DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF COSALANE, A NOVEL ANTI-HIV AGENT WHICH INHIBITS MULTIPLE FEATURES OF VIRUS REPRODUCTION

Cosalane (3), a novel anti-HIV agent having a disalicylmethane unit li nked to C-3 of cholestane by a three-carbon Linker, was synthesized fr om commercially available starting materials by a convergent route. Co salane proved to be a potent inhibitor of HIV with a broad range of ac tivity against a variety of laboratory, drug-resistant, and clinical H IV-1 isolates, HIV-2, and Rauscher murine leukemia virus. The cytotoxi city of cosalane is relatively low as reflected by an in vitro therape utic index of > 100. Although cosalane inhibits HIV-1 reverse transcri ptase and protease, time of addition experiments indicate that it prev ents the cytopathic effect of HIV by acting earlier than reverse trans cription in the viral replication cycle. The available evidence indica tes that the primary mechanism of action of cosalane involves inhibiti on of gp120-CD4 binding as well as inhibition of a postattachment even t prior to reverse transcription.