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A new class of anti-HIV-1 agents targeted toward the nucleocapsid protein NCp7: The 2,2′-dithiobisbenzamides

Authors :
Patricia J. Harvey
Michael Andrew Stier
William G. Rice
Rocco D. Gogliotti
Yuntao Song
Steve Gracheck
Peter J. Tummino
Tod P. Holler
John M. Domagala
Joseph P. Sanchez
Robert R. Schultz
John P. Bader
J. V. N. Vara Prasad
Jeffrey D. Scholten
Donald Hupe
Source :
Bioorganic & Medicinal Chemistry. 5:569-579
Publication Year :
1997
Publisher :
Elsevier BV, 1997.

Abstract

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 μM anti-HIV agents with simple chemical structures were identified as possible chemotherapeutic agents for the treatment of AIDS.

Details

ISSN :
09680896
Volume :
5
Database :
OpenAIRE
Journal :
Bioorganic & Medicinal Chemistry
Accession number :
edsair.doi.dedup.....3e7f84e04d023ef8301cb1abf0f847ab