Design, synthesis and biological evaluation of <italic>S</italic>-DAPY derivatives as novel HIV-1 inhibitors

In our previous studies, we combined the pharmacophoric group of etravirine and VRX-480773 using structure-guided molecular hybridization strategy, which led to the identification of <italic>S</italic>-DAPYs with an amide subunit that exhibited moderate potency against wild-type HIV-1 strain. However, Maurizo's discovering of <italic>S</italic>-DAPYs without the amide subunit showed excellent potency against HIV-1. To investigate the effect of the amide subunit on antiviral activity, a series of novel <italic>S</italic>-DAPYs derivatives without the amide subunit were synthesized and evaluated for their anti-HIV activities in MT-4 cell cultures. Biological results showed that three compounds (<bold>6g</bold>, <bold>6m</bold> and <bold>6s</bold>) exhibited moderate inhibitory activities against wild-type HIV-1 strain with EC₅₀ values ranging from 6.5 to 15.4 μmol/L, but inferior to that of the corresponding derivatives with the amide subunit. Molecular simulation revealed that a hydrogen bond was formed between the C=O of the amide moieties and the NH group of Lys103, and it provides ideas for more drug research in the treatment of AIDS.