RESUMEN
The current treatment of schistosomiasis is based on the anti-helminthic drug praziquantel (PZQ). PZQ affects only the adult stages of schistosomes. In addition, resistance to PZQ is emerging. We suggest a drug, which could serve as a potential alternative or complement to PZQ, and as a means of treating infections at earlier, pre-granuloma stage. Derivatives of the peroxidic antimalarial drug artemisinin have been indicated as alternatives, because both plasmodia and schistosomes are blood-feeding parasites. The mechanism of action of artemisinins is related to oxidative effects of the artemisinins on intracellular reductants leading to formation of cytotoxic reactive oxygen species. We used artemisone, which has improved pharmacokinetics and anti-plasmodial activity, and reduced toxicity compared to other artemisinins in clinical use against malaria. We infected adult mice by subcutaneous injection of S. mansoni cercariae (about 200) and treated them at various times post infection by the following methods: i. artemisone suspension administered by gavage (400-450 mg/kg); ii. subcutaneous injection of a gel containing a known concentration of artemisone (115-120 mg/kg); iii. subcutaneous insertion of the drug incorporated in a solid polymer (56-60 mg/kg); iv. intraperitoneal injection of the drug solubilized in DMSO (115-120 mg/kg). Drug administration in polymers was performed to enable slow release of the artemisone that was verified in vivo and in vitro bioassays using drug-sensitive malaria parasites. We found superior strong anti-schistosome effects up to a total reduction of worm number, mainly following repetitive treatments with the drug absorbed in the polymers (73.1% and 95.9% reduction in mice treated with artemisone in gel 7 and 14, and 21, 28 and 35 days post infection, respectively). The results indicate that artemisone has a potent anti-schistosome activity. Its main importance in this context is its effectiveness in treating hosts harboring juvenile schistosomes, before egg-deposition and induction of deleterious immune responses.
Asunto(s)
Antihelmínticos/administración & dosificación , Artemisininas/administración & dosificación , Preparaciones de Acción Retardada/administración & dosificación , Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis mansoni/tratamiento farmacológico , Administración Oral , Animales , Modelos Animales de Enfermedad , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Ratones , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Adamantano/análogos & derivados , Antimaláricos/uso terapéutico , Malaria/tratamiento farmacológico , Peróxidos/uso terapéutico , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Adamantano/administración & dosificación , Adamantano/sangre , Adamantano/farmacología , Adamantano/uso terapéutico , Animales , Antimaláricos/administración & dosificación , Antimaláricos/sangre , Antimaláricos/farmacología , Femenino , Masculino , Ratones , Peróxidos/administración & dosificación , Peróxidos/sangre , Peróxidos/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
To ascertain the structure-activity relationship of the core 1,2,4-trioxolane substructure of dispiro ozonides OZ277 and OZ439, we compared the antimalarial activities and ADME profiles of the 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both dioxolanes had very weak antimalarial properties. For the OZ277 series, the trioxane isostere had the best ADME profile, but its overall antimalarial efficacy was not superior to that of the trioxolane or tetraoxane isosteres. For the OZ439 series, there was a good correlation between the antimalarial efficacy and ADME profiles in the rank order trioxolane > trioxane > tetraoxane. As we have previously observed for OZ439 versus OZ277, the OZ439 series peroxides had superior exposure and efficacy in mice compared to the corresponding OZ277 series peroxides.
Asunto(s)
Antimaláricos/metabolismo , Antimaláricos/farmacología , Dioxolanos/química , Tetraoxanos/química , Absorción , Adamantano/análogos & derivados , Adamantano/química , Adamantano/metabolismo , Adamantano/farmacocinética , Adamantano/farmacología , Animales , Antimaláricos/química , Antimaláricos/farmacocinética , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/metabolismo , Compuestos Heterocíclicos/farmacocinética , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos con 1 Anillo/química , Compuestos Heterocíclicos con 1 Anillo/metabolismo , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Compuestos Heterocíclicos con 1 Anillo/farmacología , Masculino , Ratones , Peróxidos/química , Peróxidos/metabolismo , Peróxidos/farmacocinética , Peróxidos/farmacología , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Compuestos de Espiro/química , Compuestos de Espiro/metabolismo , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
We evaluated the in vivo antischistosomal activities of 11 structurally diverse synthetic peroxides. Of all compounds tested, ozonide (1,2,4-trioxolane) OZ418 had the highest activity against adult Schistosoma mansoni, with total and female worm burden reductions of 80 and 90% (P < 0.05), respectively. Furthermore, treatment of S. haematobium-infected mice with OZ418 reduced the total worm burden by 86%. In conclusion, OZ418 is a promising antischistosomal lead compound.
Asunto(s)
Antihelmínticos/uso terapéutico , Compuestos Heterocíclicos/uso terapéutico , Schistosoma haematobium/efectos de los fármacos , Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis Urinaria/tratamiento farmacológico , Esquistosomiasis mansoni/tratamiento farmacológico , Animales , Antihelmínticos/administración & dosificación , Antihelmínticos/química , Femenino , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/química , Ratones , Esquistosomiasis Urinaria/parasitología , Esquistosomiasis mansoni/parasitología , Resultado del TratamientoRESUMEN
Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC(50) values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.
Asunto(s)
Adamantano/análogos & derivados , Antimaláricos/administración & dosificación , Antimaláricos/uso terapéutico , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/uso terapéutico , Malaria/tratamiento farmacológico , Peróxidos/administración & dosificación , Peróxidos/uso terapéutico , Adamantano/administración & dosificación , Adamantano/química , Adamantano/farmacocinética , Adamantano/uso terapéutico , Animales , Antimaláricos/química , Antimaláricos/farmacocinética , Artemisininas/química , Artemisininas/farmacología , Artemisininas/uso terapéutico , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacocinética , Hierro/metabolismo , Malaria/parasitología , Masculino , Ratones , Peróxidos/química , Peróxidos/farmacocinética , Plasmodium berghei/fisiología , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Resultado del TratamientoRESUMEN
An unsaturated dispiro 1,2,4,5-tetraoxane formed by peroxidation of (+)-dihydrocarvone was converted into four structurally diverse derivatives. X-ray crystallographic analysis shows that the structures possess central tetraoxane rings with spiro-2,5-disubstituted cyclohexylidene substituents and 6-membered rings in classical chair conformations. As polarity in the tetraoxane series increased, in vitro potency against Plasmodium falciparum decreased.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Tetraoxanos/síntesis química , Tetraoxanos/farmacología , Cristalografía por Rayos X , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Six amide and four urea derivatives of praziquantel were synthesized and tested for antischistosomal activity against juvenile and adults stages of Schistosoma mansoni in infected mice. Only one of these had significant activity against adult worms, but, unlike praziquantel, six of these had low to modest activity against juvenile worms. A praziquantel ketone derivative had the best combination of activity against juveniles and adults, but it had no effect on the motility of adult S. mansoni in ex vivo culture. Cytochrome P450 metabolic stability data support the hypothesis that the major trans-cyclohexanol metabolite of praziquantel plays an important role in the antischistosomal activity of this drug.
Asunto(s)
Antihelmínticos/farmacología , Praziquantel/farmacología , Schistosoma mansoni/efectos de los fármacos , Animales , RatonesRESUMEN
Thirty-three N-acyl 1,2,4-dispiro trioxolanes (secondary ozonides) were synthesized. For these ozonides, weak base functional groups were not required for high antimalarial potency against Plasmodium falciparum in vitro, but were necessary for high antimalarial efficacy in Plasmodium berghei-infected mice. A wide range of LogP/D(pH)(7.4) values were tolerated, although more lipophilic ozonides tended to be less metabolically stable.
Asunto(s)
Antimaláricos/síntesis química , Compuestos Heterocíclicos/síntesis química , Animales , Antimaláricos/química , Antimaláricos/farmacocinética , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacocinética , Ratones , Plasmodium falciparum/efectos de los fármacos , RatasRESUMEN
The structure and stereochemistry of the cyclohexane substituents of analogues of arterolane (OZ277) had little effect on potency against Plasmodium falciparum in vitro. Weak base functional groups were not required for high antimalarial potency, but they were essential for high antimalarial efficacy in P. berghei-infected mice. Five new ozonides with antimalarial efficacy and ADME profiles superior or equal to that of arterolane were identified.
Asunto(s)
Antimaláricos/farmacología , Compuestos Heterocíclicos con 1 Anillo/farmacología , Peróxidos/farmacología , Plasmodium falciparum/efectos de los fármacos , Compuestos de Espiro/farmacología , Animales , Antimaláricos/efectos adversos , Antimaláricos/química , Antimaláricos/uso terapéutico , Compuestos Heterocíclicos con 1 Anillo/síntesis química , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Ratones , Conformación Molecular , Pruebas de Sensibilidad Parasitaria , Peróxidos/síntesis química , Peróxidos/farmacocinética , Peróxidos/uso terapéutico , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/uso terapéutico , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
These data suggest that iron(II) reactivity for a set of homologous spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane peroxide heterocycles is a necessary, but insufficient, property of animalarial peroxides. Heme alkylation efficiency appears to give a more accurate prediction of antimalarial activity than FeSO(4)-mediated reaction rates, suggesting that antimalarial activity is not merely dependent on peroxide bond cleavage, but also on the ability of reactive intermediates to alkylate heme or other proximal targets.
Asunto(s)
Antimaláricos/química , Compuestos Ferrosos/química , Hemo/química , Compuestos Heterocíclicos/química , Peróxidos/química , Alquilación , Animales , Antimaláricos/síntesis química , Antimaláricos/farmacología , Simulación por Computador , Compuestos Férricos/química , Ratones , Pruebas de Sensibilidad ParasitariaRESUMEN
It has been recently documented that the antimalarial drug mefloquine shows in vivo activity against schistosomes. In the present study, we assessed the effect of mefloquine on the morphology of adult Schistosoma japonicum worms. Mice were infected with S. japonicum cercariae for 35 days and then treated with a single 400-mg/kg oral dose of mefloquine. Groups of mice were killed between 24 h and 14 days post-treatment and worms were recovered from the liver and mesenteric veins, fixed in 70% alcohol, stained with acid carmine, and examined under a light microscope. Worms obtained from nontreated mice served as controls. S. japonicum recovered from mice 24 h post-treatment had severely dilated guts and the entire worm body was swollen. Meanwhile, reproductive glands, including the testis, ovary, and vitelline gland, showed signs of degeneration. Damage further progressed, particularly among vitelline glands, which resulted in disturbance of ova formation and cessation of oviposition 3 days post-treatment. Three to 7 days after mefloquine administration, adherence of host leukocytes on the damaged tegument was observed. Our results confirm that mefloquine possesses antischistosomal properties, exhibiting a rapid onset of action and causing extensive morphologic damage to adult S. japonicum.
Asunto(s)
Antihelmínticos/uso terapéutico , Mefloquina/uso terapéutico , Schistosoma japonicum/anatomía & histología , Schistosoma japonicum/efectos de los fármacos , Administración Oral , Estructuras Animales/efectos de los fármacos , Estructuras Animales/patología , Animales , Antihelmínticos/administración & dosificación , Femenino , Humanos , Hígado/parasitología , Masculino , Mefloquina/administración & dosificación , Venas Mesentéricas/parasitología , Ratones , Microscopía/métodos , Schistosoma japonicum/aislamiento & purificación , Esquistosomiasis Japónica/tratamiento farmacológico , Factores de TiempoRESUMEN
New research has shown that mefloquine, an arylaminoalcohol used against malaria, is active against Schistosoma japonicum and Schistosoma mansoni in vivo. To enhance our understanding of the potential mechanism of action of mefloquine against schistosomiasis, we examined the dynamics of histopathological changes in adult S. japonicum. Mice infected with S. japonicum for 35 days were treated intragastrically with a single dose of mefloquine (400 mg/kg). One to 35 days after mefloquine administration, drug-induced histopathological alterations were studied. Twenty-four hours after treatment, S. japonicum showed signs of degeneration, including focal roughing and swelling of the tegument and/or muscles, dilatation of the gut, focal desquamation of gut epithelial cells, and a decrease in pigment particles. There was extensive degeneration of vitelline cells and appearance of pigment particles visible in the cytoplasm in female worms. The extent and severity of histopathological changes increased over time; 48 h posttreatment, two thirds of female worms and a quarter of male worms were classified as dead. Three to 14 days posttreatment, typical histological changes observed in surviving male worms were vesiculation, swelling of parenchymal tissues, and dilatation of gut. In females, there was disintegration and infiltration of inflammatory cells, forming dead worm abscesses and early stage of dead worm granuloma. Finally, 35 days posttreatment, only dead male and female worm granuloma were found. Our results provide further evidence of in vivo activity of mefloquine against adult schistosomes.
Asunto(s)
Antihelmínticos/administración & dosificación , Mefloquina/administración & dosificación , Schistosoma japonicum/efectos de los fármacos , Esquistosomiasis Japónica/patología , Esquistosomiasis Japónica/parasitología , Animales , Femenino , Masculino , Ratones , Análisis de SupervivenciaRESUMEN
BACKGROUND: The treatment and control of schistosomiasis, an often neglected tropical disease that exacerbates poverty, depends on a single drug, praziquantel. The large-scale use of praziquantel might select for drug-resistant parasites, hence there is a need to develop new antischistosomal compounds. Here, we report that the antimalarial drug mefloquine possesses promising antischistosomal properties in mice. METHODOLOGY/PRINCIPAL FINDINGS: A single dose of mefloquine (200 or 400 mg/kg) administered orally to mice infected with adult Schistosoma mansoni or adult S. japonicum resulted in high or complete total and female worm burden reductions (72.3%-100%). Importantly, high worm burden reductions were also observed for young developing stages of S. mansoni and S. japonicum harbored in the mouse. Both mefloquine erythro-enantiomers resulted in high and comparable total and female worm burden reductions when given to mice with either a sub-patent or patent S. mansoni infection. CONCLUSIONS/SIGNIFICANCE: Our findings hold promise for the development of a novel antischistosomal drug based on an aminoalcohol functionality. Further in vitro and in vivo studies have been launched to elucidate the possible mechanism of action and to study the effect of mefloquine on S. haematobium and other trematodes. It will be interesting to investigate whether mefloquine, which is widely and effectively used for the treatment of malaria, has an impact on schistosomiasis in areas where both malaria and schistosomiasis co-exist.
Asunto(s)
Mefloquina/farmacología , Schistosoma japonicum/efectos de los fármacos , Schistosoma mansoni/efectos de los fármacos , Esquistosomicidas/farmacología , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Masculino , Mefloquina/administración & dosificación , Mefloquina/química , Ratones , Ratones Endogámicos , Esquistosomicidas/administración & dosificación , Esquistosomicidas/químicaRESUMEN
In four or five chemical steps from the 1,2,4-trioxane artemisinin, a new series of 23 trioxane dimers has been prepared. Eleven of these new trioxane dimers cure malaria-infected mice via oral dosing at 3 x 30 mg/kg. The clinically used trioxane drug sodium artesunate prolonged mouse average survival to 7.2 days with this oral dose regimen. In comparison, animals receiving no drug die typically on day 6-7 postinfection. At only 3 x 10 mg/kg oral dosing, seven dimers prolong the lifetime of malaria-infected mice to days 14-17, more than double the chemotherapeutic effect of sodium artesunate. Ten new trioxane dimers at only a single oral dose of 30 mg/kg prolong mouse average survival to days 8.7-13.7, and this effect is comparable to that of the fully synthetic trioxolane drug development candidate OZ277, which is in phase II clinical trials.
Asunto(s)
Antimaláricos/síntesis química , Artemisininas/síntesis química , Malaria/tratamiento farmacológico , Animales , Antimaláricos/química , Antimaláricos/farmacología , Artemisininas/química , Artemisininas/uso terapéutico , Ratones , Plasmodium berghei , Relación Estructura-ActividadRESUMEN
Fourteen spiro- and dispiro-1,2-dioxolanes were synthesized by peroxycarbenium ion annulations with alkenes in yields ranging from 30% to 94%. Peroxycarbenium ion precursors included triethylsilyldiperoxyketals and -acetals derived from geminal dihydroperoxides and from a new method employing triethylsilylperoxyketals and -acetals derived from ozonolysis of alkenes. The 1,2-dioxolanes were either inactive or orders of magnitude less potent than the corresponding 1,2,4-trioxolanes or artemisinin against P. falciparum in vitro and P. berghei in vivo. In reactions with iron(II), the predominant reaction course for 1,2-dioxolane 3a was two-electron reduction. In contrast, the corresponding 1,2,4-trioxolane 1 and the 1,2,4-trioxane artemisinin undergo primarily one-electron iron(II)-mediated reductions. The key structural element in the latter peroxides appears to be an oxygen atom attached to one or both of the peroxide-bearing carbon atoms that permits rapid beta-scission reactions (or H shifts) to form primary or secondary carbon-centered radicals rather than further reduction of the initially formed Fe(III) complexed oxy radicals.
Asunto(s)
Antimaláricos/síntesis química , Dioxolanos/síntesis química , Compuestos Ferrosos/química , Peróxidos/síntesis química , Compuestos de Espiro/síntesis química , Animales , Antimaláricos/química , Antimaláricos/farmacología , Dioxolanos/química , Dioxolanos/farmacología , Resistencia a Medicamentos , Malaria/tratamiento farmacológico , Ratones , Oxidación-Reducción , Peróxidos/química , Peróxidos/farmacología , Plasmodium berghei , Plasmodium falciparum/efectos de los fármacos , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
Six tetraoxanes had 50% inhibitory concentrations in the range of 10 to 100 ng/ml against Plasmodium falciparum, whereas the corresponding hexaoxonanes had minimal antimalarial activity. The lack of iron-mediated reactivity of the hexaoxonanes may explain their low activity compared to the tetraoxanes, the latter of which are able to undergo iron(II)-mediated activation.
Asunto(s)
Antimaláricos/farmacología , Peróxidos/farmacología , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Tetraoxanos/farmacología , Animales , Antimaláricos/química , Dimerización , Resistencia a Medicamentos , Concentración 50 Inhibidora , Hierro/metabolismo , Ratones , Modelos Moleculares , Pruebas de Sensibilidad Parasitaria , Peróxidos/química , Relación Estructura-Actividad , Tetraoxanos/químicaRESUMEN
Schistosomiasis is a parasitic disease that remains of considerable public health significance in tropical and subtropical environments. Since the mainstay of schistosomiasis control is chemotherapy with a single drug, praziquantel, drug resistance is a concern. Here, we present new data on the antischistosomal properties of representative synthetic 1,2,4-trioxolanes (OZs). Exposure of adult Schistosoma mansoni for 24 h to a medium containing 20 mug/ml OZ209 reduced worm motor activity, induced tegumental alterations, and killed worms within 72 h. While exposure of S. mansoni to OZ78 had no apparent effect, addition of hemin reduced worm motor activity and caused tegumental damage. Administration of single 200-mg/kg of body weight oral doses of OZ78, OZ209, and OZ288 to mice harboring a juvenile S. mansoni infection resulted in worm burden reductions of 82.0 to 95.4%. In the adult infection model in mice, single 400-mg/kg doses of these compounds resulted in a maximum total worm burden reduction of 52.2%. High worm burden reductions (71.7 to 86.5%) were observed after administration of single 200-mg/kg doses of OZ78 and OZ288 to hamsters infected with either juvenile or adult S. mansoni. A single 200-mg/kg dose of OZ78 to hamsters infected with adult Schistosoma japonicum resulted in total and female worm burden reductions of 94.2 to 100%. Our results, along with the low toxicity, metabolic stability, and good pharmacokinetic properties of the OZs, indicate the potential for the development of novel broad-spectrum antischistosomal OZ drug candidates.
Asunto(s)
Antiplatelmínticos/uso terapéutico , Schistosoma japonicum/efectos de los fármacos , Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis/tratamiento farmacológico , Esquistosomicidas/farmacología , Adamantano/análogos & derivados , Adamantano/farmacocinética , Animales , Antiplatelmínticos/farmacología , Cricetinae , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Compuestos Heterocíclicos con 1 Anillo/farmacología , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Humanos , Ratones , Schistosoma japonicum/citología , Schistosoma mansoni/citología , Esquistosomicidas/síntesis química , Esquistosomicidas/química , Esquistosomicidas/uso terapéutico , Compuestos de Espiro/farmacocinéticaRESUMEN
We examined the in vivo activity of tribendimidine against selected trematodes. A single 150-mg/kg dose of tribendimidine achieved a 99.1% reduction of Clonorchis sinensis in rats. A 400-mg/kg dose of tribendimidine reduced Opisthorchis viverrini in hamsters by 95.7%. High doses of tribendimidine showed no activity against Schistosoma mansoni and Fasciola hepatica.
Asunto(s)
Antihelmínticos/uso terapéutico , Clonorquiasis/tratamiento farmacológico , Fasciola hepatica/efectos de los fármacos , Fascioliasis/tratamiento farmacológico , Opisthorchis/efectos de los fármacos , Fenilendiaminas/uso terapéutico , Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis mansoni/tratamiento farmacológico , Esquistosomiasis mansoni/parasitología , Animales , Clonorquiasis/parasitología , Clonorchis sinensis/efectos de los fármacos , Cricetinae , Fascioliasis/parasitología , Femenino , Masculino , Mesocricetus , Ratones , Opisthorchis/parasitología , Ratas , Ratas WistarRESUMEN
Thirty weak base 1,2,4-dispiro trioxolanes (secondary ozonides) were synthesized. Amino amide trioxolanes had the best combination of antimalarial and biopharmaceutical properties. Guanidine, aminoxy, and amino acid trioxolanes had poor antimalarial activity. Lipophilic trioxolanes were less stable metabolically than their more polar counterparts.
Asunto(s)
Antimaláricos/síntesis química , Compuestos Heterocíclicos/síntesis química , Antimaláricos/farmacología , Cristalografía por Rayos X , Compuestos Heterocíclicos/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
RBx11160 (OZ277) is a promising antimalarial drug candidate that Ranbaxy Laboratories Limited and Medicines for Malaria Venture (MMV) are currently developing as a fixed combination with piperaquine. Here, we describe the in vitro (Plasmodium falciparum) and in vivo (Plasmodium berghei) activities of piperaquine in combination with RBx11160 and artemether. In vitro, both combinations demonstrated a slight tendency towards antagonism with mean sums of fractional inhibitory concentrations (mean Sigma FICs) of 1.5. In vivo, piperaquine and artemether were borderline antagonistic (mean Sigma FIC of 1.4). However, an additive in vivo interaction of piperaquine and RBx11160 (mean Sigma FIC of 1.1) was identified, suggesting that a RBx11160-piperaquine combination therapy in humans should allow each molecule to exert its full antimalarial effect.