SAR of novel benzamides and isoindolines, designed as SARS-CoV protease inhibitors - effective against SARS-CoV-2.

SAR of novel benzamides and isoindolines, designed as SARS-CoV protease inhibitors - effective against SARS-CoV-2. ChemMedChem. 2020 Sep 15;: Authors: Welker A, Kersten C, Müller C, Madhugiri R, Zimmer C, Müller P, Zimmermann RA, Hammerschmidt S, Maus H, Ziebuhr J, Sotriffer C, Schirmeister T Abstract Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the non-covalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (2b), which is known to bind into the S3 and S4 pockets of the SARS-CoV PLpro. Moreover, we report the discovery of isoindolines as a new class of potent PLpro 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 PLpro are valuable starting points for the development of new pan-coronaviral inhibitors. PMID: 32930481 [PubMed - as supplied by publisher]
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research