Activity of Hydroxyurea against
            <i>Leishmania mexicana</i>

Martínez-Rojano, Hugo; Mancilla-Ramı́rez, Javier; Quiñonez-Díaz, Laura Judith; Galindo-Sevilla, Norma

doi:10.1128/aac.00124-08

Cited by 24 publications

(12 citation statements)

References 31 publications

(31 reference statements)

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“…if it can cross the host cell membrane and act on the amastigotes inside the vacuole. Thus, assays of activity against intracellular amastigotes are the most effective way to relate the in vitro activity of a possible substance with its in vivo effectiveness [47]. The inhibition of amastigote growth was even greater at 48 h after exposure to oil, with an IC 50 of 1.92 μ g/mL, whereas the IC 50 for promastigotes was 3.04 μ g·mL −1 for the same duration of exposure.…”

Section: Discussionmentioning

confidence: 99%

Eugenia unifloraL. Essential Oil as a Potential Anti-LeishmaniaAgent: Effects onLeishmania amazonensisand Possible Mechanisms of Action

Rodrigues

Amorim

Oliveira

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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Eugenia uniflora L. is a member of the Myrtaceae family and is commonly known as Brazilian cherry tree. In this study, we evaluated the chemical composition of Eugenia uniflora L. essential oil (EuEO) by using gas chromatography-mass spectrometry (GC-MS) and assessed its anti-Leishmania activity. We also explored the potential mechanisms of action and cytotoxicity of EuEO. Thirty-two compounds were identified, which constituted 92.65% of the total oil composition. The most abundant components were sesquiterpenes (91.92%), with curzerene (47.3%), γ-elemene (14.25%), and trans-β-elemenone (10.4%) being the major constituents. The bioactivity shown by EuEO against promastigotes (IC50, 3.04 μg·mL−1) and amastigotes (IC50, 1.92 μg·mL−1) suggested significant anti-Leishmania activity. In the cytotoxicity determination, EuEO was 20 times more toxic to amastigotes than to macrophages. Hemolytic activity was 63.22% at the highest concentration tested (400 μg·mL−1); however, there appeared to be no toxicity at 50 μg·mL−1. While the data show that EuEO activity is not mediated by nitric oxide production, they do suggest that macrophage activation may be involved in EuEO anti-Leishmania activity, as evidenced by increases in both the phagocytic capacity and the lysosomal activity. More studies are needed to determine in vivo activity as well as additional mechanisms of the anti-Leishmania activity.

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Section: Discussionmentioning

confidence: 99%

Eugenia unifloraL. Essential Oil as a Potential Anti-LeishmaniaAgent: Effects onLeishmania amazonensisand Possible Mechanisms of Action

Rodrigues

Amorim

Oliveira

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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“…For this purpose, the hit 4,4=-diaminodiphenyldiselenide was modulated by two strategies: (i) the amine group was derivatized to urea, thiourea, and selenourea in order to adjust polarity, solubility, and ability to interact and form hydrogen bonds, and (ii) introduction of various aromatic systems or a cyclic or linear aliphatic chain of variable length and flexibility into the pendent amino groups of the ureidic function. Urea moiety is commonly found in various potent leishmanicidal compounds (17,18). On the other hand, the thiourea scaffold has been described for treating parasitic disorders by itself (19,20) or combined with metals (21).…”

mentioning

confidence: 99%

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

Díaz

Lucio

Moreno

et al. 2019

Antimicrob Agents Chemother

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A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC 50 ) values lower than that for the reference drug miltefosine (EC 50 , 2.84 M). In addition, the derivatives 9, 11, 42, and 47, with EC 50 between 1.1 and 1.95 M, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC 50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leishmanicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.

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“…HU treatment of macrophages infected by Toxoplasma gondii , Leishmania amazonensis , Trypanosoma cruzi , and L. mexicana has been shown to drastically reduce the number of infected cells (Melo and Beiral, 2003; Martinez-Rojano et al, 2008). Therefore, we tested whether HU would compromise the intracellular growth of Cn cells.…”

Section: Resultsmentioning

confidence: 99%

Hydroxyurea treatment inhibits proliferation of Cryptococcus neoformans in mice

Tripathi¹,

Mor²,

Bairwa³

et al. 2012

Front. Microbio.

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The fungal pathogen Cryptococcus neoformans (Cn) is a serious threat to immunocompromised individuals, especially for HIV patients who develop meningoencephalitis. For effective cryptococcal treatment, novel antifungal drugs or innovative combination therapies are needed. Recently, sphingolipids have emerged as important bioactive molecules in the regulation of microbial pathogenesis. Previously we reported that the sphingolipid pathway gene, ISC1, which is responsible for ceramide production, is a major virulence factor in Cn infection. Here we report our studies of the role of ISC1 during genotoxic stress induced by the antineoplastic hydroxyurea (HU) and methyl methanesulfonate (MMS), which affect DNA replication and genome integrity. We observed that Cn cells lacking ISC1 are highly sensitive to HU and MMS in a rich culture medium. HU affected cell division of Cn cells lacking the ISC1 gene, resulting in cell clusters. Cn ISC1, when expressed in a Saccharomyces cerevisiae (Sc) strain lacking its own ISC1 gene, restored HU resistance. In macrophage-like cells, although HU affected the proliferation of wild type (WT) Cn cells by 50% at the concentration tested, HU completely inhibited Cn isc1Δ cell proliferation. Interestingly, our preliminary data show that mice infected with WT or Cn isc1Δ cells and subsequently treated with HU had longer lifespans than untreated, infected control mice. Our work suggests that the sphingolipid pathway gene, ISC1, is a likely target for combination therapy with traditional drugs such as HU.

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Activity of Hydroxyurea against Leishmania mexicana

Cited by 24 publications

References 31 publications

Eugenia unifloraL. Essential Oil as a Potential Anti-LeishmaniaAgent: Effects onLeishmania amazonensisand Possible Mechanisms of Action

Eugenia unifloraL. Essential Oil as a Potential Anti-LeishmaniaAgent: Effects onLeishmania amazonensisand Possible Mechanisms of Action

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

Hydroxyurea treatment inhibits proliferation of Cryptococcus neoformans in mice

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