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

 

 

Furthermore, the sulphonamide group has been proven to have remarkable utility in medicinal chemistry and features in a number of clinically relevant small molecules¹¹. For instance, some currently approved drugs with sulphonamide structural skeletons include the antihypertensive agent bosentan(7)¹², the antiviral HIV protease inhibitor amprenavir(8)¹³,the phosphodiesterase-5 inhibitor sildenafil¹⁴, antidiabetic drug glibenclamide(9)¹⁵, antidiabetic nonantibiotic glimepiride  and the diuretic drug torasemide¹⁶

 

In addition, suphonamides are also highly relevant both in the animal world and the plant life cycle. For example, the breakdown of cyclic guanosine monophosphate is retarded by sildenafil, a substituted guanine analog, which keeps cut flowers fresh for another week and also strengthens plant stems to stand straight even in the midst of storm and wind¹⁷. A preserving effect on fruits and vegetable was also found, making sildenafil , a promising agent¹⁸. Today, it is marketed under the trade name of Viagra¹⁹, which is a potent drug used in erectile dysfunction in man²⁰. It has been reported that more than 150 million men worldwide have this dysfunction²¹. In another discovery, sulphonamide has been documented as highly efficient candidate with high  inhibitory activity²²

Similarly, some sulphonamides have been established as potent drugs in the treatment of insomnia and other sleep challenges in man by antagonizing orexin neural activity. Activation of orexin neurons contribute to the promotion and maintenance of wakefulness²³. Conversely, relative  inactivity of orexin neurons allows the onset of sleep²⁴. Consequently, blocking orexin signaling with receptor antagonists may provide a new mechanism for decreasing wakefulness. Thus , a novel therapeutic opportunity for the treatment of insomnia was reported using a dual receptor antagonists almorexant²⁵. Also, a low molecular weight aryl containing N-glycine-suphonamide (2-[(4-tert-butyl-benzenesulphonyl)-p-toly-amino]-N,N-dimethyl-acetamide(10), was discovered as a potent and selective  antagonist with very poor oral bioavailability (F=1%) in wister rats.²⁶

 

The mode of action of sulphonamide is by mimicking p-aminobenzoic acid (PABA), which is needed in bacteria as a substrate of the enzyme dihydropteroate synthetase for the synthesis of tetrahydrofolic acid,  a basic growth factor essential for the metabolic process of bacteria²⁷. Sulphonamide are preferred due to the ease of administration²⁸, wide spectrum of antimicrobial activity²⁹, non-interference with host defence mechanism and relative freedom from problems of super-infection^30-31

Sulphonamides have been classified using various parameters: For instance, by using the antibiotic properties, it can be classified into antibiotic (antimicrobial) sulphonamides and non antibiotic (non antimicrobial) sulphonamides³². Although, almost all therapeutically useful sulphonamides are aromatic linked as in Ar-SO₂NH₂ or Ar-SO₂NHR³³, yet, there are important distinctions between sulphonylarylamines (antimicrobial/suphonamides), nonarylamine (non antimicrobial) sulphonamides, and sulphones, with regard to allergy and other drug reactions³⁴. Sulphone , unlike  sulphonamide, has its sulphonyl unit incorporated between two carbon systems which may be part of either aliphatic or aromatic moieties ³⁵.

Most reactions to sulphonylarylamines probably results from multifactorial immunologic and toxic metabolic mechanisms, whereas less is known about the precise mechanism of reaction of other sulphur-containing drugs. Some sulphonamides such as the anticonvulsante, sultiames are  devoid of  antibacterial activity. The sulphonylurea and thiazide diuretics are newer drug groups used on the antibacterial sulphonamides³⁶. One of the sulphonamides of paramount importance is benzenesulphonamide derivatives. Benzenesulphonamide moiety is an integral part of many drugs and drug-like scaffolds³⁷. Many derivatives of benzenesulphonamide have been explored as important starting materials and reactive intermediates in various organic synthesis. For example, 2-hydroxyalkylbenzene sulphonamides  have been reported as the important starting materials ³⁸  for the structure activity relationship (SAR) study during the search for cycloxygenase-2 (COX-2) inhibitors as analgesic³⁹ and anti-inflammatory agents⁴⁰.

The chemistry of sulphonamides has recently shown them to be highly efficient synthons in the preparation of various valuable biologically active compounds⁴¹. In exploiting the chemistry of sulphonamides as ligands, various researchers have attempted and embarked upon designing and synthesizing various novel metal based sulphonamides⁴². The chiral ligands of sulphonamides designed as first , second  and third generation  ligands for catalyzing stereoselective synthesis of highly relevant asymmetric compounds⁴³ has been years odyssey. In a similar manner, a new series of sulphonamides derived Schiff bases has been synthesized by a condensation reaction of various sulphonamides with aromatic aldehydes⁴⁴. The sulphonamides obtained were further investigated for their metal complexing potential in terms of chelation  and biological properties⁴⁵ .

On the issue of side effect, it is important to make a distinction between sulpha drugs and other sulphur containing drugs and additives, such as sulphates and sulphites, which are chemically unrelated to the sulphonamide group, and do not cause the same hypersensitivity reaction seen in the sulphonamides. Although there are reported cases of allergy to sulphonamide drug but the term sulpha allergy is imprecise and misleading and therefore should be discouraged⁴⁶. Sulpha allergies are commonly reported as side effect of sulphonamide drugs, hence medications containing sulphonamides are prescribed carefully. In fact, issues in understanding the clinical evidence and drug dynamics as they relate to individuals and populations have been explored⁴⁷. Statistics have shown  that approximately 3% of the general populations show sulpha drug allergies, when treated with sulphonamides  and other similar antibiotics⁴⁸.

The potential utilization of sulpha drug compounds as corrosion inhibitors has also been established⁴⁹. The inhibitory effect of four sulpha drug compounds namely, sulphamethazine , sulphaguanidine , sulphamethoxazole and sulphadiazine , on mild steel corrosion in 1.0 M HCl solution  was evaluated using  galvanostatic polarization weight loss technique⁵⁰. All the  sulpha drug compounds examined were reported to reduce the corrosion of mild steel indicating their high potency as anti-corrosion agents. Among the compounds studied, sulphadiazine  was shown to have the best inhibition efficiency⁵¹. Some quantum mechanical studies have successfully linked the  inhibition efficiency with molecular properties for different kinds of organic compounds⁵². Sulphonmide derivatives of azo dyes achieve improved light stability, water solubility and fixation to fibre. The sulphonamide dyes, especially secondary sulphonamide dyes, exhibited superior dye exhaustion and colour fastness to washing, sublimation and rubbing on fine denier PP fabrics⁵³. They have been used as protecting groups of hydroxyl or amino  functionalities for easy removal under mild conditions⁵⁴.

Even though many synthetic methods have been reported for the preparation of sulphonamides⁵⁵, the sulphonylation of ammonia⁵⁶ or primary and secondary amines with sulphonyl chlorides in the presence of a base is still the method of choice because of high efficiency and simplicity of the reaction . Nevertheless, various acceptable techniques involve the need to reduce the amount of toxic waste and by-products arising from chemical processes required thereby increasing emphasis on the use of less toxic and environmentally compatible materials in the design of new synthetic methods⁵⁷. One of the most promising approaches is using water as the reaction media⁵⁸ while others include microwave irradiation technique, heterogeneous catalytic approach, solvent free media usage, nontoxic solid support resin⁵⁹ etc. Sulphonamides an ionizable, polar antimicrobial compounds, may reach the environment in substantial amount by the spreading of manure⁶⁰ or other means.

In a similar manner, amide formation is a fundamental reaction of great interest in organic chemistry⁶¹. The development of efficient methods for the synthesis of amides remains a great challenge because of their importance in chemistry and biology, with a wide range of industrial and pharmaceutical applications and as valuable intermediates in organic synthesis⁶². Hence, it is convincing to design the synthetic route in such a way to have a second amide functionality, being incorporated within the frame work of the synthesized sulphonamides, this will help in the comparative study of the antimicrobial activity of the ordinary sulphonamide with amide bearing sulphonamide derivatives.

Despite the various hazardous effects posed by deadly microbes⁶³, it is highly surprising to know that no new antimicrobial drug has been discovered in the last few years. Therefore, there is a continuous need for the design and synthetic formulation of new class of antimicrobial drugs in order to control rapid spread of harmful microbes.

There has been a frequent failure in treatment of infections using antibiotics. Biofilm effect is the mechanism responsible for the frequent failure of antibiotic treatment to cure infections of medical devices and other prosthetic materials⁶⁴. In the biofilm stage, a phenotypic change occur in which the bacteria require generally much higher concentrations of antibiotics to inhibit their growth. In fact, it has been recently discovered that the comparative study of the minimum inhibitory concentration (MIC) and minimum biofilm eliminating concentration (MBEC) is a potential factor determining  the changes in the pattern of antibiotic sensitivity of gram negative bacilli from the planktonic to the biofilm stage of growth⁶⁵. In addition, the rapid emergence of drug resistance has become the most urgent concern because it renders current treatments ineffective and therefore compels the scientific community to continue efforts in the design of inhibitory agents that can efficiently combat drug resistance

1.1.1 Chemical classification and Nomenclature of sulphonamides

Sulphonamides are derivatives of sulfuric acids. Sulphonamides are chemically quite stable, these are weak acids compared to carboxylic acid amides. The sulphonamide functional group is – (SO₂-NH₂, a sulfonyl group connected to an amine group). The general formula is RSO₂NH₂. where R is some organic group such as alkyl, benzyl etc..

Any sulfonamide can be considered as derived from a sulfonic acid by replacing a hydroxyl group with an amine group. In medicals, the term “sulfonamide” is sometimes used as a synonym for sulfa drug, a derivative or sulfamilamide.

 

 

 

 

1.1.2   Medicinal properties of sulfonamide 

The sulphonamide scaffold is well known for the design of many sulphonamide compounds with diverse medicinal properties. The presence of benzene ring  allows sulfonamides to partition through bacterial cell walls. Once inside of the bacteria cells, sulfonamides must be ionizable and contain both a positive and negative charge on opposite sides of its structure, which further resembles the structure of PABA and result in binding of sulfonamide.

Antibacterial activity

Kumar and coworkers⁶⁶ have reported the synthesis of some Schiff bases or sulfonamides by condensing 4–aminobenzene sulphonamide with different aromatic aldehydes in the presence or glacial acitic acid and ethanol at 50-60⁰C. The antimicrobial activity of these compounds was evaluated by agar diffusion method. Several Schiff bases derived from sulphonamide have shown good antibacterial activity.

Anti-inflammatory Activity 

Benzene sulfonamide  derivatives carrying a pyrozole moity were prepared by Abddaal et al⁶⁷ which where structurally related COX-2 inhibitor celecoxib  (celebrex_®) and were found to be potent anti-inflammatory agents with little or no tendency to evoke gastric ullercities. In these derivatives, N-Ethyl -2- (3-merthyl -5- oxo-4, 5- dihydro-pyazile -1- carboxyl)-benzensulfonamide (11) was found to be more active than the celebrex.

Growth Hormone  scretagogue Receptor

High specific activity sulfur -35- labeled sulphonamide radioligand has been developed by Dean and  co-workers⁶⁸ for the identification of a GH secretagogue receptor [355] – MK – 0677 was found to posses the necessary concentration of high selectivity, affinity and specific activity required for utilization as a radioligand in the study of this nearly discovered receptor.

Cancer-Associated carbone anhytrases (CAs)

Neogluco conjugate a new class of sulfonamide link was designed by Moore and  co-workers⁶⁹ to selectively target and inhibit the extracellular domains of the cancer-relevant CA isozymes. The carbohydrate fragment in these compounds is linked to the classical aromatic sulfonamide  CA  pharmacore to target inhibition of cancer associated CAs. The CA inhibitors design were very good CA IX inhibitors and potent CA XII inhibitors.

 

Antimicrobial activity                                                  

Iqbal and coworkers⁷⁰ synthesized benzene sulphonamides bearing 2,5 disubstituted  1,3, 4- oxadiazole  moiety and tested these compounds for antimicrobial and antifugal activity. Compound (12) exhibited significant antibacterial and significant antifugal activities due to the presence of a chloro group on position 4 of the phenyl substitutent, the free SH group at position 5 of the oxadiazole ring, and the free – NH₂ group of the sulphonamido moiety.

12

B – Lactamase inhibitors

Eidam⁷¹ synthesized new sulfonamide boronic acids, derived from the conversion of the canonical R₁ caboxamide. This has substantial inhibition activity against B- Lactamases, they also rescued antibiotic resistance when used in combination with third generation antibiotics in bacterial cell cultures. This superficially modest substitution changes the geometry of the inhibitors enough to scramble the SAR observed in the analogue carboxamides.

13

 

Protein kinase inhibitors

The isoquinoline sulphonamide (14) derivatives synthesized by Hidaka et al⁷²  had ability to inhibit protein kinases, some of the derivatives (15-20) exhibited selective inhibition towards  certain protein kinase. The inhibtors where freely reversible and of the noncompetitive type with respect to the phosphate acceptor. The isoquinoline sulphonamides which are structurally unrelated to ATP, compete with ATP for free emzyme but do not interact with same enzyme form as does the phosphate acceptor.

 

 

 

 

1.2   STATEMENT OF THE PROBLEM

Sulphonamides are a class of broad antibacterial  compounds that have a wide range of application. The group belongs to distinctive class of compounds that constitute at least five different classes of pharmacologically active agents⁷³. The basic sulfonamide group, SO₂NH-, occurs in various biologically active compounds, including antimicrobial drugs, antithyroid agents, antitumor, antibiotics and inhibitors of carbonic anhydrase⁷⁴.

There is a vast increase in resistance of infectious disease to antibiotics, which negates  treatment by   almost all the known classes of antimicrobial compounds. Under these circumstances, the development of novel classes of antimicrobial compound becomes imperative⁷⁵.

Literature survey reveales that minor modifications in the structure of sulphonamide can lead to quantitative as well as qualitative changes in the biological activity.⁷⁶

Inspite of the wide biological application of benzene sulphonamide derivatives, nothing is known of the N-heteroaryl substituted derivatives. The  biological activities of these class of compound are yet unexploited.

1.3      OBJECTIVE OF THE RESEARCH

The objectives of these research are as follows;

• To synthesize benzene sulphonamide from benzene sulphonyl chloride and amino acids.
• To synthesize the N-pyridine-3-yl derivatives of the
• To characterize the synthesizes compounds using FTIR,¹HNMR and ¹³
• To screen the new compounds for antibacterial, antifungal and antioxidant activities.

1.4   Justification Of The Study

The wide application of sulphonamides and the need to synthesize new functionalized derivatives with probable improved biological activities justifies  this research.

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