Design and synthesis of chromone-based monoamine oxidase B inhibitors with improved drug-like properties

Eur J Med Chem. 2022 Jun 3;239:114507. doi: 10.1016/j.ejmech.2022.114507. Online ahead of print.ABSTRACTThe absence of disease modifying drugs in Parkinson's disease therapy urges for new chemical entities acting on relevant PD-associated biological targets. As a result, developing selective and reversible inhibitors targeting MAO-B is still a desirable line of therapeutic research. Within this framework, a small library of chromone derivatives was synthesized and screened towards human monoamine oxidases. Structural modifications on the chromone 3-phenylcarboxamide resulted in potent MAO-B inhibitors with an improved drug-like profile, and for the first time we obtained potent and selective chromone 2-phenylcarboxamides acting in the low nanomolar range. Compounds 5-hydroxy-4-oxo-N-phenyl-4H-chromene-3-carboxamide (38) (IC50 = 13.0 nM) and N-(4-chlorophenyl)-5-hydroxy-4-oxo-4H-chromene-3-carboxamide (41) (IC50 = 8.3 nM) stood out as reversible, potent, selective and non-cytotoxic MAO-B inhibitors bearing a favourable drug-like profile. Both compounds displayed cytoprotective effects towards iron(III) oxidative stressor.PMID:35772321 | DOI:10.1016/j.ejmech.2022.114507

Source: European Journal of Medicinal Chemistry - June 30, 2022 Category: Chemistry Authors: Joana Reis Carlos Fernandes Hoda Salem Marta Maia Cl áudia Tomé Sofia Benfeito Jos é Teixeira Paulo J Oliveira Eugenio Uriarte Francesco Ortuso Stefano Alcaro Donatella Bagetta Fernando Cagide Fernanda Borges Source Type: research