Probing the Dominant Motifs within the Hydrophobic Channel Yields Oxadiazole-Containing Diarylpyrimidine Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

To develop effective non-nucleoside Reverse Transcriptase inhibitors (NNRTIs) with improved antidrug resistance profiles and drug-like properties, a series of novel diarylpyrimidine derivatives targeting the hydrophobic domain of the NNRTI-binding pocket was strategically designed, synthesized, and evaluated. Following structural optimization, 18e (EC₅₀ = 5.06-54.0 nM) emerged as the most potent inhibitor against wild-type and NNRTI-resistant strains, comparable to ETR (EC₅₀ = 3.79-51.8 nM). In particular, for Y188L and RES056 mutant strains, 18e (EC_50(Y188L) = 24.2 nM, RF = 4.79/EC_50(RES056) = 54.0 nM, RF = 10.7) showed improved antiresistance profiles versus ETR (EC_50(Y188L) = 23.4 nM, RF = 6.18/EC_50(RES056) = 51.8 nM, RF = 13.7). Molecular simulation studies indicated that the 1,3,4-oxadiazolylpyridine motif was essential for binding to Reverse Transcriptase. Moreover, 18e exhibited promising pharmacokinetic properties (T_1/2 = 2.35 h, F = 14.4%) and safety (LD₅₀ < 2000 mg/kg), positioning it as a promising anti-HIV-1 drug candidate.