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Structure-activity relationship investigation of benzamide and picolinamide derivatives containing dimethylamine side chain as acetylcholinesterase inhibitors.

ABSTRACT: A series of benzamide and picolinamide derivatives containing dimethylamine side chain (4a-4c and 7a-7i) were synthesised and evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity in vitro. Structure-activity relationship investigation revealed that the substituted position of dimethylamine side chain markedly influenced the inhibitory activity and selectivity against AChE and BChE. In addition, it seemed that the bioactivity of picolinamide amide derivatives was stronger than that of benzamide derivatives. Among them, compound 7a revealed the most potent AChE inhibitory activity (IC50: 2.49?±?0.19??M) and the highest selectivity against AChE over BChE (Ratio: 99.40). Enzyme kinetic study indicated that compound 7a show a mixed-type inhibition against AChE. The molecular docking study revealed that this compound can bind with both the catalytic site and the peripheral site of AChE.

SUBMITTER: Gao XH

PROVIDER: S-EPMC6009985 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Structure-activity relationship investigation of benzamide and picolinamide derivatives containing dimethylamine side chain as acetylcholinesterase inhibitors.

Gao Xiao-Hui XH Liu Lin-Bo LB Liu Hao-Ran HR Tang Jing-Jing JJ Kang Lu L Wu Hongnian H Cui Peiwu P Yan Jianye J

Journal of enzyme inhibition and medicinal chemistry 20181201 1

A series of benzamide and picolinamide derivatives containing dimethylamine side chain (4a-4c and 7a-7i) were synthesised and evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity in vitro. Structure-activity relationship investigation revealed that the substituted position of dimethylamine side chain markedly influenced the inhibitory activity and selectivity against AChE and BChE. In addition, it seemed that the bioactivity of picolinamide amide derivat ...[more]

PMID: 29166796

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Project description:Helices are the most extensively studied secondary structures formed by ?-peptide foldamers. Among the five known ?-peptide helices, the 12-helix is particularly interesting because the internal hydrogen bond orientation and macrodipole are analogous to those of ?-peptide helices (?-helix and 3(10)-helix). The ?-peptide 12-helix is defined by i, i+3 C?O···H-N backbone hydrogen bonds and promoted by ?-residues with a five-membered ring constraint. The 12-helical scaffold has been used to generate ?-peptides with specific biological functions, for which diverse side chains must be properly placed along the backbone and, upon folding, properly arranged in space. Only two crystal structures of 12-helical ?-peptides have previously been reported, both for homooligomers of trans-2-aminocyclopentanecarboxylic acid (ACPC). Here we report five additional crystal structures of 12-helical ?-peptides, all containing residues that bear side chains. Four of the crystallized ?-peptides include trans-4,4-dimethyl-2-aminocyclopentanecarboxylic acid (dm-ACPC) residues, and the fifth contains a ?(3)-hPhe residue. These five ?-peptides adopt fully folded 12-helical conformations in the solid state. The new crystal structures, along with previously reported data, allow a detailed characterization of the 12-helical conformation; average backbone torsion angles of ?-residues and helical parameters are derived. These structural parameters are found to be similar to those for i, i+3 C?O···H-N hydrogen-bonded helices formed by other peptide backbones generated from ?- and/or ?-amino acids. The similarity between the conformational behavior of dm-ACPC and ACPC is consistent with previous NMR-based conclusions that 4,4-disubstituted ACPC derivatives are compatible with 12-helical folding. In addition, our data show how a ?(3)-residue is accommodated in the 12-helix, thus enhancing understanding of the diverse conformational behavior of this flexible class of ?-amino acids.

Dataset Information

Structure-activity relationship investigation of benzamide and picolinamide derivatives containing dimethylamine side chain as acetylcholinesterase inhibitors.

Publications

Structure-activity relationship investigation of benzamide and picolinamide derivatives containing dimethylamine side chain as acetylcholinesterase inhibitors.

Similar Datasets

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