Design, synthesis and biological evaluations of niclosamide analogues against SARS-CoV-2

Niclosamide, a widely-used anthelmintic drug, inhibits SARS-CoV-2 virus entry through TMEM16F inhibition and replication through autophagy induction, but the relatively high cytotoxicity and poor oral bioavailability limited its application. We synthesized 22 niclosamide analogues of which compound 5 was found to exhibit the best anti-SARS-CoV-2 efficacy (IC50 = 0.057 m M) and compounds 6,10, and 11 (IC50 = 0.39, 0.38, and 0.49 m M, respectively) showed comparable efficacy to niclosamide. On the other hand, compounds 5, 6,11 contained higher stability in human plasma and liver S9 enzymes assay than niclosamide, which could improve bioavailability and half-life when administered orally. Fluorescence microscopy revealed that compound 5 exhibited better activity in the reduction of phosphatidylserine externalization compared to niclosamide, which was related to TMEM16F inhibition. The AI-predicted protein structure of human TMEM16F protein was applied for molecular docking, revealing that 40NO2 of 5 formed hydrogen bonding with Arg809, which was blocked by 20-Cl in the case of niclosamide. (c) 2022 Elsevier Masson SAS. All rights reserved.

Automated summary

22 niclosamide analogues were synthesized and compound 5 exhibited the best anti-SARS-CoV-2 efficacy. Compounds 5, 6, and 11 showed higher stability and improved oral bioavailability compared to niclosamide.