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 10n (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, 10n demonstrated excellent pharmacokinetic profile (T1/2 = 5.09 h, F = 108.96%)
compared that of DOR (T1/2 = 4.4 h, F = 57%). Additionally, 10n was also verified
to have no in vivo acute or subacute toxicity (LD50 > 2000 mg/kg), suggesting that 10n is worth
further investigation as a novel oral NNRTIs for HIV-1 therapy.