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.