Synthesis of n-(heteroaryl substituted) benzene sulphonamides and their biological activities

Thesis Overview

<p> </p><p>1.1 &nbsp; &nbsp; &nbsp; <strong>INTRODUCTION</strong></p><p>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 <em>p</em>-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 <strong>1</strong>).</p><p><strong>&nbsp; &nbsp; Scheme1: &nbsp;</strong>Synthesis of α-sulphonamide</p><p><strong>1.2 &nbsp; &nbsp; &nbsp; Background of Study</strong></p><p>Sulfa drugs are still today among the drugs first used (together with ampicillin and gentamycin) as chemotherapeutic agents in bacterial infections by <em>Escherichia coli</em>&nbsp;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.</p><p><strong>Scheme2: &nbsp;</strong>Some Example of Sulphonamides Drugs (Prontosil).</p><p>They are useful in treatment of infections caused by <em>staphylococci, streptococci, meningococci</em>, 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.</p><p>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 <em>p</em>-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 <em>N</em>-substituted derivatives of benzene sulphonamides had acetylcholinesterase, butyryl cholinesterase and lipoxygenase activities. Subhakara et al<em>.</em>&nbsp;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 <em>N</em>-phenylacetamide. They reported that this system shows the highest turnover to date for the sereactions, especially for aryl chloride substrates bearing an ortho substituent7.</p><p>&nbsp;</p><p><strong>&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; Scheme3: &nbsp;</strong><em>in vivo</em>Metabolism of Prontosil</p><p>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.</p><p>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 <strong>6</strong>. The formation of dihydrofolic acid is initiated by coupling pteridine diphosphate <strong>7 </strong>with <em>p</em>ara-aminobenzoic acid <strong>8</strong>, which can then undergo amide coupling with glutamic acid to form dihydrofolic acid <strong>10</strong>. Sulphonilamide <strong>6 </strong>displays similar core structure to that of <em>p</em>-aminobenzoic acid <strong>8 </strong>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 <strong>10 </strong>formations is interrupted35.</p><p>&nbsp;</p><p><strong>Scheme4: &nbsp;</strong>Inhibition of Dimethylformamide formation by sulfanilamide</p><p>Later steps involve reduction to tetrahydrofolic acid using dihydrofolate reductase; however this step can also be inhibited using methotrexate <strong>11 </strong>or trimethoprim <strong>12 </strong>to enhance antibacterial activity, and it is commonly taken in conjunction to increase inhibitory activity and reduced dosage.</p><p><strong>Scheme5</strong><strong>: </strong>Structures of methotrexate and trimethoprim</p><p><strong>&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; </strong>Sulphonamides are registered in Australia as antibacterials and are used widely in food producing animals because of their relatively low cost and ease of administration. Their use in veterinary medicine is wide spread, particularly as mass medicants for the control of diseases in food producing species. They are marketed in Australia either alone, or formulated in combination with other sulphonamides and/or antibiotics. They are presented as feed additives, or oral, topical, intrauterine pessaries and injectable preparations.</p><p>Sulphonamides are drugs commonly used to treat infectious diseases. Their development leads to a medical revelation in drug treatments36-38. Sulphonamides exhibit broad range of biological activities39. Several sulphonamides are used in therapy such as celecoxib, nimesulide, delavirdine, acetazolamide, methazolamide, furosemide, ethoxzolamide, dichlorphenamide, dorzolamide, brinzolamide, sulpiride, sotalol, tolbutamide, chlorpropamide, tolazamide, acetohexamide, glipizide, gliburide, glymidine, zonisamide, thiothixene and famotidine. Modifications of the sulphonamides have proven highly effective and modifications that have been made so far do not exhaust the possible changes that can be made to improve potency and efficacy of these sulphonamides. The present review highlights the recently synthesized sulphonamides possessing important potential biological activities. It would be interesting to see whether new sulphonamide derivatives can be utilized as potent therapeutic agents in future. Sulphonamides are compounds constituting diverse medicinal applications, widely used as antimicrobial40,41, anticancer42, antiinflammatory43 and antiviral agents as well as HIV protease inhibi-tors44. Sulphonamides is well recognized as an antimetabolite45.</p><p>The sulphonamides antimicrobial drugs were the first effective chemotherapeutic agents but the rapid development of widespread resistance diminished the usefulness of sulphonamides46. An evaluation of azo dyes was done and prontosil was found to protect against, and cure, <em>streptococcal</em>&nbsp;infections in mice47-50. The structure-activity study on the sulphonamide azo dyes was performed and the reductive cleavage of azo linkage to release the active antibacterial product, sulphonamides, was concluded51,52. The chemistry of sulphonamides has been recently recognized in the preparation of various valuable biologically active compounds used especially as antibacterial agents53. Today, sulphonamide – trimethoprim combinations are used extensively for opportunistic infections in patients with AIDS in addition to urinary tract infection and burn therapy54-57. Resistance to sulphonamides by bacteria, is most likely as a result of a compensatory increase in the biosynthesis of <em>p</em>-aminobenzoic acid by bacteria although other mechanisms may play a role58,59. Resistance of <em>E Coli </em>strains to sulphonamide has been shown due to their containing sulphonamide-resistant dihydropteroate synthase60. Sulphonamides have highest powerful antibacterial activity for gram negative bacteria than gram- positive and antibacterial activity decreases as the length of the carbon chain increases41. Also, novel macrocyclic bis-sulphonamides were prepared and their antimicrobial activities were measured too. Bis-sulphonamide showed antibacterial activities against most strains tested61.</p><p><strong>1.3.0 &nbsp; Classification of sulphonamides</strong></p><p>Classifications of sulphonamides are based on chemical structure, duration of action, spectrum of activity and therapeutic applications. Common classification of sulphonamides is based on their therapeutic applications. There are three groups of sulphonamides according to their duration of Action</p><p><strong>1.3.1 &nbsp; Short acting sulphonamides</strong></p><p>These are preferred for systemic infections as they are rapidly absorbed and rapidly excreted. For example, sulphadiazine <strong>13</strong>, sulphadimidine or sulphamethazine <strong>14</strong>, and sulphamethoxazole <strong>15</strong>&nbsp;in (scheme <strong>6</strong>) have been used for the treatment of urinary tract infections62.</p><p><strong>&nbsp;</strong></p><p><strong>&nbsp;</strong></p><p><strong>1.3.2 &nbsp; Intermediate or moderate acting sulphonamides</strong></p><p>These are used for infections requiring prolonged treatment. For example, sulphacetamide <strong>16</strong>, sulphadoxine <strong>17</strong>, <em>etc </em>(scheme <strong>6</strong>)<em>. </em>The sulphadoxine is an ultralonglasting sulphonamide often used in combination with pyrimethamine to treat or prevent malaria. It is also used, in combination with other drugs, to treat or prevent various infections in livestock63.</p><p><strong>1.3.3 &nbsp; Long acting sulphonamides</strong></p><p>These are rapidly absorbed and slowly excreted. For example, sulphametopyrazine, sulphasalazine <strong>18</strong>, which is marketed as azulfidine in the U.S. and salazopyrin &amp; sulazine in Europe and Hong Kong, was developed over 70 years ago specifically to treat rheumatoid arthritis. Sulphasalazine is a derivative of mesalazine and is formed by combining sulphapyridine and salicylate with an azo bond. It may be abbreviated SSZ. Sulphasalazine is also used in the treatment of inflammatory bowel disease including ulcerative colitis and Crohn’s disease. In addition, there are different types of sulphonamides which have been used in various types of infections. For example, sulphabenzamide <strong>19</strong>&nbsp;used in mucous membrane, sulphacetamide sodium <strong>20</strong>&nbsp;used for superficial ocular, sulphadiazine <strong>13</strong>&nbsp;used in urinary tract infection and sulphamethizole <strong>21</strong>&nbsp;used in bacterial infections64 (scheme<strong>&nbsp;6</strong>).</p><p>&nbsp;</p><p>&nbsp;</p><p>&nbsp;</p><p>&nbsp;</p><p>&nbsp;</p><p><strong>Scheme 6:</strong>&nbsp; Some Example of Sulphonamides</p><p>Previous studies showed that sulphonamides have being prepared, tested and found active, further modifications of these structures are still necessary. The sulphonamides thus produced by these modifications may prove to be more active and hence useful as antimicrobial agents. The active metabolite of the red azo dye known as Prontosil <strong>7</strong>&nbsp;does not possess any activity <em>in vitro</em>; however it metabolizes <em>in vivo</em>&nbsp;to give the active agent sulphanilamide <strong>8</strong>; where it can interfere with the process of bacterial DNA synthesis, and act as potent antibacterial agent. Its synthesis involves the reaction of sulphonyl chlorides using indium catalysis65. We synthesized new sulphonamides from benzene sulphonyl chloride using anhydrous acetone and dry pyridine. They are <em>N</em>-(4-methylpyridin-2-yl)benzene sulphonamide, <em>N</em>-(3-nitropyridin-2-yl)benzene sulphonamide, <em>N</em>-(3-hydroxypyridin-2-yl)benzene sulphonamide and etc.</p><p>The previous structures:</p><p>The new structure:</p><p>&nbsp;</p><p><strong>&nbsp;</strong></p><p><strong>&nbsp;</strong></p><ol><li>The objective of study is to synthesize new heteroaryyl sulphonamides and evaluate their</li></ol><p>biological activities.</p><ol><li>The specific objectives of this research work were to:</li><li>Synthesize some new sulphonamides with different substituents on the aromatic ring.</li><li>Synthesize some new sulphonamides with different substituents on the amino group.</li><li>Characterize them using spectrophotometric methods, namely, FT-IR, 1H-NMR, and 13C-</li></ol><p>NMR spectroscopy.</p><ol><li>Carry out biological activitiy of their antimicrobial activities, acute toxicity, antimalarial activity, antioxidant activity<strong>, </strong>liver and kidney function test.</li></ol><p><strong>1.6 &nbsp; &nbsp; &nbsp; Justification of study</strong></p><p><strong>&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; </strong>The recent advances in the development of sulphonamides as drugs, the synthesis and biological activities of <em>N</em>-heteroaryl derivatives of benzene sulphonamides remain largely unknown. The need to synthesize new heteroaryl derivatives of benzene sulphonamides for activities of their antimicrobial activity, acute toxicity test, antimalaria activity, antioxidant activity, liver and kidney function test potentials motivated this work. Arylsulphonamide compounds were known to possess various biological activities66; sulphonamides are synthetic antimicrobial agents which act as competitive inhibitors of the enzyme dihydropteroate synthetase. All the synthesized benzene sulphonamides have shown good activity against the tested microbes. A large number of sulphonamides derivatives have ultimately been reported to show substantial protease inhibitor properties. Some derivatives of sulphonamides are extensively used for gastrointestinal and urinary tract infections because of their ease of administration and non-interaction with defense mechanism of host. All these findings encouraged us to explore the synthesis of different <em>N</em>-substituted sulphonamides derived from <em>o</em>-anisidine with improved and different biological activity.</p><p>&nbsp;</p> <br><p></p>