|
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
efcient, 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
refux. 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 signifcant 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 ftted 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.
|