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.

Department of Chemistry Faculty of Science University of Hradec Kralove Rokitanskeho 62 500 03 Hradec Kralove Czech Republic

Department of Organic Chemistry and Inorganic Chemistry Alcalá University Alcalá de Henares 28805 Madrid Spain

Faculty of Health Camilo José Cela University of Madrid 28692 Villafranca del Castillo Spain

Institute of Chemical Research Andrés M del Río Alcalá University Alcalá de Henares 28805 Madrid Spain

Laboratoire de Chimie Organique et Thérapeutique Neurosciences Intégratives et Cliniques EA 481 University Bourgogne Franche Comté UFR Santé 19 rue Ambroise Paré F 25000 Besançon France

Laboratory of Medicinal Chemistry C Juan de la Cierva 3 28006 Madrid Spain

Lilly Research Centre Eli Lilly and Company Erl Wood Manor Windlesham Surrey GU20 6PH UK

Lilly Research Laboratories Eli Lilly and Company Avda de la Industria 30 Alcobendas 28108 Madrid Spain

Lilly Research Laboratories Eli Lilly and Company Indianapolis IN 46285 USA

Neuropsychopharmacology Unit Hospital 12 de Octubre Research Institute 28041 Madrid Spain

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