Dataset Information

Synthesis and Biological Assessment of 2-Hydroxyiminoethanones as Anti-Inflammatory and ?-Amyloid Aggregation Inhibitors.

ABSTRACT: Alzheimer's disease (AD) is a neuroinflammatory based pathologic state in which ?-amyloid aggregates are major devastating agents. In this study, a series of 2-hydroxyiminoethanones were synthesized and evaluated as anti-inflammatory in carrageenan and formalin tests and inhibitors of ?-amyloid aggregation. Compounds 1-10b were synthesized through a two-step reaction. Results: Compounds 1-5b showed more ?-amyloid disaggregation ability than reference drugs rifampicin and donepezil and compound 2b was the best compound in this series and could reduce the extent of amyloid aggregation to 50.9%. Interestingly, compounds 1b and 3b showed significant anti-inflammatory activity in carrageenan-induced paw edema compared to control group and equivalent to the reference drug indomethacin. 2-Hydeoxyiminoethanones are privileged scaffold for further drug research and development as anti-neuroinflammatory and neuroprotective agents.

SUBMITTER: Valipour M

PROVIDER: S-EPMC6934981 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Synthesis and Biological Assessment of 2-Hydroxyiminoethanones as Anti-Inflammatory and β-Amyloid Aggregation Inhibitors.

Valipour Mehdi M Davaji Issa I Abedi Niusha N Rajabi Mahsa M Küçükkılınç Tuba Tüylü TT Ayazgök Beyza B Irannejad Hamid H

Iranian journal of pharmaceutical research : IJPR 20190101 3

Alzheimer's disease (AD) is a neuroinflammatory based pathologic state in which β-amyloid aggregates are major devastating agents. In this study, a series of 2-hydroxyiminoethanones were synthesized and evaluated as anti-inflammatory in carrageenan and formalin tests and inhibitors of β-amyloid aggregation. Compounds <b>1-10b</b> were synthesized through a two-step reaction. Results: Compounds <b>1-5b</b> showed more β-amyloid disaggregation ability than reference drugs rifampicin and donepezil ...[more]

PMID: 32641939

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Project description:PurposeNonsteroidal anti-inflammatory drugs cause a series of adverse reactions. Thus, the search for new cyclooxygenase-2 selective inhibitors have become the main direction of research on anti-inflammatory drugs. Gentiopicroside is a novel selective inhibitor of cyclooxygenase-2 from Chinese herbal medicine. However, it is highly hydrophilic owing to the presence of the sugar fragment in its structure that reduces its oral bioavailability and limits efficacy. This study aimed to design and synthesize novel cyclooxygenase-2 inhibitors by modifying gentiopicroside structure and reducing its polarity.Materials and methodsWe introduced hydrophobic acyl chloride into the gentiopicroside structure to reduce its hydrophilicity and obtained some new derivatives. Their in vitro anti-inflammatory activities were evaluated against NO, TNF-α, PGE2, and IL-6 production in the mouse macrophage cell line RAW264.7 stimulated by lipopolysaccharide. The in vivo inhibitory activities were further tested against xylene-induced mouse ear swelling. Molecular docking predicted that whether new compounds could effectively bind to target protein cyclooxygenase-2. The inhibitory activity of new compounds to cyclooxygenase-2 enzyme were verified by the in vitro experiment.ResultsA total of 21 novel derivatives were synthesized, and exhibit lower polarities than the gentiopicroside. Most compounds have good in vitro anti-inflammatory activity. The in vivo activity results demonstrated that 8 compounds were more active than gentiopicroside. The inhibition rate of some compounds was higher than celecoxib. Molecular docking predicted that 6 compounds could bind to cyclooxygenase-2 and had high docking scores in accordance with their potency of the anti-inflammatory activity. The confirmatory experiment proved that these 6 compounds had significant inhibitory effect against cyclooxygenase-2 enzyme. Structure-activity relationship analysis presumed that the para-substitution with the electron-withdrawing groups may benefit the anti-inflammatory activity.ConclusionThese gentiopicroside derivatives especially PL-2, PL-7 and PL-8 may represent a novel class of cyclooxygenase-2 inhibitors and could thus be developed as new anti-inflammatory agents.

Dataset Information

Synthesis and Biological Assessment of 2-Hydroxyiminoethanones as Anti-Inflammatory and ?-Amyloid Aggregation Inhibitors.

Publications

Synthesis and Biological Assessment of 2-Hydroxyiminoethanones as Anti-Inflammatory and β-Amyloid Aggregation Inhibitors.

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