Title:Pyrazole Derivatives of Medically Relevant Phenolic Acids: Insight into Antioxidative and Anti-LOX Activity
Volume: 17
Issue: 8
Author(s): Vesna Milovanović, Zorica D. Petrović*, Slađana Novaković, Goran A. Bogdanović, Dušica Simijonović, Milan Mladenović, Jovica Branković and Vladimir P. Petrović
Affiliation:
- Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovica 12, 34000 Kragujevac,Serbia
Keywords:
Phenolic pyrazoles synthesis, X-ray crystal structure, antioxidative activity, anti-LOX activity, density functional
theory, molecular docking.
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, the single-crystal X-ray 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. The 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.