Therapeutic potential of synthetic pyrazolotriazinones for the hyperuricemia treatment

M. LOURDES SCIÚ; SANTI, D; ROCA MAGADÁN, C; CAMPILLO, N; MARTINEZ, ANA; E. L. MOYANO

BUENOS AIRES

Conferencia; Reunión Conjunta de Sociedades de Biociencias; 2017

SAFE

Abstract: Xanthine oxidase (XO) is a widely distributed enzyme involve in the laterstages of purine catabolism, catalyzing the oxidation of hypoxanthine to xanthineand of xanthine to uric acid. A high level of this acid in the blood stream producedhyperuricemia, which could develop to gout, nephrolithiasis, cardiovasculardisease, hypertension and diabetes, among others. Allopurinol is a well-knownXO inhibitor, a purine analogue, currently used for the treatment of hyperuricemia.However, numerous side effects have been reported due to Allopurinoladministration.In this study, pyrazolotriazinone compounds structurally related to purine baseswere synthesized and evaluated for their ability to inhibit XO in vitro. Moleculardocking studies has been performed to explain the binding modes of XO with theselected compounds.Pyrazolo[3,4-d][1,2,3]triazin-4-ones and ethyl 4-oxo-4,6-dihydro-3Hpyrazolo[4,3-d]triazine-7-carboxylates with different substituents in the N-7 andN-6, respectively, were synthesized with moderate to very good yields using asimple protocol. Following, all compounds were evaluated in vitro as XO inhibitorand IC50 values were calculated. Most of the tested compounds acted significantXO inhibition with IC50 values in the micromolar-submicromolar rang.Considering the experimental results, docking studies were performed todetermine the binding mode of both pyrazolotriazinones scaffolds. Maininteractions between the XO and each inhibitor were determined and thedifferences of inhibition behavior for each compound was stated.In summary, two sets of compounds containing the pyrazolotriazinone nucleuswere synthesized and identified as potent XO inhibitors. Molecular modelingprovided a reasonable explanation for the structure?activity relationshipsobserved in this study.