RESUMEN
A scaffold hopping exercise undertaken to expand the structural diversity of the fenarimol series of anti-Trypanosoma cruzi (T. cruzi) compounds led to preparation of simple 1-[phenyl(pyridin-3-yl)methyl]piperazinyl analogues of fenarimol which were investigated for their ability to inhibit T. cruzi in vitro in a whole organism assay. A range of compounds bearing amide, sulfonamide, carbamate/carbonate and aryl moieties exhibited low nM activities and two analogues were further studied for in vivo efficacy in a mouse model of T. cruzi infection. One compound, the citrate salt of 37, was efficacious in a mouse model of acute T. cruzi infection after once daily oral dosing at 20, 50 and 100 mg/kg for 5 days.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Piperazinas/química , Piperazinas/uso terapéutico , Tripanocidas/química , Tripanocidas/uso terapéutico , Trypanosoma cruzi/efectos de los fármacos , Administración Oral , Animales , Enfermedad de Chagas/parasitología , Diseño de Fármacos , Humanos , Ratones , Piperazina , Piperazinas/administración & dosificación , Piperazinas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Relación Estructura-Actividad , Tripanocidas/administración & dosificación , Tripanocidas/farmacologíaRESUMEN
BACKGROUND: Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim. RESULTS: We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T. cruzi and from these studies the discovery of two novel series currently in lead optimization. Lead compounds from these series potently and selectively inhibit growth of T. cruzi in vitro and the most advanced compound is orally active in a subchronic mouse model of T. cruzi infection. CONCLUSION: High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process.