Biodegradable polymeric nanoformulation based on the antiprotozoal canthin-6-one

The efficacy of antiprotozoal agents against intracellular infections is very often limited by an almost negligible access to the cellular level where the pathogens are hidden. As a result, high doses of the chemotherapy agents are needed to be administered, but the great incidence of severe adverse drug effects generally leads to pharmacotherapy failure. To enhance the pharmacological effect of the antiprotozoal and antifungal canthin-6-one, loading into biodegradable poly(octylcyanoacrylate) nanoparticles has been considered. The preparation of canthin-6-one nanoformulation (average size a parts per thousand 170 nm) has been performed by a single-absorption procedure with high drug loading and little burst release as determined by RP-HPLC. Further characterization of this nanoformulation has been carry out by electrophoretic measurements, analysis of the surface thermodynamics of the nanoparticles, and (1)H-NMR analysis. Nanoparticles loaded with canthin-6-one were characterized by a significant hydrophobicity and a great surface electrical charge under physiological conditions. These are two key physicochemical factors determining recognition by the reticuloendothelial system, resulting in a fast intracellular uptake by infected phagocytes. It is expected that this nanoformulation offers potential applications for an efficient canthin-6-one delivery to intracellular infections

Experimental and theoretical study of possible correlation between the electrochemistry of canthin-6-one and the anti-proliferative activity against human cancer stem cells

This work presents an approach to study the performance of novel targets able to overcome cancer stem cell chemoresistance, based on the voltammetric data for microparticulate films of natural or synthetic alkaloids from the canthin-6-one series. A comparison of this voltammetric technique with conventional solution phase electrochemistry suggests the differences in the anti-proliferative activity of canthin-6-ones could be tentatively correlated to their different capacity to generate semiquinone radical anions. These data also match theoretical calculations

Marine inspired antiplasmodial thiazinoquinones: Synthesis, computational studies and electrochemical assays

In the search for new antimalarials, we used the quinone scaffold of marine secondary metabolites as a chemical starting point to synthesize new thiazinoquinone compounds. Most of synthetic derivatives have shown a significant pharmacological activity and some structural requirements, critical for both the antiplasmodial effect and cytotoxicity, have been evidenced. The redox properties of the prepared compounds have been investigated by computational studies and electrochemical assays, which indicated that a higher antiplasmodial activity of some thiazinoquinones is related to their greater ability to form the semiquinone species and strongly interact with free Fe(III)-protoporphyrin IX

Helietta apiculata : a tropical weapon against Chagas disease

The present study pretends to evaluate the in vivo efficacy of the crude chloroform bark extract of Helietta apiculata, then the activity will be compared with the reference drug, benznidazole, in acute Trypanosoma cruzi infected mice when administered by oral route. The chloroformic extract of Helieta apiculata was administered by oral route at 5, 10 and 50 mg/kg daily for two weeks. This study has shown a moderate efficacy of the H. apiculata bark extract in reducing T. cruzi parasitaemia in 42 to 54% after a monitoring of 60 days post-infection and when compared with control groups. Concerning mice mortality, only two only two mice died, one from the control group and the other one from the group threated with 10 mg of the chlorofom extract of H. apiculata, suggesting the potential of H. apiculta extracts as a safe and inexpensive treatment of Chagas disease

The antiplasmodium effects of a traditionnal South American remedy : Zanthoxylum chiloperone var. angustifolium against chloroquine resistant and chloroquine sensitive strains of Plasmodium falciparum

Zanthoxylum chiloperone var. angustifolium Engl., Rutaceae, is used in traditional medicine to treat fungal and protozoal infections in the central area of South America. Considering the increasing resistance of Plasmodium falciparum in malarial ridden areas, we explored the anti-plasmodial effects of three compounds isolated from Z. chiloperone. The pyranocoumarin transavicennol and the canthinone alkaloids, canthin-6-one and 5-methoxycanthin-6-one, were found to have IC50 on chloroquine/mefloquine resistant and sensitive strains of P. falciparum of 0.5-2.7, 2.0-5.3 and 5.1-10.4 ƒÊg/mL, respectively. Moreover, the formation of heme adducts by these compounds is described by a novel alternative method based on MS-CID methods. The alkylamide sanshool was also identified, for first time in this plant, in the dichloromethanic and ethanolic extracts and the extracts were found to be notably non-toxic and displayed good anti-plasmodial effects

Antiproliferative activity of trans-Avicennol from Zanthoxylum chiloperone var. angustifolium against human cancer stem cells

International audienceZanthoxylum chiloperone var. angustifolium root bark was studied with the aim of finding novel molecules able to overcome cancer stem cell chemoresistance. Purification of a methanol-soluble extract resulted in the isolation of a known pyranocoumarin, trans-avicennol (1). Compound 1 demonstrated antiproliferative activity on glioma-initiating cells, whereas it was inactive on human neural stem cells. trans-Avicennol (1) activated the MAPK/ERK pathway and was also evaluated for its ability to inhibit the enzyme indoleamine-2,3-dioxygenase

Zanthoxylum chiloperone leaves extract :first sustainable Chagas disease treatment

Ethnopharmacological relevance: Zanthoxylum chiloperone var. angustifolium Engl. (Rutaceae) stem bark is used traditionally in Paraguay for its antiparasitic properties. Canthin-6-one is main compound isolated from Zanthoxylum chiloperone var angustifolium with broad spectrum antifungal, leishmanicidal and trypanocidal activities. Aim of the study: The qualitative and quantitative characterization and the isolation of main alkaloidal components of different organs of Zanthoxylum chiloperone are investigated by HPLC-UV-MS. The in vitro biological activity of each extract against trypomastigote and amastigote forms of Trypanosoma cruzi parasites were evaluated, then comparison the in vivo efficacy of the ethanolic leaves extract of Zanthoxylum chiloperone with reference drug, benznidazole, in acute Trypanosoma cruzi infected mice when administered by oral route. We have also evaluated the mutagenic and cytotoxic activity of the main component of Zanthoxylum chiloperone, i.e. canthin-6-one, by mouse bone marrow micronucleus test. Materials and methods: The compositions of the ethanol extracts obtained after the maceration process were studied by HPLC-UV-MS methods. The quantitation analysis was performed by external standard method, using a calibration curve constructed utilizing solutions containing different concentrations of the reference samples. The anti-trypomastigote activity was evaluated by the lysis effect on mouse blood trypomastigotes (Y strain Trypanosoma cruzi). The anti-amastigote Trypanosoma cruzi activity was evaluated by a modified colorimetric method with chlorophenol red-beta-D-galactopyranoside (CPRG). The cytotoxicity of extracts and compounds was performed on NCTC 929 cells. The in vivo efficacy of the ethanolic leaves extract of Zanthoxylum chiloperone and benznidazole, in acute Trypanosoma cruzi (two different strains) was evaluated in Trypanosoma cruzi infected mice; the drugs were administered by oral route. The mortality rates were recorded and parasitaemias in control and treated mice were determined once weekly for 70 days. The mutagenic and cytotoxic activity of the main component of Zanthoxylum chiloperone, canthin-6-one, by mouse bone marrow micronucleus test. Results: Canthin-6-one was the main compound of stem and root bark and 5-methoxy-canthin-6-one in leaves and fruits. The ethanolic leaves extract, canthin-6-one and benznidazole presented, approximately, the same level of in vitro activity against trypomastigote and amastigote forms of Trypanosoma cruzi. We have also evaluated the mutagenic and cytotoxic effects of canthin-6-one by micronucleus test in mice. This test showed any mutagenic and cytotoxic damages. The effects of oral or subcutaneous treatments at 10 mg/kg daily for 2 weeks with the ethanolic extract of leaves of Zanthoxylum chiloperone were examined in Balb/c mice infected acutely with Trypanosoma cruzi (CL or Y strain) and compared with benznidazole at 50 mg/kg for 2 weeks. In these experiments, 70 days after infection, parasitaemia and serological response were significantly reduced with the oral ethanolic extract treatment compared with reference drug. Conclusions: This study have shown the efficacy of the leaves extract of Zanthoxylum chiloperone in reducing Trypanosoma cruzi parasitaemia in vivo assays and could be welcomed by scientific and rural communities of Paraguay because it could help them towards the use of local resources to treat an endemic infection, Chagas disease, affecting 20% of the population of this country