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Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors are used for the treatment of Alzheimer’s disease. To design new cholinesterase inhibitors, of different structure-based design strategies was followed, including the modification of compounds from a previously developed library and a fragment-based design approach. This led to the selection of heterodimeric structures as potential inhibitors. Synthesis and biological evaluation of selected candidates confirmed that the designed compounds were acetylcholinesterase inhibitors with \(IC_{50}\) values in the mid-nanomolar to low micromolar range, and some of them were also butyrylcholinesterase inhibitors.
Inhibition of coronavirus (CoV)‐encoded papain‐like cysteine proteases (PL\(^{pro}\)) 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\(^{pro}\). Moreover, we report the discovery of isoindolines as a new class of potent PL\(^{pro}\) 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\(^{pro}\) are valuable starting points for the development of new pan‐coronaviral inhibitors.