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Design, Synthesis and hMAO Inhibitory Screening of Novel 2-Pyrazoline Analogues

[ Vol. 20 , Issue. 6 ]

Author(s):

Begum Evranos-Aksoz, Gulberk Ucar and Kemal Yelekci   Pages 510 - 521 ( 12 )

Abstract:


Aim and Objective: MAO inhibitors have a significant effect on the nervous system since they act in regulation of neurotransmitter concentrations. Neurotransmitter levels are critical for a healthy nervous system. MAO inhibitors can be used in the treatment of neurological disorders such as depression, Parkinson's disease and Alzheimer's disease, as the increase or decrease of some neurotransmitter concentrations is associated with these neurological disorders. This study was conducted to discover new and active MAO inhibitor drug candidates.

Materials and Methods: New pyrazoline derivatives have been designed with the molecular docking approach and interactions of our compounds with the MAO enzyme have been investigated using the Autodock 4.2 program. The designed pyrazoline derivative compounds were synthesized by the reaction of the chalcones and hydrazides in ethanol. hMAO inhibitory activities of the newly synthesized compounds were investigated by fluorimetric method. In vitro cytotoxicity of five most potent inhibitors were tested in HepG2 cells.

Results: (3-(5-bromo-2-hydroxyphenyl)-5-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5i) and (3-(2-hydroxy-4-methoxy phenyl)-5-p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5l) inhibited hMAO-A more potently than moclobemide (Ki values are 0.004±0.001 and 0.005±0.001, respectively). The same two compounds, 5i and 5l, inhibited hMAO-A more selectively than moclobemide (SI values are 5.55x10-5 and 0.003, respectively). Both of these compounds were found non toxic at 1 µM, 5 µM and 25µM concentrations.

Conclusion: Two of the newly synthesized compounds, (3-(5-bromo-2-hydroxyphenyl)-5-(4- methoxyphenyl)-4,5-dihydropyrazol-1-yl)(phenyl)methanone and (3-(2-hydroxy-4-methoxy phenyl)- 5-p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone were found to be promising MAO-A inhibitors due to their high inhibitory potency, high selectivity and low toxicity.

Keywords:

2-Pyrazoline, molecular docking, AutoDock 4.2, human MAO, inhibition, synthesis.

Affiliation:

Medicines and Medical Devices Agency, Analyses and Control Laboratories, Sıhhıye 06100, Ankara, Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Sıhhiye 06100, Ankara, Faculty of Engineering and Natural Sciences, Department of Bioinformatics and Genetics (Head) Cibali Campus, Kadir Has University, Fatih 34083, Istanbul



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