Design, Synthesis, In Vitro and In Silico Studies of New Thiazolylhydrazine-Piperazine Derivatives as Selective MAO-A Inhibitors

Abstract

Monoamine oxidase (MAO) isoenzymes are very important drug targets among neurological disorders. Herein, novel series of thiazolylhydrazine-piperazine derivatives were designed, synthesized and evaluated for their MAO-A and -B inhibitory activity. The structures of the synthesized compounds were assigned using different spectroscopic techniques such as 1H-NMR, 13C-NMR and HRMS. Moreover, the prediction of ADME (Absorption, Distribution, Metabolism, Elimination) parameters for all of the compounds were performed using in silico method. According to the enzyme inhibition results, the synthesized compounds showed the selectivity against MAO-A enzyme inhibition. Compounds 3c, 3d and 3e displayed significant MAO-A inhibition potencies. Among them, compound 3e was found to be the most effective derivative with an IC50 value of 0.057 ± 0.002 µM. Moreover, it was seen that this compound has a more potent inhibition profile than the reference inhibitors moclobemide (IC50 = 6.061 ± 0.262 µM) and clorgiline (IC50 = 0.062 ± 0.002 µM). In addition, the enzyme kinetics were performed for compound 3e and it was determined that this compound had a competitive and reversible inhibition type. Molecular modeling studies aided in the understanding of the interaction modes between this compound and MAO-A. It was found that compound 3e had significant and important binding property.

Design, Synthesis, and Biological Effect Studies of Novel Benzofuran–Thiazolylhydrazone Derivatives as Monoamine Oxidase Inhibitors

“…Molecular docking studies were performed using an in silico procedure to define the binding modes of the active compound ( 2l ) in the active regions of crystal structures of MAO-A (PDB ID: 2Z5X), retrieved from the Protein Data Bank server (, accessed 01 May 2021). Molecular docking studies were performed as previously reported. ,,,, …”

“…Molecular docking studies were performed as previously reported. 31,39,45,55,56 4.6. Molecular Dynamics Simulation.…”

“…As a result of our research, we also reported the synthesis and MAO inhibitory activities of many 2-thiazolylhydrazone derivatives. This study was designed mainly to continue examining the effects of different substituents of the thiazole core at C2 and C4 on MAO inhibitory activity and selectivity. − …”

Piperazine-substituted chalcones: a new class of MAO-B, AChE, and BACE-1 inhibitors for the treatment of neurological disorders

“…Currently, more than 40 piperazine-containing drugs have been FDA-approved as antianginals, antidepressants, antiserotonergics, urologicals, anthelmintics, antineoplastic agents, nootropics, and tranquillizers (Brito et al 2019). Furthermore, the substitution of one or both nitrogen atoms in the piperazine ring system with various structural motifs can result in significant MAO-A, MAO-B, and acetylcholinesterase (AChE) inhibitions (Pettersson et al 2012;Kaya et al 2017;Kumar et al 2018;Özdemir et al 2020;Sağlık et al 2020;Jevtić et al 2020;Modh et al 2013;Sahin et al 2018).…”

Chalcones with N‐Methylpiperazine Moiety: Synthesis, Monoamine Oxidase Inhibition, Neuroprotective Effect and Computer Simulation Study

“…[23] Some recent studies established that the incorporation of piperazine nucleus with other structural moieties is able to improve the interaction of the compounds with biological targets, and thereby improves the MAO inhibition properties. [14,21,[24][25][26][27][28][29][30] The unique class of enzymes known as monoamine oxidases (MAOs) is located in the mitochondria and is responsible for several biological processes. They are FAD-dependent and act as an essential catalyst in the oxidative deamination process for the metabolism of amine molecules.…”