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 <b>5i3</b> and <b>5e2</b>, with robust antiviral efficacy against wild-type HIV-1 and rilpivirine-resistant strains. Encouragingly, in vitro selection of mutant strains with <b>5i3</b> 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 <b>5i3</b> and <b>5e2</b> revealed their resilience toward resistance mutations due to enhanced conformational flexibility and positional adaptability. <b>5i3</b> 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.