Imidazole bearing chalcones as a new class of monoamine oxidase inhibitors

Sasidharan, Rani; Baek, Seung Cheol; Leelabaiamma, Manju Sreedharannair; Kim, Hoon; Mathew, Bijo

doi:10.1016/j.biopha.2018.06.064

Cited by 40 publications

(21 citation statements)

References 49 publications

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“…The relative activities of undialysed ( A U ) and dialysed ( A D ) samples were compared to determine reversibility patterns. [ 44 ]…”

Section: Methodsmentioning

confidence: 99%

Design of enamides as new selective monoamine oxidase-B inhibitors

Kavully¹,

Dev³

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives To develop of new class of selective and reversible MAO-B inhibitors from enamides. Methods Syntheses of the titled derivatives (AD1-AD11) were achieved by reacting cinnamoyl chloride and various primary and secondary amines in basic medium. All eleven compounds were investigated for in vitro inhibitory activities against recombinant human MAO-A and MAO-B. The reversibilities of lead compound inhibitions were analysed by dialysis. MTT assays of lead compounds were performed using normal VERO cell lines. Key findings Compounds AD3 and AD9 exhibited the greatest inhibitory activity against MAO-B with IC 50 values of 0.11 and 0.10 µM, respectively, and were followed by AD2 and AD1 (0.51 and 0.71 µM, respectively). Most of the compounds weakly inhibited MAO-A, with the exceptions AD9 and AD7, which had IC 50 values of 4.21 and 5.95 µM, respectively. AD3 had the highest selectivity index (SI) value for MAO-B (>363.6) and was followed by AD9 (SI 42.1). AD3 and AD9 were found to be competitive inhibitors of MAO-B with K i values of 0.044 AE 0.0036 and 0.039 AE 0.0047 µM, respectively. Reversibility experiments showed AD3 and AD9 were reversible inhibitors of MAO-B; dialysis restored the activity of MAO-B to the reference level. MTT assays revealed AD3 and AD9 were non-toxic to normal VERO cell lines with IC 50 values of 153.96 and 194.04 µg/ml, respectively. Computational studies provided hypothetical binding modes for AD3 and AD9 in the binding cavities of MAO-A and MAO-B. Conclusions These results encourage further studies on the enamide scaffold as potential drug candidates for the treatment of Alzheimer's and Parkinson's diseases.

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“…The relative activities of undialysed ( A U ) and dialysed ( A D ) samples were compared to determine reversibility patterns. [ 44 ]…”

Section: Methodsmentioning

confidence: 99%

Design of enamides as new selective monoamine oxidase-B inhibitors

Kavully¹,

Dev³

et al. 2020

Journal of Pharmacy and Pharmacology

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“…[14] On the other hand, imidazole, a nitrogenbased heterocylic molecule also showed significant inhibition of MAO. [15] Thus, prompted by the above, in the present study, we envisaged to develop hybrid conjugate of procaineimidazole as potent and selective MAO-B inhibitor. The most potent MAO-B inhibitor among the tested series was subjected for in vivo efficacy in the mouse model of PD.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Procaine‐Imidazole Derivative as Inhibitor of Monoamine Oxidase‐B for Potential Benefit in Parkinson's Disease

Liu

et al. 2020

ChemistrySelect

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The clinically utility of selective monoamine oxidase (MAO)‐B inhibitors in Parkinson disease is widely recognized due to significant improvement in altered motor function and long‐term benefit. Therefore, in the present study, a series of procaine‐imidazole was synthesized and subsequently evaluated for MAO‐A and MAO‐B inhibitory activity in an enzymatic assay. Comparative inhibitory activity suggest that, target compounds selectively inhibit MAO‐B, as compared to MAO‐A. Among the tested derivatives, compound 8 i (2‐(diethylamino)ethyl4‐(4‐(4‐fluorophenyl)‐2‐(4‐hydroxyphenyl)‐1H‐imidazol‐1‐yl)benzoate) selectively inhibited MAO‐B with IC50 of 0.032±0.002 (selectivity index over MAO‐A=475). The anti‐Parkinson effect of compound 8 i was further evaluated in MPTP (1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine) induced animal model of PD. It has been found that, compound 8 i causes significant improvement in motor function of mice as revealed by motor behavioral assessment using the footprint and horizontal wire test. Compound 8 i also improved the level of anti‐oxidant enzymes in the striatum of animal brains. Our study demonstrated the development of procaine‐imidazole derivatives as potent and selective MAO‐B inhibitor as potential agent against PD.

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“…[14][15][16][17] The chalcone is considered a privileged scaffold for the design of MAOs and ChEs inhibitors. [18][19][20][21][22][23][24][25][26][27][28][29] Chalcone scaffold can contribute to selective MAO inhibitions and multitarget agents by making diverse derivatives with heterocycles and masked chalcone motifs. [30] The introduction of various heterocycles and the incorporation of interesting pharmacophores on the chalcone aromatic nucleus can be performed in a number of ways.…”

mentioning

confidence: 99%

Selected 1,3‐Benzodioxine‐Containing Chalcones as Multipotent Oxidase and Acetylcholinesterase Inhibitors

Jeong

Kaipakasseri²,

Lee

et al. 2020

ChemMedChem

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Chalcones are considered effective templates for the development of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors. The present work describes the syntheses of selected 1,3-benzodioxine-containing chalcones (CD3, CD8 and CD10), and their inhibitory activities against MAO-A, MAO-B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Compound CD8 most potently inhibited MAO-B with an IC 50 value of 0.026 μM, followed by CD10 and CD3 (1.54 and 1.68 μM, respectively). CD8 potently and non-selectively inhibited MAO-A (IC 50 value of 0.023 μM). On the other hand, CD10 and CD8 inhibited AChE with IC 50 values of 5.40 and 9.57 μM, respectively. Kinetics and reversibility experiments showed that all synthesized molecules were competitive and reversible inhibitors, and the K i values of CD8 for MAO-A and MAO-B were 0.018 and 0.0019 μM, respectively. By in vitro and in silico analyses, all compounds were found to have high passive human gastrointestinal absorptions, blood-brain barrier permeabilities, and non-toxicities. Molecular docking simulations revealed that docking affinity of each compound for MAO-B was higher than that for MAO-A. The results indicate that CD8 is a potent non-selective MAO inhibitor, and CD10 is an effective selective MAO-B inhibitor, and both possess AChE inhibitory activity. Therefore, we suggest that CD8 and CD10 be considered potential dual-targeting inhibitors of MAO and AChE for the treatment of various neurodegenerative disorders. Multi-targeted directed ligands (MTDLs) are aimed at biasing multiple interconnected biochemical pathways. [1,2] Medicinal chemistry has shifted away from the "one drug, one target" paradigm toward the use of the molecular hybridization principle, which states that biological activities can be better explained from a basis of common pharmacophore features. [3] For instance, conventional drug developmental approaches to the treatment of complex multifactorial neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) have often been unsuccessful. [4,5] The etiology of AD is mainly associated with the overproduction of reactive oxygen species (ROS), dyshomeostasis of biometals like copper, iron and zinc, and low levels of acetylcholine (ACh), which in AD patients mediates neuronal dysfunction characterized by memory loss and mood alterations. [6] Accumulating evidence from in vitro and in vivo studies suggests that MTDLs seem to provide better outcomes than single-targeting drugs in the context of neurodegenerative diseases. [7] Recently, researchers have claimed that dual acting monoamine oxidase (MAO) and acetylcholinesterase (AChE)/ butyrylcholine-esterase (BChE) inhibitors can address the symptoms of AD and PD. [8] MAOs and cholinesterases (ChEs) have recently attracted considerable attention due to their involvement in the onset of AD. [9] MAOs are flavin adenine dinucleotide (FAD) containing enzymes and consist of two isoforms: MAO-A and MAO-B, which are involved in the oxidative deamination of biogenic amin...

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Imidazole bearing chalcones as a new class of monoamine oxidase inhibitors

Cited by 40 publications

References 49 publications

Design of enamides as new selective monoamine oxidase-B inhibitors

Design of enamides as new selective monoamine oxidase-B inhibitors

Discovery of Novel Procaine‐Imidazole Derivative as Inhibitor of Monoamine Oxidase‐B for Potential Benefit in Parkinson's Disease

Selected 1,3‐Benzodioxine‐Containing Chalcones as Multipotent Oxidase and Acetylcholinesterase Inhibitors

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