RESUMO
The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.
Assuntos
Acridonas/química , Antimaláricos/química , Acridonas/farmacocinética , Acridonas/farmacologia , Acridonas/uso terapêutico , Administração Oral , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Meia-Vida , Células Hep G2 , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária/tratamento farmacológico , Malária/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
We herein report the design and synthesis of a novel series of thiophene- and furan-based aminoquinoline derivatives which were found to be potent antimalarials and inhibitors of ß-hematin polymerization. Tested compounds were 3-71 times more potent in vitro than CQ against chloroquine-resistant (CQR) W2 strain with benzonitrile 30 being as active as mefloquine (MFQ), and almost all synthesized aminoquinolines (22/27) were more potent than MFQ against multidrug-resistant (MDR) strain C235. In vivo experiments revealed that compound 28 showed clearance with recrudescence at 40 mg/kg/day, while 5/5 mice survived in Thompson test at 160 mg/kg/day.
Assuntos
Aminoquinolinas/farmacologia , Antimaláricos/farmacologia , Furanos/farmacologia , Plasmodium berghei/efeitos dos fármacos , Tiofenos/farmacologia , Aminoquinolinas/síntese química , Aminoquinolinas/química , Animais , Antimaláricos/síntese química , Antimaláricos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Furanos/química , Células Hep G2 , Humanos , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tiofenos/químicaRESUMO
Human malaria parasite Plasmodium falciparum depends largely on glycolytic pathway for energy metabolism during the intraerythrocytic life stage. Therefore, enzymes of the glycolytic pathway could offer potential drug targets provided novel biochemical and/or structural features of the parasitic enzymes, which distinguish them from the host counterpart, could be identified. 3-Phosphoglycerate kinase (EC 2.7.2.3) catalyzes an important phosphorylation step leading to the production of ATP in the glycolytic pathway. We have expressed recombinant 3-phosphoglycerate kinase of P. falciparum in Escherichia coli. The recombinant protein purified from the soluble fraction of E. coli is enzymatically active. The apparent K(m) values determined for adenosine triphosphate (ATP) and 3-phosphoglycerate (3-PGA) are 0.63 and 0.52 mM, respectively. The enzyme activity was temperature-sensitive. Suramin was found to inhibit the recombinant enzyme with an IC(50) value of 7 microM. We have crystallized the enzyme form in hexagonal space group P6(1)22 (or its enantiomorphic space group) with unit cell parameters a=b=130.7, c=263.9 A. Native data have been collected at 3.0-A resolution.