Structure-directed linker optimization of novel HEPTs as non-nucleoside inhibitors of HIV-1 reverse transcriptase

1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymines (HEPTs) have been previously described as an important class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). In our continuously pursuing HEPT optimization efforts, a series of novel HEPTs, featuring -C(OH)CH₂R, -CC, or -CHCH₂R linker at the benzylic α-methylene unit, were developed as NNRTIs. Among these new HEPTs, the compound C20 with -CHCH₃ group at the benzylic α-methylene unit conferred the highest potency toward WT HIV-1 and selectivity (EC₅₀ = 0.23 μM, SI = 150.20), which was better than the lead compound HEPT (EC₅₀ = 7 μM, SI = 106). Also, C20 was endowed with high efficacy against clinically relevant mutant strains (EC_50(L100I) = 1.07 μM; EC_50(K103N) = 4.33 μM; EC_50(Y181C) = 5.57 μM; EC_50(E138K) = 1.06 μM; EC_{50(F227L+V106A)} = 5.45 μM) and wild-type HIV-1 reverse transcriptase (RT) with an IC₅₀ value of 0.55 μM. Molecular docking and molecular dynamics simulations, as well as preliminary structure-activity relationship (SAR) analysis of these new compounds, provided a deeper insight into the key structural features of the interactions between HEPT analogs and HIV-1 RT and laid the foundation for further modification on HEPT scaffold.