Synthetic Coumarin Derivatives as SARS-CoV-2 Major Protease Inhibitors: Design, Synthesis, Bioevaluation and Molecular Docking

Abstract

Major protease enzyme of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 Mpro) is one of the key enzymes of viral replication which amuses many scientists as a promising drug target. Nonetheless, few studies reported new synthetic small molecule inhibitors of the Mpro but many were repurposing drugs such as chloroquine or predicting the activity based on in silico results. This study had the privilege of synthesizing new coumarin-based derivatives with possible Mpro inhibition based on the previously reported ligand-based pharmacophore model. Compound 3 showed comparable Mpro inhibitory activity to chloroquine with IC50 15.0 and 13.1 μg/mL, respectively. Moreover, compounds 4 b, 4 d, 5 b, 5 c, 5 e and 5 g managed to inhibit the Mpro enzymatic activity by more than 50.0 % at 100 μM among which 5 g showed 63.9 % inhibition and IC50 25.8 μg/mL. The binding conformations of the promising compounds were illustrated using molecular docking as well as their drug-likeness and ADMET properties. A pharmacophore model was generated using the compounds with more than 50.0 % Mpro inhibition to annotate the essential moieties for enzyme binding. All compounds were fully characterized using the conventional spectroscopic and microanalyses methods.