Structure-based design and optimization lead to the identification of novel dihydrothiopyrano[3,2-d]pyrimidine derivatives as potent HIV-1 inhibitors against drug-resistant variants

With our continuous endeavors in seeking potent anti-HIV-1 agents, we reported here the discovery, biological characterization, and druggability evaluation of a class of nonnucleoside reverse transcriptase inhibitors. To fully explore the chemical space of the NNRTI-binding pocket, novel series of dihydrothiopyrano [3,2-<i>d</i>]pyrimidines were developed by employing the structure-based design strategy. Most of the derivatives were endowed with prominent antiviral activities against HIV-1 wild-type and resistant strains at nanomolar levels. Among them, compound <b>23h</b> featuring the aminopiperidine moiety was identified as the most potent inhibitor, with EC₅₀ values ranging from 3.43 to 21.4 nmol/L. Especially, for the challenging double-mutants F227L + V106A and K103N + Y181C, <b>23h</b> exhibited 2.3- to 14.5-fold more potent activity than the first-line drugs efavirenz and etravirine. Besides, the resistance profiles of <b>23h</b> achieved remarkable improvement compared to efavirenz and etravirine. The binding target of <b>23h</b> was further confirmed to be HIV-1 reverse transcriptase. Molecular modeling studies were also performed to elucidate the biological evaluation results and give guidance for the optimization campaign. Furthermore, no apparent inhibition of the major CYP450 enzymes and hERG channel was observed for <b>23h</b>. Most importantly, <b>23h</b> was characterized by good pharmacokinetic properties and excellent safety <i>in vivo</i>. Collectively, <b>23h</b> holds great promise as a potential candidate for its effective antiviral efficacy and favorable drug-like profiles.