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

0578898 - ÚEB 2024 RIV US eng J - Journal Article
Šachlevičiūtė, U. - Gonzalez, G. - Kvasnicová, M. - Štěpánková, Š. - Kleizienė, N. - Bieliauskas, A. - Zatloukal, M. - Strnad, Miroslav - Sløk, F. A. - Kvasnica, Miroslav - Šačkus, A. - Žukauskaitė, A.
Synthesis and neuroprotective activity of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives.
Archiv der Pharmazie. Roč. 356, č. 12 (2023), č. článku 2300378. ISSN 0365-6233. E-ISSN 1521-4184
R&D Projects: GA ČR(CZ) GA23-05389S
Institutional support: RVO:61389030
Keywords : acetylcholinesterase * Alzheimer disease * azetidine * neuroprotection * Parkinson disease
OECD category: Biochemistry and molecular biology
Impact factor: 5.1, year: 2022
Method of publishing: Open access
https://doi.org/10.1002/ardp.202300378

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.
Permanent Link: https://hdl.handle.net/11104/0347819