ABSTRACT
Fourteen (hetero-)(arylidene)arylhydrazide derivatives (ABH1-ABH14) were synthesized, and their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE) were evaluated. Compound ABH5 most potently inhibited MAO-B with an IC50 value of 0.025 ± 0.0019 µM; ABH2 and ABH3 exhibited high IC50 values as well. Most of the compounds weakly inhibited MAO-A, except ABH5 (IC50 = 3.31 ± 0.41 µM). Among the active compounds, ABH2 showed the highest selectivity index (SI) of 174 for MAO-B, followed by ABH5 (SI = 132). ABH3 and ABH5 effectively inhibited AChE with IC50 values of 15.7 ± 6.52 and 16.5 ± 7.29 µM, respectively, whereas the other compounds were weak inhibitors of AChE. ABH5 was shown to be a reversible competitive inhibitor for MAO-A and MAO-B with Ki values of 0.96 ± 0.19 and 0.024 ± 0.0077 µM, respectively, suggesting that this molecule can be considered as an interesting candidate for further development as a multitarget inhibitor relating to neurodegenerative disorders.
Subject(s)
Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase/metabolism , Neurodegenerative Diseases/drug therapy , Neuroprotective Agents/chemistry , Acetylcholinesterase/metabolism , AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase/metabolism , Drug Design , Humans , Hydrazines/chemistry , Molecular Docking Simulation , Monoamine Oxidase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Structure-Activity RelationshipABSTRACT
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 IC50 value of 0.026â µM, followed by CD10 and CD3 (1.54 and 1.68â µM, respectively). CD8 potently and non-selectively inhibited MAO-A (IC50 value of 0.023â µM). On the other hand, CD10 and CD8 inhibited AChE with IC50 values of 5.40 and 9.57â µM, respectively. Kinetics and reversibility experiments showed that all synthesized molecules were competitive and reversible inhibitors, and the Ki values of CD8 for MAO-A and MAO-B were 0.018 and 0.0019â µM, respectively. By inâ 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.
Subject(s)
Benzoxazines/pharmacology , Chalcones/pharmacology , Cholinesterase Inhibitors/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Acetylcholinesterase/metabolism , Benzoxazines/chemistry , Butyrylcholinesterase/metabolism , Chalcones/chemistry , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemistryABSTRACT
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 IC50 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 IC50 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 Ki values of 0.044 ± 0.0036 and 0.039 ± 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 IC50 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.
