2. Academic Validation
  3. Synthesis and neuroprotective activity of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives

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

  • Arch Pharm (Weinheim). 2023 Dec;356(12):e2300378. doi: 10.1002/ardp.202300378.
Urtė Šachlevičiūtė 1,  Gabriel Gonzalez 2 3,  Marie Kvasnicová 2,  Šárka Štěpánková 4,  Neringa Kleizienė 1,  Aurimas Bieliauskas 1,  Marek Zatloukal 5,  Miroslav Strnad 6,  Frank A Sløk 7,  Miroslav Kvasnica 6,  Algirdas Šačkus 1,  Asta Žukauskaitė 5
Affiliations

Affiliations

  • 1 Institute of Synthetic Chemistry, Kaunas University of Technology, Kaunas, Lithuania.
  • 2 Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Olomouc, Czech Republic.
  • 3 Department of Neurology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czech Republic.
  • 4 Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Pardubice, Czech Republic.
  • 5 Department of Chemical Biology, Faculty of Science, Palacký University, Olomouc, Czech Republic.
  • 6 Laboratory of Growth Regulators, Institute of Experimental Botany of the Czech Academy of Sciences & Palacký University, Olomouc, Czech Republic.
  • 7 Vipergen ApS, Copenhagen V, Denmark.
PMID: 37797174 DOI: 10.1002/ardp.202300378
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.

Keywords

Alzheimer disease; Parkinson disease; acetylcholinesterase; azetidine; neuroprotection.

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