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.
Rui Li  1 ,  Zherui Zhang  2 ,  Shuhong Huang  3 ,  Ke Peng  4 ,  Hualiang Jiang  5 ,  Jingshan Shen  1 ,  Bo Zhang  6 ,  Xiangrui Jiang  7
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: [email protected].
  • 7. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: [email protected].
PMID: 37058956 DOI: 10.1016/j.ejmech.2023.115320
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 (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.

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