Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE

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.

Myricetin Amorphous Solid Dispersions—Antineurodegenerative Potential

“…The selective index for BChE (SI (AChE/BChE) ) was 3.76 and 3.46 for MYR-PVP 1:8 w / w and 1:9 w / w respectively). The selectivity of MYR can be attributed to differences in the active sites of AChE and BChE enzymes [ 94 , 95 ]. BChE has a larger and more flexible active site compared to AChE, allowing for a wider range of interactions with inhibitors such as MYR.…”

In silico analyses of acetylcholinesterase (AChE) and its genetic variants in interaction with the anti‐Alzheimer drug Rivastigmine

“…(2021) performed 20 ns MD simulations of the uncleaved tcAChE-rivastigmine complex in triplicates using Amber16 software. Despite studying a different organism, Magar et al 82 also observed that rivastigmine is deeply buried inside the active-site gorge of AChE, interacting with the catalytic triad and nearby residues throughout the simulations. 82 Distinct interactions with rivastigmine were observed between the docking solution (Figure 3) and the representative structure of wild type hAChE (Figure 5).…”

“…Despite studying a different organism, Magar et al 82 also observed that rivastigmine is deeply buried inside the active-site gorge of AChE, interacting with the catalytic triad and nearby residues throughout the simulations. 82 Distinct interactions with rivastigmine were observed between the docking solution (Figure 3) and the representative structure of wild type hAChE (Figure 5). This difference may occur since docking algorithms assign some approximations such as rigid receptors, which can affect final predictions.…”

Computer-aided structure-based optimization of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine derivatives as DNA gyrase B inhibitors

“…Our group has previously reported several studies using this approach for different types of L–R complexes from different biological systems. 24–29 Recently, we reported a study showing the possibilities and limitations of this approach. 30…”