Domagala J M, Bader J P, Gogliotti R D, Sanchez J P, Stier M A, Song Y, Prasad J V, Tummino P J, Scholten J, Harvey P, Holler T, Gracheck S, Hupe D, Rice W G, Schultz R
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Bioorg Med Chem. 1997 Mar;5(3):569-79. doi: 10.1016/s0968-0896(96)00269-6.
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.
作为美国国立癌症研究所药物筛选计划的一部分，已鉴定出一类对人类免疫缺陷病毒HIV-1具有活性的新型抗逆转录病毒药物，并提出将HIV-1核衣壳蛋白NCp7作为抗病毒作用的靶点。2,2'-二硫代双-4'-(氨磺酰基)苯甲酰胺和2,2'-二硫代双(5-乙酰氨基)苯甲酰胺(10)代表了原型先导结构。制备了多种2,2'-二硫代双苯甲酰胺，并对其抗HIV-1活性、细胞毒性以及从NCp7的锌指中挤出锌的能力进行了测试。构效关系表明，从NCp7中挤出锌的能力存在于2,2'-二硫代双苯甲酰胺核心结构中。3,3'和4,4'异构体无活性。虽然许多基于核心结构的类似物保留了锌挤出活性，但最佳的总体抗HIV-1活性仅在一组具有羧酸、羧酰胺或苯磺酰胺官能团的狭窄衍生物中发现。这些官能团对于降低细胞毒性比提高抗病毒效力或对NCp7的活性更重要。所有具有抗病毒活性的化合物也能从NCp7中挤出锌。通过这项研究，确定了几类具有简单化学结构的低 microM抗HIV药物作为治疗艾滋病的可能化疗药物。
