Expanding the Solvent/Protein Region Occupation of the Non-Nucleoside Reverse Transcriptase Inhibitor Binding Pocket for Improved Broad-Spectrum Anti-HIV-1 Efficacy: from Rigid Phenyl-Diarylpyrimidines to Flexible Hydrophilic Piperidine-Diarylpyrimidines

Abstract

Considering the nonideal antiresistance efficacy of our previously reported non-nucleoside reverse transcriptase inhibitor 7, a series of novel piperidine-diarylpyrimidine derivatives were designed through expanding solvent/protein region occupation. The representative compound 15f proved to be exceptionally potent against Y188L (EC₅₀ = 23 nM), F227L + V106A (EC₅₀ = 15 nM) and RES056 (EC₅₀ = 45 nM), significantly better than 7. This analog exerted strong inhibition against wild-type HIV-1 (EC₅₀ = 3 nM) and single mutant strains (L100I, K103N, Y181C, E138 K). Notably, its cytotoxicity and selectivity (CC₅₀ = 18.23 μM, SI = 6537) were 4-fold better than etravirine and rilpivirine. Additionally, it exhibited minimal suppression of CYP isoenzymes and hERG, indicating low potential for drug–drug interactions and cardiotoxicity. No significant acute toxicity and tissue damage at a dose of 2 g/kg were revealed. These findings lay the groundwork for the advancement of 15f as a highly potent, safe, and broad-spectrum NNRTI for HIV therapy.