Development of enhanced HIV-1 non-nucleoside reverse transcriptase inhibitors with improved resistance and pharmacokinetic profiles.

HIV-1 infection is a manageable chronic condition, with non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) remaining a cornerstone of antiretroviral therapy. Nevertheless, drug resistance to existing therapeutics is a serious and immediate concern. Using structure-based and scaffold-hopping approaches, we designed evolved diarylpyrimidine analogs targeting reverse transcriptase (RT), exploiting chemical space surrounding the NNRTI-binding pocket. We identified compounds 5i3 and 5e2, with robust antiviral efficacy against wild-type HIV-1 and rilpivirine-resistant strains. Encouragingly, in vitro selection of mutant strains with 5i3 took 39 passages to select resistance, with no phenotypic cross-resistance observed with known RT drugs. Co-crystal structures of wild-type and mutant RT with 5i3 and 5e2 revealed their resilience toward resistance mutations due to enhanced conformational flexibility and positional adaptability. 5i3 exhibited good pharmacokinetic properties and favorable safety profiles, without substantial cytochrome P450 inhibition, and excellent oral bioavailability. These derivatives represent a promising scaffold for the development of anti-HIV drugs.