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

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

  • Eur J Med Chem. 2024 Nov 5:277:116708. doi: 10.1016/j.ejmech.2024.116708.
Zhenzhen Zhou 1,  Yanying Sun 1,  Yanyang Qin 1,  Na Wang 1,  Fabao Zhao 1,  Zhao Wang 1,  Erik De Clercq 2,  Christophe Pannecouque 2,  Peng Zhan 3,  Dongwei Kang 4,  Xinyong Liu 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, China.
  • 2 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 250012, Jinan, China. Electronic address: zhanpeng1982@sdu.edu.cn.
  • 4 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 250012, Jinan, China. Electronic address: kangdongwei@126.com.
  • 5 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 250012, Jinan, China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 39094273 DOI: 10.1016/j.ejmech.2024.116708
Abstract

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.

Keywords

2,4,6-Trisubstituted pyrimidine derivatives; DAPYs; Drug resistance; HIV-1; NNRTIs.

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