New 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine derivatives with potent antichagasic activitys

Abstract

Chagas’ disease is an infection caused by the protozoan Trypanosoma cruzi that represents a major public health threat in Latin America. Previously we developed 4carbohydrazide derivatives of 1H-pyrazolo[3,4-b]pyridine as antichagasic agents, which the hit compound was the N’-4-hydroxybenzylidene-carbohydrazide derivative. In order to verify the influence of the substituent position and the carbohydrazide moiety replacement for the 1,3,4-oxadiazoline moiety, herein we described the synthesis and in vitro evaluation of trypanocidal activity and cytotoxicity of eleven new 1,6-diphenyl-4-(substituted)-1Hpyrazolo[3,4-b]pyridine derivatives. All the new 1,6-diphenyl-3-methyl-4-(substituted)-1Hpyrazolo[3,4-b]pyridine derivatives were obtained with yields ranging from 70 to 95% and had their structures elucidated by spectroscopic methods. These compounds were evaluated in vitro against intracellular amastigote form of T. cruzi, using the benznidazole drug as the positive control and had their cytotoxicity profiles determined on LLCMK2 mammalian cells. Among the new compounds, the N’-2-hydroxybenzylidene-carbohydrazide and 2-(N’-acetyl1,3,4-oxadiazolin-2-yl)-phenyl acetate derivatives showed the most significant antichagasic activities and low cytotoxicity profile in comparison to benznidazole drug. The results suggest that the 2-substituted position of the phenyl group connected to the carbohydrazide or oxadiazoline moieties play an important role for the antichagasic activity of 1,6-diphenyl-4(substituted)-1H-pyrazolo[3,4-b]pyridines compounds. Furthermore, our results indicate a bioisosteric replacement of carbohydrazide moiety by the 1,3,4-oxadiazoline ring.