title: Design, synthesis and biological activity of 1H-indene-2-carboxamides as multi-targeted anti-Alzheimer agents.
abstract: The aim of this study was to design new molecules and evaluate their anticholinesterase and amyloid beta (Aβ1-42) inhibition activities as multifunctional drug candidates for the treatment of Alzheimer's disease (AD). A series of 5,6-dimethoxy-1H-indene-2-carboxamides (1-22) was synthesized; cholinesterase inhibitory activities of the compounds were measured according to Ellman's colorimetric assay, while the thioflavin T assay was used for measuring the inhibition of Aβ1-42aggregation. The results revealed that most compounds showed higher inhibitory activity against BuChE than AChE. Compounds 20 and 21 were found to be the most potent BuChE inhibitors with respective IC50values of 1.08 and 1.09 μM. Compounds 16, 20, 21 and 22 exhibited remarkable inhibition of Aβ1-42aggregation. Kinetic analysis showed that the most potent BuChE inhibitor (20) acted as a noncompetitive inhibitor. Docking studies suggested that inhibitor 20 displayed many potential hydrogen-bondings with the PAS of BuChE. These results suggest that compound 20 may be an especially promising multifunctional drug for the prevention and treatment of AD.
authors.affiliation: a Department of Pharmaceutical Chemistry.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Koca
authors.affiliation: a Department of Pharmaceutical Chemistry.
authors.forename: Kadir Ozden
authors.initials: KO
authors.lastname: Yerdelen
authors.affiliation: b Department of Organic Chemistry , and.
authors.forename: Baris
authors.initials: B
authors.lastname: Anil
authors.affiliation: a Department of Pharmaceutical Chemistry.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Kasap
authors.affiliation: c Department of Pharmacognosy , Ataturk University , Erzurum , Turkey.
authors.forename: Handan
authors.initials: H
authors.lastname: Sevindik
authors.affiliation: b Department of Organic Chemistry , and.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Ozyurek
authors.affiliation: a Department of Pharmaceutical Chemistry.
authors.forename: Gulsen
authors.initials: G
authors.lastname: Gunesacar
authors.affiliation: a Department of Pharmaceutical Chemistry.
authors.forename: Kubra
authors.initials: K
authors.lastname: Turkaydin
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D015394:Molecular Structure; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000614126:1H-indene-2-carboxamide; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D007192:Indenes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: AChE; Alzheimer; Aβ1–42; BuChE; molecular modeling