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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2016-03, Vol.21 (3), p.362-362
• Main Authors: Pisani, Leonardo, Farina, Roberta, Soto-Otero, Ramon, Denora, Nunzio, Mangiatordi, Giuseppe Felice, Nicolotti, Orazio, Mendez-Alvarez, Estefania, Altomare, Cosimo Damiano, Catto, Marco, Carotti, Angelo
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer’s disease; Animals; Cell Line; cholinesterase inhibitors; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; coumarins; Drug Discovery; Enzyme Activation - drug effects; Humans; MAO inhibitors; Molecular Structure; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - pharmacology; multi-target-directed ligands; Structure-Activity Relationship
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules21030362

The 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 diazepam.