Xanthine Oxidase Inhibitory and Molecular Docking Studies on Pyrimidones

Title:Xanthine Oxidase Inhibitory and Molecular Docking Studies on Pyrimidones

Volume: 14 Issue: 5

Author(s): Humaira Zafar, Sarosh Iqbal, Sumaira Javaid, Khalid M. Khan*Muhammad I. Choudhary*

Affiliation:

• H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270,Pakistan

• H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270,Pakistan

Keywords: Pyrimidine carboxylate, Xanthine Oxidase Inhibition, Hyperuricemia, Gout, Uric Acid, Structure-activity relationship.

Abstract: Background: Xanthine oxidase is an important enzyme which catalyzes the production of uric acid and superoxide anion from xanthine. The over-production of these products leads to different disease conditions. For instance, uric acid is responsible for hyperuricemia, gout, and arthritis, while superoxide anion contributes to the oxidative stress, and related diseases. Hence XO is an important pharmacological target for the treatment of a range of diseases.

Methods: Based on the structural resemblance of pyrimidines with xanthine, a series of previously synthesized ethyl 6- methyl-2-oxo-1, 2, 3, 4-tetrahydro-5-pyrimidinecarboxylate derivatives were evaluated for XO inhibitory activity.

Results: Among 25 pyrimidone derivatives, 22 were found to be good to weak inhibitors with IC50 values in the range of 14.4 - 418 µM. Compounds 3, 14, 15, 18, and 21-23 were significant inhibitors, and thus analyzed for their kinetic parameters. Among them compounds 14, 15, 18, and 23 were competitive, 21 and 22 showed non-competitive, while 23 was a mixed-type of inhibitor. Molecular docking studies highlighted the interactions of these inhibitors with critical amino acids of XO, such as Val1011, Phe649, Lys771, and others. Moreover, the cytotoxicity studies on these selected inhibitors showed all these compounds to be non-cytotoxic.

Conclusion: These non-cytotoxic, significant XO inhibitors can thus be further investigated for the treatment of hyperuricemia, and gout.

Cite this article as:

Zafar Humaira , Iqbal Sarosh , Javaid Sumaira , Khan M. Khalid *, Choudhary I. Muhammad *, Xanthine Oxidase Inhibitory and Molecular Docking Studies on Pyrimidones, Medicinal Chemistry 2018; 14 (5) . https://dx.doi.org/10.2174/1573406413666171129224919