Inhibition of Xanthine Oxidase by Pyrazolone Derivatives Bearing a 4-(Furan-2-yl)benzoic Acid Moiety

Alona V. Beiko; Oleksandr L. Kobzar; Maryna V. Kachaeva; Stepan G. Pilyo; Vsevolod Yu. Tanchuk; Andriy I. Vovk

doi:10.24959/ophcj.23.298726

Authors

Alona V. Beiko V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Ukraine https://orcid.org/0000-0003-1119-988X
Oleksandr L. Kobzar V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Ukraine https://orcid.org/0000-0003-4370-7041
Maryna V. Kachaeva V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Ukraine https://orcid.org/0000-0003-1517-4807
Stepan G. Pilyo V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Ukraine https://orcid.org/0000-0002-7089-1393
Vsevolod Yu. Tanchuk V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Ukraine https://orcid.org/0000-0001-9055-870X
Andriy I. Vovk V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Ukraine https://orcid.org/0000-0001-6167-076X

DOI:

https://doi.org/10.24959/ophcj.23.298726

Keywords:

xanthine oxidase, inhibition, pyrazolone, benzoic acid, molecular docking, molecular dynamics

Abstract

The pyrazolone-based 4-(furan-2-yl)benzoic acids have been synthesized and studied as xanthine oxidase inhibitors. This enzyme is one of the therapeutic targets for the treatment of hyperuricemia and related diseases. The compounds studied have found to exhibit low micromolar IC₅₀ values relative to the enzyme in vitro, depending on substituents in position 3 of the pyrazolone ring. However, the inhibitory effects observed are reduced in the presence of bovine serum albumin or Tween-80. Among the pyrazolone derivatives synthesized, 4-(5-((3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)methyl)furan-2-yl)benzoic acid has been found to be the most potent inhibitor of xanthine oxidase. Kinetic results have shown that this compound is a mixed-type inhibitor with higher affinity to the free enzyme than to the enzyme-substrate complex. The results of the molecular docking and molecular dynamics show that the carboxylic group of the inhibitor can form a salt bridge with Arg880 and a hydrogen bond with Thr1010. These interactions can be key factors in the enzyme-inhibitor complex stabilization.

Supporting Agency

The work was founded by the National Academy of Sciences of Ukraine.

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References

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