Synthesis, cytotoxicity, and pharmacokinetic evaluations of niclosamide analogs for anti-SARS-CoV-2
Rui Li, Zherui Zhang, Shuhong Huang, Ke Peng, Hualiang Jiang, Jingshan Shen, Bo Zhang, Xiangrui Jiang
Journal：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
IF：6.7
DOI：10.1016/j.ejmech.2023.115320
PMID：37058956
Published：2023-04-05
research field：药物设计药理学病毒学
Abstract
Niclosamide, an oral anthelmintic drug, could inhibit SARS-CoV-2 virus replication through autophagy induction, but high cytotoxicity and poor oral bioavailability limited its application. Twenty-three niclosamide analogs were designed and synthesized, of which compound 21 was found to exhibit the best anti-SARS-CoV-2 efficacy (EC 50 = 1.00 μM for 24 h), lower cytotoxicity (CC 50 = 4.73 μM for 48 h), better pharmacokinetic, and it was also well tolerated in the sub-acute toxicity study in mice. To further improve the pharmacokinetics of 21 , three prodrugs have been synthesized. The pharmacokinetics of 24 indicates its potential for further research (AUC last was 3-fold of compound 21) . Western blot assay indicated that compound 21 could down-regulate SKP2 expression and increase BECN1 levels in Vero-E6 cells, indicating the antiviral mechanism of 21 was related to modulating the autophagy processes in host cells.
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