Design and Synthesis of Michael Acceptor‐Based Peptidyl β‐Nitrostyrenes as 3CLpro Inhibitors of SARS‐CoV‐2

Abstract

AbstractSevere Acute Respiratory Syndrome coronavirus 2 main protease was found to be one of the most attractive anti‐viral targets for the development of new chemical entities to combat coronavirus and Michael acceptors were found to be appropriate 3‐chymotrypsin‐like protease inhibitors of Severe Acute Respiratory Syndrome coronavirus 2. In this regard, a series of Michael acceptor‐based peptidyl β‐nitrostyrenes were synthesized and evaluated for their Severe Acute Respiratory Syndrome coronavirus 2 3‐chymotrypsin‐like protease inhibitory potentials using a 3‐chymotrypsin‐like protease of Severe Acute Respiratory Syndrome coronavirus 2 assay kit. Among the compounds evaluated, (E)‐N‐(2‐morpholino‐2‐oxo‐1‐phenylethyl)‐2‐(4‐(2‐nitrobut‐1‐en‐1‐yl)phenoxy)acetamide demonstrated better inhibition with an effective concentration (EC50) of 58 μM. In silico ADME predictions showed that the majority of these compounds have drug‐like properties. Furthermore, free energy calculation (ΔG Bind) and docking results demonstrate the suitable fitting of most active compound at the active site of the enzyme. Based on the in vitro and in silico studies, peptidyl β‐nitrostyrene based Michael acceptors could serve as an excellent ligand for the inhibition of 3‐chymotrypsin‐like protease of Severe Acute Respiratory Syndrome coronavirus 2 and may be used as a potential template for further development of bioactive ligands to treat CORONA VIRUS Disease of 2019.