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Curcumin-based pyrazoline analogues as selective inhibitors of human monoamine oxidase A

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Abstract

A series of 2-methoxy-4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenol (pyrazoline) derivatives (2–6) have been synthesized and tested for human monoamine oxidase (hMAO) inhibitory activity. The most active derivative (2) behaved as a competitive hMAO-A inhibitor, with an inhibition constant value of 0.08 μM and a strong hMAO-A selectivity (Ki(hMAO-B)/Ki(hMAO-A) > 1751). In addition, 2 exhibited little to no cytotoxic effects up to a 25 μM concentration and provided the best blood–brain barrier permeability among the derivatives synthesized. Molecular dynamics simulations revealed that a chlorine substituent at the para-position of the phenyl ring in 2 enabled a π–π stacking interaction with Tyr407 and Tyr444 that resulted in the formation of an “aromatic sandwich” structure. Consequently, this tight-binding aromatic cage culminated in a dramatically reduced active site volume that is believed to be the origin of the observed selectivity between the hMAO-A and hMAO-B isozymes. Removal of the chlorine from 2 disrupted the favorable intermolecular interactions and resulted in a selectivity change towards hMAO-B.

Graphical abstract: Curcumin-based pyrazoline analogues as selective inhibitors of human monoamine oxidase A

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Publication details

The article was received on 12 Apr 2018, accepted on 06 Jun 2018 and first published on 08 Jun 2018


Article type: Research Article
DOI: 10.1039/C8MD00196K
Citation: Med. Chem. Commun., 2018, Advance Article
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    Curcumin-based pyrazoline analogues as selective inhibitors of human monoamine oxidase A

    C. Nath, V. N. Badavath, A. Thakur, G. Ucar, O. Acevedo, M. U. Mohd Siddique and V. Jayaprakash, Med. Chem. Commun., 2018, Advance Article , DOI: 10.1039/C8MD00196K

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