Synthesis and evaluation for biological activities of npyridin- 3-yl substituted [phenylsulphonamido] acetamide

Thesis Overview

<p> INTRODUCTION<br>1.1 Background of the study<br>The growing incidence of microbial resistance to currently used antibiotics<br>represents a serious medical problem. Therefore, there is an urgent need to develop<br>new classes of therapeutic agents to treat microbial infectious. Such new<br>therapeutic agent has to exhibit a wide spectrum of biological activities.<br>Sulphonamides, an important class of pharmaceutical compounds, exhibit a wide<br>spectrum of biological activities1. The basic sulphonamide group [SO2, NHR]<br>occurs in various biologically active compounds including antimicrobial drugs,<br>antithyroid agents, antitumor, antibiotics and inhibitors of carbonic anhydrase2 .<br>Sulphonamides are widely used to treat microbial infections by inhibiting the<br>growth of Gram negative and Gram positive bacteria, some protozoa and fungi3 .<br>Clinically, sulphonamides are used to treat several urinary tract infections and<br>gastrointestinal infections4. Sulphonamides5 that are aromatic or heteroaromatic are<br>responsible for the inhibition of the growth of tumor cells. They act as antitumor<br>agents by inhibiting carbonic anhydrase activity. They are structurally similar to paminobenzoic<br>acid (PABA) which is a cofactor that is needed by the bacteria for<br>the synthesis of folic acid. Sulphonamide antibiotics inhibit the conversion of<br>x<br>PABA into folic acid and thus ultimately inhibit the synthesis of DNA. They are<br>also used in veterinary medicine to treat infections in livestock6. In primary care<br>medicine, sulphonamides are widely used in various conditions including<br>gastrointestinal7 and urinary tract infections8. Sulphonamide is the organic<br>framework of main focus in this research and it belongs to the family of suphurcontaining<br>compounds9, which are earlier referred to as sulpha drugs . Some of<br>these sulpha drugs that have performed “healing magic” in the world of<br>chemotherapy include; sulphanilamide(1), sulphadiazine(2), sulphacetamide(3),<br>sulphamonomethoxine(4), sulphasalazine(5), sulphadoxine(6), among others.<br>Sulphonamides have long been the subject of pharmaceutical interest as a result of<br>their potent biological activities10<br>H2N<br>S<br>O<br>O<br>NH2<br>H2N<br>S<br>O O<br>N+<br>N N<br>1<br>2 H2N<br>S<br>O<br>O<br>NH O<br>CH3<br>3<br>xi<br>S<br>O O<br>NH<br>N<br>N<br>O<br>CH3<br>H2N<br>4<br>S<br>O O<br>NH<br>N<br>N N<br>N<br>O<br>HO<br>OH<br>O<br>CH3<br>5<br>S<br>O O<br>NH<br>H2N<br>N<br>N<br>O<br>CH3<br>O<br>CH3<br>6<br>Furthermore, the sulphonamide group has been proven to have remarkable utility<br>in medicinal chemistry and features in a number of clinically relevant small<br>molecules11. For instance, some currently approved drugs with sulphonamide<br>structural skeletons include the antihypertensive agent bosentan(7)12, the antiviral<br>HIV protease inhibitor amprenavir(8)13,the phosphodiesterase-5 inhibitor<br>sildenafil14, antidiabetic drug glibenclamide(9)15, antidiabetic nonantibiotic<br>glimepiride and the diuretic drug torasemide16<br>xii<br>S<br>O O<br>NH<br>H C CH3 3<br>H3C<br>N<br>N<br>O<br>N<br>N<br>O<br>OH<br>O<br>CH3<br>7<br>S<br>O<br>O<br>N<br>H2N<br>CH3<br>H3C<br>NH<br>OH<br>O<br>O<br>O<br>O<br>8<br>O<br>NH<br>S<br>O O<br>NH<br>O<br>NH<br>OMe<br>Cl<br>9<br>In addition, suphonamides are also highly relevant both in the animal world and<br>the plant life cycle. For example, the breakdown of cyclic guanosine<br>monophosphate is retarded by sildenafil, a substituted guanine analog, which keeps<br>cut flowers fresh for another week and also strengthens plant stems to stand<br>straight even in the midst of storm and wind17. A preserving effect on fruits and<br>vegetable was also found, making sildenafil , a promising agent18. Today, it is<br>xiii<br>marketed under the trade name of Viagra19, which is a potent drug used in erectile<br>dysfunction in man20. It has been reported that more than 150 million men<br>worldwide have this dysfunction21. In another discovery, sulphonamide has been<br>documented as highly efficient candidate with high inhibitory activity22<br>Similarly, some sulphonamides have been established as potent drugs in the<br>treatment of insomnia and other sleep challenges in man by antagonizing orexin<br>neural activity. Activation of orexin neurons contribute to the promotion and<br>maintenance of wakefulness23. Conversely, relative inactivity of orexin neurons<br>allows the onset of sleep24. Consequently, blocking orexin signaling with receptor<br>antagonists may provide a new mechanism for decreasing wakefulness. Thus , a<br>novel therapeutic opportunity for the treatment of insomnia was reported using a<br>dual receptor antagonists almorexant25. Also, a low molecular weight aryl<br>containing N-glycine-suphonamide (2-[(4-tert-butyl-benzenesulphonyl)-p-tolyamino]-<br>N,N-dimethyl-acetamide(10), was discovered as a potent and selective<br>antagonist with very poor oral bioavailability (F=1%) in wister rats.26<br>S<br>O O<br>N<br>N<br>N CH3<br>O<br>CH3<br>MeO<br>Cl<br>N<br>CH3<br>H3C<br>MeO<br>10<br>xiv<br>The mode of action of sulphonamide is by mimicking p-aminobenzoic acid<br>(PABA), which is needed in bacteria as a substrate of the enzyme dihydropteroate<br>synthetase for the synthesis of tetrahydrofolic acid, a basic growth factor essential<br>for the metabolic process of bacteria27. Sulphonamide are preferred due to the ease<br>of administration28, wide spectrum of antimicrobial activity29, non-interference<br>with host defence mechanism and relative freedom from problems of superinfection30-<br>31<br>Sulphonamides have been classified using various parameters: For instance, by<br>using the antibiotic properties, it can be classified into antibiotic (antimicrobial)<br>sulphonamides and non antibiotic (non antimicrobial) sulphonamides32. Although,<br>almost all therapeutically useful sulphonamides are aromatic linked as in Ar-<br>SO2NH2 or Ar-SO2NHR33, yet, there are important distinctions between<br>sulphonylarylamines (antimicrobial/suphonamides), nonarylamine (non<br>antimicrobial) sulphonamides, and sulphones, with regard to allergy and other drug<br>reactions34. Sulphone , unlike sulphonamide, has its sulphonyl unit incorporated<br>between two carbon systems which may be part of either aliphatic or aromatic<br>moieties 35.<br>Most reactions to sulphonylarylamines probably results from multifactorial<br>immunologic and toxic metabolic mechanisms, whereas less is known about the<br>precise mechanism of reaction of other sulphur-containing drugs. Some<br>xv<br>sulphonamides such as the anticonvulsante, sultiames are devoid of antibacterial<br>activity. The sulphonylurea and thiazide diuretics are newer drug groups used on<br>the antibacterial sulphonamides36. One of the sulphonamides of paramount<br>importance is benzenesulphonamide derivatives. Benzenesulphonamide moiety is<br>an integral part of many drugs and drug-like scaffolds37. Many derivatives of<br>benzenesulphonamide have been explored as important starting materials and<br>reactive intermediates in various organic synthesis. For example, 2-<br>hydroxyalkylbenzene sulphonamides have been reported as the important starting<br>materials 38 for the structure activity relationship (SAR) study during the search<br>for cycloxygenase-2 (COX-2) inhibitors as analgesic39 and anti-inflammatory<br>agents40.<br>The chemistry of sulphonamides has recently shown them to be highly efficient<br>synthons in the preparation of various valuable biologically active compounds41. In<br>exploiting the chemistry of sulphonamides as ligands, various researchers have<br>attempted and embarked upon designing and synthesizing various novel metal<br>based sulphonamides42. The chiral ligands of sulphonamides designed as first ,<br>second and third generation ligands for catalyzing stereoselective synthesis of<br>highly relevant asymmetric compounds43 has been years odyssey. In a similar<br>manner, a new series of sulphonamides derived Schiff bases has been synthesized<br>by a condensation reaction of various sulphonamides with aromatic aldehydes44.<br>xvi<br>The sulphonamides obtained were further investigated for their metal complexing<br>potential in terms of chelation and biological properties45 .<br>On the issue of side effect, it is important to make a distinction between sulpha<br>drugs and other sulphur containing drugs and additives, such as sulphates and<br>sulphites, which are chemically unrelated to the sulphonamide group, and do not<br>cause the same hypersensitivity reaction seen in the sulphonamides. Although there<br>are reported cases of allergy to sulphonamide drug but the term sulpha allergy is<br>imprecise and misleading and therefore should be discouraged46. Sulpha allergies<br>are commonly reported as side effect of sulphonamide drugs, hence medications<br>containing sulphonamides are prescribed carefully. In fact, issues in understanding<br>the clinical evidence and drug dynamics as they relate to individuals and<br>populations have been explored47. Statistics have shown that approximately 3% of<br>the general populations show sulpha drug allergies, when treated with<br>sulphonamides and other similar antibiotics48.<br>The potential utilization of sulpha drug compounds as corrosion inhibitors has also<br>been established49. The inhibitory effect of four sulpha drug compounds namely,<br>sulphamethazine , sulphaguanidine , sulphamethoxazole and sulphadiazine , on<br>mild steel corrosion in 1.0 M HCl solution was evaluated using galvanostatic<br>polarization weight loss technique50. All the sulpha drug compounds examined<br>were reported to reduce the corrosion of mild steel indicating their high potency as<br>xvii<br>anti-corrosion agents. Among the compounds studied, sulphadiazine was shown to<br>have the best inhibition efficiency51. Some quantum mechanical studies have<br>successfully linked the inhibition efficiency with molecular properties for different<br>kinds of organic compounds52. Sulphonmide derivatives of azo dyes achieve<br>improved light stability, water solubility and fixation to fibre. The sulphonamide<br>dyes, especially secondary sulphonamide dyes, exhibited superior dye exhaustion<br>and colour fastness to washing, sublimation and rubbing on fine denier PP<br>fabrics53. They have been used as protecting groups of hydroxyl or amino<br>functionalities for easy removal under mild conditions54.<br>Even though many synthetic methods have been reported for the preparation of<br>sulphonamides55, the sulphonylation of ammonia56 or primary and secondary<br>amines with sulphonyl chlorides in the presence of a base is still the method of<br>choice because of high efficiency and simplicity of the reaction . Nevertheless,<br>various acceptable techniques involve the need to reduce the amount of toxic waste<br>and by-products arising from chemical processes required thereby increasing<br>emphasis on the use of less toxic and environmentally compatible materials in the<br>design of new synthetic methods57. One of the most promising approaches is using<br>water as the reaction media58 while others include microwave irradiation<br>technique, heterogeneous catalytic approach, solvent free media usage, nontoxic<br>solid support resin59 etc. Sulphonamides an ionizable, polar antimicrobial<br>xviii<br>compounds, may reach the environment in substantial amount by the spreading of<br>manure60 or other means.<br>In a similar manner, amide formation is a fundamental reaction of great interest in<br>organic chemistry61. The development of efficient methods for the synthesis of<br>amides remains a great challenge because of their importance in chemistry and<br>biology, with a wide range of industrial and pharmaceutical applications and as<br>valuable intermediates in organic synthesis62. Hence, it is convincing to design the<br>synthetic route in such a way to have a second amide functionality, being<br>incorporated within the frame work of the synthesized sulphonamides, this will<br>help in the comparative study of the antimicrobial activity of the ordinary<br>sulphonamide with amide bearing sulphonamide derivatives.<br>Despite the various hazardous effects posed by deadly microbes63, it is highly<br>surprising to know that no new antimicrobial drug has been discovered in the last<br>few years. Therefore, there is a continuous need for the design and synthetic<br>formulation of new class of antimicrobial drugs in order to control rapid spread of<br>harmful microbes.<br>There has been a frequent failure in treatment of infections using antibiotics.<br>Biofilm effect is the mechanism responsible for the frequent failure of antibiotic<br>treatment to cure infections of medical devices and other prosthetic materials64. In<br>xix<br>the biofilm stage, a phenotypic change occur in which the bacteria require<br>generally much higher concentrations of antibiotics to inhibit their growth. In fact,<br>it has been recently discovered that the comparative study of the minimum<br>inhibitory concentration (MIC) and minimum biofilm eliminating concentration<br>(MBEC) is a potential factor determining the changes in the pattern of antibiotic<br>sensitivity of gram negative bacilli from the planktonic to the biofilm stage of<br>growth65. In addition, the rapid emergence of drug resistance has become the most<br>urgent concern because it renders current treatments ineffective and therefore<br>compels the scientific community to continue efforts in the design of inhibitory<br>agents that can efficiently combat drug resistance<br>1.1.1 Chemical classification and Nomenclature of sulphonamides<br>Sulphonamides are derivatives of sulfuric acids. Sulphonamides are<br>chemically quite stable, these are weak acids compared to carboxylic acid amides.<br>The sulphonamide functional group is – (SO2-NH2, a sulfonyl group connected to<br>an amine group). The general formula is RSO2NH2. where R is some organic group<br>such as alkyl, benzyl etc..<br>Any sulfonamide can be considered as derived from a sulfonic acid by<br>replacing a hydroxyl group with an amine group. In medicals, the term<br>xx<br>“sulfonamide” is sometimes used as a synonym for sulfa drug, a derivative or<br>sulfamilamide.<br>1.1.2 Medicinal properties of sulfonamide<br>The sulphonamide scaffold is well known for the design of many sulphonamide<br>compounds with diverse medicinal properties. The presence of benzene ring<br>allows sulfonamides to partition through bacterial cell walls. Once inside of the<br>bacteria cells, sulfonamides must be ionizable and contain both a positive and<br>negative charge on opposite sides of its structure, which further resembles the<br>structure of PABA and result in binding of sulfonamide.<br>Antibacterial activity<br>Kumar and coworkers66 have reported the synthesis of some Schiff bases or<br>sulfonamides by condensing 4–aminobenzene sulphonamide with different<br>aromatic aldehydes in the presence or glacial acitic acid and ethanol at 50-600C.<br>The antimicrobial activity of these compounds was evaluated by agar diffusion<br>xxi<br>method. Several Schiff bases derived from sulphonamide have shown good<br>antibacterial activity.<br>Anti-inflammatory Activity<br>Benzene sulfonamide derivatives carrying a pyrozole moity were prepared<br>by Abddaal et al67 which where structurally related COX-2 inhibitor celecoxib<br>(celebrex®) and were found to be potent anti-inflammatory agents with little or no<br>tendency to evoke gastric ullercities. In these derivatives, N-Ethyl -2- (3-merthyl –<br>5- oxo-4, 5- dihydro-pyazile -1- carboxyl)-benzensulfonamide (11) was found to<br>be more active than the celebrex.<br>S<br>O O<br>NHC2H5<br>O<br>N<br>N<br>CH3<br>O<br>11<br>Growth Hormone scretagogue Receptor<br>High specific activity sulfur -35- labeled sulphonamide radioligand has been<br>developed by Dean and co-workers68 for the identification of a GH secretagogue<br>receptor [355] – MK – 0677 was found to posses the necessary concentration of<br>high selectivity, affinity and specific activity required for utilization as a<br>radioligand in the study of this nearly discovered receptor.<br>xxii<br>Cancer-Associated carbone anhytrases (CAs)<br>Neogluco conjugate a new class of sulfonamide link was designed by Moore and<br>co-workers69 to selectively target and inhibit the extracellular domains of the<br>cancer-relevant CA isozymes. The carbohydrate fragment in these compounds is<br>linked to the classical aromatic sulfonamide CA pharmacore to target inhibition<br>of cancer associated CAs. The CA inhibitors design were very good CA IX<br>inhibitors and potent CA XII inhibitors.<br>Antimicrobial activity<br>Iqbal and coworkers70 synthesized benzene sulphonamides bearing 2,5<br>disubstituted 1,3, 4- oxadiazole moiety and tested these compounds for<br>antimicrobial and antifugal activity. Compound (12) exhibited significant<br>antibacterial and significant antifugal activities due to the presence of a chloro<br>group on position 4 of the phenyl substitutent, the free SH group at position 5 of<br>the oxadiazole ring, and the free – NH2 group of the sulphonamido moiety.<br>Cl<br>S<br>O<br>H2N O<br>N N<br>O SH<br>12<br>xxiii<br>B – Lactamase inhibitors<br>Eidam71 synthesized new sulfonamide boronic acids, derived from the<br>conversion of the canonical R1 caboxamide. This has substantial inhibition activity<br>against B- Lactamases, they also rescued antibiotic resistance when used in<br>combination with third generation antibiotics in bacterial cell cultures. This<br>superficially modest substitution changes the geometry of the inhibitors enough to<br>scramble the SAR observed in the analogue carboxamides.<br>R S<br>O O<br>NH<br>B<br>HO OH 13<br>Protein kinase inhibitors<br>The isoquinoline sulphonamide (14) derivatives synthesized by Hidaka et<br>al72 had ability to inhibit protein kinases, some of the derivatives (15-20) exhibited<br>selective inhibition towards certain protein kinase. The inhibtors where freely<br>reversible and of the noncompetitive type with respect to the phosphate acceptor.<br>The isoquinoline sulphonamides which are structurally unrelated to ATP, compete<br>with ATP for free emzyme but do not interact with same enzyme form as does the<br>phosphate acceptor.<br>xxiv<br>N<br>S<br>O<br>O<br>R<br>14<br>R= N<br>H3C<br>H3C<br>CH3<br>NH<br>N<br>CH3<br>CH3<br>H3C<br>NH<br>H3C NH<br>H3C<br>H2N<br>HN<br>CH3<br>NH<br>N<br>H3C<br>CH3<br>15<br>16 17<br>19 20<br>1.2 STATEMENT OF THE PROBLEM<br>Sulphonamides are a class of broad antibacterial compounds that have a wide<br>range of application. The group belongs to distinctive class of compounds that<br>constitute at least five different classes of pharmacologically active agents73. The<br>basic sulfonamide group, SO2NH-, occurs in various biologically active<br>compounds, including antimicrobial drugs, antithyroid agents, antitumor,<br>antibiotics and inhibitors of carbonic anhydrase74.<br>xxv<br>There is a vast increase in resistance of infectious disease to antibiotics, which<br>negates treatment by almost all the known classes of antimicrobial compounds.<br>Under these circumstances, the development of novel classes of antimicrobial<br>compound becomes imperative75.<br>Literature survey reveales that minor modifications in the structure of<br>sulphonamide can lead to quantitative as well as qualitative changes in the<br>biological activity.76<br>Inspite of the wide biological application of benzene sulphonamide derivatives,<br>nothing is known of the N-heteroaryl substituted derivatives. The biological<br>activities of these class of compound are yet unexploited.<br>1.3 OBJECTIVE OF THE RESEARCH<br>The objectives of these research are as follows;<br>Ø To synthesize benzene sulphonamide from benzene sulphonyl chloride and<br>amino acids.<br>Ø To synthesize the N-pyridine-3-yl derivatives of the<br>Ø benzenesulphonamides.<br>Ø To characterize the synthesizes compounds using FTIR,1HNMR and<br>13CNMR.<br>Ø To screen the new compounds for antibacterial, antifungal and antioxidant<br>activities.<br>1.4 Justification Of The Study<br>xxvi<br>The wide application of sulphonamides and the need to synthesize new<br>functionalized derivatives with probable improved biological activities justifies<br>this research. <br></p>