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


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 ?M 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 ?M 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 ?-? 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.

SUBMITTER: Nath C 

PROVIDER: S-EPMC6071705 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Nath Chandrani C   Badavath Vishnu Nayak VN   Thakur Abhishek A   Ucar Gulberk G   Acevedo Orlando O   Mohd Siddique Mohd Usman MU   Jayaprakash Venkatesan V  

MedChemComm 20180608 7


A series of 2-methoxy-4-(5-phenyl-4,5-dihydro-1<i>H</i>-pyrazol-3-yl)phenol (pyrazoline) derivatives (<b>2-6</b>) have been synthesized and tested for human monoamine oxidase (hMAO) inhibitory activity. The most active derivative (<b>2</b>) behaved as a competitive hMAO-A inhibitor, with an inhibition constant value of 0.08 μM and a strong hMAO-A selectivity (<i>K</i><sub>i</sub>(hMAO-B)/<i>K</i><sub>i</sub>(hMAO-A) > 1751). In addition, <b>2</b> exhibited little to no cytotoxic effects up to a  ...[more]

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