New trypanocidal hybrid compounds from the association of hydrazone moieties and benzofuroxan heterocycle.
Hybrid compounds containing hydrazones and benzofuroxan pharmacophores were designed as potential Trypanosoma cruzi-enzyme inhibitors. The majority of the designed compounds was successfully synthesized and biologically evaluated displaying remarkable in vitro activity against different strains of T. cruzi. Unspecific cytotoxicity was evaluated using mouse macrophages, displaying isothiosemicarbazone 10 and thiosemicarbazone 12 selectivity indexes (macrophage/parasite) of 21 and 27, respectively. In addition, the mode of anti-trypanosomal action of the derivatives was investigated. Some of these derivatives were moderate inhibitors of cysteinyl active site enzymes of T. cruzi, cruzipain and trypanothione reductase. ESR experiments using T. cruzi microsomal fraction suggest that the main mechanism of action of the trypanocidal effects is the production of oxidative stress into the parasite.
Departamento de Química Orgánica, Facultad de Ciencias-Facultad de Química, Igua 4225, 11400 Montevideo, Uruguay.
Williams
W
Porcal
Paola
P
Hernández
Lucía
L
Boiani
Mariana
M
Boiani
Ana
A
Ferreira
Agustina
A
Chidichimo
Juan J
JJ
Cazzulo
Claudio
C
Olea-Azar
Mercedes
M
González
Hugo
H
Cerecetto
D000818:Animals; D001583:Benzoxazoles / Q000737:chemistry*; D003546:Cysteine Endopeptidases / Q000187:drug effects; D005978:Glutathione / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D006835:Hydrazones / Q000737:chemistry*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D015800:Protozoan Proteins; D013095:Spermidine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010069:Oxadiazoles
D001583:Benzoxazoles; D003546:Cysteine Endopeptidases; D005978:Glutathione; D006835:Hydrazones; D015800:Protozoan Proteins; D013095:Spermidine; D014344:Trypanocidal Agents; C014354:benzofuroxan; D010069:Oxadiazoles; C044809:trypanothione; C063214:cruzipain