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Antiprotozoal activity of novel diaryliminophenazines
Full text linkRecently, we synthesized a set of novel iminofenazines bearing a bicyclic basic head linked through an alkyl chain to the imino nitrogen in position 3 on the phenazine nucleus (Fig.1).
Most of these compounds inhibited the growth of different species of Leishmania promastigotes as well as of chloroquine sensitive (CQ-S) and chloroquine resistant (CQ-R) strains of P. falciparum with IC50 in the submicromolar range. Unfortunately, these compounds exhibited also a significant toxicity against the human endothelial cell line HMEC-1 with IC50 in the low micromolar range and with a consequent low selectivity index.
Figure1.Structures of the previously synthesized compounds.
To continue the studies on the antiprotozoal potentialities of this class of compounds and with the aim to improve their activity and selectivity on protozoa, we have now synthesized novel compounds characterized by the replacement of the aniline moiety in pos. 2 of the phenazine nucleus with an aminopyridine, and/or by a quaternarization of the basic nitrogen in the side chain with a methyl group (Fig.2).
Figure 2. Structures of the new compounds synthesized.
The in vitro activity of the new compounds on Leishmania promastigotes and on CQ-S and CQ-R strains of P. falciparum, as well as on the HMEC-1 cell line will be presented and discussed.
References
[1] A. Barteselli, M. Gavazzi, N. Basilico, S. Parapini, D. Taramelli, A. Sparatore. Clofazimine analogs with antileishmanial and antimalarial activities. XXII National Meeting on Medicinal Chemistry, Roma 2013
TRANSFERRED-NOESY NMR EXPERIMENTS ON LIVING CELLS : RGD DERIVATIVES BIND PLATELET INTEGRIN aIIbb3
No full textHaem metabolism in Plasmodium falciparum : consequences for the parasites and host cells
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Endothelin-1 production by a microvascular endothelial cell line treated with Plasmodium falciparum parasitized red blood cells
No full textIn this study, we investigated the production of endothelin 1 (ET-1) by a human microvascular endothelial cell line, HMEC-1, co-cultured with Plasmodium falciparum-parasitized red blood cells (pRBCs). The results indicate that hypoxia increased the basal level of ET-1 production by HMEC-1 cells after 24 or 48 h of treatment. However, the co-incubation of HMEC-1 cells with pRBCs, but not with uninfected RBCs, induced a dose-dependent decrease of both constitutive and hypoxia-induced ET-1 production. The inhibition was not due to a decrease in cell viability, as lactate dehydrogenase release remained constant. These results indicate that pRBCs are able to interfere with both the constitutive and stimulated ET-1 release from the microvascular endothelium, thus inducing local modifications of the vascular tone and of the inflammatory response. This could be of relevance in the pathogenesis of the most severe forms of P. falciparum infections, such as cerebral malaria or malaria during pregnancy
Immunità e patologie correlate : risposte immunitarie specifiche - immunopatologia - immunoprofilassi
No full textStability of the antimalarial drug dihydroartemisinin in under physiologically-relevant conditions : implications for clinical treatment, pharmacokinetic and in vitro assays
Full text linkArtemisinins are peroxidic antimalarial drugs known to be very potent but chemically highly unstable; they degrade in the presence of ferrous iron, Fe(II)-heme or biological reductants. Less documented is how this translates into chemical stability and antimalarial activity across a range of conditions applying to in vitro testing and clinical situations. Dihydroartemisinin (DHA) is studied here because it is both an antimalarial drug on its own and the main metabolite of other artemisinins. The behavior of DHA in PBS, plasma or erythrocytes lysate at different temperatures and pH ranges was examined. The antimalarial activity of the residual drug was evaluated using the chemosensitivity assay on P. falciparum, and the extent of decomposition of DHA was established through use of HPLC-ECD analysis. The role of the Fe(II)-heme was investigated by blocking its reactivity using carbon monoxide. A significant reduction in the antimalarial activity of DHA was seen after incubation in plasma and to a lesser extent in erythrocytes lysate: activity was reduced by half after 3 hours and almost completely abolished after 24 hours. Serum-enriched media also affected DHA activity. Effects were temperature and pH-dependent and paralleled the increased rate of decomposition of DHA from pH 7 upwards and in plasma. These results suggest that particular care should be taken in conducting and interpreting in vitro studies, prone as they are to experimental and drug storage conditions. Disorders such as fever, hemolysis or acidosis associated with malaria severity may contribute to artemisinins instability and reduce their clinical efficacy
Synthesis and evaluation of the antiplasmodial activity of novel indeno[2,1-c]quinoline derivatives
No full textWith the aim to explore the potentiality of new chemical scaffolds for the design of new antimalarials, a set of new indeno[2,1-c]quinolines bearing different basic heads has been synthesized and tested in vitro against chloroquine sensitive (CQ-S) and chloroquine resistant (CQ-R) strains of Plasmodium falciparum. Most of the synthesized compounds exhibited a moderate antiplasmodial activity, inhibiting the growth of both CQ-S and CQ-R strains of P. falciparum with IC50 ranging from 0.24 to 6.9μM and with a very low resistance index. The most potent compounds (1.2-1.3-fold the CQ on the W-2 strain) can be considered as promising 'lead compounds' to be further optimized to improve efficacy and selectivity against Plasmodia
Effects of antimalarial drugs on the vasoactive and inflammatory properties of human endothelial cells : modulation of endothelin-1 production
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