Design, synthesis, and biological evaluation of benzo[4,5]thieno[2,3-d]pyrimidine derivatives as novel HIV-1 NNRTIs

Inspired by our previous studies to discover novel human immunodeficiency virus-1（HIV-1） nonnucleoside reverse transcriptase inhibitors（NNRTIs） by targeting the tolerant region II of the NNRTIs binding pocket（NNIBP）, a series of novel benzo[4,5]thieno[2,3-d]pyrimidine derivatives were designed through structure-based drug design as novel potent HIV-1 NNRTIs. The results showed that compound16b was the most active inhibitor, exhibiting 50% effective concentration（EC50） values from 0.021 μmol/L to 0.298 μmol/L against wild-type（WT） and a panel of NNRTIs-resistant HIV-1 strains. Moreover, 16b was demonstrated with a significantly low 50% cytotoxicity concentration(CC50) value（>200 μmol/L） and high selectivity index（SI） values. In addition, 16b yielded moderate reverse transcriptase（RT） enzyme inhibition with a 50% inhibition concentration(IC50) value of 0.183 μmol/L, which demonstrated that it acted as HIV-1 NNRTIs. The binding mode of 16b with RT was also illustrated via molecular docking. Overall, this work provided a novel lead compound for developing potent HIV-1 NNRTIs.