ABSTRACT
Malaria is still one of the most prevalent parasitic infections in the world, with half of the world's population at risk for malaria. The effectiveness of current antimalarial therapies, even that of the most recent class of antimalarial drugs (artemisinin-combination therapies, ACTs), is under continuous threat by the spread of resistant Plasmodium strains. As a consequence, there is still an urgent requirement for new antimalarial drugs. We previously reported the identification of 4(1 H)-pyridones as a novel series with potent antimalarial activities. The low solubility was identified as an issue to address. In this paper, we describe the synthesis and biological evaluation of 4(1 H)-pyridones with potent antimalarial activities in vitro and in vivo and improved pharmacokinetic profiles. Their main structural novelties are the presence of polar moieties, such as hydroxyl groups, and the replacement of the lipophilic phenyl rings with pyridines on their lipophilic side chains.
Subject(s)
Antimalarials/pharmacology , Pyridones/pharmacology , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacokinetics , Female , Mice , Molecular Structure , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Plasmodium yoelii/drug effects , Pyridones/chemical synthesis , Pyridones/chemistry , Pyridones/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile.
Subject(s)
2,2'-Dipyridyl/analogs & derivatives , Antimalarials/pharmacology , Oxadiazoles/pharmacology , 2,2'-Dipyridyl/administration & dosage , 2,2'-Dipyridyl/chemical synthesis , 2,2'-Dipyridyl/pharmacology , 2,2'-Dipyridyl/toxicity , Animals , Antimalarials/administration & dosage , Antimalarials/chemical synthesis , Antimalarials/toxicity , Atovaquone/pharmacology , Chloroquine/pharmacology , Drug Design , Female , Humans , Hydrazines/metabolism , Mice , Mutagenicity Tests , Mutagens/metabolism , Oxadiazoles/administration & dosage , Oxadiazoles/chemical synthesis , Oxadiazoles/toxicity , Parasitemia/drug therapy , Plasmodium falciparum/drug effects , Pyrimethamine/pharmacology , Structure-Activity RelationshipABSTRACT
Antiparasitic oral drugs have been associated to lipophilic molecules due to their intrinsic permeability. However, these kind of molecules are associated to numerous adverse effects, which have been extensively studied. Within the Tres Cantos Antimalarial Set (TCAMS) we have identified two small, soluble and simple hits that even presenting antiplasmodial activities in the range of 0.4-0.5 µM are able to show in vivo activity.
ABSTRACT
Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Plasmodium falciparum/drug effects , Pyridones/chemistry , Pyridones/pharmacology , Animals , Antimalarials/chemical synthesis , Chemistry, Physical , Crystallography, X-Ray , Dogs , Dose-Response Relationship, Drug , Hydrogen-Ion Concentration , Mice , Models, Molecular , Molecular Structure , Parasitic Sensitivity Tests , Pyridones/chemical synthesis , Solubility , StereoisomerismABSTRACT
Diversos reportes clínicos y de investigación sustentan la existencia de una relación positiva entre espiritualidad y salud, lo cual ha generado un amplio campo de desarrollo, así como la consideración de los factores religiosos y espirituales en el cuidado de los enfermos. En el presente trabajo se explora el vínculo histórico entre la espiritualidad y el cuidado de la salud, se establece una aproximación conceptual en el contexto médico y efectúa una revisión crítica de la literatura existente con base en lo cual se propone una guía clínica práctica orientada a auxiliar a médicos y enfermeras en la incorporación del factor espiritual en su práctica cotidiana con sus enfermos. Finalmente se señalan líneas futuras de investigación en este campo
Subject(s)
Humans , Professional-Family Relations , Professional-Patient Relations , Patient-Centered Care , Religion and Medicine , ChristianityABSTRACT
El IPU ha sido creada con el fin de cumplir efectivamente con los postulados de la Universidad Boliviana en general, y en particular con el Estatuto Organico de la Univeraidad Mayor de San Simon que en sus articulos 16 y 17 pone a la Universidad al servicio del pueblo, a traves de la concresion de una oferta academica para la formacion de recursos humanos de caracter tecnico, destinados a la region y al pais, como aporte a la resolucion de los problmas regionales y nacionales...
