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

Roberta Farina¹  Cosimo Damiano Altomare¹  Marco Catto¹  Orazio Nicolotti¹  Leonardo Pisani¹  Giuseppe Felice Mangiatordi¹  Angelo Carotti¹  Nunzio Denora¹  Estefania Mendez-Alvarez²  Ramon Soto-Otero² 

[1] Dipartimento di Farmacia—Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, via E. Orabona, 4, I-70125 Bari, Italy;Grupo de Neuroquimica, Departamento de Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad de Santiago de Compostela, San Francisco I, E-15782 Santiago de Compostela, Spain;

关键词: Alzheimer’s disease;    cholinesterase inhibitors;    coumarins;    MAO inhibitors;    multi-target-directed ligands;   

DOI  :  10.3390/molecules21030362

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown