Thiadiazole Derivatives: Highly Potent and Selective Inhibitors of Human Immunodeficiency Virus Type 1 (HIV‐1) Replications In Vitro

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Abstract
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 μM) 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.