Synthesis and Biological Evaluation of New Thiosemicarbazone Derivative Schiff Bases as Monoamine Oxidase Inhibitory Agents.

Betül Çavuşoğlu,Ulviye Acar Çevik,Zafer Kaplancıklı,Serkan Levent,Abdullah Karaduman,Begüm Sağlık,Derya Osmaniye,Yusuf Özkay

doi:10.3390/molecules23010060

Betül Çavuşoğlu, Ulviye Acar Çevik + Show 6 more

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https://doi.org/10.3390/molecules23010060

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Abstract

Twenty-six novel thiosemicarbazone derivative B1–B26 were synthesized via condensation reactions between the corresponding thiosemicarbazides and aldehydes. The chemical characterization of the compounds was carried out by infrared (IR), mass (MS), proton and carbon nuclear magnetic resonance (1H- and 13C-NMR) spectroscopic analyses. The compounds were investigated for their monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) inhibitory activity and most of them were more potent against MAO-A enzyme when compared with MAO-B enzyme. N-Cyclohexyl-2-[4-[(4-chlorophenyl)thio]benzylidene]hydrazine-1-carbothioamide (B24) was the most active compound against MAO-A. The enzyme kinetics study revealed that compound B24 has a reversible and competitive mode of binding. Interaction modes between compound B24 and MAO-A were clarified by docking studies. In addition, the favourable absorption, distribution, metabolism, and excretion (ADME) properties and non-toxic nature of compound B24 make this compound a promising MAO-A inhibitor.

Highlights

IntroductionMonoamine oxidases (MAOs) are flavoproteins bound to the outer membranes of mitochondria throughout the brain, catalysing the oxidative deamination of monoamine neurotransmitters, thereby participating in this mechanism by modulating the levels of neurotransmitters [1,2]
The process of synaptic neurotransmission is ensured by the correct functioning of enzymes.Monoamine oxidases (MAOs) are flavoproteins bound to the outer membranes of mitochondria throughout the brain, catalysing the oxidative deamination of monoamine neurotransmitters, thereby participating in this mechanism by modulating the levels of neurotransmitters [1,2]
The synthetic pathways and structural features of the compounds B1–B26 are outlined in Scheme 1

Summary

Introduction

Monoamine oxidases (MAOs) are flavoproteins bound to the outer membranes of mitochondria throughout the brain, catalysing the oxidative deamination of monoamine neurotransmitters, thereby participating in this mechanism by modulating the levels of neurotransmitters [1,2]. MAO-A preferentially oxidizes norepinephrine and serotonin and is selectively inhibited by clorgyline, while MAO-B preferentially deaminates dopamine and is irreversibly inhibited by L-deprenyl [5,6]. Both isoforms are significant drug targets in the therapy of neuropsychiatric and neurodegenerative disorders. Adverse effects of irreversible and nonselective MAO inhibitors [10] have led to great interest in the discovery of novel and selective drug candidates

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