Synthesis and molecular modelling of novel substituted-4,5-dihydro-(1H)-pyrazole derivatives as potent and highly selective monoamine oxidase-A inhibitors |
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Authors: | Chimenti Franco Bolasco Adriana Manna Fedele Secci Daniela Chimenti Paola Granese Arianna Befani Olivia Turini Paola Alcaro Stefano Ortuso Francesco |
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Affiliation: | Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi di Roma La Sapienza, P.le Aldo Moro 5, 00185 Rome, Italy. |
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Abstract: | This report describes novel pyrazoline derivatives investigated for their ability to selectively inhibit the activity of the A and B isoforms of monoamine oxidase. These new synthetic compounds proved to be reversible, potent, and selective inhibitors of monoamine oxidase-A rather than of monoamine oxidase-B, and are promising candidates to further advance drug discovery efforts. The most active compounds show inhibitory activity on monoamine oxidase-A in the 1.0x10(-8)-8.6x10(-9) M range. Moreover, it should be pointed out that for some compounds a high IC50>or=10(-9) M value is associated with a high A-selectivity (Selectivity Index monoamine oxidase-B/monoamine oxidase-A in the 10,000-12,500 range). Further insight to understand enzyme-inhibitor molecular interaction was obtained by docking experiments with the monoamine oxidase-A and monoamine oxidase-B isoforms. |
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Keywords: | molecular modelling monoamine oxidase (1H)‐pyrazole derivatives reversible monoamine oxidase‐A inhibitors selective monoamine oxidase‐A inhibitors |
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