NEW YDROIMIDAZO[4,5,1-JK][1,4]-BENZODIAZEPIN-2(1H)-ONE AND OIMIDAZO[4,5,1-JK][1,4]-BENZODIAZEPIN-2(1H)-THIONE DERIVATIVES ARE POTENT INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION AND ARE SYNERGISTIC WITH 2',3'-DIDEOXYNUCLEOSIDE ANALOGS

Tetrahydro-imidazo [4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) derivatives were shown to specifically block human immunodefic iency virus type 1 (HIV-1) replication through a unique interaction wi th the HIV-1 reverse transcriptase (RT). Through further modification of the lead compounds and structure-activity relationship analysis sev eral new TIBO derivatives that show high potency, selectivity, and spe cificity against HIV-1 have been obtained. A new TIBO derivative, R861 83, inhibits the replication of HIV-1, but not HIV-2, in a variety of CD4(+) T cell lines and peripheral blood lymphocytes, at a concentrati on of 0.3 to 30 nM, which is at least 4 orders of magnitude lower than the 50% cytotoxic concentration. Whereas an HIV-1 strain containing t he Leu-100-->Ile mutation in the RT gene is about 400-fold less suscep tible, R86183 still inhibits the replication of an HIV-1 strain contai ning the Tyr-181-->Cys RT mutation by 50% at a concentration of 130 nM . R86183 inhibits the poly(C) oligo(dG)(12-18)-directed HIV-1 RT react ion by 50% at a concentration of 57 nM. The antiviral activity of 22 T IBO derivatives in cell culture correlated well with their activity ag ainst HIV-1 RT. No such correlation was found for their cytotoxicity. The combination of R86183 with either zidovudine or didanosine resulte d in a synergistic inhibition of HIV-1 (strain IIIb) replication. Comb ination of R86183 with the protease inhibitor Ro31-8959 was found to b e additive. Also described is a dilution protocol circumventing overes timation and underestimation of antiviral activity due to adherence to plastic surfaces.