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SYNTHESIS, CHARACTERIZATION AND SOLVENT EXTRACTION STUDIES OF 3,5-BIS[(2-HYDROXY-BENZYLIDENE)-AMINO]-BENZOIC ACID AND ITS Co(II) AND Ni(II) COMPLEXES

ABSTRACT

In this study, a series of N-pyridin-3-yl substituted [phenylsulphonamido] acetamide has been synthesized. The reaction of phenylsulphonyl chloride with various amino acids in basic medium yielded phenylsulphonamido alkanoic acid which, on chlorination with thionyl chloride, gave acid chloride derivatives of phenylsulphonamido alkanoic acid in situ. The acid chloride derivatives on condensation with 3-aminopyridine gave corresponding acetamide in good to excellent yield. The compounds were characterized by FTIR, 1H-NMR and 13C-NMR and screened for antibacterial, antifugal and antioxidant activities. The result revealed that the compounds possess antibacterial activities.One the compounds, 2-[(phenylsulfonyl)amido]propanoic acid had better antibacterial activities than ciprofloxacin the reference drug  while others are less active. All the compounds has less antifungal activities than ketokonazole the reference drug. 2-[(phenylsulfonyl)amido]propanoic acid had the best antioxidant properties of all the compounds.

 

 

 

TABLE OF CONTENTS

Title page    –        –        –        –        –        –        –        –        –        –        -i

Approval page     –        –        –        –        –        –        –        –        –        -ii

Dedication  –        –        –        –        –        –        –        –        –        –        -iii

Acknowledgement         –        –        –        –        –        –        –        –        –        -iv

Abstract      –        –        –        –        –        –        –        –        –        –        -v

Table of contents  –        –        –        –        –        –        –        –        –        -vi

CHAPTER ONE

  • Introduction      –        –        –        –        –        –        –        –        -1

1.1.       Background of the study      –        –        –        –        –        –        -1

1.1.1.    Chemistry and nomenclature of sulphonamides         –        –        –        -11

1.1.2.    Medicinal important or sulfonamides     –        –        –        –        -12

1.2.       Statement of the problem or research question –        –        –        -16

1.3.        Objective of the research     –        –        –        –        –        –        -17

1.4.         Justification of the study    –        –        –        –        –        –        -18

 CHAPTER TWO

Literature review

2.1.     History of sulphonamide drug discovery  –        –        –        –        -19

2.2.     Synthesis of sulphonamides –        –        –        –        –        –        -21

2.2.1.   Synthesis from amination of chalcones    –        –        –        –        -26

2.2.2.   Chloromethylsulphonylation of benzylisothiourea               –        –        -26

2.2.3.   Copper ii oxide catalytic sulphonylation method        –        –        –        -27

2.2.4.   Synthesis from ionic liquid mediated approach –        –        –        -28

2.2.5.   Synthesis from heteroaryl thiols     –        –        –        –        –        -29

2.3.      Sulphonamide as antimicrobial agents     –        –        –        –        -29

CHAPTER THREE 

3.0.    Experimental section     –        –        –        –        –        –        –        -31

3.1.     Materials and method   –        –        –        –        –        –        –        -31

3.2      Synthesis of benzensulphonamide   –        –        –        –        –        -31

3.2.1.   Synthesis  [(phenylsulfonyl)amido]acetic acid   –        –        –        -32

3.2 .2   Synthesis of  4-methyl-2-[(phenylsulfonyl)amido]pentanoic acid  -32

3.2.3    Synthesis of  2-[(phenylsulfonyl)amido]propanoic acid –               –        -33

3.2.4    Sythesis of 3-phenyl-2-[(phenylsulfonyl)amido]propanoic acid     –        -34

3.2.5     Synthesis of 4-(methylsulfanyl)-2-[(phenylsulfonyl)amido]

butanoic acid    –        –        –        –        –        –        –        –        -34

3.3.   General method of synthesis of N-heteroaryl substituted

Benzensulphonamide       –        –        –        –        –        –        –        -35

3.3.1    2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)acetamide –        –        -36

3.3.2.   4-methyl-2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)pentanamide.         -36

3.3.3.   2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)propanamide     –        -37

3.3.4.   3-phenyl-2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)propanamide         -38

3.3.5.   5-(methylsulfanyl)-3-[(phenylsulfonyl)amido]-N-(pyridin-3-            yl)pentanamide. –          –        –        –        –        –        –        –        -39

3.4        Biological activities    –        –        –        –        –        –        –        -40

3.4.1    Antimicrobial activity –        –        –        –        –        –        –        -40

3.5.      Evaluation of antioxidant activity  –        –        –        –        –        -40

3.5.1.    Scavenging of dpph radical  –        –        –        –        –        –        -41

3.5.2      Reducing power        –        –        –        –        –        –        –        –        -41

3.5.3.    Ferrous sulphate induced lipid peroxidation scavenging     –        –        -42

 

CHAPTER FOUR

4.0       Results and discussion          –        –        –        –        –        –        –        -44

4.1       Benzene sulphonamides        –        –        –        –        –        –        –        -44

4.1.1    [(phenylsulphonyl)amido]acetic acid       –        –        –        –        –        -44

4.1.2.   4-methyl-2-[(phenylsulfonyl)amido]pentanoic acid     –        –        -45

4.1.3     2-[(phenylsulfonyl)amido]propanoic acid,       –        –        –        –        -46

4.1.4.    3-phenyl-2-[(phenylsulfonyl)amido]propanoic acid   –        –        -47

4.1.5.    4-(methylsulfanyl)-2-[(phenylsulfonyl)amido]butanoic acid          –        -49

4.2.       Synthesis of  N-pyridine-3-yl substituted benzensulphonamide    –        -50

4.2.1.     2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)acetamide        –        –        -51

4.2.2.     4-methyl-2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)pentanamide        -51

4.2.3.     2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)propanamide   –        -53

4.2.4.     3-phenyl-2-[(phenylsulfonyl)amido]-N-(pyridin-3-yl)propanamide       -44

4.2.5      5-(methylsulfanyl)-3-[(phenylsulfonyl)amido]

N-(pyridin-3-yl)pentanamide         –        –        –        –        –        –        -56

4.3       Biological activities.    –        –        –        –        –        –        –        -57

4.3.1    Minimum Inhibitory Concentration(MIC) mg/ml        –        –        –        -57

4.3.2    Results of sensitivity test      –        –        –        –        –        –        -59

4.4       Anti oxidant evaluation        –        –        –        –        –        –        –        -60

4.4.1    Invitro free radical scavenging effect of samples by dpph method -60

4.4.2.   Ferrous sulphate induced lipid peroxidation     –        –        –        –        -62

4.4.3    FRAP       –        –        –        –        –        –        –        –        –        -63

CHAPTER FIVE

5.1.    Conclusion –        –        –        –        –        –        –        –        –        -64

5.2      References –        –        –        –        –        –        –        –        –        -65

 

CHAPTER ONE

INTRODUCTION

1.1 Background of the study

The growing incidence of microbial resistance to currently used antibiotics represents a serious medical problem. Therefore, there is an urgent need to develop new classes of therapeutic agents to treat microbial infectious. Such new therapeutic agent has to exhibit a wide spectrum of biological activities. Sulphonamides, an important class of pharmaceutical compounds, exhibit a wide spectrum of biological activities1. The basic sulphonamide group [SO2, NHR] occurs in various biologically active compounds including antimicrobial drugs, antithyroid agents, antitumor, antibiotics and inhibitors of carbonic anhydrase2 . Sulphonamides are widely used to treat microbial infections by inhibiting the growth of Gram negative and Gram positive bacteria, some protozoa and fungi3 . Clinically, sulphonamides are used to treat several urinary tract infections and gastrointestinal infections4. Sulphonamides5 that are aromatic or heteroaromatic are responsible for the inhibition of the growth of tumor cells. They act as antitumor agents by inhibiting carbonic anhydrase activity. They are structurally similar to p-aminobenzoic acid  (PABA) which is a cofactor that is needed by the bacteria for the synthesis of folic acid. Sulphonamide antibiotics inhibit the conversion of PABA into folic acid and thus ultimately inhibit the synthesis of DNA. They are also used in veterinary medicine to treat infections in livestock6. In primary care medicine, sulphonamides are widely used in various conditions including gastrointestinal7 and urinary tract infections8. Sulphonamide is the organic framework of main focus in this research and it belongs to the family of suphur-containing compounds9, which are earlier referred to as sulpha drugs . Some of these sulpha drugs that have performed “healing magic” in the world of chemotherapy include; sulphanilamide(1), sulphadiazine(2), sulphacetamide(3), sulphamonomethoxine(4), sulphasalazine(5), sulphadoxine(6), among others. Sulphonamides have long been the subject of pharmaceutical interest as a result of their potent biological activities10

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