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

• Main Authors: Óscar M. Bautista-Aguilera, Lhassane Ismaili, Mourad Chioua, Rudolf Andrys, Monika Schmidt, Petr Bzonek, María Ángeles Martínez-Grau, Christopher D. Beadle, Tatiana Vetman, Francisco López-Muñoz, Isabel Iriepa, Bernard Refouvelet, Kamil Musilek, José Marco-Contelles
• Format: Article
• Language: English
• Published: MDPI AG 2020-05-01
• Series: International Journal of Molecular Sciences
• Subjects: Alzheimer’s disease; ChE/MAO inhibition; contilisant; dihydroquinolinones; docking; quinolinones
• Online Access: https://www.mdpi.com/1422-0067/21/11/3913
• ISSN: 1661-6596; 1422-0067

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