Structure-Based Optimization of 2,4,5-Trisubstituted Pyrimidines as Potent HIV‑1 Non-Nucleoside Reverse Transcriptase Inhibitors: Exploiting the Tolerant Regions of the Non-Nucleoside Reverse Transcriptase Inhibitors’ Binding Pocket

Although non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
exhibit potent anti-HIV-1 activity and play an important role in the
active antiretroviral therapy of AIDS, the emergence of drug-resistant
strains has seriously reduced their clinical efficacy. Here, we report
a series of 2,4,5-trisubstituted pyrimidines as potent HIV-1 NNRTIs
by exploiting the tolerant regions of the NNRTI binding pocket. Compounds 16b and 16c were demonstrated to have excellent
activity (EC50 = 3.14–22.1 nM) against wild-type
and a panel of mutant HIV-1 strains, being much superior to that of
etravirine (EC50 = 3.53–52.2 nM). Molecular modeling
studies were performed to illustrate the detailed interactions between
RT and 16b, which shed light on the improvement of the
drug resistance profiles. Moreover, 16b possessed favorable
pharmacokinetic (T1/2 = 1.33 h, F = 31.8%) and safety profiles (LD50 > 2000
mg/kg),
making it a promising anti-HIV-1 drug candidate for further development.