RESUMO
Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 (2) and OZ165 (3). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.
Assuntos
Adamantano/uso terapêutico , Ácidos Carboxílicos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Esquistossomicidas/uso terapêutico , Compostos de Espiro/uso terapêutico , Adamantano/análogos & derivados , Adamantano/farmacocinética , Adamantano/toxicidade , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/toxicidade , Linhagem Celular Tumoral , Feminino , Células HEK293 , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/farmacocinética , Compostos Heterocíclicos com 1 Anel/toxicidade , Humanos , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/síntese química , Esquistossomicidas/farmacocinética , Esquistossomicidas/toxicidade , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Compostos de Espiro/toxicidade , Relação Estrutura-AtividadeRESUMO
We report a series of novel inhibitors of protein farnesyltransferase based on the 2-oxotetrahydroquinoline scaffold. We developed an efficient synthesis of these compounds. These compounds show selective inhibtion of the malaria versus human farnesyltransferase and inhibit the growth of the malaria parasite in the low nanomolar range. Some of the compounds are at least an order of magnitude more stable to metabolic degradation than the corresponding tetrahydroquinolines.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antimaláricos/síntese química , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/síntese química , Alquil e Aril Transferases/química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Cristalografia por Raios X , Estabilidade de Medicamentos , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Plasmodium falciparum/enzimologia , Quinolinas/química , Quinolinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.