Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE

MAGAR, PRATIBHA; PARRAVICINI, OSCAR; STEPÁNKOVÁ, SÁRKA; SVRCKOVÁ, KATARINA; GARRO, ADRIANA D.; JENDRZEJEWSKA, IZABELA; PAUK, KAREL; HOSEK, JAN; JAMPÍLEK, JOSEF; ENRIZ, RICARDO D.; IMRAMOVSKÝ, ALES

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL-MDPI

Año: 2021 vol. 22

1422-0067

A series of 14 target benzyl [2-(arylsulfamoyl)-1-substituted-ethyl]carbamates was preparedby multi-step synthesis and characterized. All the final compounds were tested for their ability toinhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and the selectivityindex (SI) was determined. Except for three compounds, all compounds showed strong preferentialinhibition 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 (IC 50 = 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. Inaddition, the selectivity index of 5c and 5j was approx. 10 and that of 5k was even 34. The processof carbamylation and reactivation of BChE was studied for the most active derivatives 5k, 5j. Thedetailed information about the mode of binding of these compounds to the active site of both BChEand 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.