Monoamine Oxidase Inhibitors: Perspective Design for the Treatment of Depression and Neurological Disorders

Mathew, Bijo; Mathew, Githa Elizabeth; Suresh, Jerad; Uçar, Gülberk; Sasidharan, Rani; Anbazhagan, S.; Vilapurathu, Jobin Kunjumon; Jayaprakash, Venkatesan

doi:10.2174/1573408012666160402001715

Cited by 35 publications

(18 citation statements)

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“…Elevated central nervous system (CNS) levels of MAO‐B in PD patients leads to an increased production of hydrogen peroxide and reactive oxygen species . These toxic metabolites are responsible for neurodegeneration, leading to the death of dopamine‐containing neurons.…”

Section: Figurementioning

confidence: 99%

Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives

Mathew

Uçar

Mathew³

et al. 2016

ChemMedChem

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Numerous studies have shown that chalcones are promising scaffolds for the development of new monoamine oxidase-B (MAO-B) inhibitors. As a continuation of our ongoing research into the development of reversible human MAO-B (hMAO-B) inhibitors, two series of twenty chalcones containing electron-donating and electron-withdrawing substituents were synthesized. All compounds were found to be competitive, selective, and reversible inhibitors of hMAO-B except (2E)-1-(4-methylphenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P7) and (2E)-1-(4-chlorophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P17), which were found to be selective inhibitors of hMAO-A. The most potent hMAO-B inhibitor, (2E)-1-(4-chlorophenyl)-3-(4-ethylphenyl)prop-2-en-1-one (P16), showed a K value of 0.11±0.01 μm. Molecular docking simulations were carried out to identify the hypothetical binding mode for the most potent compounds in the active sites of hMAO-A and B. The ability of the compounds to cross the blood-brain barrier was assessed by parallel artificial membrane permeability assay (PAMPA). Additionally, the most potent hMAO-B inhibitor P16 showed no toxicity in cultured hepatic cells at concentrations of 5 and 25 μm.

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Section: Figurementioning

confidence: 99%

Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives

Mathew

Uçar

Mathew³

et al. 2016

ChemMedChem

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“…MAO−A and MAO−B are the two distinct isoforms which exhibit about 70% sequence characteristics at the amino acid level but diverge predominantly in their inhibitor selectivity, substrate specificity and tissue distribution in the body . MAO−A is primarily responsible for the breakdown of serotonin in the CNS and its inhibition can be used for the management of depressive states in mood disorders ,. MAO−B selective inhibitors are found to be effective for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD), mostly in combination with dopamine to reduce the metabolic degradation of dopamine and increase its half‐life ,.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Thienylchalcones as hMAO‐B Inhibitors: Synthesis, Biochemistry and Molecular Dynamics Studies

et al. 2017

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The design of selective, reversible and non‐toxic hMAO−B inhibitors has received increasing attention due to their perceived utility in targeting of neurological disorders like Alzheimer's and Parkinson's diseases. For this purpose, herein, we report the inhibitory studies on monoamine oxidase of a series of (2E)‐1‐(2, 5‐dichlorothiophen‐3‐yl)‐3‐(4‐substitutedphenyl) prop‐2‐en‐1‐ones (S1‐S9). All the compounds were found to be competitive, selective, and reversible inhibitors of hMAO−B except (2E)‐1‐(2, 4‐dichlorothiophen‐3‐yl)‐3‐(4‐nitrophenyl) prop‐2‐en‐1‐one (S6) which is found to be non‐selective MAO inhibitor. The potent hMAO−B inhibitor, (2E)‐1‐(2, 4‐dichlorothiophen‐3‐yl)‐3‐[4‐(dimethylamino) phenyl] prop‐2‐en‐1‐one (S4), showed a Ki value of 0.041 μM better than the standard drug, selegiline (hMAO−B with Ki= 0.302 μM). Moreover, S4, was nontoxic in cultured hepatic cells at 5 and 25 μM, with 94.44 and 88.00% viable cells, respectively. Molecular docking and molecular dynamics simulation studies were carried out using Autodock‐vina and Amber 14 to understand the molecular level interaction and energy relation of MAO isoforms with selective MAO−B inhibitor, S4.

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“…The altered concentrations of the neurotransmitters in the brain are linked with the pathology of various neurological disorders including depression, Parkinson's disease (PD) and Alzheimer's disease (AD) and both MAO isoforms are involved in the pathogenesis of these diseases due to their pivotal role in key physiological processes. As a result, MAO has attracted a great deal of interest as a promising target for the development of central nervous system (CNS) agents …”

Section: Introductionmentioning

confidence: 99%

“…Selective MAO‐A inhibitors are being developed as drug candidates for the management of depression and anxiety disorders. On the other hand, selective MAO‐B inhibitors are found to be effective for the treatment of PD and AD with a better safety profile as compared to nonselective MAO inhibitors …”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, in vitro and in silico evaluation of new pyrrole derivatives as monoamine oxidase inhibitors

Altıntop

Sever

Osmaniye

et al. 2018

Archiv der Pharmazie

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In an effort to develop potent monoamine oxidase (MAO) inhibitors, new pyrrole derivatives were obtained via the selective reduction of the CC bonds of 1-(1-methyl-1H-pyrrol-2-yl)-3-[5-(aryl)furan-2-yl]prop-2-en-1-ones through palladium catalyzed hydrogenation in ethanol. The synthesized compounds were screened for their inhibitory effects on MAO-A and MAO-B by an in vitro fluorometric method. The selectivity index (SI) value was given as the ratio of IC (MAO-A)/IC (MAO-B) for each compound. 3-(5-(4-Chlorophenyl)furan-2-yl)-1-(1-methyl-1H-pyrrol-2-yl)propan-1-one (6) was identified as the most selective MAO-A inhibitor in this series, with an IC value of 0.162 µM and a SI value of 0.002. Kinetic studies were also carried out to assess the nature of MAO-A inhibition by compound 6. According to Lineweaver-Burk plots, compound 6 was found to be a competitive MAO-A inhibitor and the K value of compound 6 was determined as 0.1221 μM. Docking studies were performed for compound 6 and clorgyline using the human MAO-A crystal structure (PDB ID: 2Z5Y). The docking results showed that compound 6 presented similar interactions as clorgyline in the active center cavity of the enzyme. Molinspiration software was used to determine the physicochemical parameters of all compounds for an evaluation of their compliance to Lipinski's rule of five. Compound 6 did not violate Lipinski's rule, making it a potential orally bioavailable therapeutic agent.

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Monoamine Oxidase Inhibitors: Perspective Design for the Treatment of Depression and Neurological Disorders

Cited by 35 publications

References 0 publications

Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives

Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives

Characterization of Thienylchalcones as hMAO‐B Inhibitors: Synthesis, Biochemistry and Molecular Dynamics Studies

Design, synthesis, in vitro and in silico evaluation of new pyrrole derivatives as monoamine oxidase inhibitors

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