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

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-1-benzimidazol-1-yl)--arylacetamides - 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 - were carried out through reaction of 5(6)-nitro-1-benzimidazol-2-amine () with 2-chlroactemides -, 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 coincided with the experimental chemical displacements of the regioisomers. Comparisons between the NMR prediction and the experimental data revealed that the regioisomer -1,6-NO₂ predominated in the reaction. The in vitro antiparasitic activity of these compounds on intestinal unicellular parasites ( and ) and a urogenital tract parasite () were tested. Compound showed an IC of 3.95 μM and was 7 time more active against than benznidazole. Compounds and showed 4 times more activity against compared with benznidazole.