2. Academic Validation
  3. 5-Cyano substituted diarylpyridines as potent HIV-1 NNRTIs: Rational design, synthesis, and activity evaluation

5-Cyano substituted diarylpyridines as potent HIV-1 NNRTIs: Rational design, synthesis, and activity evaluation

  • Eur J Med Chem. 2023 Nov 5;259:115686. doi: 10.1016/j.ejmech.2023.115686.
Hao Song 1,  Yu Xia 1,  Tao Zhang 1,  Caiyun Dun 1,  Bairu Meng 1,  Erik De Clercq 2,  Christophe Pannecouque 2,  Dongwei Kang 3,  Peng Zhan 4,  Xinyong Liu 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
PMID: 37536208 DOI: 10.1016/j.ejmech.2023.115686
Abstract

To develop more potent HIV-1 inhibitors against a variety of NNRTIs-resistant strains, a series of 5-cyano substituted diarylpyridines was designed based on the cocrystal structural analysis. Among them, I-5b showed the greatest potency (EC50 = 5.62-171 nM) against the wild-type (WT) and mutant HIV-1 strains. Especially for K103 N, I-5b exhibited outstanding activity with EC50 values of 9.37 nM, being much superior to that of NVP (EC50 = 5128 nM) and EFV (EC50 = 114 nM) and comparable to that of ETR (EC50 = 3.45 nM). In addition, the target of all compounds was turned out to be HIV-1 RT with moderate RT Enzyme inhibitory activity (IC50 = 0.094-12.0 μM). Moreover, the binding mode of representative compounds with RT was elaborated via molecular docking.

Keywords

Diarylpyridines; HIV-1; NNRTIs; SARs.

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