THIAZOLOBENZIMIDAZOLE - BIOLOGICAL AND BIOCHEMICAL ANTIRETROVIRAL ACTIVITY OF A NEW NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITOR

Thiazolobenzimidazole (NSC 625487) was a highly potent inhibitor of hu man immunodeficiency virus-induced cell killing and viral replication in a variety of human cell lines, as well as fresh human peripheral bl ood lymphocytes and macrophages. The compound was active against a pan el of biologically diverse laboratory and clinical strains of HIV-1, i ncluding the AZT-resistant strain G910-6. However, the agent was inact ive against HIV-2 and a pyridinone-resistant strain (A17) of HIV-1, a strain which is cross-resistant to several structurally diverse member s of a common pharmacologic class of nonnucleoside reverse transcripta se inhibitors. The compound selectively inhibited HIV-1 reverse transc riptase but not HIV-2 reverse transcriptase. Combinations of thiazolob enzimidazole with either AZT or ddI synergistically inhibited HIV-1 in duced cell killing in vitro. Thiazolobenzimidazole also inhibited the replication of the Rauscher murine leukemia retrovirus. Thus, thiazolo benzimidazole is a new active anti-HIV-1 chemotype and may represent a subclass of nonnucleoside reverse transcriptase inhibitors with an en hanced range of anti-retroviral activity.