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Pyrazole Derivatives of Medically Relevant Phenolic Acids: Insight into Antioxidative and Anti-LOX Activity

Author(s):

Vesna Milovanović, Zorica D. Petrović*, Slađana Novaković, Goran A. Bogdanović, Dušica Simijonović, Milan Mladenović, Jovica Branković and Vladimir P. Petrović   Pages 1 - 13 ( 13 )

Abstract:


Background: From the point of view of medicinal chemistry, compounds containing phenolic and pyrazolic moiety are significant since they are often constituents of bioactive compounds.

Objective: The aims of this study were to synthesize pyrazole derivatives of medically relevant phenolic acids, confirm their structure, and evaluate their antioxidative and anti-LOX activities.

Methods: Phenolic pyrazole derivatives were obtained starting from esters of medically relevant phenolic acids. The structures of all obtained compounds were determined by NMR and IR spectroscopy, and UV-Vis spectrophotometry. In addition, single-crystal Xray diffraction was used. Pyrazole derivatives were tested for their in vitro antioxidative (DPPH assay), and lipoxygenase (LOX) inhibitory activities. Radical quenching mechanism was estimated using DFT and thermodynamic approach, while molecular docking was used to estimate the binding mode within the enzyme.

Results: Pyrazole derivatives were obtained in high yields. Crystal structure of a new compound 3e was determined. Pyrazole derivative with catechol moiety 3d exhibited excellent radical scavenging activity, while compound 3b exhibited the best anti-LOX activity. Molecular docking study revealed that there is no direct interaction of any ligand with the active site of LOX-Ib, but pyrazoles 3a-e behave as inhibitors blocking the approach of linoleic acid to the active site.

Conclusion: In this research, protocatechuic and vanillic acid pyrazole derivatives have been obtained for the first time. In vitro antioxidative assay suggests that pyrazole derivate of protocatechuic acid is a powerful radical scavenger, while anti-LOX assay indicates a pyrazole derivative with 4-hydroxyphenyl moiety.

Keywords:

Phenolic pyrazoles synthesis, X-ray crystal structure, Antioxidative activity, Anti-LOX activity, Density functional theory, Molecular docking.

Affiliation:

Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Vinča Institute of Nuclear Sciences,University of Belgrade, P.O. Box 522, 11001 Belgrade, Vinča Institute of Nuclear Sciences,University of Belgrade, P.O. Box 522, 11001 Belgrade, Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Center for Computational Biochemistry, Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac



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