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- W1991774739 abstract "Current pharmacotherapy of Alzheimer's disease (AD) is dependent on small molecules that primarily act as cholinesterase inhibitors. However they provide only symptomatic relief. The pathophysiology of Alzheimer's disease (AD) is complex and involves the cholinergic, amyloid and oxidative stress pathways. The multifactorial nature of AD indicates that it is imperative to develop small molecules to target multiple pathological routes of AD as disease-modifying agents A cross-disciplinary approach was used where computational chemistry, synthetic chemistry and biochemical evaluations were applied to design, synthesize and evaluate target small molecules. We synthesized a chemical library of small molecules based on novel heterocyclic rings that were characterized by analytic methods such as NMR, MS and HPLC. The molecules were evaluated in vitro to assess their ability to inhibit cholinesterases (acetylcholinesterase AChE and butyrylcholinesterase BuChE) by UV-Vis spectroscopy, AChE-induced amyloid aggregation, self-induced amyloid aggregation (fluorescence spectroscopy) and antioxidant properties (UV-Vis spectroscopy). Furthermore, amyloid aggregation kinetics and morphology were evaluated using transmission electron microscopy (TEM). Our results indicate that small molecules based on novel heterocyclic ring scaffolds are able to target multiple pathophysiological routes of AD. Based on the steric and electronic properties at various positions, they were able to inhibit acetyl and butyrylcholinesterase enzymes. Furthermore, specific pharmacophores were able to bind to the peripheral anionic site (PAS) of AChE and were also able to prevent AChE-induced amyloid aggregation (e.g., 3,4-dimethoxybenzyl). Novel pharmacophores were developed that are capable of exhibiting antioxidant properties. Structure activity relationship studies identified novel heterocyclic rings that possess unique pharmacophoric features necessary to exhibit optimum combination of cholinesterase and amyloid inhibition along with antioxidant properties. These studies indicate that hybrid disease-modifying agents that target multiple pathological routes represent a new approach to treat AD." @default.
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- W1991774739 date "2012-07-01" @default.
- W1991774739 modified "2023-09-27" @default.
- W1991774739 title "P1-267: Alzheimer's disease: Small molecules as disease-modifying agents" @default.
- W1991774739 doi "https://doi.org/10.1016/j.jalz.2012.05.547" @default.
- W1991774739 hasPublicationYear "2012" @default.
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