2-Pyrazoline derivatives in neuropharmacology
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Date
2017-05-08
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Abstract
A novel series of 1,3,5-trisubstituted-2-pyrazoline derivatives (PFC-1 to PFC-16) were synthesized
in a three step reaction using conventional and microwave assisted green chemistry approach. The
synthesized derivatives were characterized and their chemical structures were established by
various physicochemical methods such as IR, Mass, 1H-NMR, 13C-NMR and elemental analysis. The
synthesized compounds were tested for their neurophar- macological potential. The compounds
exhibited significant antidepressant and anti-anxiety activities against var- ious behavioral in
vivo models. Compounds PFC-3 and PFC-12 were found to be the most active derivatives in the series.
The 2-pyrazoline analogs, having 2-hydroxyphenyl and anthracen-9-yl substitution at 3rd position
while 4-benzyloxyphenyl and 4-methylphenyl substitution at 5th position, were decisive in eliciting
good antidepressant and anxiolytic properties, respectively. The docking experiments revealed that
the synthesized derivatives were potential inhibitors of MAO-A protein, which plays a central role
in managing depression and anxiety disorders. The most potent derivatives were found to be involved
in some key interactions with Tyr407, Tyr444, Phe352 and Ala68 amino acid residues at the binding
site of MAO-A protein. All the synthesized derivatives successfully passed the pharmacokinetic
barriers of absorption, distribution, metabolism and elimination as predicted using in silico
techniques without showing any substantial indication of acute and neurotoxicity. This was further
confirmed in the laboratory by performing acute toxicity studies as per OECD guidelines.
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Keywords
4,5-Dihydro-(1H)-pyrazoles, antidepressant, anxiolytic, MAO inhibitors, neurotoxicity, microwave synthesis, molecular docking