Discovery of novel benzothiazolesulfonamides as potent inhibitors of HIV-1 protease.

Srinivasan R Nagarajan, Gary A De Crescenzo, Daniel P Getman, Hwang Fun Lu, James A Sikorski, Jeffrey L Walker, Joseph J McDonald, Kathryn A Houseman, Geralyn P Kocan, Nandini Kishore, Pramod P Mehta, Christie L Funkes-Shippy, Lisa Blystone

Index: Bioorg. Med. Chem. 11(22) , 4769-77, (2003)

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Abstract

The human immunodeficiency virus (HIV) has been shown to be the causative agent for AIDS. The HIV virus encodes for a unique aspartyl protease that is essential for the production of enzymes and proteins in the final stages of maturation. Protease inhibitors have been useful in combating the disease. The inhibitors incorporate a variety of isosteres including the hydroxyethylurea at the protease cleavage site. We have shown that the replacement of t-butylurea moiety by benzothiazolesulfonamide provided inhibitors with improved potency and antiviral activities. Some of the compounds have shown good oral bioavailability and half-life in rats. The synthesis of benzothiazole derivatives led us to explore other heterocycles. During the course of our studies, we also developed an efficient synthesis of benzothiazole-6-sulfonic acid via a two-step procedure starting from sulfanilamide.