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

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Discovery

Background:

• COVID-19 remains a global health concern, necessitating the development of novel antiviral agents.
• The SARS-CoV-2 Main protease (M^pro) is a critical enzyme for viral replication and a key target for antiviral drug development.

Purpose of the Study:

• To design and synthesize novel benzosuberone/indanone-linked thiazole derivatives as potential inhibitors of SARS-CoV-2 M^pro.
• To evaluate the in vitro antiviral activity and cytotoxicity of the synthesized compounds against SARS-CoV-2.

Main Methods:

• Synthesis of thiazole derivatives via reaction of thiosemicarbazone derivatives with α-halocarbonyl compounds.
• Structural confirmation using spectral data.
• In vitro inhibition assays against SARS-CoV-2 M^pro (IC₅₀), viral replication assays (EC₅₀), and cytotoxicity assays (CC₅₀).
• Molecular docking studies to assess binding interactions with SARS-CoV-2 M^pro.

Main Results:

• Novel benzosuberone/indanone-linked thiazoles were successfully synthesized and characterized.
• Compounds 9d and 14 exhibited potent inhibition of SARS-CoV-2 M^pro with IC₅₀ values of 5.94 µM and 8.47 µM, respectively.
• Antiviral assays showed that compounds 9d and 14 inhibited SARS-CoV-2 replication with EC₅₀ values of 9.33 µM and 28.75 µM, respectively.
• Compounds 9d and 14 displayed favorable safety profiles with CC₅₀ values of 289.63 µM and 229.42 µM, respectively, and selectivity indices (SI) of 31.0 and 7.9.
• Docking studies indicated favorable binding of the compounds within the M^pro active site.

Conclusions:

• The designed benzosuberone/indanone-linked thiazoles are promising candidates for further development as anti-COVID-19 agents targeting SARS-CoV-2 M^pro.
• Compounds 9d and 14 represent lead compounds with significant antiviral potential and acceptable safety profiles.