New perspectives on the synthesis and antichagasic activity of 3-alkoxy-1-alkyl-5-nitroindazoles.
The synthesis and antiprotozoal activity of some 3-alkoxy-1-alkyl- (1, 4) and 3-alkoxy-1-(ω-aminoalkyl)-5-nitroindazoles (2, 3, 5-8) against different morphological forms of Trypanosoma cruzi are reported. These compounds were prepared using simple alkylation reactions and, usually, taking advantage of the reactivity of some indazole-derived betaines previously studied by us. Most indazole derivatives showed in vitro activities similar or higher than those of the reference drug benznidazole; this fact, along with low unspecific cytotoxicities against Vero cells shown by some of them, led to very good selectivity indexes (SI). The high efficiency of 5-nitroindazoles 1 and 2 against T. cruzi was confirmed by further in vitro studies on infection rates and by an additional in vivo study in a murine model of acute and chronic Chagas disease. Complementary analyses of the changes in the metabolites excreted by the parasite and on the ultrastructural alterations induced after treatment with indazole derivatives 1 and 2 were also conducted.
Instituto de Química Médica (IQM), CSIC, c/ Juan de la Cierva 3, E-28006 Madrid, Spain.
Beatriz
B
Muro
Instituto de Química Médica (IQM), CSIC, c/ Juan de la Cierva 3, E-28006 Madrid, Spain.
Felipe
F
Reviriego
Instituto de Química Médica (IQM), CSIC, c/ Juan de la Cierva 3, E-28006 Madrid, Spain.
Pilar
P
Navarro
Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
Clotilde
C
Marín
Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
Inmaculada
I
Ramírez-Macías
Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
María José
MJ
Rosales
Departamento de Parasitología, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain. Electronic address: msanchem@ugr.es.
Manuel
M
Sánchez-Moreno
Instituto de Química Médica (IQM), CSIC, c/ Juan de la Cierva 3, E-28006 Madrid, Spain. Electronic address: vjaran@iqm.csic.es.
Vicente J
VJ
Arán
D000818:Animals; D014355:Chagas Disease / Q000517:prevention & control*; D002522:Chlorocebus aethiops; D006801:Humans; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014709:Vero Cells
D007191:Indazoles
Chagas disease; Cytotoxicity; In vitro assays; In vivo assays; Nitroindazoles