Ocheretniuk A. Thiazolium salts as cholinesterase inhibitors

Inhibition of acetyl- and butyrylcholinesterase by inhibitors with thiazolium scaffold. А new direction of designing potential cholinesterase inhibitors with thiazolium scaffold was proposed. Based on in vitro studies, selective AChE and BChE inhibitors have been found for the first time among O-acyl-substituted vitamin B1 derivatives. It was found that derivatives of 3-phenacyl-4-methyl-5-substituted thiazolium salts can inhibit the activity of BChE and AChE, demonstrating micromolar IC50 values. It was discovered that O-adamantoyl-substituted 3-phenacyl-4-methyl-5-(2-hydroxy)ethylthiazolium salts are able of selectively inhibit BChE in comparison with AChE. The potential of O-acyl-substituted 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazole chloride derivatives as promising nanomolar inhibitors of AChE and BChE, who characterized by significant selectivity for one of the cholinesterases was established. For the first time, kinetic regularities of inhibition of AChE and BChE by O-acyl-substituted thiazolium salts were established, and their activity was analyzed depending on the structure of the substituents in positions 3 and 5 of the heterocycle. Based on molecular docking calculations, molecular mechanisms have been substantiated and modes for the inhibitor binding to the active and peripheral active sites have been proposed.