New potent 5-nitroindazole derivatives as inhibitors of Trypanosoma cruzi growth: synthesis, biological evaluation, and mechanism of action studies.
New 5-nitroindazole derivatives were developed and their antichagasic properties studied. Eight compounds (14-18, 20, 26 and 28) displayed remarkable in vitro activities against Trypanosoma cruzi (T. cruzi). Its unspecific cytotoxicity against macrophages was evaluated being not toxic at a concentration at least twice that of T. cruzi IC(50), for some derivatives. The electrochemical studies, parasite respiration studies and ESR experiment showed that 5-nitroindazole derivatives not be able to yield a redox cycling with molecular oxygen such as occurs with nifurtimox (Nfx). The study on the mechanism of action proves to be related to the production of reduced species of the nitro moiety similar to that observed with benznidazole.
Rodríguez
Jorge
J
Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Chile.
Arán
Vicente J
VJ
Boiani
Lucía
L
Olea-Azar
Claudio
C
Lavaggi
María Laura
ML
González
Mercedes
M
Cerecetto
Hugo
H
Maya
Juan Diego
JD
Carrasco-Pozo
Catalina
C
Cosoy
Hernán Speisky
HS
D014355:Chagas Disease / Q000188:drug therapy* / Q000235:genetics; D018360:Crystallography, X-Ray; D016054:DNA, Protozoan / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000493:pharmacokinetics / Q000506:poisoning*; D014349:Trypanosoma cruzi / Q000187:drug effects*
D016054:DNA, Protozoan; D007191:Indazoles; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; C530840:5-nitroindazole; C009999:benzonidazole