In VivoAnti-Chagas Vinylthio-, Vinylsulfinyl-, and Vinylsulfonylbenzofuroxan Derivatives

Abstract

New benzofuroxans were developed and studied as antiproliferative Trypanosoma cruzi agents. Compounds displayed remarkable in vitro activities against different strains, Tulahuen 2, CL Brener and Y. Its unspecific cytotoxicity was evaluated using human macrophages being not toxic at a concentration at least 8 times, and until 250 times, that of its T. cruzi IC50. Some biochemical pathways were studied, namely parasite respiration, cysteinyl active site enzymes and reaction with glutathione, as target for the mechanism of action. Not only T. cruzi respiration but also Cruzipain or trypanothione reductase were not affected, however the most active derivatives, the vinylsulfinyl- and vinylsulfonyl-containing benzofuroxans, react with glutathione in a redox pathway. Furthermore, the compounds showed good in vivo activities when they were studied in an acute murine model of Chagas' disease. The compounds were able to reduce the parasite loads of animals with fully established T. cruzi infections.

Activity on Trypanosoma cruzi, erythrocytes lysis and biologically relevant physicochemical properties of Pd(II) and Pt(II) complexes of thiosemicarbazones derived from 1-indanones

“…The occurrence of the epimastigote form of T. cruzi as an obligate mammalian intracellular stage has been reevaluated and confirmed [42][43][44]. Furthermore, it should be noted that a good correlation between antiproliferative epimastigote activity and in vivo anti-T. cruzi activity was observed with several compounds [45][46][47][48][49].…”

Heterocyclic-2-carboxylic Acid (3-Cyano-1,4-di-N-oxidequinoxalin-2-yl)amide Derivatives as Hits for the Development of Neglected Disease Drugs

“…Trypanosoma cruzi epimastigotes (Tulahuen 2 strain) were grown at 28 ºC in an axenic medium (BHI-Tryptose) as previously described [ 28 , 29 , 30 ], supplemented with 5% fetal bovine serum (FBS). Cells from a 10-day-old culture (stationary phase) were inoculated into 50 mL of fresh culture medium in order to give an initial concentration of 1 × 10 6 cells/mL.…”

Synthetic Medicinal Chemistry in Chagas’ Disease: Compounds at The Final Stage of “Hit-To-Lead” Phase

“…Our group at Universidad de la República (Uruguay), in collaboration with Argentinean and Paraguayan teams has assessed nineteen nitroheterocyclic derivatives and ten N- oxide derivatives in different murine models of acute Chagas’ disease [131,132,133,134,135,136]. In our first approach, we found that each 5-nitrofuran derivative was more in vivo active than the corresponding 5-nitrothiophene analogue, e.g., comparing animals’ survival rates of derivatives 65 , 66 , 67 and 68 (Figure 5) where they were administered orally during 10 days at 66 mg/kg b. w./day.…”