Dataset Information

Metformin and its sulphonamide derivative simultaneously potentiateanti-cholinesterase activity of donepezil and inhibit beta-amyloid aggregation.

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 ?-amyloid aggregation. Sulphonamide 5 with para-trifluoromethyl- and ortho-nitro substituents in aromatic ring inhibited AChE in a mixed-type manner at micromolar concentrations (IC₅₀?=?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 IC₅₀ value by 170 times. Compound 5 at 200?µmol/L inhibited A? aggregation by ?20%. In conclusion, para-trifluoromethyl-ortho-nitro-benzenesulphonamide presents highly beneficial anti-AChE and anti-A? aggregation properties which could serve as a promising starting point for the design and development of novel biguanide-based candidates for AD treatment.

SUBMITTER: Markowicz-Piasecka M

PROVIDER: S-EPMC6161601 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Metformin and its sulphonamide derivative simultaneously potentiateanti-cholinesterase activity of donepezil and inhibit beta-amyloid aggregation.

Markowicz-Piasecka Magdalena M Huttunen Kristiina M KM Sikora Joanna J

Journal of enzyme inhibition and medicinal chemistry 20181201 1

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 ...[more]

PMID: 30251898

Similar Datasets

Project description:The misfolding and aggregation of amyloid-β (Aβ) peptides into amyloid fibrils is regarded as one of the causative events in the pathogenesis of Alzheimer's disease (AD). Tanshinones extracted from Chinese herb Danshen (Salvia Miltiorrhiza Bunge) were traditionally used as anti-inflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. A number of studies have suggested that tanshinones could protect neuronal cells. In this work, we examine the inhibitory activity of tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, on the aggregation and toxicity of Aβ1-42 using atomic force microscopy (AFM), thioflavin-T (ThT) fluorescence assay, cell viability assay, and molecular dynamics (MD) simulations. AFM and ThT results show that both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2. Live/dead assay further confirms that introduction of a very small amount of tanshinones enables protection of cultured SH-SY5Y cells against Aβ-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent Aβ peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic β-sheet groove formed by the C-terminal residues of I31-M35 and M35-V39 and several aromatic residues. Meanwhile, the differences in binding distribution, residues, sites, population, and affinity between TS1-Aβ and TS2-Aβ systems also interpret different inhibitory effects on Aβ aggregation as observed by in vitro experiments. More importantly, due to nonspecific binding mode of tanshinones, it is expected that tanshinones would have a general inhibitory efficacy of a wide range of amyloid peptides. These findings suggest that tanshinones, particularly TS1 compound, offer promising lead compounds with dual protective role in anti-inflammation and antiaggregation for further development of Aβ inhibitors to prevent and disaggregate amyloid formation.

Dataset Information

Metformin and its sulphonamide derivative simultaneously potentiateanti-cholinesterase activity of donepezil and inhibit beta-amyloid aggregation.

Publications

Metformin and its sulphonamide derivative simultaneously potentiateanti-cholinesterase activity of donepezil and inhibit beta-amyloid aggregation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets