RESUMO
Three Annonaceous acetogenins exhibited in vitro antimalarial activities on a chloroquine-resistant Plasmodium falciparum strain, with IC50s ranging from 5 to 10 microM. Structure-activity relationships showed that maximal antimalarial activity occurred in the presence of at least one tetrahydrofuran moiety and a synergistic action with chloroquine was observed. These acetogenins partially inhibited the P. falciparum adenylate translocase.
Assuntos
Aminoquinolinas/farmacologia , Antimaláricos/farmacologia , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Álcoois Graxos/farmacologia , Lactonas/farmacologia , Extratos Vegetais/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Acetogeninas , Aminoquinolinas/química , Animais , Antimaláricos/química , Resistência Microbiana a Medicamentos , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/microbiologia , Testes de Sensibilidade Microbiana , Translocases Mitocondriais de ADP e ATP/antagonistas & inibidores , Translocases Mitocondriais de ADP e ATP/metabolismo , Plasmodium falciparum/isolamento & purificação , Sensibilidade e Especificidade , Relação Estrutura-AtividadeRESUMO
Gossypol, a disesquiterpene extracted from cotton seeds, is known to inhibit strongly the Plasmodium falciparum lactate dehydrogenase, but its high toxicity has stopped any antimalarial drug development. A series of Schiffs bases was synthesized from gossypol by modification of the aldehyde groups responsible for its toxicity. A total of 13 compounds showing low cytotoxicity were then selected and were compared with gossypol for activity against 2 chloroquine-resistant strains of P. falciparum (PFB, FCB1). These in vitro activities were evaluated using an isotope-based drug-susceptibility semiautomated microdilution test followed by determination of IC50 values (50% inhibitory concentration). In all, 12 of the 13 compounds tested were active; 3 of them displayed antimalarial activity comparable with that of gossypol itself.
