2. Academic Validation
  3. Further exploring the tolerant region II: Identification of 2,4,5-trisubstituted pyrimidines as HIV-1 reverse transcriptase allosteric inhibitors with desirable antiviral activities and reduced cytotoxicity

Further exploring the tolerant region II: Identification of 2,4,5-trisubstituted pyrimidines as HIV-1 reverse transcriptase allosteric inhibitors with desirable antiviral activities and reduced cytotoxicity

  • Eur J Med Chem. 2025 Nov 5:297:117992. doi: 10.1016/j.ejmech.2025.117992.
Zhenzhen Zhou 1,  Lin Zheng 1,  Wenbo Jiang 1,  Wenbo Zhang 1,  Fabao Zhao 1,  Zhening Liang 1,  Erik De Clercq 2,  Christophe Pannecouque 2,  Peng Zhan 3,  Dongwei Kang 4,  Xinyong Liu 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR 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, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 250012, Jinan, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
  • 4 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 250012, Jinan, PR China. Electronic address: kangdongwei@126.com.
  • 5 Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 250012, Jinan, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 40706448 DOI: 10.1016/j.ejmech.2025.117992
Abstract

Here, we report a series of 2,4,5-trisubstituted pyrimidines as potent HIV-1 non-nucleoside Reverse Transcriptase inhibitors (NNRTIs) by further exploring the potential tolerant region II within NNIBP. Most compounds were identified with potent inhibitory activity against HIV-1 wild-type (WT) strain with lower cytotoxicity. Among them, 14l exhibited the most outstanding Antiviral activity (EC50 = 6.50-52.9 nM) against WT and a panel of mutant HIV-1 strains with much-reduced cytotoxicity (CC50 = 228 μM) and higher selectivity index (SI = 31434) than that of the lead 36a (CC50 = 45.6 μM; SI = 20550). Furthermore, the detailed molecular modeling studies revealed that the 3-thienyl substituent of 14l engages in multiple stable contacts with conserved residues within tolerant region II, providing a structural basis for the observed potent Antiviral efficacy and enhanced anti-resistance profile. These findings collectively position 14l as a promising candidate for subsequent development as a novel lead compound.

Keywords

2,4,5-Trisubstituted pyrimidine; DAPYs; HIV-1; NNRTIs; Tolerant region II.

Figures
Products