TY - JOUR
T1 - Curcumin-based pyrazoline analogues as selective inhibitors of human monoamine oxidase A
AU - Nath, Chandrani
AU - Badavath, Vishnu Nayak
AU - Thakur, Abhishek
AU - Ucar, Gulberk
AU - Acevedo, Orlando
AU - Mohd Siddique, Mohd Usman
AU - Jayaprakash, Venkatesan
N1 - Funding Information:
Authors acknowledge Central Instrumentation Facility (CIF) and of Birla Institute of Technology and Dr. Reddy's Institute of Life Science, Hyderabad for spectral characterization. C.N. acknowledges the Junior Research Fellowship from the University Grants Commission, New Delhi, India. Gratitude is expressed by A.T. and O.A. to the Center for Computational Science at the University of Miami for support of this research.
Publisher Copyright:
© The Royal Society of Chemistry.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
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U2 - 10.1039/c8md00196k
DO - 10.1039/c8md00196k
M3 - Article
AN - SCOPUS:85050517566
VL - 9
SP - 1164
EP - 1171
JO - MedChemComm
JF - MedChemComm
SN - 2040-2503
IS - 7
ER -