RESUMEN
The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for developing next-generation antimalarial drugs. Using an integrated chemogenomics approach that combined drug resistance selection, whole-genome sequencing, and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl-tRNA (transfer RNA) synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivative halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. We show that treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS. We further demonstrate in the Plasmodium berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is active against both liver and asexual blood stages of the malaria parasite. Halofuginol, unlike halofuginone and febrifugine, is well tolerated at efficacious doses and represents a promising lead for the development of dual-stage next-generation antimalarials.
Asunto(s)
Aminoacil-ARNt Sintetasas/antagonistas & inhibidores , Antimaláricos/farmacología , Inhibidores Enzimáticos/farmacología , Malaria Falciparum/tratamiento farmacológico , Piperidinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Proteínas Protozoarias/antagonistas & inhibidores , Quinazolinas/farmacología , Quinazolinonas/farmacología , Aminoacil-ARNt Sintetasas/metabolismo , Animales , Antimaláricos/química , Antimaláricos/toxicidad , Diseño Asistido por Computadora , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Resistencia a Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/toxicidad , Eritrocitos/parasitología , Hígado/parasitología , Malaria Falciparum/sangre , Malaria Falciparum/parasitología , Ratones , Modelos Moleculares , Estructura Molecular , Terapia Molecular Dirigida , Piperidinas/química , Piperidinas/toxicidad , Plasmodium falciparum/enzimología , Proteínas Protozoarias/metabolismo , Quinazolinas/química , Quinazolinas/toxicidad , Quinazolinonas/química , Quinazolinonas/toxicidad , Relación Estructura-Actividad , Factores de TiempoRESUMEN
The antiepileptic activity of nine derivatives of valpromide is discussed. They comply with a pharmacophore model that establishes the essential structural and electronic features responsible for the protection against the MES test. The model results from the comparison of 17 structures, using density functional methodologies combined with an active analog approach. The derivatives of valpromide have been tested for anticonvulsant activity in mice. These compounds displayed a phenytoin-like profile, being active in the MES test and inactive in the PTZ test. 4-(Valproylamido)benzenesulfonamide is the most active compound, with an ED(50) of 53 micromol/kg and no neurotoxicity at doses up to 1000 micromol/kg. The pharmacological behavior of the drugs points to a sodium channel blocking effect as one of the associated mechanisms. This mechanism was tested positive for N-ethylvalpromide through its competition with the binding of [(3)H]batrachotoxin-A-20 alpha-benzoate to the voltage-dependent sodium channels from rat brain synaptosomes.