Novel Benzosuberone/Indanone‐Linked Thiazoles as Small‐Molecule SARS‐CoV‐2 Main Protease Inhibitors
Thoraya A. Farghaly, Elham N. Bifari, Mariam A. Al‐Sheikh, Afaf Y. Khormi, Hanadi Y. Medrasi, Jihan Qurban, Hanan Gaber Abdulwahab · Drug Development Research · 2025
ABSTRACT Herein, novel benzosuberone/indanone‐linked thiazoles were designed and synthesized as small‐molecule SARS‐CoV‐2 Main protease (Mpro) 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 Mpro 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 Mpro.