Megazol and its bioisostere 4H-1,2,4-triazole: comparing the trypanocidal, cytotoxic and genotoxic activities and their in vitro and in silico interactions with the Trypanosoma brucei nitroreductase enzyme
Mem. Inst. Oswaldo Cruz
; 109(3): 315-323, 06/2014. tab, graf
Article
en En
| LILACS
| ID: lil-711722
Biblioteca responsable:
BR1.1
ABSTRACT
Megazol (7) is a 5-nitroimidazole that is highly active against Trypanosoma cruzi and Trypanosoma brucei, as well as drug-resistant forms of trypanosomiasis. Compound 7 is not used clinically due to its mutagenic and genotoxic properties, but has been largely used as a lead compound. Here, we compared the activity of 7 with its 4H-1,2,4-triazole bioisostere (8) in bloodstream forms of T. brucei and T. cruzi and evaluated their activation by T. brucei type I nitroreductase (TbNTR) enzyme. We also analysed the cytotoxic and genotoxic effects of these compounds in whole human blood using Comet and fluorescein diacetate/ethidium bromide assays. Although the only difference between 7 and 8 is the substitution of sulphur (in the thiadiazole in 7) for nitrogen (in the triazole in 8), the results indicated that 8 had poorer antiparasitic activity than 7 and was not genotoxic, whereas 7 presented this effect. The determination of Vmax indicated that although 8 was metabolised more rapidly than 7, it bounds to the TbNTR with better affinity, resulting in equivalent kcat/KM values. Docking assays of 7 and 8 performed within the active site of a homology model of the TbNTR indicating that 8 had greater affinity than 7.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
LILACS
Asunto principal:
Tiadiazoles
/
Triazoles
/
Tripanocidas
/
Trypanosoma brucei brucei
/
Nitrorreductasas
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Mem. Inst. Oswaldo Cruz
Asunto de la revista:
MEDICINA TROPICAL
/
PARASITOLOGIA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Brasil