Nature 343, 470 - 474 (01 February 1990); doi:10.1038/343470a0

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

Rudi Pauwels^*, Koen Andries^†, Jan Desmyter^*, Dominique Schols^*, Michael J. Kukla^‡, Henry J. Breslin^‡, Alfons Raeymaeckers^†, Jozef Van Gelder^†, Robert Woestenborghs^†, Jozef Heykants^†, Karel Schellekens^†, Marcel A. C. Janssen^†, Erik De Clercq^* & Paul A. J. Janssen^†

^*Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
^†Janssen Research Foundation, Turnhoutseweg 30, B-2340 Beerse, Belgium
^‡Janssen Research Foundation, Bethlehem Pike, Spring House, Pennsylvania 19477, USA

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][l,4]-benzodiazepin-2(1H)-one and -thione (TIBO) derivatives inhibit the replication of HIV-1 (refs 1, 2), the main aetiological agent of AIDS, but not of HIV-2 (ref. 3), or of any other DNA or RNA viruses. In five cell systems, HIV-1 is inhibited by TIBO derivatives in nanomolar amounts, which are 10⁴–10⁵ 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^5–8. 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.

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