RESUMO
Malaria is one of the world's most devastating parasitic diseases, causing almost one million deaths each year. Growing resistance to classical antimalarial drugs, such as chloroquine, necessitates the discovery of new therapeutic agents for successful control of this global disease. Here, we report the synthesis of some 6-halo-ß-carbolines as analogues of the potent antimalarial natural product, manzamine A, retaining its heteroaromatic core whilst providing compounds with much improved synthetic accessibility. Two compounds displayed superior activity to chloroquine itself against a resistant Plasmodium falciparum strain, identifying them as promising leads for future development. Furthermore, in line with previous reports of similarities in antimalarial and antiprion effects of aminoaryl-based antimalarial agents, the 1-amino-ß-carboline libraries were also found to possess significant bioactivity against a prion-infected cell line.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Carbolinas/síntese química , Plasmodium falciparum/efeitos dos fármacos , Carbazóis/química , Carbolinas/farmacologia , Linhagem Celular , Cloroquina/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Resistência Microbiana a Medicamentos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Príons/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
A selection of 1-amino-substituted beta-carbolines have been prepared by amination of 1-chloro-beta-carboline as simple mimics of manzamine A and chloroquine and their intercalating ability, anticancer and antimalarial activity were studied.