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  3. Discovery of novel diarylpyrimidine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors: Design, synthesis and biological activity evaluation

Discovery of novel diarylpyrimidine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors: Design, synthesis and biological activity evaluation

  • Bioorg Chem. 2026 Mar:170:109456. doi: 10.1016/j.bioorg.2025.109456.
Hao Lin 1,  Zhongxia Zhou 2,  Lin Zheng 1,  Ying Liu 1,  Da Feng 1,  Xiangyi Jiang 1,  Yanying Sun 1,  Xiangkai Ji 1,  Erik De Clercq 3,  Christophe Pannecouque 3,  Chin-Ho Chen 4,  Dongwei Kang 5,  Peng Zhan 6,  Xinyong Liu 7
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, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
  • 2 Shandong University Cancer Center, Shandong University, 250012 Jinan, Shandong, PR China. Electronic address: [email protected].
  • 3 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium.
  • 4 Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
  • 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, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: [email protected].
  • 6 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, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: [email protected].
  • 7 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, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: [email protected].
PMID: 41512352 DOI: 10.1016/j.bioorg.2025.109456
Abstract

Our previous efforts have led to the development of potent NNRTI K-5a2, but it suffered from poor metabolic stability and aqueous solubility. Another work resulted in compounds XJ2-56 and XJ2-90 with reduced activity against the Y188L mutant strain. In this work, 24 novel DAPY derivatives were designed based on a fragment hybridization strategy. The anti-HIV-1 activity in MT-4 cells demonstrated that 29 was the most potent inhibitor for HIV-1 IIIB, with an EC50 of 1.38 nM. Moreover, it also exhibited excellent potency against a panel of mutant HIV-1 strains with EC50 ranging from 1.61 to 119 nM. The enzyme inhibition assay showed that these compounds acted as HIV-1 NNRTIs. In addition, the aqueous solubility of 29 (S = 3.35 μg/mL) was greatly improved. Molecular docking was also conducted to clarify the binding mode of the newly designed compounds with RT.

Keywords

DAPY; HIV-1; Molecular hybridization; NNIBP; NNRTIs.

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