Structure-Based Drug Design Yields Diarylpyrimidine Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Human immunodeficiency virus type-1 (HIV-1) resistance severely compromises the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs). This study developed novel DAPY-derived NNRTIs via a structure-based drug design strategy with <b>K-5a2</b> as the lead. All designed compounds demonstrate potent antiviral activity against the HIV-1 wild-type (WT) strain (EC₅₀ = 3.03-21.1 nM). Notably, compound <b>19</b> was identified as the most potent inhibitor against a panel of clinically relevant mutant strains (EC₅₀ = 5.03-37.7 nM) with resistance fold (RF) values (RF = 0.746-5.59) superior to that of ETR (RF = 1.11-15.5). Mechanistic studies confirmed that <b>19</b> potently inhibits HIV-1 RT (IC₅₀ = 0.107 μM). Molecular docking and MM/GBSA calculations validate its stable binding with NNIBP, mediated by extensive hydrogen bond networks, hydrophobic interactions, and π-π stacking. Collectively, this work delivers <b>19</b> as a highly promising next-generation NNRTI lead compound with exceptional resilience against drug-resistant HIV-1.