ABSTRACT
The aim of this study was to design new molecules and evaluate their anticholinesterase and amyloid beta (Aß1-42) 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 Aß1-42 aggregation. 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 IC50 values of 1.08 and 1.09 µM. Compounds 16, 20, 21 and 22 exhibited remarkable inhibition of Aß1-42 aggregation. 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.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Drug Design , Indenes/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/prevention & control , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Indenes/chemical synthesis , Indenes/chemistry , Kinetics , Molecular Structure , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Structure-Activity RelationshipABSTRACT
Amyloid beta (Aß) and cholinesterase enzymes (AChE, BuChE) are important biological targets for the effective treatment of Alzheimer's disease. In this study, the aim was to synthesize new donepezil-like secondary amide compounds that display a potent inhibition of cholinesterases and Aß with antioxidant and metal chelation abilities. All test compounds showed activities against both ChEs and ß1-42 inhibition. The most encouraging compound, 20, is an AChE inhibitor with high anti-aggregation activity (55.3%). Based on the results, compound 20 may be a promising structure in further research for new anti-Alzheimer's agents.
Subject(s)
Alzheimer Disease/drug therapy , Drug Design , Indans/chemical synthesis , Piperidines/chemical synthesis , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Amyloid beta-Peptides/chemistry , Catalytic Domain , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Donepezil , Indans/chemistry , Indans/therapeutic use , Inhibitory Concentration 50 , Models, Molecular , Piperidines/chemistry , Piperidines/therapeutic use , Structure-Activity RelationshipABSTRACT
Thymus praecox ssp. grossheimii (RONNIGER) JALAS var. grossheimii (Lamiaceae) is used as an herbal tea for cold, stomachache, cough, and infections in Turkey. There are no phytochemical studies on this species. We performed phytochemical studies and quantitative analysis of rosmarinic acid and luteolin 5-O-ß-D-glucopyranoside in the methanol extract of the plant. Several chromatographic methods were used for the isolation of major compounds. HPLC methods were applied for quantitative analysis of rosmarinic acid and luteolin 5-O-ß-D-glucopyranoside in the methanol extract. In this study, ursolic acid (1), oleanolic acid (2), methyl rosmarinate (3), ethyl rosmarinate (4), rosmarinic acid (5), luteolin 5-O-ß-D-glucopyranoside (6), and thymoquinol 2,5-O-ß-diglucopyranoside (7) were isolated from the aerial parts of the plant. The relative contents of rosmarinic acid and luteolin 5-O-ß-D-glucopyranoside in the extract were 15.2 and 57.8 mg/g of dry weight, respectively. Compounds isolated from this plant and the contents of rosmarinic acid and luteolin 5-O-ß-D-glucopyranoside provided reasonable evidence for the traditional usages of this plant.
Subject(s)
Cinnamates/analysis , Depsides/analysis , Flavones/analysis , Glucosides/analysis , Phytochemicals/analysis , Thymus Plant/chemistry , Chromatography, High Pressure Liquid , Molecular Conformation , Rosmarinic AcidABSTRACT
Sonchus erzincanicus (Asteraceae) is an endemic species in Turkey, where six Sonchus species grow. In this study, a phytochemical study was performed on the aerial parts of the plant. The study describes the isolation and structure elucidation of five flavonoids and two a-ionone glycosides from S. erzincanicus. The compounds were isolated using several and repeated chromatographic techniques from ethyl acetate and aqueous phases that were partitioned from a methanol extract obtained from the plant. 5,7,3',4'-Tetrahydroxy-3-methoxyflavone (1) and quercetin 3-O-beta-D-glucoside (2) were isolated from the ethyl acetate phase, while corchoionoside C 6'-O-sulfate (3), corchoionoside C (4), luteolin 7-O-glucuronide (5) and luteolin 7-O-beta-D-glucoside (6), apigenin 7-O-glucuronide (7) were isolated from the aqueous phase. Corchoionoside C 6'-O-sulfate (3), isolated for the first time from a natural source, was a new compound. The structures of the compounds were elucidated by means of 1H-NMR, 13C-NMR, 2D-NMR (COSY, HMQC, HMBC) and ESI-MS.
