Searching for Multi-Targeting Neurotherapeutics against Alzheimer’s: Discovery of Potent AChE-MAO B Inhibitors through the Decoration of the 2H-Chromen-2-one Structural Motif

Pisani, LeonardoFarina, RobertaSoto-Otero, RamónDenora, NunzioMangiatordi, Giuseppe FeliceNicolotti, OrazioCatto, MarcoCarotti, Angelo2017-10-212017-10-212016-03-17Pisani, L.; Farina, R.; Soto-Otero, R.; Denora, N.; Mangiatordi, G.F.; Nicolotti, O.; Mendez-Alvarez, E.; Altomare, C.D.; Catto, M.; Carotti, A. Searching for Multi-Targeting Neurotherapeutics against Alzheimer’s: Discovery of Potent AChE-MAO B Inhibitors through the Decoration of the 2H-Chromen-2-one Structural Motif. Molecules 2016, 21, 3621420-3049http://hdl.handle.net/10347/15952The need for developing real disease-modifying drugs against neurodegenerative syndromes, particularly Alzheimer’s disease (AD), shifted research towards reliable drug discovery strategies to unveil clinical candidates with higher therapeutic efficacy than single-targeting drugs. By following the multi-target approach, we designed and synthesized a novel class of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors through the decoration of the 2H-chromen-2-one skeleton. Compounds bearing a propargylamine moiety at position 3 displayed the highest in vitro inhibitory activities against MAO-B. Within this series, derivative 3h emerged as the most interesting hit compound, being a moderate AChE inhibitor (IC50 = 8.99 µM) and a potent and selective MAO-B inhibitor (IC50 = 2.8 nM). Preliminary studies in human neuroblastoma SH-SY5Y cell lines demonstrated its low cytotoxicity and disclosed a promising neuroprotective effect at low doses (0.1 µM) under oxidative stress conditions promoted by two mitochondrial toxins (oligomycin-A and rotenone). In a Madin-Darby canine kidney (MDCK)II-MDR1 cell-based transport study, Compound 3h was able to permeate the BBB-mimicking monolayer and did not result in a glycoprotein-p (P-gp) substrate, showing an efflux ratio = 0.96, close to that of diazepameng© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/)Alzheimer’s diseaseCholinesterase inhibitorsCoumarinsMAO inhibitorsMulti-target-directed ligandsSearching for Multi-Targeting Neurotherapeutics against Alzheimer’s: Discovery of Potent AChE-MAO B Inhibitors through the Decoration of the 2H-Chromen-2-one Structural Motifjournal article10.3390/molecules21030362open access