A Triazinone Derivative Inhibits HIV‐1 Replication by Interfering with Reverse Transcriptase Activity

A novel HIV‐1 inhibitor, 6‐( tert ‐butyl)‐4‐phenyl‐4‐(trifluoromethyl)‐1 H ,3 H ‐1,3,5‐triazin‐2‐one (compound 1 ), was identified from a compound library screened for the ability to inhibit HIV‐1 replication. EC 50 values of compound 1 were found to range from 107.9 to 145.4 n m against primary HIV‐1 clinical isolates. In in vitro assays, HIV‐1 reverse transcriptase (RT) activity was inhibited by compound 1 with an EC 50 of 4.3 μ m . An assay for resistance to compound 1 selected a variant of HIV‐1 with a RT mutation (RT L100I ); this frequently identified mutation confers mild resistance to non‐nucleoside RT inhibitors (NNRTIs). A recombinant HIV‐1 bearing RT L100I exhibited a 41‐fold greater resistance to compound 1 than the wild‐type virus. Compound 1 was also effective against HIV‐1 with RT K103N , one of the major mutations that confers substantial resistance to NNRTIs. Computer‐assisted docking simulations indicated that compound 1 binds to the RT NNRTI binding pocket in a manner similar to that of efavirenz; however, the putative compound 1 binding site is located further from RT K103 than that of efavirenz. Compound 1 is a novel NNRTI with a unique drug‐resistance profile.