Rev. Med. Chir. Soc. Med. Nat., Iaşi – 2013 – vol. 117, no. 2

PHARMACY UPDATES

IMPORTANCE OF MOIETY IN CURRENT AND FUTURE THERAPY

Oana Maria Parasca (Dragostin)1, FlorentinaGheaţă (Lupaşcu)2, Andreea Pânzariu2, Ioana Geangalău (Vasincu)2, Lenuţa Profire2 University of Medicine and Pharmacy ’’Grigore T. Popa’’- Iaşi Faculty of Pharmacy 1. Ph.D. student 2. Discipline of Pharmaceutical Chemistry

IMPORTANCE OF SULFONAMIDE MOIETY IN CURRENT AND FUTURE THERAPY (Abstract): Sulfonamides and their different derivatives are extensively used in therapy due to their pharmacological properties. Sulfa drugs were amongst the oldest synthesized antimi- crobial agents and are still widely used today to treat different microbial . Clinical treatment with sulfonamides has regained confidence with the use of a combination of sul- famethoxazole and to treat urinary tract bacterial infections. Today, they are widely used as antimicrobial agents, chiefly because of their low cost, low toxicity and ex- cellent activity against bacterial diseases. Over the course of time, the application of sulfon- amides has been extended from their use as antimicrobial agents to anticancer agents, an- tiglaucoma agents, inhibitors of γ-secretase, cyclooxgenase-2 and lipoxygenase, anticonvul- sivant agents, hypoglycemic agents. Keywords: SULFONAMIDES, ANTIMICROBIAL, LOW TOXICITY.

The introduction of sulfonamides in bonic anhydrase inhibitors, hypoglycaemic 1935 marked a turning point, a true „thera- agents, thyroid inhibitors, and protease peutic revolution”, and opened the era of inhibitors (1). In recent years, molecules ’’miracle drugs’’. After the discovery of containing sulfamide group have also been penicillin followed by other investigated as inhibitors of ATP-sensitive sulfonamides became less used, but later potassium channels, carboxy-peptidase A, they started to attract attention for their γ-secretase, glycosidase, HCV polymerase synergic activity in the combination with (NS5B), HIV-1 integrase, HIV-1 protease, trimethoprim. histone deacetylase, human chymase, hu- Sulfonamides proved to be the starting man leukocyte elastase, kinesin spindle point for a series of structural changes and protein, monoamine reuptake, plasma cell this has led to the discovery of new drugs membrane protein-1, and thrombin; as or classes of drugs used today not just in agonists of androgen receptor, β3- combating bacterial infections, but also in andrenergic receptor, and as antagonists of other diseases. They have widespread use CXCR2 (2). in a variety of applications including anti- The chemical class of sulphonamides bacterials, antitumor agents, diuretics, car- shares a common moiety with

558 Importance of sulfonamide moiety in current and future therapy

an aromatic amino group at the C4-position, severe hypersensitivity reactions. differing in the substitution of sulfamoil group at the C1-position. A tetrahedral sulfur SULFONAMIDES atom and multiple vectors for substitution of AS ANTIVIRAL AGENTS the nitrogen atoms lead to conformational The effectiveness of sulfonamides has and structural diversity (fig. 1). also been proven over time in the context of viral infections. A large number of struc- NH2 turally novel sulfonamide derivatives have 4 ultimately been reported to show substan- tial antiviral activity in vitro and in vivo. Hepatitis C virus (HCV) is a common 1 pathogen that can lead to cirrhosis, hepato- H cellular carcinoma (HCC), and liver failure. O2S N R It is estimated that 170 million people were Fig. 1. The backbone of the sulphonamides infected worldwide by the year 2000, and

that the virus is responsible for at least The characterization of sulfonamides as 10.000 deaths annually in the United States chemotherapics is more than half a century alone. Moreover, existing therapies are old. Since then, the sulfonamide group - hampered by drug-related toxicities. There- SO NH- has been found as a key structural 2 fore, there is a particular need for new motif shared by a large number of bioactive therapies directed to genotype 1 HCV in- compounds, spanning a wide variety of fection. An attractive strategy for the biological effects, such as antimicrobial treatment of liver with hepatitis C activity, specific enzyme inhibition, hor- virus was the synthesis of some compounds mone regulation, among others. They are with sulfonamidic structure (4). On the usually classified as short-acting sulfona- other hand, Delavirdine (Figure 2), a sec- mides, with half lives (in serum) of 5–10 ond-generation bis(heteroaryl) piperazine, hours (i.e. sulfisoxazole, and is licensed for the treatment of HIV infec- ); intermediate-acting sul- tion and it is used in combination with fonamides, with half lives of 10–12 h (i.e. other anti-HIV agents (5). , and sulfamethazine); and finally long-acting sulfonamides, with half lives from 40 h SULFONAMIDES AS ANTIBACTERIAL AGENTS onwards (i.e. and sulfa- They are used in urinary tract infec- methoxypyridazine) (3). Sulfadiazine and tions, meningitis, streptococcal pharyngitis, more recent compounds, including sulfa- bacillary dysentery, trachoma, chancroid, furazole (sulfisoxazole), sulfa-methoxa- malaria, toxoplasmosis, nocardiasis, and zole, , sulfacitine and sulfame- conjunctivitis. The most popular sulfona- thizole, are quickly absorbed and eliminat- mides are p-aminobenzensulfonamides, or ed. Compared with the older generation , which are bacteriostatic due they are more soluble, less toxic, and prob- to their resemblance to p-aminobenzoic ably less allergenic. Long-acting sulfona- acid (PABA), used by bacteria in the bio- mides include sulfametoxydiazine, sul- synthesis of folic acid required for their fadimethoxine, and other compounds, of growth (6). They interfere with the use of which many are no longer available, due to p-aminobenzoic acid (PABA) in the bio- the fact that they were associated with

559 Oana Maria Parasca (Dragostin) et al. synthesis of tetrahydrofolic acid, which is a complexes have proved to be relevant cata- growth factor that is vital for bacterial lysts in chemical reactions, such as Zn- metabolism. Sulfonamides have a wide sulfonamide complexes that catalyze enan- range of antimicrobial activity against both tio selective cyclopropanations, and also Gram-positive and Gram-negative bacterial reagents for the cleavage of nucleic acids. strains. These drugs act on the bacteria On the other hand, numerous sulphonamide themselves and either prevent their growth complexes have been studied as simple (bacteriostatic) or act as germicides (bacte- models of metal-protein interactions. In ricides). addition, some metal sulfonamides have The topical use of sulfonamides has drawn much attention due to the fact that been limited, because of the high risk of they are mainly used in medicine as anti- hypersensitivity. bacterial drugs (9). Nevertheless, and sul- Sulfonamides and their different deriva- fadicramide are still used topically for eye tives are among the most widely used anti- infections. microbial agents, chiefly because of their Because systemic antibiotics are inef- low cost, low toxicity and excellent activity fective in reducing bacterial counts in against bacterial diseases. granulation wounds, the use of a suitable topical antibacterial agent may substantial- SULFONAMIDES ly decrease wound sepsis and benefit over- AS ANTICANCER AGENTS all management. The actions of topical 1% Among the wide range of compounds silver sulfadiazine and of topical 5% mafe- tested as antitumor agents, sulphonamides nide acetate in Acinetobacter strains have attracted great attention, as many wound infection have been investigated (7). sulphonamide derivatives were reported to Metal-based drugs for the treatment of have interesting antitumor activity. many ailments have gained much attention Recently, it has been showed that β- over the last decade. The ability of metal carbonic anhydrase from Mycobacterium ions to bind in vivo with proteins and pep- tuberculosisis inhibited by several sulfon- tides is an important feature of metal-based amides at low concentration. Sulfa methox- drugs. Simple and N-substituted sulphona- azole was shown to inhibit dihydropteroate mides have attracted much attention in this synthase of Mycobacterium avium and context. Modified toxicological and phar- affected the growth of three strains of My- macological properties have been observed cobacterium avium complex with when some of these sulphonamides are MIC50/80 about 30 mg/mL. Also other administered in the form of their metal sulfonamides were active against Mycobac- complexes. For example, Ag(I)- terium avium complex (10). sulfadiazine, Ce(III)-sulfadiazine, Ni(II)- There are a variety of mechanisms for sulfadimethoxine and Cu(II)-sulfacetamide their anticancer action, such as disruption have shown higher antimicrobial activity of microtubule assembly, cell cycle arrest than free ligands. Several authors have in the G1 phase, functional suppression of conductingstudies on the coordination the transcriptional activator NF-Y, angio- forms of sulphonamides with Cu (II), re- genesis and carbonic anhydrase inhibition ported the versatility of these ligands and (11). The most prominent of these mecha- the importance of their complexes in coor- nisms was the inhibition of carbonic anhy- dination chemistry (8). Some sulphonamide drase isozymes (12). It has been shown that

560 Importance of sulfonamide moiety in current and future therapy two carbonic anhydrase isozymes (CA IX carbonic anhydrase activation may provide and CA XII) are prominently associated in a novel therapy for Alzheimer’s disease many tumors. They are involved in crucial (17), the most prevalent form of dementia processes associated with cancer progres- that affects approximately 24 million peo- sion and response to therapy. Aromatic or ple worldwide. A number of structurally heteroaromatic sulfonamides have been diverse γ-secretase inhibitors have been shown to reverse the effect of tumor acidi- reported and several advanced into clinical fication; consequently they inhibit the trials. Recently, the structure–activity rela- growth of cancer cells and supress carbonic tionships of a series of N-bridged bicyclic anhydrase-mediated tumor invasion (13). sulfonamides as inhibitors of γ-secretase Methanesulfonamides (CH3SO2NH2) are have been reported (18). Begacestat (Fig. also used in drug industry because of their 2) is a novel thiophene sulfonamide gam- biological activity on a large scale. Me- ma-secretase inhibitor that selectively in- thanesulfonamide derivatives have DNA hibits cleavage of amyloid precursor pro- binding ability, show cytostatic effects, and tein (APP) (19). some of them, such as Amsacrine (Fig. 2), are used in cancer chemotherapy. In addi- SULFONAMIDES tion, some sulfonyl hydrazines are known AS ANTICONVULSANT AGENTS to have antineoplastic effects which pre- A new class of anticonvulsant structures vent malignant cells growth and spread that belong to the family of sulfamides has (14). been designed. In recent years, several compounds, such as topiramate and zonis- SULFONAMIDES amide (Fig. 2) have been approved as anti- AS ANTIGLAUCOMA AGENTS convulsant drugs. Their anticonvulsant Several sulfonamides, such as acetazo- action is probably due to CO2 retention lamide, methazolamide, ethoxzolamide or secondary to inhibition of red cell and brain dichlorophenamide, are clinically used as carbonic anhydrase enzyme, but other systemic antiglaucoma agents for more mechanisms of action, such as sodium than 50 years. In the mid 90s, the first clin- channels blockade were proved for some of ically used, topically effective anti- them (20). glaucoma sulfonamide, dorzolamide, was discovered (15). More recently, another SULFONAMIDES AS COX-2 AND topically acting antiglaucoma sulfonamide LIPOXYGENASE INHIBITORS is also available: brinzolamide (Figure 2). Sulfasalazine (salicylazosulfapyridine), However the main drawback of these com- a compound in which is pounds, and of many sulfonamides reported linked to 5-aminosalicylate by a diazo bond so far in the literature, is their lack of selec- has been and still is widely used to treat tivity, as they usually inhibit most of the ulcerative colitis and regional ileitis catalytically active isoforms of carbonic (Crohn’s disease). Sulfasalazine is not used anhydrase in the low nano/ micromolar for the antibacterial properties of the sulfa- range (16). pyridine, but for the local anti- inflammatory effect of 5-aminosalicylate. SULFONAMIDES Selective cyclooxygenase-2 inhibitors IN ALZHEIMER’S DISEASE (COX-2) (Celecoxib, Parecoxib, Valdecox- Furthermore, recent studies suggest that ib) are compounds with sulfonamide struc-

561 Oana Maria Parasca (Dragostin) et al. ture that are indicated for the relief of signs found to be the key constituent of a new and symptoms of osteoarthritis and rheu- class of compounds as potential inhibitors matoid arthritis but also for the treatment of lipoxygenase (21), enzyme that catalyzes of primary dysmenorrhea. the oxidation of polyunsaturated fatty ac- Recently, sulfonamide group has been ids.

O S O N N O NH H O O N H3C S S O HN O H H S O N N S NH2 O H N O H C NH H N 3 Delavirdine Amsacrine Dorzolamide F F F F O NH2 F F S H OH O S S O O N O N S NH 2 O S O O O H O NH S O O O H H Cl Brinzolamide Begacestat Topiramate O H N 2 O O S O O S N N N CF H O N O 3

S NH2 O O N

Zonisamide Celecoxib Parecoxib

N O

CH3

H2N S O O Valdecoxib

Fig. 2. Drugs with sulfonamide structure

562 Importance of sulfonamide moiety in current and future therapy

SULFONAMIDES a selective PDE5 inhibitor, inhibits cGMP AS HYPOGLYCEMIC AGENTS degradation and improves the relaxation of Sulfonylureas are known to act by clos- the smooth muscles in the corpus caverno- ing the adenosine triphosphate-sensitive sum (23). potassium (KATP) channels in the pancreas through binding to the sulphonylurea re- CONCLUSIONS ceptor (SUR) 1 (an integral component of Compounds with sulfonamide structure pancreatic KATP channels), leading to beta enjoy a vast applicability. In this context, cell insulin release. The beta cells of pa- they have been widely studied for many tients taking these drugs are chronically years, for their chemotherapeutic activity. stimulated. Sulfonylureas have been re- The application of sulfonamides has greatly garded as being unsuitable for overweight been extended over the years from their func- diabetics, who primarily need to lose tion as antimicrobial agents to COX-2 inhibi- weight. However, KATP channels are also tors, diuretics, carbonic anhydrase inhibitors found in coronary vascular smooth muscle and even as an anti-impotence drug. In con- cells and cardiomyocytes, but here the SUR clusion, sulfonamides represent a diverse and components are of the SUR 2A and SUR relevant class of therapeutic drugs. The sul- 2B subtypes, respectively (22). fonamide group remains a important strating point for the discovery of new compounds to OTHER APPLICATIONS treat an increasing portfolio of diseases. OF SULFONAMIDES Today, one of the most widely used sul- ACKNOWLEDGMENTS. fonamide drugs is sildenafil, marketed as Oana-Maria Dragostin thanks AM- Viagra®. It is a drug used to treat erectile POSDRU for financial support of the re- dysfunction and pulmonary arterial hyper- search in the project “Doctoral Scholar- tension by inhibiting cGMP specific phos- ships for increasing competitiveness in the phodiesterase type 5, an enzyme that regu- medical and pharmaceutical field” lates blood flow in the penis. Sildenafil, as (POSDRU/88/1.5/S/58965).

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