title: Design, Synthesis and Biological Evaluation of 2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-arylacetamides as Antiprotozoal Agents.
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-arylacetamides1-8as 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 compounds1-8were carried out through reaction of 5(6)-nitro-1H-benzimidazol-2-amine (12) with 2-chlroactemides10a-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 molecule1coincided with the experimental chemical displacements of the regioisomers. Comparisons between the NMR prediction and the experimental data revealed that the regioisomerendo-1,6-NO₂ predominated in the reaction. The in vitro antiparasitic activity of these compounds on intestinal unicellular parasites (GiardiaintestinalisandEntamoebahistolytica) and a urogenital tract parasite (Trichomonasvaginalis) were tested. Compound7showed an IC50of 3.95 μM and was 7 time more active againstG.intestinalisthan benznidazole. Compounds7and8showed 4 times more activity againstT.vaginaliscompared with benznidazole.
authors.affiliation: CONACYT, Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Mérida, Mérida 97310, Yucatán, Mexico. emanuel.hernandez@cinvestav.com.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Hernández-Núñez
authors.affiliation: Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca 62210, Morelos, Mexico. tlahuext@uaem.mx.
authors.forename: Hugo
authors.initials: H
authors.lastname: Tlahuext
authors.affiliation: Unidad Interinstitucional de Investigación Médica, Instituto Mexicano del Seguro Social/Universidad Autónoma de Yucatán, Mérida 97150, Yucatán, México. moopuc@gmail.com.
authors.forename: Rosa
authors.initials: R
authors.lastname: Moo-Puc
authors.affiliation: Facultad de Ingeniería, Universidad Autónoma de Yucatán, Mérida 97310, Yucatán, Mexico. diegomorenor@gmail.com.
authors.forename: Diego
authors.initials: D
authors.lastname: Moreno
authors.affiliation: CONACYT, Centro de Investigación Científica de Yucatán, Mérida 97200, Yucatán, Mexico. maria.gonzalez@cicy.mx.
authors.forename: María Ortencia
authors.initials: MO
authors.lastname: González-Díaz
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico. gabriel_navarrete@uaem.mx.
authors.forename: Gabriel Navarrete
authors.initials: GN
authors.lastname: Vázquez
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry*; D015195:Drug Design; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests
chemical_list: D000577:Amides; D000981:Antiprotozoal Agents; D001562:Benzimidazoles; C031000:benzimidazole
keywords: NMR prediction; antiprotozoal; benzimidazole