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Eur J Med Chem ; 125: 853-864, 2017 Jan 05.
Article in English | MEDLINE | ID: mdl-27744252

ABSTRACT

A series of 7-substituted coumarin derivatives were designed and synthesised to display ChE and MAO-B inhibitory activity. The compounds consisted out of a coumarin structure (MAO-B inhibitor) and benzyl-, piperidine-, N-benzylpiperidine- or p-bromo-N-benzylpiperizine moiety, resembling the N-benzylpiperidine function of donepezil (ChE inhibitor), connected via an alkyl ether linkage at the 7 position. The biological assay results indicated that all the compounds (1-25) displayed selective inhibition to hMAO-B over hMAO-A, with the benzyloxy series (1-8, 10-13) showing nano-molar hMAO-B inhibition (IC50: 0.5-73 nM). Limited ChE inhibitory activity was however observed for the benzyloxy series with the exception of 2 and especially 3 showing selective BuChE inhibition. From this series 3 showed the best multifunctional activity (eqBuChE IC50 = 0.96 µM, hMAO-A IC50 = 2.13 µM, hMAO-B IC50 = 0.0021 µM). Within the N-benzylpiperidine (16-19) and p-bromo-N-benzylpiperizine (21-24) series the compounds in general showed moderate ChE and MAO-B inhibitory activity. Of these compounds 19 was the most potent multifunctional agent showing good eeAChE and eqBuChE inhibition (IC50 = 9.10 µM and 5.90 µM, respectively), and relatively potent and selective hMAO-B inhibition (IC50 = 0.30 µM, SI = >33). Molecular modeling revealed that 19 was able to bind simultaneously to the CAS, mid-gorge and PAS sites of AChE and BuChE suggesting that it will be able to inhibit AChE induced Aß aggregation. From this study, compounds that 3 and 19 can be considered as promising multifunctional lead compounds.


Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/chemical synthesis , Coumarins/therapeutic use , Monoamine Oxidase Inhibitors/chemical synthesis , Amyloid beta-Peptides/drug effects , Animals , Benzyl Compounds/chemistry , Binding Sites , Cholinesterase Inhibitors/pharmacology , Coumarins/chemical synthesis , Coumarins/chemistry , Coumarins/pharmacology , Dose-Response Relationship, Drug , Humans , Monoamine Oxidase/drug effects , Monoamine Oxidase Inhibitors/pharmacology , Peptide Fragments/drug effects , Piperidines/chemistry , Protein Aggregation, Pathological/drug therapy , Protein Aggregation, Pathological/prevention & control , Protein Binding , Structure-Activity Relationship
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