Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer’s Disease Therapy

Óscar Bautista-Aguilera , Lhassane Ismaili (1) , Mourad Chioua , Rudolf Andrys , Monika Schmidt , Petr Bzonek , María Ángeles Martínez-Grau , Christopher Beadle , Tatiana Vetman , Francisco López-Muñoz , Isabel Iriepa , Bernard Refouvelet , Kamil Musilek , José Marco-Contelles

1 Laboratoires de neurosciences intégratives et cliniques (EA 481)

In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer’s disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 µM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.

Domaines: Chimie organique; Chimie thérapeutique

Óscar Bautista-Aguilera, Lhassane Ismaili, Mourad Chioua, Rudolf Andrys, Monika Schmidt, et al.. Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer’s Disease Therapy. International Journal of Molecular Sciences, 2020, 21 (11), pp.3913. ⟨10.3390/ijms21113913⟩. ⟨hal-03654611⟩