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Synthesis, cytotoxicity, and pharmacokinetic evaluations of niclosamide analogs for anti-SARS-CoV-2

文献类型：期刊论文

作者Li, Rui1,3; Zhang, Zherui2,4; Huang, Shuhong3,4; Peng, Ke2; Jiang, Hualiang1,3,5; Shen, Jingshan1,3; Zhang, Bo2; Jiang, Xiangrui3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-05-05
卷号253页码:11
ISSN号0223-5234
关键词SARS-CoV-2 Niclosamide analogs Cytotoxicity Pharmacokinetic SKP2 inhibition
DOI10.1016/j.ejmech.2023.115320
通讯作者Zhang, Bo(zhangbo@wh.iov.cn) ; Jiang, Xiangrui(jiangxiangrui@simm.ac.cn)
英文摘要Niclosamide, an oral anthelmintic drug, could inhibit SARS-CoV-2 virus replication through autophagy induc-tion, 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 (EC50 = 1.00 mu M for 24 h), lower cytotoxicity (CC50 = 4.73 mu M 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 (AUClast 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.
WOS关键词CORONAVIRUS
资助项目Science and Technology Commission of Shanghai Municipal[20431900100] ; Shanghai Institute of Materia Medica[SIMM020107] ; Shanghai Institute of Materia Medica[SIMM020120]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:000981678600001
源URL[http://119.78.100.183/handle/2S10ELR8/306499]  
专题新药研究国家重点实验室
通讯作者Zhang, Bo; Jiang, Xiangrui
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Chinese Acad Sci, Wuhan Inst Virol, Ctr Biosafety Mega Sci, Key Lab Special Pathogens & Biosafety, 262 Jinlong St, Wuhan 430207, Hubei, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
5.Lingang Lab, Shanghai 200031, Peoples R China
推荐引用方式
GB/T 7714		 Li, Rui,Zhang, Zherui,Huang, Shuhong,et al. Synthesis, cytotoxicity, and pharmacokinetic evaluations of niclosamide analogs for anti-SARS-CoV-2[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,253:11.
APA Li, Rui.,Zhang, Zherui.,Huang, Shuhong.,Peng, Ke.,Jiang, Hualiang.,...&Jiang, Xiangrui.(2023).Synthesis, cytotoxicity, and pharmacokinetic evaluations of niclosamide analogs for anti-SARS-CoV-2.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,253,11.
MLA Li, Rui,et al."Synthesis, cytotoxicity, and pharmacokinetic evaluations of niclosamide analogs for anti-SARS-CoV-2".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 253(2023):11.

入库方式： OAI收割

来源：上海药物研究所

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