Structure- and Privileged Fragment-Based Iterative Optimization: Discovery of 2,4-Disubstituted-6-aminopyrimidines as Novel HIV-1 NNRTIs with Potent Activity against Drug-Resistant Strains and Favorable Safety Profiles

There is an urgent need to develop next-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) to combat the rapid emergence of drug-resistant HIV-1 variants. Guided by cocrystal structures of ETR and K-5a2 bound to HIV-1 reverse transcriptase (RT), a privileged-fragment hybridization strategy was employed to enhance antiviral activity and resistance profiles. Through three rounds of optimization, compound <b>18d</b> exhibited potent activity against wild-type (WT) and seven clinically relevant mutant HIV-1 strains, with EC₅₀ values of 1.5-31 nM, surpassing ETR (2.6-41 nM). Molecular dynamics simulations revealed that the aminopyrimidine and pyridine fragments of <b>18d</b> formed extensive hydrogen bonds with surrounding residues, contributing to its strong resistance barrier. Moreover, <b>18d</b> displayed favorable metabolic stability <i>in vivo</i> (<i>T</i>_1/2 = 1.42 h) and an excellent safety profile. Collectively, these findings highlight <b>18d</b> as a promising next-generation NNRTI candidate for further development.