Protease inhibitors of the sulfonamide type: Anticancer, antiinflammatory, and antiviral agents

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Abstract
The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anticarbonic anhydrase, diuretic, hypoglycemic, and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial protease inhibitory properties. Of particular interest are some metalloprotease inhibitors belonging to this class, which by inhibiting several matrix metalloproteases (MMPs) show interesting antitumor properties. Some of these compounds are currently being evaluated in clinical trials. The large number of sulfonamide MMP inhibitors ultimately reported also lead to the design of effective tumor necrosis factor-α converting enzyme (TACE) inhibitors, potentially useful in the treatment of inflammatory states of various types. Since both MMPs and TACE contribute synergistically to the pathophysiology of many diseases, such as arthritis, bacterial meningitis, tumor invasion; the dual inhibition of these enzymes emerged as an interesting target for the drug design of anticancer/antiinflammatory drugs, and many such sulfonamide derivatives were recently reported. Human neutrophyl elastase (HNE) inhibitors of the sulfonamide type may also be useful in the treatment of inflammatory conditions, such as emphysema, cystic fibrosis, chronic bronchitis, ischemia reperfusion injury, and acute respiratory distress syndrome. Inhibition of some cysteine proteases, such as several caspase and cathepsin isozymes, may lead to the development of pharmacological agents effective for the management of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, brain damage, and stroke. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Some clinically used HIV protease inhibitors (such as amprenavir) possess sulfonamide moieties in their molecules, which are critical for the potency of these drugs, as shown by means of X-ray crystallography, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with lower toxicity or augmented activity against viruses resistant to the such first generation drugs. Other viral proteases, such as those isolated from several types of herpes viruses may be inhibited by sulfonamide derivatives, leading thus to more effective classes of antiviral drugs. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 5, 535–558, 2003