Complexation of the anti-Trypanosoma cruzi drug benznidazole improves solubility and efficacy.
The ruthenium complex, trans-[Ru(Bz)(NH 3) 4SO 2](CF 3SO 3) 2 1, Bz = benznidazole ( N-benzyl-2-(2-nitro-1 H-imidazol-1-yl)acetamide), is more hydrosoluble and more active (IC 50try/1 h = 79 +/- 3 microM) than free benznidazole 2 (IC 50try/1 h > 1 mM). 1 also exhibits low acute toxicity in vitro (IC 50macrophages > 1 mM) and in vivo (400 micromol/kg < LD 50 < 600 micromol/kg) and the formation of hydroxylamine is more favorable in 1 than in 2 by 9.6 kcal/mol. In murine acute models of Chagas' disease, 1 was more active than 2 even when only one dose was administrated. Moreover, 1 at a thousand-fold smaller concentration than the considered optimal dose for 2 (385 micromol/kg/day = 100 mg/kg/day), proved to be sufficient to protect all infected mice, eliminating the amastigotes in their hearts and skeletal muscles as observed in H&E micrographics.
Departamento de Quimica e Fisica Molecular, Instituto de Quimica de Sao Carlos, Universidade de Sao Paulo (USP), Sao Carlos, SP, Brazil.
Jean Jerley
JJ
Nogueira Silva
Wander Rogério
WR
Pavanelli
Fredy R Salazar
FR
Gutierrez
Francisco Chagas
FC
Alves Lima
Albérico Borges
AB
Ferreira da Silva
João
J
Santana Silva
Douglas
D
Wagner Franco
D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy; D004195:Disease Models, Animal; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D009593:Nitroimidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013056:Spectrophotometry, Ultraviolet; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects*
D009593:Nitroimidazoles; D014344:Trypanocidal Agents; C009999:benzonidazole