2. Academic Validation
  3. Discovery of novel fused-heterocycle-bearing diarypyrimidine derivatives as HIV-1 potent NNRTIs targeting tolerant region I for enhanced antiviral activity and resistance profile

Discovery of novel fused-heterocycle-bearing diarypyrimidine derivatives as HIV-1 potent NNRTIs targeting tolerant region I for enhanced antiviral activity and resistance profile

  • Eur J Med Chem. 2025 Jan 5:281:117033. doi: 10.1016/j.ejmech.2024.117033.
Jiaojiao Dai 1,  Xiangyi Jiang 1,  Heng Gao 1,  Boshi Huang 1,  Erik De Clercq 2,  Christophe Pannecouque 2,  Shaoqing Du 3,  Xinyong Liu 4,  Peng Zhan 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, 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 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, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: 202290000013@sdu.edu.cn.
  • 4 Department of Medicinal Chemistry, 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; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
  • 5 Department of Medicinal Chemistry, 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; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
PMID: 39536498 DOI: 10.1016/j.ejmech.2024.117033
Abstract

As an important part of anti-AIDS therapy, HIV-1 non-nucleoside Reverse Transcriptase inhibitors are plagued by resistance and toxicity issues. Taking our reported XJ-18b1 as lead compound, we designed a series of novel diarypyrimidine derivatives by employing a scaffold hopping strategy to discover potent NNRTIs with improved anti-resistance properties and drug-like profiles. The most active compound 3k exhibited prominent inhibitory activity against wild-type HIV-1 (EC50 = 0.0019 μM) and common mutant strains including K103 N (EC50 = 0.0019 μM), L100I (EC50 = 0.0087 μM), E138K (EC50 = 0.011 μM), along with low cytotoxicity and high selectivity index (CC50 = 21.95 μM, SI = 11478). Additionally, compound 3k demonstrated Antiviral activity against HIV-2 with EC50 value of 6.14 μM. The enzyme-linked immunosorbent assay validated that 3k could significantly inhibit the activity of HIV-1 Reverse Transcriptase (IC50 = 0.025 μM). Furthermore, molecular dynamics simulation studies were performed to illustrate the potential binding mode and binding free energy of the RT-3k complex, and in silico prediction revealed that 3k possessed favorable drug-like profiles. Collectively, 3k proved to be a promising lead compound for further optimization to obtain anti-HIV drug candidates.

Keywords

AIDS; Diarylpyrimidine; Drug resistance; NNRTIs; Rational drug design.

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