title: Synthesis and evaluation of 7-substituted coumarin derivatives as multimodal monoamine oxidase-B and cholinesterase inhibitors for the treatment of Alzheimer's disease.
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 Aβ aggregation. From this study, compounds that 3 and 19 can be considered as promising multifunctional lead compounds.
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville, South Africa. Electronic address: jjoubert@uwc.ac.za.
authors.forename: Jacques
authors.initials: J
authors.lastname: Joubert
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville, South Africa.
authors.forename: Germaine B
authors.initials: GB
authors.lastname: Foka
authors.affiliation: School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, South Africa.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Repsold
authors.affiliation: School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, South Africa.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Oliver
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville, South Africa.
authors.forename: Erika
authors.initials: E
authors.lastname: Kapp
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville, South Africa.
authors.forename: Sarel F
authors.initials: SF
authors.lastname: Malan
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000187:drug effects; D000818:Animals; D001593:Benzyl Compounds / Q000737:chemistry; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008995:Monoamine Oxidase / Q000187:drug effects; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D010446:Peptide Fragments / Q000187:drug effects; D010880:Piperidines / Q000737:chemistry; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000517:prevention & control; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D001593:Benzyl Compounds; D002800:Cholinesterase Inhibitors; D003374:Coumarins; D008996:Monoamine Oxidase Inhibitors; D010446:Peptide Fragments; D010880:Piperidines; C078592:amyloid beta-protein (1-40); D008995:Monoamine Oxidase
keywords: Alzheimer's disease; Cholinesterase; Coumarin; Donepezil; MAO-B; Molecular modeling