Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease.

doi:10.1021/jm200853t

Paper

Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease.

Published Nov 15, 2011 · Irene Bolea, Jordi Juárez-Jiménez, C. de los Ríos

Journal of medicinal chemistry

Q1 SJR score

195

Citations

4

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Abstract

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50=5.2±1.1 nM) and MAO-B (IC50=43±8.0 nM) and is a moderately potent inhibitor of AChE (IC50=0.35±0.01 μM) and BuChE (IC50=0.46±0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.

In Vitro Study

Highly Cited

Study Snapshot

New compounds show promise as multitarget drug candidates for Alzheimer's disease therapy, inhibiting key enzymes involved in the disease.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease.

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References

Synthesis and biological evaluation of novel thiazolidinedione analogues as 15-hydroxyprostaglandin dehydrogenase inhibitors.

Novel thiazolidinedione analogues as 15-PGDH inhibitors can increase cochlear blood flow and improve wound healing in various cell types.

Structural determinants of the multifunctional profile of dual binding site acetylcholinesterase inhibitors as anti-Alzheimer agents.

Dual binding site acetylcholinesterase inhibitors show potential as anti-Alzheimer agents due to their multifunctional profile, targeting multiple enzymes involved in the neurodegenerative cascade.

Structural optimization and biological evaluation of substituted bisphenol A derivatives as beta-amyloid peptide aggregation inhibitors.

Compound 43, a novel bisphenol A derivative, shows promising potential as an Alzheimer's disease treatment by suppressing aggregation and enhancing cell viability without causing neuronal cell toxicity.

Site-activated chelators targeting acetylcholinesterase and monoamine oxidase for Alzheimer's therapy.

This study developed a new strategy for designing site-activated chelators targeting both acetylcholinesterase and monoamine oxidase, potentially offering safer and more effective treatments for Alzheimer's and other metal-related diseases.

Amyloid-β-Acetylcholinesterase complexes potentiate neurodegenerative changes induced by the Aβ peptide. Implications for the pathogenesis of Alzheimer's disease

A-acetylcholinesterase complexes can exacerbate neurodegeneration in Alzheimer's disease, and activating Wnt signaling and NMDAR inhibition may help protect neurons.

Citations