SYNTHESIS OF N-(HETEROARYL SUBSTITUTED) BENZENE SULPHONAMIDES AND THEIR BIOLOGICAL ACTIVITIES

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.

CHAPTER ONE

1.1      INTRODUCTION

The basic sulphonamide group –SO2NH- occurs in various biological active compounds including antimicrobial drugs, antithyroid agents, antitumor antibiotics and inhibitors of carbonic anhydrase1,2.   Sulphonamides are widely used to treat microbial infection 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. Sulphonamides that are aromatic or hetroaromatic are responsible for the inhibition of the growth of tumor cells. They act as antitumor agents by inhibiting carbonic anhydrase. Sulphonamides are structurally similar to p-aminobenzoic acid (PABA) which is a cofactor that in needed by the

bacteria for the synthesis of folic acid. Sulphonamides antibiotics inhibit the synthesis of purine and DNA in the microorganism. Sulphonamide antibiotics are used as veterinary medicines to treat infections in livestock herds5,6. Sulphonamides are extremely useful pharmaceutical compounds because they exhibit a wide range of biological activities such as anticancer, anti- inflammatory and antiviral functions7-11. The sulphonylation of amines with sulphonyl chlorides in the presence of a base is still being used as the method of choice because of high efficiency and simplicity of the reaction12. However, this approach is limited by the formation of undesired disulphonamides with primary amines and by the need of harsh reaction conditions for less nucleophilic amines such as anilines13. Additionally, side reactions take place in the presence of a base. Sulphonamides have been used as protecting groups of OH or NH functionalities for easy removal under mild conditions14-15. In recent years, molecular iodine has been extensively used for a plethora of organic transformations as an inexpensive, nontoxic, readily available catalyst under very mild and convenient conditions to afford the corresponding products in excellent yields with high selectivity16-22. This can be seen in the case of efficient molecular iodine

catalyzed method developed for preparing sulphonamides (Scheme 1).                                     3

Scheme1: Synthesis of α-sulphonamide

1.2      Background of Study

Sulfa drugs are still today among the drugs first used (together with ampicillin and gentamycin) as chemotherapeutic agents in bacterial infections by Escherichia coli in humans23. Sulfa drugs also known as sulphonamides have acquired a somewhat specific position in the family of organic sulphur compounds. This is largely due to their involvement in diverse area of utility,  which include the  pharmaceutical fields  in which they are  used  as antidiabetic24,25, antithyroid26,etc. The first antibacterial compounds used were the sulphonamides and the antibacterial properties of the dyestuff, Prontosil rubrum were found to be associated with the sulphonamide group of the compound. Today, the sulphonamides have been largely replaced by

the antibiotics. The main reasons for this are as follows: (i) antibiotics have greater potency and (ii) several strains of bacteria have acquired resistance to sulphonamides. Some of the compounds, however, are still in use. A large number of derivatives of sulphonamides have been prepared by substituting the  hydrogen atoms of the amino radicals with other groups. The sulphonamides are bacteriostatic rather than bactericidal. Their value lies in their ability to slow down or prevent bacterial multiplication in wounds or infected systems without appreciable

toxicity to the body tissues.

Scheme2: Some Example of Sulphonamides Drugs (Prontosil).

They are useful in treatment of infections caused by staphylococci, streptococci, meningococci, and urinary infections caused by gram-negative bacteria. However, organisms develop resistance to sulphonamides in the course of therapeutic use: Those still used include sulfabenzamide,  sulfamethoxazole,  sulfacetamide,  sulfasalazine,  and  sulfathiazole. Sulphonamides are of fundamental chemical interest as many of them possess pharmacological, fungicidal,  or  herbicidal activities.  The  sulphonamides in  general are  thought to  have  low potential for adverse health effects, supported by their long history of safe therapeutic use in humans.  Acute  toxic  effects  have  been  rarely  reported  and  these  compounds  are  also

nongenotoxic and nonteratogenic in laboratory animals at concentrations similar to therapeutic levels in humans. It is well known that their biological properties correlate strongly with the structure and conformational properties of the respective compounds. Recently, a study has been reported on the geometric structure and conformation of benzene sulphonamides, C6H5SO2NH2, on  the  basis  of  combined  study of  gas  electron  diffraction (GED)  and  quantum  chemical calculations27. Calculations also show that the sterically unfavorable orientation of the NH2 group is stabilized by intramolecular hydrogen bonds between O and H atoms of the sulphonamide  group28.  We  have  recently  reported  on  the  quantum  chemical  studies  of  a particular set of sulphonamides (sulfaguanidine, sulfamethazine, sulfamethoxazole, and sulfadiazine) as corrosion inhibitors for mild steel in acidic medium using density functional theory (DFT) and some semi empirical methods and the correlation between the inhibition efficiency and the electronic properties of the studied molecules were discussed29.

Sulphonamides were  the  first  efficient  treatment  to be  employed  systematically for  the prevention and cure of bacterial infections30. Mechanistically, sulphonamides act as antimetabolites. They compete for incorporation with p-amino benzoic acid into folic acid. This principle introduced and  sustained the concept of selective  antagonism. Sulphonamides are widely used  in  medicinal chemistry because  of  their  low  cost,  low  toxicity and  excellent biological activities. Many infectious diseases caused by bacteria are cured by widely use of sulphonamides3. In reported that various N-substituted derivatives of benzene sulphonamides had acetylcholinesterase, butyryl cholinesterase and lipoxygenase activities. Subhakara et al. has

reported sulphonamides derived from C-8 alkyl chain of anacardic acid mixture isolated from cashew nut shellliquid to possess fascinating antibacterial activity31. So Subhrbera et al. has reported pazopanib hydrochloride containing a sulphonamide moiety as a potent and selective 5 multi-targeted receptor of tyrosinekinase that blocks tumour growth and inhibits angiogenesis32. Fors et al. has successfully used a new biarylphospine ligand (t-Bu Brettphos) for palladium catalyzed cross coupling reactions of 1-chloro-2-methylbenzene and acetamide to produce N– phenylacetamide. They reported that this system shows the highest turnover to date for the sereactions, especially for aryl chloride substrates bearing an ortho substituent7.

Scheme3: in vivoMetabolism of Prontosil

Apart from the commercialized application as antibacterial/antibiotic agents, various sulphonamides are also known to inhibit several enzymes such as carbonic anhydrase, cysteine protease, HIV protease and  cyclooxygenase33. Moreover, the  widespread potential value of sulphonamides, have led to the discovery of various other therapeutic applications, in cancer chemotherapy, diuretics, hypoglyceamia and the anti- impotence agent Viagra34.

Due to the inability of bacteria to acquire dihydrofolic acid from their environment, as part of bacteria’s DNA biosynthesis, inhibition of dihydrofolic acid synthase poses a desirable target for bacteriostatic agents (Scheme 3)35. Inhibition of these enzymes has been achieved with early sulphonamides such as sulphanilamide 6. The formation of dihydrofolic acid is initiated by coupling pteridine diphosphate 7 with para-aminobenzoic acid 8, which can then undergo amide coupling with glutamic acid to form dihydrofolic acid 10. Sulphonilamide 6 displays similar core structure to that of p-aminobenzoic acid 8 and act as a competitive inhibitor. Dihydrofolic acid formation is interrupted during the second step; due to a lack of acidic terminal available to couple with glutamic acid, hence dihydrofolic acid 10 formations is interrupted35.

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