RESUMEN
In this work, the synthesis of a series of 2-arylazoimidazole derivatives 6-20 has been achieved through the reaction of imidazole with aryldiazonium salts, followed by ultrasound-assisted alkylation. This approach has important advantages including higher yield, shorter reaction times and milder reaction conditions. The structures of the compounds obtained were determined by MS, IR; and 1H and 13C NMR. The anti-Trypanosoma cruzi activity of the 15 compounds obtained was evaluated. Two compounds with piperidino substituents in the carboxamide moiety proved to be effective inhibitors of epimastigote proliferation, obtaining inhibition values comparable to those achieved with the reference drug Benznidazole. Besides, these compounds displayed low cytotoxicity on mammalian cells. In vivo, both compounds protected mice against a challenge with a lethal Trypanosoma cruzi strain. These results allow us to propose 2-arylazoimidazoles as lead compounds for the design of novel drugs to treat Chagas' disease.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Imidazoles/química , Imidazoles/uso terapéutico , Tripanocidas/química , Tripanocidas/uso terapéutico , Trypanosoma cruzi/efectos de los fármacos , Alquilación , Animales , Línea Celular , Enfermedad de Chagas/parasitología , Humanos , Imidazoles/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Sonicación , Tripanocidas/farmacología , Trypanosoma cruzi/citologíaRESUMEN
Imidazolidine derivatives were studied as anti-Trypanosoma cruzi agents. Imidazolines can be considered as ethylenediamine/carbonyl precursors and therefore interfere with the biosynthesis of polyamines into the parasite. Some of the derivatives were found to have high and selective activity against the proliferative stages of the parasite, with IC(50) values against the epimastigote form in the low micromolar range as the reference drug Nifurtimox. The imidazolidines demonstrated to be stable after five days of incubation in buffer glucose, pH 7, indicating that diamines were not obtained in these conditions. But it was found that two of the studied diamine precursors were as active as the parent compounds. Probably, the imidazolidines affect the mitochondrial integrity according to the excreted end-products found in the NMR studies. The QSAR studies indicated that the bioactivities are correlated with the lipophilicities. In conclusion, we have described a new and relevant bioactivity for imidazolidines. The results support further in vivo studies of some of these imidazolidine derivatives.
Asunto(s)
Imidazolidinas/química , Imidazolidinas/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Etilenos/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Synthesis, spectroscopic and biological properties of new bis(3-arylimidazolidinyl-1)methanes are described. These compounds were synthesized by condensation reaction between N-arylethylenediamines and formaldehyde. Chemical structures were confirmed by means of their (1)H- and (13)C-NMR and mass spectroscopic data. Investigation of in vitro antimicrobial activity was performed using Gram-negative and Gram-positive bacteria as well as antifungal studies against Aspergillus niger and Candida albicans. Minimal inhibitory concentrations of active compounds were determined.
Asunto(s)
Antibacterianos , Imidazoles , Metano/análogos & derivados , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Etilenodiaminas/química , Formaldehído/química , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacología , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Metano/química , Metano/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
An analysis of the (1)H- and (13)C-NMR spectra of a series of 1,2-diaryl-1H-4,5-dihydroimidazoles and comparisons with 4,5-dihydroimidazoles having different substitution patterns are presented. The influence of different 1-aryl and 2-aryl group substituents on spectroscopic parameters of the heterocyclic ring and on the contributions of possible mesomeric structures in the system was determined. Spectroscopic features are coherent with the presence of two conjugated systems (Ar(1)-N and Ar(2)-C=N) which compete with the delocalization characteristics of the amidine system.