Discovery of novel diarypyrimidine derivatives as potent HIV-1 NNRTIs by exploiting the tolerant region I within NNRTI binding pocket.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) serve as an essential component of antiretroviral treatment regimens, but they encounter challenges such as resistance mutations, poor solubility, and adverse effects. This study presents the design, synthesis, and biological evaluation of novel diarylpyrimidine (DAPY)-typed derivatives targeting the tolerant region I within the NNRTI binding pocket (NNIBP). We introduced aliphatic ring structures with high Fsp3 value, aiming to enhance target affinity while simultaneously improving water solubility. Among them, compound 9k demonstrated excellent potency against wild-type HIV-1 (EC50 = 0.0014 μM) and key single-mutant strains K103 N (EC50 = 0.0041 μM) and E138K (EC50 = 0.0077 μM), which outperformed the positive drugs ETR, NVP and EFV. Molecular modeling studies were conducted to elucidate the detailed interactions between RT and 9k, providing insights into the enhanced drug resistance profiles. Additionally, 9k demonstrated a notable improvement in water solubility (1.38 μg/mL, pH = 7) compared to ETR (≪ 1 μg/mL, pH = 7). These findings provide a foundation for further optimization of NNRTIs with improved anti-resistance profiles and pharmacokinetics.