Structure-based design of novel heterocycle-substituted ATDP analogs as non-nucleoside reverse transcriptase inhibitors with improved selectivity and solubility

Following on our recently developed biphenyl-ATDP non-nucleoside reverse transcriptase inhibitor ZLM-66 (SI = 2019.80, <i>S</i> = 1.9 μg/mL), a series of novel heterocycle-substituted ATDP derivatives with significantly improved selectivity and solubility were identified by replacement of the biphenyl moiety of ZLM-66 with heterocyclic group with lower lipophilicity. Evidently, the representative analog <b>7w</b> in this series exhibited dramatically enhanced selectivity and solubility (SI = 12,497.73, <i>S</i> = 4472 μg/mL) in comparison with ZLM-66 (SI = 2019.80, <i>S</i> = 1.9 μg/mL). This new NNRTI conferred low nanomolar inhibition of wild-type HIV-1 strain and tested mutant strains (K103N, L100I, Y181C, E138K, and K103N + Y181C). The analog also demonstrated favorable safety and pharmacokinetic profiles, as evidenced by its insensitivity to CYP and hERG, lack of mortality and pathological damage, and good oral bioavailability in rats (<i>F</i> = 27.1%). Further development of <b>7w</b> for HIV therapy will be facilitated by this valuable information.