Indo American Journal of Pharmaceutical Research, 2013

ISSN NO: 2231-6876

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INDO AMERICAN JOURNAL OF PHARMACEUTICAL RESEARCH

SYNTHESIS OF NOVEL BENZENESULPHOMIDE DERIVATIVES AND BIOLOGICAL EVALUATION: A REVIEW

C.P. Rathod *., P.H. Bhosale., K.G. Patil., R.M. Rajurkar., A.A. Phadtare., S.S. Hindole.
1

Department of pharmaceutical chemistry, School of Pharmacy, Swami Ramanand Teerth Marathwada University, Vishnupuri, Nanded - 431 606 2 Channabasweshwar College of Pharmacy Latur-413512, Maharashtra, India.

ARTICLE INFO Article history

Received 20/03/2013 Available online 01/04/2013

Keywords
Benzene sulphonamides, Antibacterial, Antifungal and antiinflammatory activity.

ABSTRACT The benzene sulphonamides moiety exploited to prepared anticancer drugs. Benzene Sulphonamides posses many types of biological activities and representatives of this class of pharmacological agents are widely used in clinic as antibacterial antifungal, hypoglycaemic, diuretic and anti-carbonic anhydrase among others. Recently, a host of structurally novel sulfonamide derivatives have been reported to show substantial antitumor activity in vitro and/or in-vivo. Also, quinoline derivatives are important biologically active compounds showing anticancer activity.

_______________________________________________________________________________________ Corresponding author: C.P. Rathod, Department of pharmaceutical chemistry, School of Pharmacy, Swami Ramanand Teerth Marathwada University, Vishnupuri, Nanded - 431 606

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Copy right 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Please cite this article in press as C.P. Rathod et.al. SYNTHESIS OF NOVEL BENZENESULPHOMIDE DERIVATIVES AND BIOLOGICAL EVALUATION: A REVIEW. Indo American Journal of Pharm Research.2013:3(3).

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INTRODUCTION Benzene sulfonamides nucleus is a constituent of many bioactive heterocyclic compounds that are of wide interest because of their diverse biological and clinical applications. Moreover, Benzene sulfonamides derivatives are structural isosters of naturally occurring nucleotides, which allows them to interact easily with the biopolymers of the living system. This created interest in researchers who have synthesized variety of Benzene sulfonamides derivatives. The parent scaffold for benzene sulphonamides is as follows:

So there is a need to develop or to synthesize new compound having substitution of different groups at different position of parent scaffold so, that correlation may established with respect to structure and activities. The incorporation of Benzene sulfonamides nucleus, a biologically accepted pharmacophore in medicinal compounds, has made it a versatile heterocyclic moiety possessing wide spectrum of biological activities. Studies on structure-activity relationships and their influence on the design of new drugs have rendered them one of the most useful and thus important activities of pharmacochemistry, a modern component science in the group of pharmaceutical sciences.1-2 , Despite the advances in medical and pharmaceutical sciences, there are still many diseases which are incurable or can only be treated symptomatically, and at a great economic and social cost owing to only moderately effective or even to the lack of appropriate therapeutic agents. Of the 30000 or so diseases or disorders currently known, only one-third can somehow be treated with drugs. Furthermore, there are incurable maladies, like viral diseases (influenza, AIDS), CNS disorders (Alzheimers disease), cancer and autoimmune disorders, which can be fatal or cause great suffering and disability .3 SULPHONAMIDES: 18 History of sulphonamides: The best examples of antibacterial agents acting as antimetabolites are the sulphonamides (sometimes called the sulpha drugs). The sulfonamide story began in 1935 when it was discovered that a red dye called prontosil had antibacterial properties in vivo (i.e. when given to laboratory animals). Strangely enough, no antibacterial effect was observed in vitro. In other words, prontosil could not kill bacteria grown in the test tube. This remained a mystery until it was discovered that prontosil was not in fact the antibacterial agent. Instead, it was found that the dye was metabolized by bacteria present in the small intestine of the test animal, and broken down to give a product called sulphanilamide (Fig.1). It was this compound which was the true antibacterial agent. Thus, prontosil was the first example of a prodrug. Sulphanilamide was synthesized in the laboratory and became the first synthetic antibacterial agent active against a wide range of infections.

Fig.1.1.1 Metabolism of Prontosil

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2.2 Structure-activity relationships (SAR) of Sulphonamides:

Fig.1.1.2. Sulphonamide Analogue The Investigations on Structure Activity Relationship shows that the p-amino group is essential for activity and must be unsubstituted (i.e. R = H). The only exception is when R = acyl (i.e. amides). The amides themselves are inactive but can be metabolized in the body to regenerate the active compound (Fig.3). Thus amides can be used as sulfonamide prodrugs. The aromatic ring and the sulfonamide functional group are both required. The aromatic ring must be Para-substituted only. The sulfonamide nitrogen must be secondary. R" is the only possible site that can be varied in sulphonamides.18

Fig.1.1.3. Metabolism of acyl group to regenerate active compound R" can be varied by incorporating a large range of heterocyclic or aromatic structures which affects the extent to which the drug binds to plasma protein. This in turn controls the blood levels of the drug such that it can be short acting or long acting. Thus, a drug which binds strongly to plasma protein will be slowly released into the blood circulation and will be longer lasting. Changing the nature of the group R" has also helped to reduce the toxicity of some sulphonamides. The primary amino group of sulphonamides are acetylated in the body and the resulting amides have reduced solubility which can lead to toxic effects. For example, the metabolite formed from sulfathiazole (an early sulfonamide) (Fig.4) is poorly soluble and can prove fatal if it blocks the kidney tubules. It is interesting to note that certain nationalities are more susceptible to this than others. For example, the Japanese and Chinese metabolize sulfathiazole more quickly than the Americans and are therefore more susceptible to its toxic effects. It was discovered that the solubility problem could be overcome by replacing the thiazole ring in sulfathiazole with a pyrimidines ring to give sulfadiazine. The reason for the improved solubility lies in the acidity of the sulfonamide NH proton (Fig.5). In sulfathiazole, this proton is not very acidic (high pKa). Therefore, sulfathiazole and its metabolite are mostly un-ionized at blood PH. Replacing the thiazole ring with a more electron withdrawing pyrimidines ring increases the acidity of the NH proton by stabilizing the anion which results. Therefore, sulfadiazine and its metabolite are significantly ionized at blood pH. Sulfadiazine was also found to be more active than sulfathiazole and soon replaced it in therapy. To conclude, varying R" can affect the solubility of sulphonamides or the extent to which they bind to plasma protein. These variations are therefore affecting the pharmacodynamics of the drug, rather than its mechanism of action.18

Fig.1.1.4. Metabolism of Sulphathiazole

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Fig.1.1. 5.Sulphadiazine 2.3. Applications of sulphonamides: Before the appearance of penicillin, the sulpha drugs were the drugs of choice in the treatment of infectious diseases. Indeed, they played a significant part in world history by saving Winston Churchill's life during the Second World War. Whilst visiting North Africa, Churchill became ill with a serious infection and was bedridden for several weeks. At one point, his condition was deemed so serious that his daughter was flown out from Britain to be at his side. Fortunately, he responded to the novel sulfonamide drugs of the day. Penicillins largely superseded sulphonamides in the fight against bacterial infections revival of interest with the discovery of a new 'breed' of longer lasting sulphonamides. One example of this new generation is Sulfamethazine (Fig.6) which is so stable in the body that it need only be taken once a week. The sulpha drugs are mainly used in Treatment of urinary tract infections, Eye infection, Infections of mucous membranes, and Treatment of gut infections etc. Sulfonamides have been particularly useful against infections of the intestine and can be targeted specifically to that site by the use of prodrugs. 2.4 Mechanism of action:The sulphonamides act as competitive enzyme inhibitors and block the biosynthesis of vitamin folic acid in bacterial cells (Fig.7). They do this by inhibiting the enzyme responsible for linking together the component parts of folic acid. The consequences of this are disastrous for the cell. Under normal conditions, folic acid is the precursor for tetrahydrofolatea compound which is crucial to cell biochemistry since it acts as the carrier for one-carbon units, necessary for many biosynthetic pathways. If tetrahydrofolate is no longer synthesized, then any biosynthetic pathway requiring one-carbon fragments is disrupted. The biosynthesis of nucleic acids is particularly disrupted and this leads to the cessation of cell growth and division. Note that sulphonamides do not actively kill bacterial cells. Sulfonamides act as inhibitors by mimicking paminobenzoic acid (PABA) (Fig.7) one of the normal constituents of folic acid. The sulfonamide molecule is similar enough in structure to PABA that the enzyme is fooled into accepting it into its active site (Fig.8). Once it is bound, the sulfonamide prevents PABA from binding. As a result, folic acid is no longer synthesized. Since folic acid is essential to cell growth, the cell will stop dividing. Because of structural similarity with PABA & interfere with the utilization of PABA, As a result folic acid is no longer synthesized since folic acid is essencial for cell growth,the cell will stop dividing .Sulfonamides are competitive enzyme inhibitors and as such the effect can be reversible.Carbonic anhydrase inhibitor due to presence of sulfonyl group attached to benzene or heterocyclic ring (ArSo2NH2) This is demonstrated by certain organisms such as staphylococci, pneumococci, and gonococci which can acquire resistance by synthesizing more PABA. The more the PABA in the cell, the more effectively it competes with the sulfonamide inhibitor to reach the enzyme's active site. In such cases, the dose level of sulfonamide has to be increased to bring back the same level of inhibition.18 3. Carbonic Anhydrase Inhibitors: The chemical characteristic of carbonic anhydrase inhibitor is the presence of one (sometimes two) sulfamyl groups attached to benzene or heterocyclic ring, ArSO2NH2. Most of the sulphonamides diuretics and thiazides are either strong or weak carbonic anhydrase inhibitors, but only the strong inhibitors produce a diuretic effect.4 At least 14 different carbonic anhydrase isomers were isolated in higher vertebrates where these zinc enzymes play crucial physiological roles.4 Some of these isoenzymes are cystolic (CA I, CA II, CA III, CA
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VII), others are membrane bound (CA IV, CAIX, CA XII and CA XIV), CA V is Mitochondrial and CA VI is secreted in saliva. Three acatalytic forms are also known, which are denominated CA related proteins (CARP), CARP VIII, CARP X and CARP XI.4 Several important physiological and physio-pathological functions are played by many isozymes, which are strongly inhibited by aromatic and heterocyclic sulphonamides as well as inorganic, metal complexing anions.

Fig.1.1.7.Mechanism of Action of Sulphonamides

Fig.1.1.8. Sulphonamide Prevents PABA from Binding by Mimicking PABA Important advances in the design of topically acting antiglaucoma sulphonamides, isozymes-specific inhibitors, inhibitors with modified sulphonamides moieties, antitumor sulphonamides, as well as diagnostic tools sulphonamides as diagnostic tools for PET (Position Emission Tomography) 5 and biosensor based on this class of pharmacological agents. Krebs reported6 in 1948 that, the substitution of sulphonamides moiety in compound of type ArSO2NH2 drastically reduced the CA inhibitory properties as compared to the corresponding derivatives possessing primary sulphonamide group ArSO2NH2. Recently several detailed studies regarding the possible modification of the sulphonamide moiety, compatible with the retention of strong binding to the enzyme, have been reported in thiols, phosphonates, carboxylates, hydroxamates etc.7-10

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4. Anticancer Agents: Despite improvements in prevention, surgical management and advances in adjuvant radio-and chemotherapy, the ability of curing cancer patients remain an elusive goal, with strong need to develop alternative more effective therapies.11 Conventional cancer chemotherapy is primarily inadequate due to lack of selectivity of large majority of drugs for targeting cancer cells over their non cancerous counter parts on one hand, and the constant emergence of drug resistant and multi-drug resistant tumours on the other hand. Thus, a massive sensor of new anticancer agents has primarily been fuelled by the unveiling of new molecular targets on which to intervene, followed by the discovery of novel classes of compounds that interact with such targets.11-12 A classical clinical agent from this class is acetazolamide.13-14 Teicher et al. reported15 that one of these derivatives, acetazolamide which is strong inhibitor of several CA isozymes, is a potential modulator of cancer therapies in combination with different cytotoxic agents (alkylating agents, nucleoside analogs, platinum derivatives etc.) probably due to the acidification of intratumoral environment resulting CA inhibition. Chegwidden and Spencer16 showed that acetazolamide inhibited the growth of lymphoma cells .more recently, Pastoreks group have shown17 that acetazolamide strongly reduces in vitro the invasiveness of some renal cancer cell lines by the inhibition of isozymes CA-II and CA-XII. BENZENE SULFONAMIDES SYNTHESIS: Due to the broad applicability of sulphonamides, it is desirable to find general and effective methods for their synthesis. Although a comprehensive review of this is not provided the following section provides several of the most common and recent methods of sulfonamide synthesis. Here we have included some common synthetic procedures for benzenesulfonamides.1 1. Sulfonamides from sulphonyl chlorides and sulfonic acids: The traditional and general method for preparing sulphonamides 2 is via coupling of sulphonyl chloride 1 with primary or secondary amine (Scheme 1). The sulphonyl chloride is normally prepared from the corresponding sulfonic/sulfinic acid with SOCl2, PCl5 or POCl3,19-22 or from bubbling chlorine gas through thiols in aqueous acid.23 However, this method requires excess oxidant and aqueous acid, and is not compatible with acid sensitive substrates.24

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Wright et al. reported a method for the formation of sulphonamides from thiols, requiring the in situ synthesis of a sulphonyl chloride using sodium hypochlorite (commercial bleach) mediated oxidation of thiols. This methodology introduces several advantages, such as readily availability of the reagents as well as controlled amount of the oxidant used. The resulting sulphonyl chlorides 3 were then trapped with benzylamine in the subsequent reaction to produce sulphonamides 4 up to 98% yield (Scheme 2)24

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Bonk et al. have developed a methodology of using trichlorocyanuric acid (TCCA) and benzyltrimethyl ammonium chloride in water to generate a controlled amount of chlorine into aprotic solvent (MeCN). The use of TCCA introduces the advantage of high-purity chlorine production compare to that of hypochlorite. In order to optimize the reaction conditions, the group then further modified the methodology by adding the subsequent amine into a one-pot reaction, generating sulphonyl chloride 5 in situ, and furnishing sulphonamides 6 under 1 hour (Scheme 3)60

Even though a wide variety of sulphonamides can be generated from these procedures, several steps are required. Furthermore, the conditions are fairly harsh and therefore restrict the functional group compatibility. In an alternative, Barrett et al. reported the use of Grignard reagent 7 to increase diversity on sulphur in a onepot sulfonamide synthesis (Scheme 4). Aromatic halides are mixed with magnesium to form Grignard reagent 7, which can then attack sulphur dioxide to form sulfinic acid salt 8. Subsequent chlorination using sulfuryl chloride generates sulphonyl chloride, and aminolysis furnishes sulphonamides 9 in one-pot. A wide range of organohalides were studied, but only aromatic and heteroaromatic halides produced desirable results.27

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It would appear that some general limitations to sulfonamide synthesis exist including, excessive amount of highly toxic chlorinating agents (SO2Cl2, PCl5 and POCl3) and organolithium and Grignard reagents are incompatible with several functional groups (-OH, -SH and -COOH)

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Charasiri et al. reported the use of trichloroacetonitrile-triphenylphosphine complex (Cl3CCN/PPh3) for sulfonamide formation. It was found that the optimal yield is reached when 3:3:1 (Cl3CCN: PPh3: sulfonic acid) ratio and dichloromethane are used, however the yields are not reproducible in other solvents and ratios (Scheme 5), One of the notable advantages of this methodology is that it is not limited to aromatic sulphonyl chlorides, and can be applied to heterocyclic and aliphatic sulphonyl chlorides.28

2. Sulfonamides from sulfenamides: Another innovative example of sulphonamides synthesis is illustrated in the synthesis of 6uracilsulfonamide (an antagonist of orotic acid) by Greenbaum et al. In this approach the sulfonamide is reasonably effectively oxidized from 6- uracilsulfenamide using KMnO4 with 64% yield.30 Schwam et al. also used similar methodology for the synthesis of 6-hydroxybenzothiazole-2-sulfonamide 12 as a potential carbonic anhydrase inhibitor in 80% yield (Scheme 8).31

3.3 Sulfonamides from N-arylation The aforementioned methods do have some limitations in as much as they do not allow diversification of substituent on sulphur or nitrogen. An alternative approach is to carry out synthetic modification of a primary sulfonamide.36 Transition-metal catalyzed C-N bond formation has been studied extensively, where the most well-known, palladium catalyzed N-arylation is the Buchwald-Hartwig reaction.36-39 However there are few reports of N-arylation on sulphonamides. The first example used cupric acetate and arylboronic acid to give Narylsulfonamide. Lam et al. described an effective protocol using 0.1 equivalent of copper (II) acetate in air, to give near-quantitative yield (Scheme 10).39,40

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Mechanism of the Chan-Lam Coupling: The reaction with a stoichiometric amount of copper (II) is also facilitated by oxygen, because reductive elimination from a copper (III) species is faster.

Mechanism of the Chan-Lam Coupling More recently, Guo et al. have synthesized a range of sulphonamides using copper (I) catalysed coupling using aryl bromide/iodide (Scheme 11). During the optimization process, they found that using an amino acid as a ligand introduces several advantages such as easy removal after the reaction. After screening several amino acids, they found that N-methylglycine and N, N-dimethylglycine are the most effective with Cu (I). Together with K3PO4 as base, and DMF as the solvent, all desired N-arylsulfonamide can be generated in up to 99% yield (Figure 11-A).42

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Despite the advances in transition metal catalysis, few applications have been reported for sulfonamide synthesis, 44,45 and even fewer under microwave heating.45 Cao et al. reported the palladium catalysed Narylation of sulphonamides under microwave irradiation. In their report they describe the effect of modifying the ligands, bases and solvents, and identified optimal reaction conditions under microwave heating at 180 C for 10 minutes (Scheme 12). Unfortunately this method led to only modest yield of N-arylsulfonamide.

. 3.4 Sulfonamides from sulfonates esters: Pentafluorophenyl (PFP) sulfonates esters have been recently introduced to replace sulphonyl chlorides for sulfonamide preparation. The use of PFP sulfonates esters 19 may introduce several advantages such as reduced toxicity, enhanced shelf stability, and makes them desirable as precursors. Caddick et al. have reported that the aminolysis of sulfonates in refluxing THF can be used as an effective method for the synthesis of sulphonamides 20 in good to excellent yield. It was further shown that a range of amines (primary, secondary, aromatic, and aliphatic) could undergo reaction 30 with PFP sulfonates esters 19 to produce a wide range of sulphonamides (Scheme 13).45

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BIOLOGICAL ACTIONS OF BENZENESULFONAMIDES: Benzene sulfonamides are remarkably effective compounds both with respect to their inhibitory activity and their favorable selectivity ratio. Extensive biochemical and pharmacological studies have confirmed that Benzene sulfonamides molecules are effective against various strains of microorganisms. Benzene sulfonamides are regarded as a promising class of bioactive heterocyclic compounds that exhibit a range of biological activities. This ring system is present in numerous antibacterial[1],antifungal[1],, hypoglycaemic[2], diuretic[3,4] and anti-carbonic anhydrase [3,5] activities among others. Resistance to number of antimicrobial agents (-lactam antibiotics, macrolides, quinolones, and vancomycin) among a variety of clinically significant species of bacteria is becoming increasingly important global problem. In particular, increasing drug resistance among Gram-positive bacteria such as staphylococci, enterococci, and streptococci is a significant health matter. There is real perceived need for the discovery of new compounds endowed with antibacterial activity, possibly acting through mechanisms of action, which are distinct from those of well-known classes of antibacterial agents to which may clinically relevant pathogens are now resistant.10,12 Benzenesulfonamides also act as anti-inflammatory agents. Inflammation is a local reaction of the vascular and supporting elements of a tissue to injury resulting in the formation of a protein-rich exudates; it is a protective response of the nonspecific immune system that serves to localize, neutralize, or to destroy an injurious agent in preparation for the process of healing. Cause of inflammation includes physical agents, chemical agents, immunological reactions, and infection by pathogenic organism. Inflammation is divided into acute and chronic patterns. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the choice treatment in various inflammatory diseases such as arthritis, rheumatisms as well as to relieve the aches and pain of everyday life. Benzenesulfonamides derivatives recently attracted medicinal chemists in exploring their potential as anticancer agents. Cancer is a malignant disease characterized by uncontrolled proliferation of cells which may be rapid or slow, depending on the type of cancer; a number of anticancer drugs are currently in clinical practice. Cancer is becoming biggest health hazard in world. Development of resistance among anticancer drugs keeps research window open in search of newer anticancer molecules. But the window passage has become narrower because it is rather difficult to search a molecule that can selectively inhibit proliferation of abnormal cells with least or no effect on normal cells. The identification of novel efficient and less toxic anticancer drug remains an important and challenging task in cancer biology. Many benzene sulfonamides derivatives are widely used for the treatment of parasitic diseases. Original results of investigations devoted to the antihelminth properties of benzene sulfonamides derivatives, were published within the time period from the middle 1960s to the beginning 1970s. Benzene sulfonamides derivatives are of wide interest because of their diverse biological activity and clinical applications. Some of the Benzene sulfonamides derivatives effectively suppress the proton pump function of parietal cells of the stomach, thus blocking the final stage of hydrochloric acid secretion. Benzene sulfonamides derivatives have wide range of biological actions & industrial applications.
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