A series of 2-phenyloxazoles bearing an amide group at position 4 were designed and synthesized for evaluation as potential inhibitors of human recombinant monoamine oxidases (hrMAOs). Results of kinetics experiments demonstrated that all compounds behave as competitive MAO inhibitors, with good selectivity toward the MAO-B isoform. The most potent and selective derivatives are characterized by inhibition constant (Ki) values in the sub-micromolar range and a good selectivity index (Ki MAO-A/Ki MAO-B>50). Some derivatives were also found to be able to inhibit MAO activity in nerve growth factor (NGF)-differentiated PC12 cells, taken as a model of neuronal cells. In particular, 2-(2-hydroxyphenyl)-N-phenyloxazole-4-carboxamide (compound 4 a) may be a promising new scaffold, exerting the highest selectivity and inhibitory effect toward MAOs in NGF-differentiated PC12 cell lysates, without compromising cell viability. Molecular docking analysis allowed a rationalization of the experimentally observed binding affinity and selectivity.

2-Phenyloxazole-4-carboxamide as a Scaffold for Selective Inhibition of Human Monoamine Oxidase B / M.L. Di Paolo, M.S. Christodoulou, A.M. Calogero, L. Pinzi, G. Rastelli, D. Passarella, G. Cappelletti, L. Dalla Via. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 14:18(2019 Sep), pp. 1641-1652.

2-Phenyloxazole-4-carboxamide as a Scaffold for Selective Inhibition of Human Monoamine Oxidase B

M.S. Christodoulou;A.M. Calogero;D. Passarella;G. Cappelletti;
2019

Abstract

A series of 2-phenyloxazoles bearing an amide group at position 4 were designed and synthesized for evaluation as potential inhibitors of human recombinant monoamine oxidases (hrMAOs). Results of kinetics experiments demonstrated that all compounds behave as competitive MAO inhibitors, with good selectivity toward the MAO-B isoform. The most potent and selective derivatives are characterized by inhibition constant (Ki) values in the sub-micromolar range and a good selectivity index (Ki MAO-A/Ki MAO-B>50). Some derivatives were also found to be able to inhibit MAO activity in nerve growth factor (NGF)-differentiated PC12 cells, taken as a model of neuronal cells. In particular, 2-(2-hydroxyphenyl)-N-phenyloxazole-4-carboxamide (compound 4 a) may be a promising new scaffold, exerting the highest selectivity and inhibitory effect toward MAOs in NGF-differentiated PC12 cell lysates, without compromising cell viability. Molecular docking analysis allowed a rationalization of the experimentally observed binding affinity and selectivity.
2-phenyloxazole-4-carboxamides; competitive inhibitors; cytotoxicity; molecular modeling; monoamine oxidases
Settore CHIM/06 - Chimica Organica
Settore CHIM/08 - Chimica Farmaceutica
set-2019
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/676235
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