Progress Toward the Synthesis of Next Generation Nonpeptidic Inhibitors of Sars-CoV-2 Main Protease

Abstract

The main protease (Mpro) of SARS-CoV-2, also known as 3CL, is a drug target of interest due to its critical function in cleaving the polyprotein which is translated from the viral RNA. Paxlovid, the FDA-approved drug from Pfizer, is a peptide-based inhibitor that covalently inhibits Mpro. My laboratory has developed a very potent series of nonpeptidic Mpro inhibitors that have several desirable properties compared to Paxlovid. The objective of this research was to develop a successful synthetic route to modify the lead nonpeptidic molecules in order to improve the pharmacological properties. The primary usefulness of the target molecule lies within its improved solubility in comparison to the lead inhibitor. Molecular modeling suggests that the target molecule will also increase the potency through an additional hydrogen bond to the Mpro enzyme. Herein is the reported progress toward the synthesis of next generation nonpeptidic inhibitors, CF1 and CF2. Use of 1H NMR and LC-MS spectral data for the synthetic intermediates was used to gauge the success of the chemical reactions within several attempted trials. CF1 has been successfully synthesized; its efficacy is being tested and the crystal structure of the compound bound to Mpro will be evaluated.