As part of the National Cancer Institute's
Drug Screening Program, a new class of antiretrovirals active against the human immunodeficiency virus HIV-1 has been identified, and the HIV-1
nucleocapsid protein NCp7 was proposed as the target of
antiviral action. The 2,2'-dithiobis-[4'-(sulfamoyl)
benzanilide] (3x) and the 2,2'-dithiobis(5-acetylamino)benzamide (10) represented the prototypic lead structures. A wide variety of 2,2'-dithiobisbenzamides were prepared and tested for anti-HIV-1 activity, cytotoxicity, and their ability to extrude
zinc from the zinc fingers for NCp7. The structure-activity relationships demonstrated that the ability to extrude
zinc from NCp7 resided in the 2,2'-dithiobisbenzamide core structure. The 3,3' and the 4,4' isomers were inactive. While many analogs based upon the core structure retained the
zinc extrusion activity, the best overall anti-HIV-1 activity was only found in a narrow set of derivatives possessing
carboxylic acid, carboxamide, or phenylsulfonamide functional groups. These functional groups were more important for reducing cytotoxicity than improving
antiviral potency or activity vs NCp7. All of the compounds with
antiviral activity also extruded
zinc from NCp7. From this study several classes of low microM
anti-HIV agents with simple chemical structures were identified as possible chemotherapeutic agents for the treatment of
AIDS.