Design, synthesis and biological evaluation of 2-(2-amino-5(6)-nitro-1H-benzimidazol-1-yl)-narylacetamides as antiprotozoal agents

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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 1-8 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 1-8 were carried out through reaction of 5(6)-nitro- 1H-benzimidazol-2-amine (12) with 2-chlroactemides 10a-h, 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.

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Hernández-Núñez, E., Tlahuext, H., Moo-Puc, R., Moreno, D., González-Díaz, M. O., & Vázquez, G. N. (2017). Design, synthesis and biological evaluation of 2-(2-amino-5(6)-nitro-1H-benzimidazol-1-yl)-narylacetamides as antiprotozoal agents. Molecules, 22(4). https://doi.org/10.3390/molecules22040579

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