Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives

Irene Pachón Angona , Helene Martin , Solene Daniel , Ignacio Moraleda , Alexandre Bonet , Artur Wnorowski , Maciej Maj , Krzysztof Jozwiak , Isabel Iriepa , Bernard Refouvelet , José Marco-Contelles , Lhassane Ismaili (1)

1 Laboratoires de neurosciences intégratives et cliniques (EA 481)

We report herein the design, synthesis, biological evaluation, and molecular modelling of new inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), able to block Ca+2 channels also showing antioxidant and neuroprotective activities. The new MTDL, dialkyl 2,6-dimethyl-4-(4-((5-aminoalkyl)oxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate 3a-p, have been obtained via Hantzsch reaction from appropriate and commercially available precursors. Pertinent biological analysis has prompted us to identify MTDL 3h [dimethyl-4-(4-((5-(4-benzylpiperidin-1-yl)pentyl)oxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate] as an attractive inhibitor of AChE (1.8 μM) and BuChE (2 μM), Ca+2 channel antagonist (47.72% at 10 μM), and antioxidant (2.54 TE) agent, showing significant neuroprotection 28.68% and 38.29% against H2O2, and O/R, respectively, at 0.3 μM, thus being considered a hit-compound for further investigation in our search for anti-Alzheimer’s disease agents.

Domaines: Chimie organique; Chimie thérapeutique

Irene Pachón Angona, Helene Martin, Solene Daniel, Ignacio Moraleda, Alexandre Bonet, et al.. Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives. International Journal of Molecular Sciences, 2020, 21 (20), pp.7652. ⟨10.3390/ijms21207652⟩. ⟨hal-03654589⟩