Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE

Authors:
Open Access
Publisher website
Google Scholar
Abstract
A series of 14 target benzyl [2-(arylsulfamoyl)-1-substituted-ethyl]carbamates was prepared by multi-step synthesis and characterized. All the final compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and the selectivity index (SI) was determined. Except for three compounds, all compounds showed strong preferential inhibition of BChE, and nine compounds were even more active than the clinically used rivastigmine. Benzyl {(2S)-1-[(2-methoxybenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5k), benzyl {(2S)-1-[(4-chlorobenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5j), and benzyl [(2S)-1-(benzylsulfamoyl)-4-methylpentan-2-yl]carbamate (5c) showed the highest BChE inhibition (IC50 = 4.33, 6.57, and 8.52 µM, respectively), indicating that derivatives 5c and 5j had approximately 5-fold higher inhibitory activity against BChE than rivastigmine, and 5k was even 9-fold more effective than rivastigmine. In addition, the selectivity index of 5c and 5j was approx. 10 and that of 5k was even 34. The process of carbamylation and reactivation of BChE was studied for the most active derivatives 5k, 5j. The detailed information about the mode of binding of these compounds to the active site of both BChE and AChE was obtained in a molecular modeling study. In this study, combined techniques (docking, molecular dynamic simulations, and QTAIM (quantum theory of atoms in molecules) calculations) were employed.
Funding Information
  • Grantová Agentura České Republiky (GA 18-03847S)
  • Agentúra na Podporu Výskumu a Vývoja (APVV-17-0373 and APVV-18-0302)
  • Agencia Nacional de Promoción Científica y Tecnológica (PICT 2015-1769)
  • Ministerstvo Školství, Mládeže a Tělovýchovy (“FIT” CZ.02.1.01/0.0/0.0/15_003/0000495)
  • Ministerstvo Zemědělství (. RO0518)

This publication has 92 references indexed in Scilit: