RESUMEN
Due to an increased need for new antimalarial chemotherapies that show potency against Plasmodium falciparum, researchers are targeting new processes within the parasite in an effort to circumvent or delay the onset of drug resistance. One such promising area for antimalarial drug development has been the parasite mitochondrial electron transport chain (ETC). Efforts have been focused on targeting key processes along the parasite ETC specifically the dihydroorotate dehydrogenase (DHOD) enzyme, the cytochrome bc 1 enzyme and the NADH type II oxidoreductase (PfNDH2) pathway. This review summarizes the most recent efforts in antimalarial drug development reported in the literature and describes the evolution of these compounds.
Asunto(s)
Antimaláricos/farmacología , Transporte de Electrón/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Plasmodium falciparum/efectos de los fármacos , Proteínas Protozoarias/antagonistas & inhibidores , Antimaláricos/química , Dihidroorotato Deshidrogenasa , Complejo III de Transporte de Electrones/antagonistas & inhibidores , Complejo III de Transporte de Electrones/química , Complejo III de Transporte de Electrones/metabolismo , Inhibidores Enzimáticos/química , Humanos , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Simulación del Acoplamiento Molecular , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/química , NADH NADPH Oxidorreductasas/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/química , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Plasmodium falciparum/enzimología , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Relación Estructura-ActividadRESUMEN
Extensive drug resistance in Plasmodium falciparum emphasizes the urgent requirement for novel antimalarial agents. Here we report potent antimalarial activity of a number of diamidine compounds. The lead compound pentamidine is concentrated 500-fold by erythrocytes infected with P. falciparum. Pentamidine accumulation can be blocked by inhibitors of hemoglobin digestion, suggesting that the drug binds to ferriprotoporphyrin IX (FPIX). All of the compounds bound to FPIX in vitro and inhibited the formation of hemozoin. Furthermore, inhibitors of hemoglobin digestion markedly antagonized the antimalarial activity of the diamidines, indicating that binding to FPIX is crucial for the activity of diamidine drugs. Pentamidine was not accumulated into uninfected erythrocytes. Pentamidine transport into infected cells exhibits an initial rapid phase, nonsaturable in the micromolar range and sensitive to inhibition by furosemide and glibenclamide. Changing the counter-ion in the order Cl(-) < Br(-) < NO(2)(-) < I(-) Asunto(s)
Eritrocitos/metabolismo
, Pentamidina/farmacocinética
, Plasmodium falciparum/metabolismo
, Tripanocidas/farmacocinética
, Animales
, Transporte Biológico
, Permeabilidad de la Membrana Celular
, Cristalización
, Sistemas de Liberación de Medicamentos
, Diseño de Fármacos
, Eritrocitos/efectos de los fármacos
, Eritrocitos/parasitología
, Hemoproteínas/efectos de los fármacos
, Hemina/química
, Hemina/metabolismo
, Humanos
, Técnicas In Vitro
, Modelos Moleculares
, Pruebas de Sensibilidad Parasitaria
, Pentamidina/administración & dosificación
, Pentamidina/farmacología
, Plasmodium falciparum/efectos de los fármacos
, Tritio
, Tripanocidas/administración & dosificación
, Tripanocidas/farmacología
RESUMEN
A new series of 4-aminoquinoline Mannich base derivatives have been synthesized, in which the 3'-diethylamino function of amodiaquine (AQ) is replaced by a 3'-tert-butylamino group and an aliphatic hydrocarbon entity is incorporated into the 5'-position of the 4'-hydroxyanilino side chain. Seven alkyl Mannich base derivatives were screened and found to be active against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. The propyl and isopropyl alkyl derivatives were found to be the most active; consequently these derivatives were tested against a nonsensitive strain of Plasmodium berghi in vivo and found to be 3-fold more active than AQ, irrespective of the route of administration (oral or intraperitoneal).