SAR and molecular mechanism studies of monoamine oxidase inhibition by selected chalcone analogs

Shalaby, Raed; Petzer, Jacobus P.; Petzer, Anél; Ashraf, Usman; Atari, Ealla; Alasmari, Fawaz; Kumarasamy, Sivarajan; Sari, Youssef; Khalil, Ashraf

doi:10.1080/14756366.2019.1593158

Cited by 43 publications

(20 citation statements)

References 27 publications

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“…Highlighting residues Cys172 and Tyr326, which are important for the active site of the rMAO-B flavoprotein. Tyr326 and Cys172 are key residues that determines substrate and inhibitor specificity, also exhibits conformational changes on the inhibitor binding and restricts the binding of certain inhibitors (e.g., harmine) to human MAO-B [ 38 ]. These results documents that ChC4 is a reversible inhibitor of rMAO-B.…”

Section: Resultsmentioning

confidence: 99%

Coumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies

et al. 2021

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Fourteen coumarin-derived compounds modified at the C3 carbon of coumarin with an α,β-unsaturated ketone were synthesized. These compounds may be designated as chalcocoumarins (3-cinnamoyl-2H-chromen-2-ones). Both chalcones and coumarins are recognized scaffolds in medicinal chemistry, showing diverse biological and pharmacological properties among which neuroprotective activities and multiple enzyme inhibition, including mitochondrial enzyme systems, stand out. The evaluation of monoamine oxidase B (MAO-B) inhibitors has aroused considerable interest as therapeutic agents for neurodegenerative diseases such as Parkinson’s. Of the fourteen chalcocumarins evaluated here against MAO-B, ChC4 showed the strongest activity in vitro, with IC50 = 0.76 ± 0.08 µM. Computational docking, molecular dynamics and MM/GBSA studies, confirm that ChC4 binds very stably to the active rMAO-B site, explaining the experimental inhibition data.

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Section: Resultsmentioning

confidence: 99%

Coumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies

et al. 2021

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“…Recent studies have reported that the presence of electrondonating groups, such as methyl, methoxy, ethyl, dimethylamino, and ethyl acetohydroxamate, at the para position of the phenyl B ring of chalcones confers greater MAO-B inhibition than MAO-A inhibition. Lipophilic halogen atoms (fluorine, chlorine, and bromine) at the same position also resulted in outstanding MAO-B inhibition (Morales-Camilo et al 2015;Reeta et al 2019;Shalaby et al 2019). In addition, the presence of an aliphatic or methyl-containing amino group or a nitrogen-derived pharmacophore in chalcones is required for AChE inhibition (Liu et al 2016;Xiao et al 2017;Bai et al 2019).…”

Section: Discussionmentioning

confidence: 99%

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

Mathew

Baty

et al. 2021

Environ Sci Pollut Res

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Eleven piperazine-containing 1,3-diphenylprop-2-en-1-one derivatives (PC1-PC11) were evaluated for their inhibitory activities against monoamine oxidases (MAOs), cholinesterases (ChEs), and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with a view toward developing new treatments for neurological disorders. Compounds PC10 and PC11 remarkably inhibited MAO-B with IC 50 values of 0.65 and 0.71 μM, respectively. Ten of the eleven compounds weakly inhibited AChE and BChE with > 50% of residual activities at 10 μM, although PC4 inhibited AChE by 56.6% (IC 50 = 8.77 μM). Compound PC3 effectively inhibited BACE-1 (IC 50 = 6.72 μM), and PC10 and PC11 moderately inhibited BACE-1 (IC 50 =14.9 and 15.3 μM, respectively). Reversibility and kinetic studies showed that PC10 and PC11 were reversible and competitive inhibitors of MAO-B with K i values of 0.63 ± 0.13 and 0.53 ± 0.068 μM, respectively. ADME predictions for lead compounds revealed that PC10 and PC11 have central nervous system (CNS) drug-likeness. Molecular docking simulations showed that fluorine atom and trifluoromethyl group on PC10 and PC11, respectively, interacted with the substrate cavity of the MAO-B active site. Our results suggested that PC10 and PC11 can be considered potential candidates for the treatment of neurological disorders such as Alzheimer's disease and Parkinson's disease.

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“…Recent studies have reported that the presence of electron-donating groups, such as methyl, methoxy, ethyl, dimethylamino, and ethyl acetohydroxamate, at the para position of the phenyl B ring of chalcones confers greater MAO-B inhibition than MAO-A inhibition. Lipophilic halogen atoms ( uorine, chlorine, and bromine) at the same position also resulted in outstanding MAO-B inhibition (Morales-Camilo et al, 2015;Reeta et al, 2019;Shalaby et al, 2019). In addition, the presence of an aliphatic or methyl containing amino group or a nitrogen-derived pharmacophore in chalcones is required for AChE inhibition (Liu et al, 2016;Xiao et al, 2017;Bai et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Piperazine-Substituted Chalcones: A New Class of MAO-B, AChE, and BACE-1 Inhibitors for the Treatment of Neurologic Al Disorders

Mathew

Al-Rashed

et al. 2021

Preprint

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Eleven piperazine-containing 1,3-diphenylprop-2-en-1-one derivatives (PC1-PC11) were evaluated for their inhibitory activities against monoamine oxidases (MAOs), cholinesterases (ChEs), and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with a view toward developing new treatments for neurological disorders. Compounds PC10 and PC11 remarkably inhibited MAO-B inhibition with IC50 values of 0.65 and 0.71 µM, respectively. Ten of the eleven compounds weakly inhibited AChE and BChE with > 50% of residual activities at 10 µM, although PC4 inhibited AChE by 56.6% (IC50 = 8.77 µM). Compound PC3 effectively inhibited BACE-1 (IC50 = 6.72 µM), and PC10 and PC11 moderately inhibited BACE-1 (IC50 =14.9 and 15.3 µM, respectively). Reversibility and kinetic studies showed that PC10 and PC11 were reversible and competitive inhibitors of MAO-B with Ki values of 0.63 ± 0.13 and 0.53 ± 0.068 µM, respectively. ADME predictions for lead compounds revealed that PC10 and PC11 have central nervous system (CNS) drug-likeness. Molecular docking simulations showed that fluorine atom and trifluoromethyl group on PC10 and PC11, respectively, interacted with the substrate cavity of the MAO-B active site. Our results suggested that PC10 and PC11 be considered potential candidates for the treatment of neurological disorders such as Alzheimer’s disease and Parkinson’s disease.

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SAR and molecular mechanism studies of monoamine oxidase inhibition by selected chalcone analogs

Cited by 43 publications

References 27 publications

Coumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies

Coumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies

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

Piperazine-Substituted Chalcones: A New Class of MAO-B, AChE, and BACE-1 Inhibitors for the Treatment of Neurologic Al Disorders

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