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

Abstract

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.

Natural products as inhibitors of recombinant cathepsin L of Leishmania mexicana

“…Specifically a naphthoquinone derivative epoxy-α-lapachone that showed efficiency on L. amazonensis in vitro and in vivo, which mechanism suggested is associated to the inhibition of oligopeptidase B, a serine proteinase from Leishmania spp. , 2015.…”

Antileishmanial Activity of 2-Methoxy-4H-spiro-[naphthalene-1,2′-oxiran]-4-one (Epoxymethoxy-lawsone): A Promising New Drug Candidate for Leishmaniasis Treatment

“…As this compound is also derived from the α-lapachone molecule by an epoxidation reaction, and shares most of chemical and structural features with epoxy-α-lapachone, is possible that the new oxirane also acts by inhibiting proteases from Leishmania sp. and other trypanosomatids, as previously reported [ 12 , 14 , 20 , 21 ], however further studies are needed to prove this hypothesis.…”

“…We have demonstrated that epoxy-α-lapachone was capable to kill promastigote forms of Leishmania ( Viannia ) braziliensis and Leishmania ( Leishmania ) amazonensis and intracellular amastigotes in human macrophages [ 13 ]. Furthermore, reduction of the lesion size in the paw of BALB/c mice infected was observed after four weeks of treatment [ 14 ].…”

The combination therapy of meglumine antimoniate and oxiranes (epoxy-α-lapachone and epoxymethyl-lawsone) enhance the leishmanicidal effect in mice infected by Leishmania (Leishmania) amazonensis

“…Recently, we have demonstrated that LAP and LAW (Fig. 1), were effective against Leishmania in both in vitro and in vivo experimental infections and showed low toxicity for mammalian cells (Oliveira et al, 2018; Souza-Silva et al, 2014, 2015).

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