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 (EC 50 = 3.14-22.1 nM) against wild-type and a panel of mutant HIV-1 strains, being much superior to that of etravirine (EC 50 = 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 ( T 1/2 = 1.33 h, F = 31.8%) and safety profiles (LD 50 > 2000 mg/kg), making it a promising anti-HIV-1 drug candidate for further development.