Structure-Activity Relationships of Benzamides and Isoindolines Designed As SARS-CoV Protease Inhibitors Effective Against SARS-CoV-2

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2020 Sep 15

PMID 32930481

Citations 24

Authors

Armin Welker

Christian Kersten

Christin Muller

Ramakanth Madhugiri

Collin Zimmer

Patrick Muller

Robert Zimmermann

Stefan Hammerschmidt

Hannah Maus

John Ziebuhr

Christoph Sotriffer

Tanja Schirmeister

Affiliations

Soon will be listed here.

Abstract

Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PL ) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS-CoV PL . Moreover, we report the discovery of isoindolines as a new class of potent PL inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PL are valuable starting points for the development of new pan-coronaviral inhibitors.

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