Multi-target-directed ligands for Alzheimer's disease: Discovery of chromone-based monoamine oxidase/cholinesterase inhibitors
Autor
Reis J.
Cagide F.
Valencia M.E.
Teixeira J.
Bagetta D.
Pérez C.
Uriarte E.
Oliveira P.J.
Ortuso F.
Alcaro S.
Rodríguez-Franco M.I.
Borges F.
Resumen
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. © 2018
Colecciones
Ítems relacionados
Mostrando ítems relacionados por Título, autor o materia.
-
Article
Fine-tuning the neuroprotective and blood-brain barrier permeability profile of multi-target agents designed to prevent progressive mitochondrial dysfunction (2020)
Benfeito S.; Oliveira C.; Fernandes C.; Cagide F.; Teixeira J.; Amorim R.; Garrido J.; Martins C.; Sarmento B.; Silva R.; ... (Elsevier Masson SAS, 2019) -
Article
PEGylated PLGA Nanoparticles As a Smart Carrier to Increase the Cellular Uptake of a Coumarin-Based Monoamine Oxidase B Inhibitor (2020)
Fernandes C.; Martins C.; Fonseca A.; Nunes R.; Matos M.J.; Silva R.; Garrido J.; Sarmento B.; Remião F.; Otero-Espinar F.J.; ... (American Chemical Society, 2018) -
Article
Synthesis, biological evaluation, and molecular simulation of chalcones and aurones as selective MAO-B inhibitors (2020)
Morales-Camilo N.; Salas C.O.; Sanhueza C.; Espinosa-Bustos C.; Sepúlveda-Boza S.; Reyes-Parada M.; Gonzalez-Nilo F.; Caroli-Rezende M.; Fierro A. (Blackwell Publishing Ltd, 2015)