We have recently reported that
thiadiazole (TDA) derivatives are highly potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication. These compounds belong to the family of nonnucleoside
reverse transcriptase inhibitors (NNRTIs). In an attempt to develop more effective and pharmacologically favorable compounds, novel TDA derivatives have been synthesized and examined for their anti-HIV-1 activity in vitro. Among them,
RD4-2217 was found to be the most potent inhibitor of HIV-1 replication. It inhibited replication of the HTLV-IIIB strain in MT-4 cells at a concentration of 6 nM.
RD4-2217 was also inhibitory to clinical isolates and
zidovudine-resistant mutants of HIV-1. The combination of
RD4-2217 with
zidovudine or the
protease inhibitor A-75925 synergistically inhibited HIV-1 replication. Studies on the emergence of
drug-resistant mutants revealed that, although much higher concentrations (1-10 microM) were required,
RD4-2217 completely suppressed the breakthrough of HIV-1 in the supernatants during long-term culturing of infected cells. Furthermore,
RD4-2217 at low concentrations (10 or 100 nM), in combination with
zidovudine, also completely inhibited viral breakthrough. In addition,
RD4-2217 had lower lipophilicity and improved protein binding as compared to its congener RD4-2024 and
loviride. These results suggest that
RD4-2217, one of the TDA derivatives, is worth pursuing as a candidate
drug for the treatment of HIV-1
infections.