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

Severe 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 beta-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 mu M. In silico ADME predictions showed that the majority of these compounds have drug-like properties. Furthermore, free energy calculation (Delta G 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 beta-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.