Study of 5-nitroindazoles' anti-Trypanosoma cruzi mode of action: Electrochemical behaviour and ESR spectroscopic studies

J. RODRÍGUEZ; A. GERPE; G. AGUIRRE; U. KEMMERLING; O. E. PIRO; V. J. ARÁN; J. D. MAYA; C. OLEA-AZAR; M. GONZÁLEZ; H. CERECETTO

European Journal of Medicinal Chemistry

Elsevier

Año: 2009 vol. 44 p. 1545 - 1553

New indazole derivatives have been developed to know about structural requirements for adequate anti-Trypanosoma cruzi activity. In relation to position 1 of indazole ring, we have observed that a butylaminopentyl substituent (14) affords good activity, but N-oxidation of u-tertiary amino moiety yields completely inactive compounds (17, 18); the substituent at position 3 of indazole ring affects drastically the in vitro activity, 3-OH derivative 13 being completely inactive. On the other hand, since compound 22, denitro-analogue of active compound 4, does not show activity, the 5-nitro substituent of indazole ring seems to be essential. Intramolecular cyclization of side chain at position 1 also affords inactive compounds (19, 20). The electrochemical studies showed that the trypanocidal 5-nitroindazole derivatives yielded nitro-anion radical via one-electron process at physiological pH. This electrochemical behaviour occurs in the parasite according to ESR experiment with the T. cruzi microsomal fraction showing that 5-nitroindazole derivatives suffer bio-reduction without reactive oxygen species generation.