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Diacetal Ditellurides as Highly Active and Selective Antiparasitic Agents toward Leishmania amazonensis.

ABSTRACT: Leishmaniasis is a neglected tropical disease and a public health concern in at least 98 countries, affecting mainly the poorest populations. Pharmaceuticals and chemotherapies available for leishmaniasis treatment have several limitations, which clearly justify the efforts to find new potential antileishmanial drugs. In this context, antiprotozoal activities toward different Leishmania species have been reported for hypervalent tellurium compounds, which motivated us to investigate, for the first time, the leishmanicidal properties of some nonhypervalent diaryl ditellurides. Thus, this work describes in vitro activity against Leishmania amazonensis and the cytotoxicities of diaryl ditellurides. Ditelluride LQ7 revealed a strong leishmanicidal activity on promastigotes and amastigotes at submicromolar levels (IC₅₀ = 0.9 ± 0.1 and 0.5 ± 0.1 μmol L^-1, respectively) and presented selectivity indexes greater than those of reference drug miltefosine. This preliminary study suggests that diaryl ditellurides may be promising scaffolds for the development of new agents for leishmaniasis treatment.

SUBMITTER: Bandeira PT

PROVIDER: S-EPMC6511953 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Diacetal Ditellurides as Highly Active and Selective Antiparasitic Agents toward <i>Leishmania amazonensis</i>.

Bandeira Pamela T PT Souza João Pedro A JPA Scariot Débora B DB Garcia Francielle P FP Nakamura Celso V CV de Oliveira Alfredo R M ARM Piovan Leandro L

ACS medicinal chemistry letters 20190409 5

Leishmaniasis is a neglected tropical disease and a public health concern in at least 98 countries, affecting mainly the poorest populations. Pharmaceuticals and chemotherapies available for leishmaniasis treatment have several limitations, which clearly justify the efforts to find new potential antileishmanial drugs. In this context, antiprotozoal activities toward different <i>Leishmania</i> species have been reported for hypervalent tellurium compounds, which motivated us to investigate, for ...[more]

PMID: 31098003

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Project description:BackgroundArginase is an enzyme that converts L-arginine to urea and L-ornithine, an essential substrate for the polyamine pathway supporting Leishmania (Leishmania) amazonensis replication and its survival in the mammalian host. L-arginine is also the substrate of macrophage nitric oxide synthase 2 (NOS2) to produce nitric oxide (NO) that kills the parasite. This competition can define the fate of Leishmania infection.Methodology/principal findingsThe transcriptomic profiling identified a family of oxidoreductases in L. (L.) amazonensis wild-type (La-WT) and L. (L.) amazonensis arginase knockout (La-arg-) promastigotes and axenic amastigotes. We highlighted the identification of an oxidoreductase that could act as nitric oxide synthase-like (NOS-like), due to the following evidences: conserved domain composition, the participation of NO production during the time course of promastigotes growth and during the axenic amastigotes differentiation, regulation dependence on arginase activity, as well as reduction of NO amount through the NOS activity inhibition. NO quantification was measured by DAF-FM labeling analysis in a flow cytometry.Conclusions/significanceWe described an arginase-dependent NOS-like activity in L. (L.) amazonensis and its role in the parasite growth. The increased detection of NO production in the mid-stationary and late-stationary growth phases of La-WT promastigotes could suggest that this production is an important factor to metacyclogenesis triggering. On the other hand, La-arg- showed an earlier increase in NO production compared to La-WT, suggesting that NO production can be arginase-dependent. Interestingly, La-WT and La-arg- axenic amastigotes produced higher levels of NO than those observed in promastigotes. As a conclusion, our work suggested that NOS-like is expressed in Leishmania in the stationary growth phase promastigotes and amastigotes, and could be correlated to metacyclogenesis and amastigotes growth in a dependent way to the internal pool of L-arginine and arginase activity.

Dataset Information

Diacetal Ditellurides as Highly Active and Selective Antiparasitic Agents toward Leishmania amazonensis.

Publications

Diacetal Ditellurides as Highly Active and Selective Antiparasitic Agents toward <i>Leishmania amazonensis</i>.

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