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Molecules 2017, 22(4), 579; doi:10.3390/molecules22040579

Design, Synthesis and Biological Evaluation of 2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-arylacetamides as Antiprotozoal Agents

1
CONACYT, Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Mérida, Mérida 97310, Yucatán, Mexico
2
Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca 62210, Morelos, Mexico
3
Unidad Interinstitucional de Investigación Médica, Instituto Mexicano del Seguro Social/Universidad Autónoma de Yucatán, Mérida 97150, Yucatán, México
4
Facultad de Ingeniería, Universidad Autónoma de Yucatán, Mérida 97310, Yucatán, Mexico
5
CONACYT, Centro de Investigación Científica de Yucatán, Mérida 97200, Yucatán, Mexico
6
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico
*
Author to whom correspondence should be addressed.
Academic Editor: Diego Muñoz-Torrero
Received: 24 January 2017 / Revised: 31 March 2017 / Accepted: 31 March 2017 / Published: 4 April 2017
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
View Full-Text   |   Download PDF [3051 KB, uploaded 19 April 2017]   |  

Abstract

Parasitic diseases are a public health problem affecting millions of people worldwide. One of the scaffolds used in several drugs for the treatment of parasitic diseases is the benzimidazole moiety, a heterocyclic aromatic compound. This compound is a crucial pharmacophore group and is considered a privileged structure in medicinal chemistry. In this study, the benzimidazole core served as a model for the synthesis of a series of 2-(2-amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-arylacetamides 18 as benznidazole analogues. The in silico pharmacological results calculated with PASS platform exhibited chemical structures highly similar to known antiprotozoal drugs. Compounds 1–8 when evaluated in silico for acute toxicity by oral dosing, were less toxic than benznidazole. The synthesis of compounds 18 were carried out through reaction of 5(6)-nitro-1H-benzimidazol-2-amine (12) with 2-chlroactemides 10ah, in the presence of K2CO3 and acetonitrile as solvent, showing an inseparable mixture of two regioisomers with the -NO2 group in position 5 or 6 with chemical yields of 60 to 94%. The prediction of the NMR spectra of molecule 1 coincided with the experimental chemical displacements of the regioisomers. Comparisons between the NMR prediction and the experimental data revealed that the regioisomer endo-1,6-NO2 predominated in the reaction. The in vitro antiparasitic activity of these compounds on intestinal unicellular parasites (Giardia intestinalis and Entamoeba histolytica) and a urogenital tract parasite (Trichomonas vaginalis) were tested. Compound 7 showed an IC50 of 3.95 μM and was 7 time more active against G. intestinalis than benznidazole. Compounds 7 and 8 showed 4 times more activity against T. vaginalis compared with benznidazole. View Full-Text
Keywords: benzimidazole; antiprotozoal; NMR prediction benzimidazole; antiprotozoal; NMR prediction
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MDPI and ACS Style

Hernández-Núñez, E.; Tlahuext, H.; Moo-Puc, R.; Moreno, D.; González-Díaz, M.O.; Vázquez, G.N. Design, Synthesis and Biological Evaluation of 2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-arylacetamides as Antiprotozoal Agents. Molecules 2017, 22, 579.

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