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

Abstract

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 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 can be considered potential candidates for the treatment of neurological disorders such as Alzheimer's disease and Parkinson's disease.

• Authors: Bijo Mathew, Jong Min Oh, Roua S Baty, Gaber El-Saber Batiha, Della Grace Thomas Parambi, Nicola Gambacorta, Orazio Nicolotti, Hoon Kim
• Journal: Environmental science and pollution research international (Environ Sci Pollut Res Int) Vol. 28 Issue 29 Pg. 38855-38866 (Aug 2021) ISSN: 1614-7499 [Electronic] Germany
• PMID: 33743158 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Chalcones
• Cholinesterase Inhibitors
• Monoamine Oxidase Inhibitors
• Piperazine
• Monoamine Oxidase

Topics

• Alzheimer Disease (drug therapy)
• Chalcones (pharmacology)
• Cholinesterase Inhibitors (pharmacology)
• Humans
• Kinetics
• Molecular Docking Simulation
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (pharmacology)
• Piperazine
• Structure-Activity Relationship