Novel Benzosuberone/Indanone-Linked Thiazoles as Small-Molecule SARS-CoV-2 Main Protease Inhibitors.

Abstract

Herein, novel benzosuberone/indanone-linked thiazoles were designed and synthesized as small-molecule SARS-CoV-2 Main protease (M^pro) inhibitors with potential anti-COVID activity. All thiazole derivatives were synthesized from the reaction of thiosemicarbazone derivatives with α-halocarbonyl derivatives. The structures of novel benzosuberone/indanone-linked thiazoles were confirmed based on their spectral data. Thiazolyl-benzosuberone 9d and thiazolyl-indanone 14 were the most potent against M^pro displaying one-digit IC₅₀ values of 5.94 and 8.47 µM, respectively, compared to ritonavir (IC₅₀ = 2.4 µM). Moreover, antiviral assay revealed the ability of compounds 9d and 14 to inhibit the replication of SARS-CoV-2 in Vero cells at EC₅₀ values of 9.33 and 28.75 µM, respectively, relative to ritonavir (EC₅₀ = 1.72 µM). Cytotoxicity assay in Vero cells was also conducted. 9d and 14 showed CC₅₀ values of 289.63 and 229.42 µM and SI of 31.0 and 7.9, respectively. In addition, a docking study revealed proper orientation and well-fitting of title compounds into the binding pocket of SARS-CoV-2 M^pro.