4.7 Article

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

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出版社

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114209

关键词

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

资金

  1. CAMS Innovation Fund for Medical Sciences [2021-12M-1-048]
  2. National Natural Science Foundation of China [81872912]

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In this study, 32 derivatives of clofazimine, including 22 new compounds, were synthesized and evaluated for their antiviral effects. Compound 15f showed superior or comparable antiviral activities against rabies virus and pseudo-typed SARS-CoV-2, making it a potential broad-spectrum antiviral candidate.
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 mM and 14.6 mM 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. (c) 2022 Elsevier Masson SAS. All rights reserved.

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