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.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative brain disorder with characteristic clinical and pathological symptoms [1,2,3]
We have formerly reported and described the molecular interactions established in the active site of AChE and BChE when complexed with the well-known cholinesterase inhibitors RIV [66,67] and galantamine [68,69,70,71] and other ligands with great structural variability, including alkaloids [69,70], carbamates [67], 4-[(alkoxycarbonyl)amino]benzoates [66], and N-benzyl-2-phenylethanamine derivatives [72]
The selectivity index of 5c and 5j was 10 and that of 5k was 34. These results show that the compounds reported here bind to the same active site of the molecular targets as rivastigmine
Summary
Alzheimer’s disease (AD) is a neurodegenerative brain disorder with characteristic clinical and pathological symptoms [1,2,3]. BChE is able to hydrolyze ACh as well as other esters and plays probably only a supportive role [12,13,14] These two enzymes display diverse kinetic characteristics depending on ACh concentrations. Experiments performed on mouse models demonstrated the role of BChE to maintain the cholinesterase function even in the absence of AChE [17]. The treatment of AD has been based on the inhibition of ChEs in order to maintain the proper level of ACh. So far, the U.S Food and Drug Administration (FDA) has approved four cholinesterase inhibitors for therapy of AD, but tacrine was discontinued due to the aforementioned adverse effects and liver toxicity [29]. The selective inhibition of BChE might well constitute a therapeutic target for clinical use in progressed AD [12,13,29], where AChE inhibitors fail. Iunsiandgdaitnioanly,siins opredrerretsoiedvuael.uIanteadindimtioonre, idneotradilesrtthoeemvaollueactuelainr minoterreadcetitoanilss othfedmiffoelreecnutlamroinletecuralcatriocnoms opfldexifefesrwenet umsoedlecquulaanrtcuommtphleeoxreys owfeatuosmeds iqnumanotluemcultehse(oQryTAofIMat)ocmalscuinlamtioonlesc[u5l4e]s. (QTAIM) calculations [54]
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