2. Academic Validation
  3. Synthesis and biological evaluation of 2-methyl-1H-benzimidazole-5-carbohydrazides derivatives as modifiers of redox homeostasis of Trypanosoma cruzi

Synthesis and biological evaluation of 2-methyl-1H-benzimidazole-5-carbohydrazides derivatives as modifiers of redox homeostasis of Trypanosoma cruzi

  • Bioorg Med Chem Lett. 2017 Aug 1;27(15):3403-3407. doi: 10.1016/j.bmcl.2017.06.013.
Silvia Melchor-Doncel de la Torre 1,  Citlali Vázquez 2,  Zabdi González-Chávez 2,  Lilián Yépez-Mulia 3,  Rocío Nieto-Meneses 3,  Ricardo Jasso-Chávez 2,  Emma Saavedra 4,  Francisco Hernández-Luis 5
Affiliations

Affiliations

  • 1 Programa de Maestría y Doctorado Ciencias Químicas, Universidad Nacional Autónoma de México, México, DF 04510, Mexico; Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, México, DF 04510, Mexico.
  • 2 Departamento de Bioquímica, Instituto Nacional de Cardiología, Ignacio Chávez, México, DF 14080, Mexico.
  • 3 Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Instituto Mexicano del Seguro Social, México, DF 06720, Mexico.
  • 4 Departamento de Bioquímica, Instituto Nacional de Cardiología, Ignacio Chávez, México, DF 14080, Mexico. Electronic address: emma_saavedra@hotmail.com.
  • 5 Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, México, DF 04510, Mexico. Electronic address: franher@unam.mx.
PMID: 28648464 DOI: 10.1016/j.bmcl.2017.06.013
Abstract

Twelve novel benzimidazole derivatives were synthesized and their in vitro activities against epimastigotes of Trypanosoma cruzi were evaluated. Two derivatives (6 and 7), which have 4-hydroxy-3-methoxyphenyl moiety in their structures, proved to be the most active in inhibiting the Parasite growth. Compound 6 showed a trypanocidal activity higher than benznidazole (IC50=5µM and 7.5µM, respectively) and less than nifurtimox (IC50=3.6µM). In addition, the ability of 6 and 7 to modify the redox homeostasis in T cruzi epimastigote was studied; cysteine and glutathione increased in parasites exposed to both compounds, whereas trypanothione only increased with 7 treatment. These results suggest that the decrease in viability of T. cruzi may be attributed to the change in cellular redox balance caused by compound 6 or 7. Furthermore, compounds 6 and 7 showed CC50 values of 160.64 and 160.66µM when tested in mouse macrophage cell line J774 and selectivity indexes (macrophage/Parasite) of 32 and 20.1, respectively.

Keywords

Benzimidazole; Chagas disease; Oxidative stress; Trypanosoma cruzi.

Figures