RESUMEN
Trypanosoma cruzi carbonic anhydrase (TcCA) has recently emerged as an interesting target for the design of new compounds to treat Chagas disease. In this study we report the results of a structure-based virtual screening campaign to identify novel and selective TcCA inhibitors. The combination of properly validated computational methodologies such as comparative modelling, molecular dynamics and docking simulations allowed us to find high potency hits, with KI values in the nanomolar range. The compounds also showed trypanocidal effects against T. cruzi epimastigotes and trypomastigotes. All the candidates are selective for inhibiting TcCA over the human isoform CA II, which is encouraging in terms of possible therapeutic safety and efficacy.
Asunto(s)
Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Enfermedad de Chagas/tratamiento farmacológico , Ciclamatos/farmacología , Tripanocidas/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Enfermedad de Chagas/metabolismo , Ciclamatos/síntesis química , Ciclamatos/química , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Modelos Moleculares , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/química , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/enzimologíaRESUMEN
Today, there are approximately 8 million cases of Chagas disease in the southern cone of South America alone, and about 100 million people are living with the risk of becoming infected. The present pharmacotherapy is sometimes ineffective and has serious side effects. Here, we report a series of 4,5-dihydroisoxazoles incorporating hydroxamate moieties, which act as effective inhibitors of the carbonic anhydrase (CA) from Trypanosoma cruzi (TcCA). One compound (5g) was evaluated in detail and shows promising features as an antitrypanosomal agent. Excellent values for the inhibition of growth for all three developmental forms of the parasite were observed at low concentrations of 5g (IC50 values from 7.0 to <1 µM). The compound has a selectivity index (SI) of 6.7 and no cytotoxicity to macrophage cells. Preliminary in vivo data showed that 5g reduces bloodstream parasites and that all treated mice survived; it was also more effective than the standard drug benznidazole.