A NEW CLASS OF ANTI-HIV-1 AGENTS TARGETED TOWARD THE NUCLEOCAPSID PROTEIN NCP7 - THE 2,2'-DITHIOBISBENZAMIDES

As part of the National Cancer Institute's Drug Screening Program, a n ew class of antiretrovirals active against the human immunodeficiency virus HIV-1 has been identified, and the HIV-I nucleocapsid protein NC p7 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 vari ety of 2,2'-dithiobisbenzamides were prepared and tested for anti-HIV- l activity, cytotoxicity, and their ability to extrude zinc from the z inc fingers for NCp7. The structure-activity relationships demonstrate d that the ability to extrude zinc from NCp7 resided in the 2,2'-dithi obisbenzamide core structure. The 3,3' and the 4,4' isomers were inact ive. While many analogs based upon the core structure retained the zin c extrusion activity, the best overall anti-HIV-1 activity was only fo und in a narrow set of derivatives possessing carboxylic acid, carboxa mide, 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 acti vity also extruded zinc from NCp7. From this study several classes of low mu M anti-HIV agents with simple chemical structures were identifi ed as possible chemotherapeutic agents for the treatment of AIDS. (C) 1997 Elsevier Science Ltd.