2-Phenyloxazole-4-carboxamide as a Scaffold for Selective Inhibition of Human Monoamine Oxidase?B |
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Authors: | Dr Maria L Di Paolo Dr Michael S Christodoulou Dr Alessandra M Calogero Dr Luca Pinzi Prof Giulio Rastelli Prof Daniele Passarella Prof Graziella Cappelletti Prof Lisa Dalla Via |
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Affiliation: | 1. Dipartimento di Medicina Molecolare, Università degli Studi di Padova, Via G. Colombo 3, 35131 Padova, Italy;2. DISFARM, Sezione di Chimica Generale e Organica “A. Marchesini”, Università degli Studi di Milano, via Venezian 21, 20133 Milano, Italy;3. Dipartimento di Bioscienze, Università degli Studi di Milano, via Celoria 26, 20133 Milano, Italy;4. Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, via Campi 103, 41125 Modena, Italy;5. Dipartimento di Chimica, Università degli Studi di Milano, via C. Golgi 19, 20133 Milano, Italy;6. Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via F. Marzolo 5, 35131 Padova, Italy |
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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. |
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Keywords: | 2-phenyloxazole-4-carboxamides competitive inhibitors cytotoxicity molecular modeling monoamine oxidases |
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