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

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.

SUBMITTER: Li R 

PROVIDER: S-EPMC10073089 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature