Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2

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 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 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.

SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment

“…The search for PLpro inhibitors has already begun. So far, most studies focus on trying to utilize previously developed noncovalent SARS-CoV inhibitors or their derivatives [7,24,29] or to design specific, covalent inhibitors [30,31]. However, covalent protease inhibitors come with risks of toxicity due to high reactivity and, in some cases, low selectivity and nonspecific binding off the target [32][33][34].…”

GNPS-guided discovery of xylacremolide C and D, evaluation of their putative biosynthetic origin and bioactivity studies of xylacremolide A and B

“…In line with our long-term mission to identify pharmacologically relevant protease inhibitors, we tested the inhibitory activity of the two most abundant derivatives, xylacremolides A and B, on various pharmacologically important proteases using an established uorescence-based assay (Table 2). [26][27][28][29] Both rhodesain (Rd), and cruzain, cysteine proteases belonging to the papain-family, play central roles in the life cycle of the parasitic protists Trypanosoma brucei (Human African Trypanosomiasis (HAT)) 30 and Trypanosoma cruzi (Chagas-disease), 31 respectively. Three proteases were selected for their important functions in cancer cells (Cath L, Cath B, urokinase (uPA)).…”

“…Protease inhibition assays. [26][27][28][29] Compounds were dissolved in DMSO (20 mM). Fluorometric assays were performed at a concentration of 200 mM.…”

Main Chemotypes of SARS-CoV-2 Reproduction Inhibitors

“…1-(Naphthalen-1-yl)ethyl derivatives 190-196 [138][139][140][141][142] (Fig. 21) have been studied in suffi cient detail.…”