Discovery of novel dual-active 3-(4-(dimethylamino)phenyl)-7-aminoalcoxy-coumarin as potent and selective acetylcholinesterase inhibitor and antioxidant.
Gabriela Alves de SouzaSoraia John da SilvaCatarina de Nigris Del CistiaPaulo Pitasse-SantosLucas de Oliveira PiresYulli Moraes PassosYraima CordeiroCristiane Martins CardosoRosane Nora CastroCarlos Mauricio R Sant'AnnaArthur Eugen KümmerlePublished in: Journal of enzyme inhibition and medicinal chemistry (2019)
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.