Abstract
BackgroundThe therapeutic arsenal for the treatment of Leishmaniasis is limited and includes toxic compounds (antimonials, amphotericin B, pentamidine and miltefosine). Given these aspects, the search for new compounds based on floristic biodiversity is crucial. In the present work, we report the isolation, characterization and antileishmanial activity of six related neolignans (1–6) of bioactive extract from Nectandra leucantha (Lauraceae) twigs.MethodsDried and powdered twigs of N. leucantha were exhaustively extracted using n-hexane. The crude extract was dereplicated by HPLC/HRESIMS and subjected to column chromatography to yield pure compounds 1–6. Their chemical structures were identified via NMR and comparison of obtained data with those previously published in the literature. Biological assays of compounds 1–6 and their respective monomers (eugenol and methyleugenol) were performed using promastigote and amastigote forms of Leishmania (L.) infantum.ResultsDereplication procedures followed by chemical characterization of isolated compounds by NMR enabled the identification of related neolignans 1–6. Neolignans 2, 4 and 6 showed potential against amastigote forms of L. (L.) infantum (EC50 values of 57.9, 67.7 and 13.7 μM, respectively), while compounds 1 and 3 were inactive. As neolignans 2–4 are chemically related, it may be suggested that the presence of the methoxyl group at C4 constitutes an important structural aspect to increase antileishmanial potential against amastigote forms. Compound 6, which consists of a methylated derivative of compound 5 (inactive) showed antileishmanial activity similar to that of the standard drug miltefosine (EC50 = 16.9 μM) but with reduced toxicity (SI = 14.6 and 7.2, respectively). Finally, two related monomers, eugenol and methyleugenol, were also tested and did not display activity, suggesting that the formation of dimeric compounds by oxidative coupling is crucial for antiparasitic activity of dimeric compounds 2, 4 and 6.ConclusionThis study highlights compound 6 against L. (L.) infantum amastigotes as a scaffold for future design of new compounds for drug treatment of visceral leishmaniasis.
Highlights
The therapeutic arsenal for the treatment of Leishmaniasis is limited and includes toxic compounds
Leishmaniasis is a neglected tropical disease (NTD) that affects more than one billion people in tropical and subtropical countries, including parts of Latin America, Africa and Asia [1, 2]
Aiming to characterize its bioactive compounds, the crude extract was subjected to dereplication procedures using HPLC/HRESIMS to enable the identification of six related neolignans (1–6)
Summary
General 1H and 13C NMR spectra were recorded at 300 and 75 MHz, respectively, in a Bruker Ultrashield 300 Avance III spectrometer with a QNP 300 (5 mm) probe, using CDCl3 (Aldrich) as the solvent and TMS as the internal standard. Fraction G3 (386 mg) was chromatographed over a silica gel column eluted with mixtures of n-hexane:EtOAc (8:2, 7:3, 1:1, 3:7, 1:9, and 0:1) to obtain five fractions (G3/1 – G3/5). - promastigotes To determine the antileishmanial activity and the 50% effective concentration (EC50 value) against promastigotes, crude n-hexane extract and pure compounds 1–6 were dissolved in DMSO (30 mg/mL) and diluted with M-199 medium in 96-well microplates. To determine the antileishmanial potential, crude extract was tested at 300 μg/mL while compounds 1–6 and positive control miltefosine were tested at top concentration 200 μg/mL and were 2-fold serially diluted into seven concentrations (100, 50, 25, 12.5, 6.75, 3.37, and 1.69 μg/mL). To the assays conducted to promastigote forms, the potential of crude n-hexane extract was evaluated at 300 μg/mL while the activities of compounds 1–6 and positive control miltefosine against amastigote forms of L. The Mann–Whitney test was used for the significance test (P value)
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