Anti-Trypanosoma cruzi Activity and Molecular Docking Studies of 1Hpyrazolo[ 3, 4-b]pyridine Derivatives

Abstract

Background: Untargeted studies led to the development of some pyrazolopyridine derivatives for the antiparasitic profile, particularly the derivatives containing the structural carbohydrazide subunit. In this work, we proceeded in the biological screening of 27 N’- (substitutedphenylmethylene)- 4-carbohydrazide-3-methyl-1-phenyl-1H-pyrazolo[3, 4-b]pyridine derivatives against T. cruzi as well as the cytotoxic evaluation. To obtain more information about the trypanocidal activity of this class of compounds, we carried out molecular docking simulations to get an insight into putative targets in T. cruzi. Methods: The assays were evaluated against both trypomastigote and amastigote forms of T. cruzi and cytotoxicity assays on LLCMK2 cells. The predominant conformational compounds were analyzed and molecular docking simulations performed. Results: The results from trypanocidal activity screening of this series showed that just the compounds with phenyl group at C-6 position exhibited activity and the N’-4-hydroxyphenylmethylene derivative presented the best profile against both trypomastigote and amastigote forms of T. cruzi. Docking simulation results showed that this compound has a binding affinity with both CYP51 and cruzain targets of T. cruzi. Conclusion: Our results indicate that the hydroxyl substituent at the N’-substituted-phenylmethylene moiety and the phenyl ring at C-6 of 1H-pyrazolo[3,4-b]pyridine system are relevant for the trypanocidal activity of this class of compounds. Also, docking simulations showed that activity presented can be related to more than one target of the parasite.