Abstract
New N-acetyl/N-thiocarbamoylpyrazoline derivatives were designed and synthesized in high yields to assess their inhibitory activity and selectivity against human monoamine oxidase A and B. The most important chiral compounds were separated into their single enantiomers and tested. The impact of the substituents at N1, C3 and C5 positions as well the influence of the configuration of the C5 on the biological activity were analyzed. Bulky aromatic groups at C5 were not tolerated. p-Prenyloxyaryl moiety at C3 oriented the selectivity toward the B isoform. The results were also corroborated by molecular modelling studies providing new suggestions for the synthesis of privileged structures to serve as lead compounds for the treatment of mood disorders and neurodegenerative diseases.
Highlights
Monoamine oxidases, (MAOs) have been widely recognised as important pharmacological targets for the treatment of mood disorders and neurodegeneration (Parkinson’s disease, PD) as the results of their effects on monoamine metabolism and level [1,2]
The results showed that compound P6 was ineffective as an inhibitor of human monoamine oxidase (hMAOs)-A, retaining activity in the high micromolar range only against hMAO-B
This research paper aimed to reinforce the privileged relationship between the pyrazoline scaffold and the hMAO inhibitory activity
Summary
Monoamine oxidases, (MAOs) have been widely recognised as important pharmacological targets for the treatment of mood disorders (anxiety, depression) and neurodegeneration (Parkinson’s disease, PD) as the results of their effects on monoamine metabolism and level [1,2]. Two isoforms (MAO-A and MAO-B) have been characterized based on structural homology, tissue localization, substrate and inhibitor selectivity, active site differences and catalytic efficiency [3]. Both of them could be the target of selective inhibitors acting as reversible or irreversible agents. Pyrazoline derivatives have been extensively studied in the past as a valid scaffold for the design of human monoamine oxidase (hMAOs) inhibitors [1,2,3,9]. Our research group has explored the effect of changes involving mainly positions (N1, C3 and C5) of pyrazoline ring on Molecules 2019, 24, 484; doi:10.3390/molecules24030484 www.mdpi.com/journal/molecules
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