N-(Benzofuran-3-ylmethyl)isatin derivatives as potential SARS-CoV-2 main protease inhibitors: Synthesis, biological evaluation, kinetic analysis, and molecular modeling insights

Abstract

The SARS-CoV-2 pandemic, which emerged in late 2019, severely impacted global health and the economy. Accordingly, antiviral drug design and discovery stand out as a top priority for academia and the pharmaceutical industry. On account of their well-reported anti-SARS-CoV-2 activity, isatin scaffold was utilized in this study to develop a new set of N-(benzofuran-3-ylmethyl)isatin derivatives (WDa-k) as potential SARS-CoV-2 Main Protease (Mpro) inhibitors. The FRET assay was employed to initially screen all the target molecules at a single concentration of 100 μM against the SARS-CoV-2 Mpro. The IC50 values for the most effective inhibitors (WD-d, WD-f, and WD-i) were evaluated afterward. Moreover, the cytotoxicity of these compounds against the normal IMR90 cell line was assessed to explore their safety profile. Michaelis-Menten kinetics were carried out with the three most potent inhibitors against Mpro at different concentrations to elucidate their interaction dynamics and the mode of inhibition they exert. Finally, molecular modeling investigations were performed to predict the plausible interactions of the synthesized derivatives with the Mpro binding site.