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Metformin and its sulphonamide derivative simultaneously potentiateanti-cholinesterase activity of donepezil and inhibit beta-amyloid aggregation.
- Source :
-
Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2018 Dec; Vol. 33 (1), pp. 1309-1322. - Publication Year :
- 2018
-
Abstract
- The aim of this study was to assess in vitro the effects of sulphenamide and sulphonamide derivatives of metformin on the activity of human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), establish the type of inhibition, and assess the potential synergism between biguanides and donepezil towards both cholinesterases (ChEs) and the effects on the β-amyloid aggregation. Sulphonamide 5 with para-trifluoromethyl- and ortho-nitro substituents in aromatic ring inhibited AChE in a mixed-type manner at micromolar concentrations (IC <subscript>50</subscript> = 212.5 ± 48.3 µmol/L). The binary mixtures of donepezil and biguanides produce an anti-AChE effect, which was greater than either compound had alone. A combination of donepezil and sulphonamide 5 improved the IC <subscript>50</subscript> value by 170 times. Compound 5 at 200 µmol/L inhibited Aβ aggregation by ∼20%. In conclusion, para-trifluoromethyl-ortho-nitro-benzenesulphonamide presents highly beneficial anti-AChE and anti-Aβ aggregation properties which could serve as a promising starting point for the design and development of novel biguanide-based candidates for AD treatment.
- Subjects :
- Acetylcholinesterase blood
Acetylcholinesterase metabolism
Alzheimer Disease drug therapy
Alzheimer Disease metabolism
Butyrylcholinesterase blood
Butyrylcholinesterase metabolism
Cholinesterase Inhibitors chemistry
Donepezil
Dose-Response Relationship, Drug
Healthy Volunteers
Humans
Indans chemistry
Inhibitory Concentration 50
Kinetics
Metformin chemistry
Molecular Structure
Piperidines chemistry
Protein Binding drug effects
Structure-Activity Relationship
Amyloid beta-Peptides metabolism
Cholinesterase Inhibitors pharmacology
Indans pharmacology
Metformin analogs & derivatives
Metformin pharmacology
Piperidines pharmacology
Sulfonamides chemistry
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1475-6374
- Volume :
- 33
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of enzyme inhibition and medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30251898
- Full Text :
- https://doi.org/10.1080/14756366.2018.1499627