Multi-target-directed ligands for Alzheimer's disease: Discovery of chromone-based monoamine oxidase/cholinesterase inhibitors.
There has been a substantial research effort to design multi-target ligands for the treatment of Alzheimer's disease (AD), an approach that is moved by the knowledge that AD is a complex and multifactorial disease affecting many linked to pathological pathways. Accordingly, we have devoted efforts to develop multi-target ligands based on the chromone scaffold. As a result, a small library of chromone derivatives was synthesized and screened towards human cholinesterases and monoamine oxidases. Compounds 2-(dimethylamino)ethyl (E)-3-(4-oxo-2-(p-methylphenlcarbamoyl)-4H-chromen-6-yl)acrylate (9a) and 2-(dimethylamino)ethyl (E)-3-(4-oxo-3-(phenylcarbamoyl)-4H-chromen-6-yl)acrylate (23a) were identified as the most promising multi-target inhibitors of the series. Compound 9a acted as a potent, selective and bifunctional AChEI (IC50 = 0.21 μM, Ki = 0.19 μM) and displayed dual hMAO inhibitory activity (hMAO-A IC50 = 0.94 μM, Ki = 0.057 μM and hMAO-B IC50 = 3.81 μM, Ki = 0.48 μM). Compound 23a acted as a selective IMAO-B (IC50 = 0.63 μM, Ki = 0.34 μM) while still displaying hChE inhibitory and bifunctional activity in the low micromolar range. Overall, these two compounds stand out as reversible multi-target inhibitors with favourable permeability, toxicological and drug-like profiles, thus being valid candidates for subsequent optimization and pre-clinical studies.
['Reis|Joana|J|', 'Cagide|Fernando|F|', 'Valencia|Martín Estrada|ME|', 'Teixeira|José|J|', 'Bagetta|Donatella|D|', 'Pérez|Concepción|C|', 'Uriarte|Eugenio|E|', 'Oliveira|Paulo J|PJ|', 'Ortuso|Francesco|F|', 'Alcaro|Stefano|S|', 'Rodríguez-Franco|María Isabel|MI|', 'Borges|Fernanda|F|']
D000544:Alzheimer Disease D001812:Blood-Brain Barrier D002800:Cholinesterase Inhibitors D002802:Cholinesterases D002867:Chromones D015195:Drug Design D056945:Hep G2 Cells D006801:Humans D008024:Ligands D062105:Molecular Docking Simulation D058990:Molecular Targeted Therapy D008995:Monoamine Oxidase D008996:Monoamine Oxidase Inhibitors
Multi-target-directed ligands Alzheimer's disease Chromone AChE inhibitors MAO-B inhibitors New chemical entities