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

• Published in: Journal of medicinal chemistry 2023-02, Vol.66 (3), p.2102-2115
• Main Authors: Zhao, Fabao, Zhang, Heng, Xie, Minghui, Meng, Bairu, Liu, Na, Dun, Caiyun, Qin, Yanyang, Gao, Shenghua, De Clercq, Erik, Pannecouque, Christophe, Tang, Ya-Jie, Zhan, Peng, Liu, Xinyong, Kang, Dongwei
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Drug Design; HIV Reverse Transcriptase - metabolism; HIV-1 - metabolism; Pyrimidines - chemistry; Pyrimidines - pharmacology; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01875

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 (T 1/2 = 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.