Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease

Autor: Hormoz Pourtaher, Alireza Hasaninejad, Aida Iraji
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Scientific Reports, Vol 12, Iss 1, Pp 1-22 (2022)
Druh dokumentu: article
ISSN: 2045-2322
DOI: 10.1038/s41598-022-18224-6
Popis: Abstract The objective of this study was to design new polysubstituted pyrrole derivatives as selective acetylcholinesterase (AChE) inhibitors to target Alzheimer's disease. In this context, a highly efficient, one-pot, sequential, multi-component synthesis of a diverse range of polysubstituted pyrroles was developed through a sequential domino strategy by the condensation of amines with 1,1-bis(methylthio)-2-nitroethene (BMTNE), Knovenagle reaction of arylglyoxals with malono derivatives and subsequent Michael addition and intramolecular cyclization reaction in EtOH at reflux. Thirty-nine synthesized compounds were evaluated as AChE and butyrylcholinesterase (BChE) inhibitors. Among the synthesized compounds, compound 4ad (IC50 = 2.95 ± 1.31 µM) was the most potent and selective AChE inhibitor with no significant inhibition against butyrylcholinesterase BChE. A kinetic study of 4ad revealed that this compound inhibited AChE in an uncompetitive mode. Based on a molecular modeling study, compound 4ad due to its small size properly fitted into the active site of AChE compared to BChE and stabilized by H-bond and hydrophobic interactions with the critical residues of the AChE binding pocket. Consequently, it was proposed that the 4ad derivative can be an ideal lead candidate against AD with a simple and practical operation of synthetic procedures.
Databáze: Directory of Open Access Journals
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