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

Article abstract of DOI:10.1016/j.bmcl.2017.06.013

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 m

Full text of DOI:10.1016/j.bmcl.2017.06.013

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Accepted Manuscript
Synthesis and biological evaluation of 2-methyl-1H-benzimidazole-5-carbohy-
drazides derivatives as modifiers of redox homeostasis of Trypanosoma cruzi
Silvia Melchor−Doncel de la Torre, Citlali Vázquez, Zabdi González-Chávez,
Lilián Yépez-Mulia, Rocío Nieto-Meneses, Ricardo Jasso−Chávez, Emma
Saavedra, Francisco Hernández-Luis
PII:
S0960-894X(17)30614-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.06.013
BMCL 25047
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 February 2017
1 June 2017
2 June 2017
Please cite this article as: de la Torre, S.M., Vázquez, C., González-Chávez, Z., Yépez-Mulia, L., Nieto-Meneses,
R., Jasso−Chávez, R., Saavedra, E., Hernández-Luis, F., Synthesis and biological evaluation of 2-methyl-1H-
benzimidazole-5-carbohydrazides derivatives as modifiers of redox homeostasis of Trypanosoma cruzi, Bioorganic
& Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.06.013
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Synthesis and biological evaluation of 2-methyl-1H-benzimidazole-5-carbohydrazides
derivatives as modifiers of redox homeostasis of Trypanosoma cruzi
Silvia Melchor−Doncel de la Torrea,b, Citlali Vázquezc, Zabdi González−Chávezc, Lilián
Yépez−Muliad, Rocío Nieto‒Menesesd, Ricardo Jasso−Chávez,c Emma Saavedrac*, Francisco
Hernández−Luisb*
aPrograma de Maestría y Doctorado Ciencias Químicas, Universidad Nacional Autónoma de
México, México, DF 04510, Mexico
bDepartamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de
México, México, DF 04510, Mexico
cDepartamento de Bioquímica, Instituto Nacional de Cardiología, Ignacio Chávez, México, DF
14080, Mexico
dUnidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Instituto
Mexicano del Seguro Social, México, DF 06720, Mexico
*Correspondig author:
E-mail adress: franher@unam.mx (Francisco Hernández-Luis), Tel./fax+52 56225286
E-mail adress: emma_saavedra@hotmail.com (Emma Saavedra), Tel. +52 55732911 ext 1298

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
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= 5 µM and 7.5 µM, respectively) and less than nifurtimox (IC50= 3.6 µM). 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 160.66
µM when tested in mouse macrophage cell line J774 and selectivity indexes
(macrophage/parasite) of 32 and 20.1, respectively.
Keywords: Trypanosoma cruzi; benzimidazole; oxidative stress; Chagas disease
Abbreviations: nifurtimox, Nfx; benznidazole, Bnz; glutathione reductase, GR;
malondialdehyde, MDA; glutathione, GSH; glutathione disulfide, GSSG; Trypanothione
T(SH)2.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Chagas disease, caused by the protozoa Trypanosoma cruzi, affects approximately 6 million
inhabitants on the American continent. It is listed by the World Health Organization as one of
the 17 Neglected Tropical Diseases (NTD).1 The parasite is transmitted to humans either by
blood-sucking triatomine vectors ("kissing" bug), by blood transfusion or by congenital
transmission. This ailment is manifested in two clinical phases: acute and chronic. The acute
infection is usually asymptomatic, but the ensuing chronic infection has been associated with
high rates of morbidity and mortality.2
Despite over 100 years have passed since the clinical description of Chagas disease, and the
tremendous efforts in the development of vaccines, so far chemotherapy remains as the only
economical and practical means to achieve its control. The current treatment against this
infection rely on two nitroheterocyclic drugs, benznidazole (Bnz) and nifurtimox (Nfx); which
were introduced to the clinic over thirty years ago.3 Both compounds are effective for acute
infections, but controversy exists on their use for chronic patients due to undesirable side
effects frequently forcing the abandonment of the treatment, besides their poor indices of
apparent cure, and a lack of consensus about criteria for parasitological cure. Because Bnz and
Nfx are far from being considered ideal trypanocidal drugs, the search for new compounds
effective against T. cruzi, with low toxicities and increased efficacies during the chronic phase,
continues. Trypanocidal effect of Bnz and Nfx depends on the formation of reactive
metabolites which mediate parasite killing.4 In fact, the reduction of Bnz by type I
nitroreductase activity leads to formation of glyoxal, a well–known toxic metabolite.5