ESR spin trapping studies of free radicals generated from nitrofuran derivative analogues of nifurtimox by electrochemical and Trypanosoma cruzi reduction.
Electron spin resonance (ESR) spectra of radicals obtained from two analogues of the antiprotozoal drug nifurtimox by electrolytic and Trypanosoma cruzi reduction were analyzed. The electrochemistry of these compounds was studied using cyclic voltammetry. STO 3-21G ab initio and INDO molecular orbital calculations were performed to obtain the optimized geometries and spin distribution, respectively. The antioxidant effect of glutathione on the nitroheterocycle radical was evaluated. DMPO spin trapping was used to investigate the possible formation of free radicals in the trypanosome microsomal system. Nitro1 and Nitro2 nitrofuran analogues showed better antiparasitic activity than nifurtimox. Nitro2 produced oxygen redox cycling in T. cruzi epimastigotes. The ESR signal intensities were consistent with the trapping of either the hydroxyl radical or the Nitro2 analogue radicals. These results are in agreement with the biological observation that Nitro2 showed anti-Chagas activity by an oxidative stress mechanism.
Olea-Azar
Claudio
C
Department of Inorganic and Analytical Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, P.O. Box 233, Santiago 1, Chile. colea@uchile.cl
Rigol
Carolina
C
Mendizabal
Fernando
F
Morello
Antonio
A
Maya
Juan Diego
JD
Moncada
Claudio
C
Cabrera
Eliana
E
Di Maio
Rossana
R
González
Mercedes
M
Cerecetto
Hugo
H
D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology; D004563:Electrochemistry; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000032:analysis; D009547:Nifurtimox / Q000737:chemistry* / Q000494:pharmacology; D009581:Nitrofurans / Q000737:chemistry* / Q000494:pharmacology; D019097:Spin Trapping; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000502:physiology*
D000981:Antiprotozoal Agents; D005609:Free Radicals; D009581:Nitrofurans; D009547:Nifurtimox