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

doi:10.1016/j.ejmech.2023.115320

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

Eur J Med Chem. 2023 May 5:253:115320. doi: 10.1016/j.ejmech.2023.115320. Epub 2023 Apr 5.

Authors

Rui Li¹, Zherui Zhang², Shuhong Huang³, Ke Peng⁴, Hualiang Jiang⁵, Jingshan Shen¹, Bo Zhang⁶, Xiangrui Jiang⁷

Affiliations

¹ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
² Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, 262 Jinlong Street, Jiangxia, Wuhan, Hubei, 430207, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
⁴ Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, 262 Jinlong Street, Jiangxia, Wuhan, Hubei, 430207, China.
⁵ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Lingang Laboratory, Shanghai 200031, China.
⁶ Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, 262 Jinlong Street, Jiangxia, Wuhan, Hubei, 430207, China. Electronic address: zhangbo@wh.iov.cn.
⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: jiangxiangrui@simm.ac.cn.

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 (EC₅₀ = 1.00 μM for 24 h), lower cytotoxicity (CC₅₀ = 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.

Keywords: Cytotoxicity; Niclosamide analogs; Pharmacokinetic; SARS-CoV-2; SKP2 inhibition.

MeSH terms

Animals
Antiviral Agents / pharmacology
COVID-19*
Chlorocebus aethiops
Imidazoles
Mice
Niclosamide / pharmacology
SARS-CoV-2*
Vero Cells

Substances

Niclosamide
compound 21
Imidazoles
Antiviral Agents