Structure-Based design of [(2-Hydroxyethoxy)methyl]-6-(phenylthio)-thymine derivatives as nonnucleoside HIV-1 reverse transcriptase Inhibitors: From HEPTs to Sulfinyl-substituted HEPTs

The [(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogs were reported to be a kind of promising lead compounds as nonnucleoside HIV-1 Reverse Transcriptase inhibitors. In this work, a series of novel sulfinyl-substituted analogs were designed by structure-based design strategy with the purpose of improving the activity of HEPT, followed by evaluating their anti-HIV-1 activity in MT-4 cells. Most of the final compounds had moderate to strong activity against wild-type HIV-1 strain (III_B) with EC₅₀ values in the range of 0.21-1.91 μM, which were around 4 ∼ 32-fold better than the reference compound HEPT. Some of them showed higher sensitivity toward clinically relevant mutant L100I and E138K viruses than NVP. Selected compounds were further evaluated for their activity against wild-type Reverse Transcriptase (RT), and most of them exhibited nanomolar activity, suggesting a good correlation with the cell-based activity. The compounds 11h, 11l, and 11ab displayed the best anti-HIV-1 activity against wild-type HIV-1 strain (EC₅₀ = 0.280, 0.209, and 0.290 μM) and nanomolar activity against mutant strains (L100I and E138K), superior to HEPT and NVP. Molecular modeling studies were also performed to elucidate the biological activity, providing a structural insight for follow-up research on HEPT optimization.