 45

3.10.1 N- (pyridin - 2 -yl)benzene sulphonamides 45

3.10.2 N- (4-methylpyridin - 2 -yl)benzene sulphonamides 45

3.10.3 N- (3-nitropyridin - 2 -yl)benzene sulphonamides 46

3.10.4 N- 5-nitropyridin - 2 -yl)benzene sulphonamides 46

3.10.5 N- (3-hydroxypyridin - 2 -yl)benzene sulphonamides 46

3.10.6 N- (5-chloropyridin - 2 -yl)benzene sulphonamides 46

3.10.7 N- (2,6-dichloropyridin - 2 -yl)benzene sulphonamides 47

3.10.8 N- (3,5-dichloropyridin - 2 -yl)benzene sulphonamides 47

CHAPER FOUR

4.0 Results and discussion 48

4.1.1 N- (pyridin - 2 -yl)benzene sulphonamides 48

4.1.2 N-(4-methylpyridin–2-yl)benzene sulphonamide 49

4.1.3 N- (3-nitropyridin - 2 -yl)benzene sulphonamides 49

4.1.4 N- (5-nitropyridin - 2 -yl)benzene sulphonamides 50

4.1.5 N- (3-hydroxypyridin - 2 -yl)benzene sulphonamides 50

4.1.6 N- (5-chloropyridin - 2 -yl) benzene sulphonamides 51

4.1.7 N- (2,6-dichloropyridin - 2 -yl)benzen esulphonamides 51

4.1.8 N- (3,5-dichloropyridin - 2 -yl)benzene sulphonamides 52

4.2 Result of Antimicrobial Activity 52

4.3 Result of Acute Toxicity Study (LD50) 54

4.4 Result of Percentage Parasitaema 57

4.5.0 Result of determination of the Antioxidant Activity: 58

4.5.1 Result of determination of the Superoxide Dismutase (SOD) 58

4.5.2 Result of determination of the Catalase 59

4.5.3 Result of determination of the Glutathione 60

4.6.0 Result of determination of the Liver Function Test Activity: 61

4.6.1 Result of Aspartate aminotranferasa (AST) Activity in Mice 62

4.6.2 Result of Alanine aminotranferasa (ALT) Activity in Mice 62

4.7.0 Result of determination of Kidney Function Test Activity: 64

4.7.1 Result of Urea 64

4.7.2 Result of Creatinine 65

4.4 Discussion 66

CHAPTER FIVE

5.0 Conclusions 69

5.2 Recommendation 69

References 70