Discovery of Novel Aryl Triazolone Dihydropyridines (ATDPs) Targeting Highly Conserved Residue W229 as Promising HIV-1 NNRTIs

NNRTI is an important component of the highly active antiretroviral therapy (HAART), but the rapid emergence of drug resistance and poor pharmacokinetics limited their clinical application. Herein, a series of novel aryl triazolone dihydropyridines (ATDPs) were designed by structure-guided design with the aim of improving drug resistance profiles and pharmacokinetic profiles. Compound <b>10n</b> (EC₅₀ = 0.009-17.7 μM) exhibited the most active potency, being superior to or comparable to that of doravirine (DOR) against the whole tested viral panel. Molecular docking was performed to clarify the reason for its higher resistance profiles. Moreover, <b>10n</b> demonstrated excellent pharmacokinetic profile (<i>T</i>_1/2 = 5.09 h, <i>F</i> = 108.96%) compared that of DOR (<i>T</i>_1/2 = 4.4 h, <i>F</i> = 57%). Additionally, <b>10n</b> was also verified to have no <i>in vivo</i> acute or subacute toxicity (LD₅₀ > 2000 mg/kg), suggesting that <b>10n</b> is worth further investigation as a novel oral NNRTIs for HIV-1 therapy.