Synthesis and neuroprotective activity of 3‐aryl‐3‐azetidinyl acetic acid methyl ester derivatives

doi:10.1002/ardp.202300378

Paper

Synthesis and neuroprotective activity of 3‐aryl‐3‐azetidinyl acetic acid methyl ester derivatives

Published Oct 5, 2023 · Urtė Šachlevičiūtė, Gabriel Gonzalez, M. Kvasnicová

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Abstract

A library of 3‐aryl‐3‐azetidinyl acetic acid methyl ester derivatives was prepared from N‐Boc‐3‐azetidinone employing the Horner‐Wadsworth‐Emmons reaction, rhodium(I)‐catalyzed conjugate addition of arylboronic acids, and subsequent elaborations to obtain N‐unprotected hydrochlorides, N‐alkylated and N‐acylated azetidine derivatives. The compounds were evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, revealing several derivatives to possess AChE inhibition comparable to that of the AChE inhibitor rivastigmine. The binding mode of the AChE inhibitor donepezil and selected active compounds 26 and 27 within the active site of AChE was studied using molecular docking. Furthermore, the neuroprotective activity of the prepared compounds was evaluated in models associated with Parkinson's disease (salsolinol‐induced) and aspects of Alzheimer's disease (glutamate‐induced oxidative damage). Compound 28 showed the highest neuroprotective effect in both salsolinol‐ and glutamate‐induced neurodegeneration models, and its protective effect in the glutamate model was revealed to be driven by a reduction in oxidative stress and caspase‐3/7 activity.

In Vitro Study

Study Snapshot

Compound 28, a 3aryl-3azetidinyl acetic acid methyl ester derivative, shows the highest neuroprotective effect in both Parkinson's disease and Alzheimer's disease models, driven by reduced oxidative stress and caspase-3/7 activity.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Paper

Synthesis and neuroprotective activity of 3‐aryl‐3‐azetidinyl acetic acid methyl ester derivatives

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