THERAPEUTIC POTENTIAL OF SYNTHETIC PYRAZOLOTRIAZINONES FOR THE HYPERURICEMIA TREATMENT

M. LOURDES SCIÚ; NURIA E. CAMPILLO; CARLOS ROCA MAGADÁN; M. DANIELA SANTI; ANA MARTINEZ

Buenos Aires

Otro; Reunión conjunta de sociedades de Biociencias; 2017

SAA, SAB, SAIC, SAIB, SAI, SAFE, SAH,SAP, SAB,SAFIS

XO inhibitor, a purine analogue, currently used for the treatment ofhyperuricemia. However, numerous side effects have been reporteddue to Allopurinol administration, such as hepatitis, nephropathy,and allergic reactions.In this study, pyrazolotriazinone compounds structurally relatedto purine bases were synthesized and evaluated for their ability toinhibit XO in vitro. Molecular docking studies were performed to explainthe binding mode of XO with the selected compounds.Pyrazolo[3,4-d][1,2,3]triazin-4-ones and ethyl 4-oxo-4,6-dihydro-3H-pyrazolo[4,3-d]triazine-7-carboxylates with different substituentsin the N-7 and N-6, respectively, were synthesized with moderateto very good yields using a simple protocol (Colomer et. al).Following, all compounds were evaluated as XO inhibitor as indicatedby Schmeda-Hirschmann et. al. and IC50 values were estimated.As a result, most of the tested compounds presented significant XOinhibition with IC50 values in the micromolar-submicromolar range(0,9-8,5 μM).Considering the experimental results, docking studies were performedto determine the binding mode of both pyrazolotriazinonesscaffolds. Main interactions between catalytic residues of XO (PDBID: 1N5X) and each inhibitor were determined and the differences ofinhibition behavior for each compound were stablished.In summary, two sets of compounds containing the pyrazolotriazinonenucleus were synthesized and identified as potent XO inhibitors.Molecular modeling provided a reasonable explanation for thestructure?activity relationships observed in the in vitro assays.Keywords: xanthine oxidase, pyrazolotriazinones,