Evidences for leishmanicidal activity of the naphthoquinone derivative epoxy-α-lapachone

Souza-Silva, Franklin; Nascimento, Samara Braga do; Bourguignon, Saulo Cabral; Pereira, Bernardo Acácio Santini; Carneiro, Paula F.; Silva, Wellington Seguis da; Alves, Carlos Roberto; Pinho, Rosa Teixeira de

doi:10.1016/j.exppara.2014.10.002

Cited by 25 publications

(21 citation statements)

References 12 publications

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“…The results presented show that both epoxy-␣-lapachone and Glucantime had effects in the reduction of paw lesions in the treated BALB/c mice. These results, in association with the previous data on the low toxicity of epoxy-␣-lapachone for mammalian cells (15,17), are strong indicators of the potential use of this compound in the treatment of leishmaniasis. Possibly the effects of epoxy-␣-lapachone in the control of lesions in mice are due to multifactorial actions on parasite physiology.…”

Section: Discussionsupporting

confidence: 76%

“…We therefore aimed to assess the potential leishmanicidal activity of epoxy-␣-lapachone in the treatment of experimental murine infections and to identify the targets in the parasite affected by this compound. This compound was selected for further analysis because of its previously reported low cytotoxicity in mammalian cells (10,15), which highlighted its usefulness to serve as a basis for the development of novel antileishmanial drugs.…”

Section: Discussionmentioning

confidence: 99%

“…1) is a good candidate to serve as the basis for antileishmanial treatments, as it has been shown to have low cytotoxicity for mammalian cells (10,11) while being effective against L. (V.) braziliensis and L. (L.) amazonensis (15); it was able to kill promastigotes of both species in vitro and affected amastigotes infecting human macrophages. We previously reported that epoxy-␣-lapachone can inhibit serine and cysteine proteinase activities in Trypanosoma cruzi (17), but we have not yet assessed this possibility in Leishmania spp.…”

mentioning

confidence: 99%

“…In this context, some natural products obtained from plant extracts or their derivatives, such as quinones, alkaloids, terpenes, and phenolic derivatives, have been proposed for leishmaniasis chemotherapy (9). Recently, we reported evidence that quinone derivatives exhibited promising properties against protozoan parasites, such as Trypanosoma cruzi (10)(11)(12)(13)(14), Leishmania (Viannia) braziliensis, and Leishmania (Leishmania) amazonensis (15). These compounds can be isolated from Bignoniaceae or Verbenaceae trees, and their antimicrobial properties have been well established (16).…”

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confidence: 99%

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Epoxy-α-Lapachone Has In Vitro and In Vivo Anti-Leishmania (Leishmania) amazonensis Effects and Inhibits Serine Proteinase Activity in This Parasite

Souza-Silva

Bourguignon

Pereira

et al. 2015

Antimicrob Agents Chemother

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Leishmania (Leishmania) amazonensis is a protozoan that causes infections with a broad spectrum of clinical manifestations. The currently available chemotherapeutic treatments present many problems, such as several adverse side effects and the development of resistant strains. Natural compounds have been investigated as potential antileishmanial agents, and the effects of epoxy-␣-lapachone on L. (L.) amazonensis were analyzed in the present study. This compound was able to cause measurable effects on promastigote and amastigote forms of the parasite, affecting plasma membrane organization and leading to death after 3 h of exposure. This compound also had an effect in experimentally infected BALB/c mice, causing reductions in paw lesions 6 weeks after treatment with 0.44 mM epoxy-␣-lapachone (mean lesion area, 24.9 ؎ 2.0 mm 2 ), compared to untreated animals (mean lesion area, 30.8 ؎ 2.6 mm 2 ) or animals treated with Glucantime (mean lesion area, 28.3 ؎ 1.5 mm 2 ). In addition, the effects of this compound on the serine proteinase activities of the parasite were evaluated. Serine proteinase-enriched fractions were extracted from both promastigotes and amastigotes and were shown to act on specific serine proteinase substrates and to be sensitive to classic serine proteinase inhibitors (phenylmethylsulfonyl fluoride, aprotinin, and antipain). These fractions were also affected by epoxy-␣-lapachone. Furthermore, in silico simulations indicated that epoxy-␣-lapachone can bind to oligopeptidase B (OPB) of L. (L.) amazonensis, a serine proteinase, in a manner similar to that of antipain, interacting with an S1 binding site. This evidence suggests that OPB may be a potential target for epoxy-␣-lapachone and, as such, may be related to the compound's effects on the parasite.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Epoxy-α-Lapachone Has In Vitro and In Vivo Anti-Leishmania (Leishmania) amazonensis Effects and Inhibits Serine Proteinase Activity in This Parasite

Souza-Silva

Bourguignon

Pereira

et al. 2015

Antimicrob Agents Chemother

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“…Epoxy- α -lapachone led to a dose- and time-dependent decrease in the numbers of promastigotes of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis . This compound was able to kill amastigotes inside human macrophages [ 24 ]. In addition, this reduction of the lesion size in the paw of BALB/c mice infected by L. (L.) amazonensis was observed until six weeks after treatment and negatively affected the activity of serine proteinase of both promastigote and amastigote forms [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Evidence for Tissue Toxicity in BALB/c Exposed to a Long-Term Treatment with Oxiranes Compared to Meglumine Antimoniate

Oliveira

Souza-Silva

Cysne-Finkelstein

et al. 2017

BioMed Research International

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Leishmaniasis remains a serious public health problem in developing countries without effective control, whether by vaccination or chemotherapy. Part of the failure of leishmaniasis control is due to the lack of new less toxic and more effective drugs able to eliminate both the lesions and the parasite. Oxiranes derived from naphthoquinones now being assayed are promising drugs for the treatment of this group of diseases. The predicted pharmacokinetic properties and toxicological profiles of epoxy-α-lapachone and epoxymethoxy-lawsone have now been compared to those of meglumine antimoniate, and histological changes induced by these drugs in noninfected BALB/c mice tissues are described. Effects of these compounds on liver, kidney, lung, heart, and cerebral tissues of healthy mice were examined. The data presented show that both these oxiranes and meglumine antimoniate induce changes in all BALB/c mice tissues, with the lung, heart, and brain being the most affected. Epoxymethoxy-lawsone was the most toxic to lung tissue, while most severe damage was caused in the heart by epoxy-α-lapachone. Meglumine antimoniate caused mild-to-moderate changes in heart and lung tissues.

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Concise Synthesis and Pharmacological Applications of New α‐Lapachone Analogues

Hamama

Hassanien

Zoorob

2017

Journal of Heterocyclic Chem

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Synthesis of novel 1,4‐naphthoquinones structurally related to α‐lapachone skeleton and its annulated compounds were synthesized from lawsone (2‐hydroxynaphthalene‐1,4‐dione). Pharmacological studies provided indication of biological activities, including effects against hepatocellular carcinoma (HePG‐7) and mammary gland breast cancer (MCF‐7). The molecular structures of the target molecules were examined.

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Evidences for leishmanicidal activity of the naphthoquinone derivative epoxy-α-lapachone

Cited by 25 publications

References 12 publications

Epoxy-α-Lapachone Has In Vitro and In Vivo Anti-Leishmania (Leishmania) amazonensis Effects and Inhibits Serine Proteinase Activity in This Parasite

Epoxy-α-Lapachone Has In Vitro and In Vivo Anti-Leishmania (Leishmania) amazonensis Effects and Inhibits Serine Proteinase Activity in This Parasite

Evidence for Tissue Toxicity in BALB/c Exposed to a Long-Term Treatment with Oxiranes Compared to Meglumine Antimoniate

Concise Synthesis and Pharmacological Applications of New α‐Lapachone Analogues

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