Discovery of 2,4,6-trisubstituted pyrimidine derivatives as novel potent HIV-1 NNRTIs by exploiting the tolerant region II of the NNIBP

• Published in: European journal of medicinal chemistry 2024-11, Vol.277, p.116708, Article 116708
• Main Authors: Zhou, Zhenzhen, Sun, Yanying, Qin, Yanyang, Wang, Na, Zhao, Fabao, Wang, Zhao, Clercq, Erik De, Pannecouque, Christophe, Zhan, Peng, Kang, Dongwei, Liu, Xinyong
• Format: Article
• Language: English
• Subjects: 2,4,6-Trisubstituted pyrimidine derivatives; DAPYs; Drug resistance; HIV-1; NNRTIs
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116708

The rapid emergence of drug resistance severely reduces the clinical response of human immunodeficiency virus-1 (HIV-1) to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, a series of 2,4,6-trisubstituted pyrimidine derivatives was designed and synthesized, with the aim to identify novel anti-HIV-1 agents with improved drug resistance profiles. The antiviral activity results demonstrated that all compounds showed excellent potency to wild-type (WT) HIV-1 strain (EC50 = 3.61–15.5 nM). Moreover, 13c was proved to be the most potent inhibitor against the whole tested viral panel, with EC50 ranging from 4.68 to 229 nM. In addition, 13c yielded moderate HIV-1 RT inhibition with IC50 value of 0.231 μM, which demonstrated it was a classical NNRTI. Molecular docking was further conducted to illustrate its binding mode with HIV-1 RT. These encouraging results indicated that 13c can be used as a lead compound for further study. [Display omitted] •24 novel 2,4,6-trisubstituted pyrimidine derivatives were designed through structure-based drug design.•13c exhibited potent anti-HIV-1 activity against the whole tested viral panel with EC50 ranging from 4.68 to 229 nM.•HIV-1 RT inhibition and molecular docking experiments validate the target of 13c, illustrating its binding mode with RT.