2. Academic Validation
  3. Clofazimine derivatives as potent broad-spectrum antiviral agents with dual-target mechanism

Clofazimine derivatives as potent broad-spectrum antiviral agents with dual-target mechanism

  • Eur J Med Chem. 2022 Apr 15;234:114209. doi: 10.1016/j.ejmech.2022.114209.
Xintong Zhang 1,  Yulong Shi 1,  Zhihao Guo 1,  Xiaoqiang Zhao 1,  Jiajing Wu 2,  Shouchun Cao 2,  Yonghua Liu 1,  Yuhua Li 2,  Weijin Huang 2,  Youchun Wang 2,  Qiang Liu 2,  Yinghong Li 3,  Danqing Song 4
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China.
  • 2 National Institutes for Food and Drug Control, Beijing, 100050, China.
  • 3 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China. Electronic address: [email protected].
  • 4 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China. Electronic address: [email protected].
PMID: 35279610 DOI: 10.1016/j.ejmech.2022.114209
Abstract

Thirty-two clofazimine derivatives, of which twenty-two were new, were synthesized and evaluated for their Antiviral effects against both rabies virus and pseudo-typed SARS-CoV-2, taking clofazimine (1) as the lead. Among them, compound 15f bearing 4-methoxy-2-pyridyl at the N5-position showed superior or comparable Antiviral activities to lead 1, with the EC50 values of 1.45 μM and 14.6 μM and the SI values of 223 and 6.1, respectively. Compound 15f inhibited rabies and SARS-CoV-2 by targeting G or S protein to block membrane fusion, as well as binding to L protein or nsp13 to inhibit intracellular biosynthesis respectively, and thus synergistically exerted a broad-spectrum Antiviral effect. The results provided useful scientific data for the development of clofazimine derivatives into a new class of broad-spectrum Antiviral candidates.

Keywords

Broad-spectrum; Clofazimine analogues; Rabies virus; SARS-CoV-2; Structure–activity relationship.

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