2. Academic Validation
  3. Discovery of novel diarypyrimidine derivatives as potent HIV-1 NNRTIs by exploiting the tolerant region I within NNRTI binding pocket

Discovery of novel diarypyrimidine derivatives as potent HIV-1 NNRTIs by exploiting the tolerant region I within NNRTI binding pocket

  • Eur J Med Chem. 2025 Oct 5:295:117787. doi: 10.1016/j.ejmech.2025.117787.
Xiangkai Ji 1,  Xiangyi Jiang 1,  Zhen Gao 1,  Heng Gao 1,  Erik De Clercq 2,  Christophe Pannecouque 3,  Dongwei Kang 4,  Peng Zhan 5,  Xinyong Liu 6
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 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U.Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium. Electronic address: christophe.pannecouque@kuleuven.be.
  • 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: zhanpeng1982@sdu.edu.cn.
  • 6 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: 40435828 DOI: 10.1016/j.ejmech.2025.117787
Abstract

Non-nucleoside Reverse Transcriptase inhibitors (NNRTIs) serve as an essential component of antiretroviral treatment regimens, but they encounter challenges such as resistance mutations, poor solubility, and adverse effects. This study presents the design, synthesis, and biological evaluation of novel diarylpyrimidine (DAPY)-typed derivatives targeting the tolerant region I within the NNRTI binding pocket (NNIBP). We introduced aliphatic ring structures with high Fsp3 value, aiming to enhance target affinity while simultaneously improving water solubility. Among them, compound 9k demonstrated excellent potency against wild-type HIV-1 (EC50 = 0.0014 μM) and key single-mutant strains K103 N (EC50 = 0.0041 μM) and E138K (EC50 = 0.0077 μM), which outperformed the positive drugs ETR, NVP and EFV. Molecular modeling studies were conducted to elucidate the detailed interactions between RT and 9k, providing insights into the enhanced drug resistance profiles. Additionally, 9k demonstrated a notable improvement in water solubility (1.38 μg/mL, pH = 7) compared to ETR (≪ 1 μg/mL, pH = 7). These findings provide a foundation for further optimization of NNRTIs with improved anti-resistance profiles and pharmacokinetics.

Keywords

Anti-resistance properties; Diarylpyrimidine; Fsp(3); HIV-1 NNRTIs; Water solubility.

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