Synthetic Coumarin Derivatives as SARS‐CoV‐2 Major Protease Inhibitors: Design, Synthesis, Bioevaluation and Molecular Docking
Nada M. Mohamed, Rania Farag A. El‐Telbany · ChemistrySelect · 2021
Abstract Major protease enzyme of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2 M pro ) 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 M pro 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 M pro inhibition based on the previously reported ligand‐based pharmacophore model. Compound 3 showed comparable M pro inhibitory activity to chloroquine with IC 50 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 M pro enzymatic activity by more than 50.0 % at 100 μM among which 5 g showed 63.9 % inhibition and IC 50 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 % M pro inhibition to annotate the essential moieties for enzyme binding. All compounds were fully characterized using the conventional spectroscopic and microanalyses methods.