Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives.

In the search for compounds active against human immunodeficiency virus (HIV), we have found that members of a novel series of tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and -thione (TIBO) derivatives inhibit the replication of HIV-1, the main aetiological agent of AIDS, but not of HIV-2, or of any other DNA or RNA viruses. In five cell systems, HIV-1 is inhibited by TIBO derivatives in nanomolar amounts, which are 10(4)-10(5) times lower than the cytotoxic concentration. The unprecedented specificity of these compounds may be due to an interaction with a reverse transcriptase-associated process. By contrast, AZT (3'-azido-2',3'-dideoxythymidine), which is used for the treatment of AIDS, and DDC (2',3'-dideoxycytidine) and DDI (2',3'-dideoxyinosine), whose clinical application is being assessed, inhibit both HIV-1 and HIV-2 at concentrations that, depending on the cell systems, are 2 to 4 orders of magnitude below their cytotoxic concentration. TIBO-derivatives are new chemicals unrelated to any other antiviral agents. We believe that they are the most specific and potent inhibitors of HIV-1 replication studied so far.