Novel cinnamic acid-based N-benzyl pyridinium analogs: potent dual cholinesterase inhibitors with neuroprotective properties for Alzheimer's disease
Maryam Esmkhani, Mohammad Mahdavi, Shahrzad Javanshir, Aida Iraji
TL;DR
This study develops new compounds that effectively inhibit enzymes linked to Alzheimer's and protect brain cells from damage.
Contribution
The paper introduces novel cinnamic acid-based compounds with dual cholinesterase inhibition and neuroprotective properties.
Findings
Compound 7b showed strong inhibition of AChE and BChE with IC50 values of 0.89 µM and 0.11 µM, respectively.
Compound 7b exhibited significant neuroprotection in SH-SY5Y cells without cytotoxicity.
Molecular docking and simulations confirmed stable binding interactions in enzyme active sites.
Abstract
This study reports the design and synthesis of a novel series of cinnamic acid-based analogs bearing an N-benzyl pyridinium moiety against Alzheimer's disease (AD), aiming at dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), alongside neuroprotective effects. A total of 15 derivatives were synthesized, among which compound 7b exhibited the most potent dual inhibition (AChE IC50 = 0.89 µM; BChE IC50 = 0.11 µM), and significant neuroprotection against H2O2-induced oxidative stress in SH-SY5Y cells, with no cytotoxicity under the tested concentration. Structure–activity relationship (SAR) analysis revealed that small electron-withdrawing substituents (e.g. ortho-fluoro, methyl) enhanced inhibitory activity, whereas meta and para substitutions generally reduced potency. Enzyme kinetics also determined compound 7b to be a competitive inhibitor of AChE (Ki =…
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Taxonomy
TopicsCholinesterase and Neurodegenerative Diseases · Enzyme function and inhibition · Alzheimer's disease research and treatments