Abstract
A series of 3-substituted-7-aminoalcoxy-coumarin was designed and evaluated as cholinesterase inhibitors and antioxidants. All compounds were effective in inhibiting AChE with potencies in the nanomolar range. The 3-(4-(dimethylamino)phenyl)-7-aminoethoxy-coumarin (6a) was considered a hit, showing good AChE inhibition potency (IC50 = 20 nM) and selectivity (IC50 BuChE/AChE = 354), quite similar to the reference drug donepezil (IC50 = 6 nM; IC50 BuChE/AChE = 365), also presenting antioxidant properties, low citotoxicity and good-predicted ADMET properties. The mode of action (mixed-type) and SAR analysis for this series of compounds were described by means of kinetic and molecular modeling evaluations.
Keywords:
Coumarins; antioxidant; bioisosterism; cholinesterase.
MeSH terms
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Acetylcholinesterase / metabolism*
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Animals
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Antioxidants / chemical synthesis
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Antioxidants / chemistry
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Antioxidants / pharmacology*
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Butyrylcholinesterase / metabolism*
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Cell Survival / drug effects
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Cholinesterase Inhibitors / chemical synthesis
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Cholinesterase Inhibitors / chemistry
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Cholinesterase Inhibitors / pharmacology*
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Coumarins / chemical synthesis
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Coumarins / chemistry
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Coumarins / pharmacology*
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Dose-Response Relationship, Drug
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Drug Discovery*
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Electrophorus
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Horses
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Mice
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Models, Molecular
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Molecular Structure
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Antioxidants
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Cholinesterase Inhibitors
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Coumarins
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Acetylcholinesterase
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Butyrylcholinesterase
Grants and funding
Fellowship and financial support for this study was provided by the CNPq (BR), FAPERJ (BR) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.