Epoxy-α-lapachone (2,2-Dimethyl-3,4-dihydro-spiro[2H-naphtho[2,3-b]pyran-10,2'-oxirane]-5(10H)-one): a promising molecule to control infections caused by protozoan parasites

Abstract

Natural products and their derivatives have been sources of search and research for new drugs for the treatment of neglected diseases. Naphthoquinones, a special group of quinones, are products of natural metabolites with a wide spectrum of biological activities and represent a group of interesting molecules for new therapeutic propositions. Among these compounds, lapachol stands out as a molecule from the heartwood of Tabebuia sp. whose structural changes resulted in compounds considered promising, such as epoxy-α-lapachone (ELAP). The biological activity of ELAP has been demonstrated, so far, for parasitic protozoa such as Leishmania spp., Trypanosoma cruzi and Plasmodium spp., species causing diseases needing new drug development and adequate health policy. This work gathers in vitro and in vivo studies on these parasites, as well as the toxicity profile, and the probable mechanisms of action elucidated until then. The potential of ELAP-based technology alternatives for a further drug is discussed here.

Keywords: Chagas disease; Epoxy-α-lapachone; Leishmaniasis; Malaria; Naphthoquinone; Treatment.

Fig. 1

Naphthoquinone anti-parasitic activity plot based on experimental assays. The compounds α-lapachone (A), β-lapachone (B), 2,2-dimethylspiro[3H-benzo[f][1]benzofuran-9,2′-oxirane]-4-one (C), 2,2-dimethylspiro[3,4,6,7,8,9-hexahydrobenzo[g]chromene-10,2′-oxirane]-5-one (D), 2,2-dimethylspiro[3,4-dihydrobenzo[h]chromene-6,2′-oxirane]-5-one (E) and epoxy-α -lapachone (F) were selected according to structural similarity (>50%) using the ChEMBL Database (https://www.ebi.ac.uk/chembl/). This analysis shows the activities of these molecules against to Plasmodium spp. (purple circle), Trypanosoma cruzi (yellow circle), and Leishmania spp. (green circle) based on IC₅₀ values normalized (pChEMBL value). The circle sizes show a predict values of permeability (ALogP) of these compounds.

Fig. 2

Predicted epoxy-α-lapachone regions interactions with amino acid residues of the active site of trypanosomatid proteases. Epoxy-α-lapachone (2,3-Dihydro-3,3-dimethylspiro[1H-4-oxanthracene-5,2′-oxiran]−10(5H)-one) is formed by an aromatic ring (A), a central six-membered ring (B) and a ring with two methyl groups (C). The chiral center being the C12 atom, which is also part of the three-membered epoxide ring. CID: 12,000,280; molecular formula:C₁₆H₁₆O₃ and molecular mass: 256.3 g/mol. Epoxy-α-lapachone regions interactions with amino acid residues of cysteine-proteinase (green) of Trypanosoma cruzi and serine-proteinase (orange) of Leishmania (Leishmania) amazonensis.