Lead Optimization and Avoidance of Metabolic-perturbing Motif Developing Novel Diarylpyrimidines as Potent HIV-1 NNRTIs

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent an indispensable part of anti-HIV-1 therapy. To discover novel HIV-1 NNRTIs with increased drug resistance profiles and improved pharmacokinetic (PK) properties, a series of novel diarylpyrimidine derivatives were generated via the cocrystal structure-based drug design strategy. Among them, <b>36a</b> exhibited outstanding antiviral activity against HIV-1 IIIB and a panel of mutant strains (L100I, K103N, Y181C, Y188L, E138K, F227L + V106A, and RES056), with EC₅₀ ranging from 2.22 to 53.3 nM. Besides, <b>36a</b> was identified with higher binding affinity (<i>K</i>_D = 2.50 μM) and inhibitory activity (IC₅₀ = 0.03 μM) to HIV-1 RT. Molecular docking and molecular dynamics simulation were performed to rationalize the design and the improved drug resistance of these novel inhibitors. Additionally, <b>36a·HCl</b> exhibited favorable PK (<i>T</i>_1/2 = 5.12 h, <i>F</i> = 12.1%) and safety properties (LD₅₀ > 2000 mg/kg). All these suggested that <b>36a·HCl</b> may serve as a novel drug candidate anti-HIV-1 therapy.