RESUMEN
Malaria is still one of the most prevalent parasitic infections in the world, with half of the world's population at risk for malaria. The effectiveness of current antimalarial therapies, even that of the most recent class of antimalarial drugs (artemisinin-combination therapies, ACTs), is under continuous threat by the spread of resistant Plasmodium strains. As a consequence, there is still an urgent requirement for new antimalarial drugs. We previously reported the identification of 4(1 H)-pyridones as a novel series with potent antimalarial activities. The low solubility was identified as an issue to address. In this paper, we describe the synthesis and biological evaluation of 4(1 H)-pyridones with potent antimalarial activities in vitro and in vivo and improved pharmacokinetic profiles. Their main structural novelties are the presence of polar moieties, such as hydroxyl groups, and the replacement of the lipophilic phenyl rings with pyridines on their lipophilic side chains.
Asunto(s)
Antimaláricos/farmacología , Piridonas/farmacología , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Antimaláricos/farmacocinética , Femenino , Ratones , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/efectos de los fármacos , Plasmodium yoelii/efectos de los fármacos , Piridonas/síntesis química , Piridonas/química , Piridonas/farmacocinética , Relación Estructura-ActividadRESUMEN
A new synthesis of the antimalarial clinical candidate GSK932121 is described. This approach has two key reactions, the selective acylation of an unprotected 3-hydroxymethyl-5-methyl isoxazole and the reductive N-O bond cleavage of the previously functionalized isoxazole derivative, to give the 4-(1H)pyridone ring present in the final structure. The complete synthesis consists of 5 steps (versus 10 steps in previously published reports) and has enabled the preparation of the material in kilogram scale to support clinical studies.
RESUMEN
Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Piridonas/química , Piridonas/farmacología , Animales , Antimaláricos/síntesis química , Química Física , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Concentración de Iones de Hidrógeno , Ratones , Modelos Moleculares , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Piridonas/síntesis química , Solubilidad , EstereoisomerismoRESUMEN
A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasmodium falciparum in vitro and murine Plasmodium yoelii in vivo. These were derived from the anticoccidial drug clopidol through a systematic study of the effects of varying the side chain on activity. Relative to clopidol the most active compounds show >500-fold improvement in IC50 for inhibition of P. falciparum in vitro and about 100-fold improvement with respect to ED50 against P. yoelii in mice. These compounds have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc1 complex.
Asunto(s)
Antimaláricos/síntesis química , Malaria/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Plasmodium yoelii , Piridonas/síntesis química , Animales , Antimaláricos/química , Antimaláricos/farmacología , Ratones , Pruebas de Sensibilidad Parasitaria , Piridonas/química , Piridonas/farmacología , Relación Estructura-ActividadRESUMEN
A series of Sordarin derivatives bearing alkyl substituted tetrahydrofuran rings fused to C3'-C4' bond of the sugar moiety have been prepared and their antifungal properties evaluated. Most of them show remarkable antifungal activity against Candida spp and Cryptococcus neoformans.
Asunto(s)
Antifúngicos/química , Antifúngicos/farmacología , Furanos/síntesis química , Furanos/farmacología , Antifúngicos/síntesis química , Fluconazol/farmacología , Furanos/química , Indenos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
A number of novel 3'-O-acyl and alkyl sordarins were synthesised for structure-activity relationship studies. Many of these derivatives exhibit high activity against Candida albicans, Candida pseudotropicalis, Candida tropicalis and Cryptococcus neoformans.