Noncovalent Inhibitors of SARS-CoV-2 Main Protease: A Rescaffolding Attempt

Abstract

Out of the results of the sole large-scale screening for inhibitors of SARS-CoV-1 main protease reported in 2013, attempts to improve the identified 3-pyridyl-bearing hits have been conducted in research laboratories, either on this enzyme or more recently on the closely related SARS-CoV-2 main protease. From the resulting structural information reported, we sought to design analogues featuring some of the components providing an affinity for the active site of these proteases along with a different scaffold, which would allow for further structure-activity relationship studies and/or pharmacological improvements. We describe here the introduction of a bridging component with the aim of stabilizing the ligand conformation adopted when bound to these proteases. Accordingly, this led us to prepare 3,3-disubstituted piperazin-2-ones from an array of ketones, via either a Bargellini reaction or a multistage condensation/cyclization/hydrolysis involving ethylene diamine and potassium cyanide. However, even the most elaborate and lipophilic biphenyl-bearing analogues displayed only a weak effect in a bioluminescence-based SARS-CoV-2 main protease inhibition assay.

Key words

medicinal chemistry - phase-transfer catalysis - SARS-CoV-2 main protease - Bargellini reaction - piperazinone

Publication History

Received: 23 September 2024

Accepted after revision: 19 January 2025

Accepted Manuscript online:
19 January 2025

Article published online:
03 March 2025

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