Identification of pyrazolotriazinones as potential agents for hyperuricemia treatment by using in vitro and in silico studies

Heterocyclic compounds structurally related to purine bases have been described as anticonvulsants, antifungal, antiviral, anticancer, enzyme inhibitors, among others. In this work, pyrazolo[3,4-d][1-3]triazin-4-ones (2) and pyrazolo[4,3-d][1-3]triazin-4-ones (3) derivatives were evaluated as xanthine oxidase (XO) inhibitors. Compounds 3 showed the best activity with IC50 values range of 0.9–2.9 µM. While the inhibition performance of pyrazolotriazinones was not more active than reference inhibitor allopurinol (IC50 = 0.247 ± 0.004) µM, these nuclei provide a platform for new and more potent XO inhibitors. Accordingly, molecular modeling methods were carried out to understand the compounds-enzyme binding mode. First, we have performed a qualitative SAR study using the MOE™ SAR tool. This study showed three common scaffolds and the most active was identified. These results are certainly valuable and will be taken into account in future synthesis of structurally related compounds. Furthermore, QSAR 2D and 3D studies were performed and structural requirements for the activity are reported. The obtained results led us to present the structural improvements for the rational design and synthesis of new pyrazolotriazinone derivatives with greater xanthine oxidase inhibitory activity than allopurinol.