RESUMEN
Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors of the parasite lactate dehydrogenase (LDH), central to NAD(+) regeneration, therefore potentially provide a route to new antimalarial drugs directed against a novel molecular target. A series of heterocyclic, azole-based compounds are described that preferentially inhibit P. falciparum LDH at sub-micromolar concentrations, typically at concentrations about 100-fold lower than required for human lactate dehydrogenase inhibition. Crystal structures show these competitive inhibitors form a network of interactions with amino acids within the active site of the enzyme, stacking alongside the nicotinamide ring of the NAD(+) cofactor. These compounds display modest activity against parasitized erythrocytes, including parasite strains with known resistance to existing anti-malarials and against Plasmodium berghei in BALB/c mice. Initial toxicity data suggest the azole derivatives have generally low cytotoxicity, and preliminary pharmoco-kinetic data show favorable bioavailability and circulation times. These encouraging results suggest that further enhancement of these structures may yield candidates suitable for consideration as new therapeutics for the treatment of malaria. In combination these studies also provide strong support for the validity of targeting the Plasmodium glycolytic pathway and, in particular, LDH in the search for novel anti-malarials.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Azoles/química , Azoles/farmacología , L-Lactato Deshidrogenasa/antagonistas & inhibidores , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/enzimología , Animales , Dominio Catalítico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Técnicas In Vitro , L-Lactato Deshidrogenasa/química , L-Lactato Deshidrogenasa/genética , Malaria/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Plasmodium berghei , Plasmodium falciparum/genética , 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.
Asunto(s)
Antifúngicos/síntesis química , Antifúngicos/farmacología , Antifúngicos/química , Candida/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Indenos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
A number of novel 3',4'-fused dioxolane and dioxane sordarin derivatives were synthesised for structure-activity relationship studies. Many of these derivatives exhibit high activity against Candida spp. and Cryptococcus neoformans.