Sesquiterpenoids and flavonoids from Inula viscosa induce programmed cell death in kinetoplastids

• Published in: Biomedicine & pharmacotherapy 2020-10, Vol.130, p.110518, Article 110518
• Main Authors: Zeouk, Ikrame, Sifaoui, Ines, López-Arencibia, Atteneri, Reyes-Batlle, María, Bethencourt-Estrella, Carlos J., Bazzocchi, Isabel L., Bekhti, Khadija, Lorenzo-Morales, Jacob, Jiménez, Ignacio A., Piñero, José E.
• Format: Article
• Language: English
• Subjects: Animals; Antiprotozoal Agents - pharmacology; Apoptosis - drug effects; Cell Line; Flavonoids; Flavonoids - pharmacology; Flavonoids - toxicity; Inula - chemistry; Inula viscosa; Leishmania - drug effects; Leishmanicidal; Macrophages - drug effects; Oxidative Stress - drug effects; Phosphorylcholine - analogs & derivatives; Phosphorylcholine - pharmacology; Plant Extracts - pharmacology; Plant Extracts - therapeutic use; Programmed cell death; Sesquiterpenes - pharmacology; Sesquiterpenes - toxicity; Sesquiterpenoids; Structure-Activity Relationship; Trypanocidal; Trypanosoma - drug effects
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.110518

[Display omitted] •Neglected tropical diseases such as leishmaniasis and American trypanosomiasis are among the potentially life-threatening parasitic diseases.•Inula viscosa sesquiterpenoids and flavonoids show promising activity against kinetoplastids without toxicity on murine macrophages.•Lactonization or oxidation of these compounds enhances the biological profile.•Inula viscosa sesquiterpenoids and flavonoids induce apoptosis in Leishmania spp. and Trypanosma cruzi. Neglected tropical diseases such as leishmaniasis and American trypanosomiasis represent an increasing health problem. Current treatments are not satisfactory which remains an urgent need for novel, cheap and safe chemotherapies. In the course of our ongoing search for new potential anti-protozoal agents, this study aimed to perform a bio-guided fractionation of Inula viscosa (Asteraceae) using in vitro assays against three strains of Leishmania and Trypanosma genus. Eight known compounds were identified from the ethanolic extract of leaves, sesquiterpenoids (3 and 4) and flavonoids (5 and 6) were characterized as the main bioactive constituents. Sesquiterpene lactones 3 and 4 (IC50 values between 4.99 and 14.26 μM) showed promising antiparasitic activity against promastigotes of L. donovani, L. amazonensis and epimastigotes of T. cruzi. Their structures were successfully characterized by spectroscopic techniques including 1D and 2D NMR experiments. Furthermore, the main bioactive compounds 4, 5 and 6 displayed higher potency (IC50 values between 0.64 and 2.13 μM) against amastigotes of L. amazonensis than miltefosine (IC50 3.11 μM), and a low toxicity on macrophages cell line (SI > 45). The analysis of structure-activity relationship (SAR) of the anti-protozoal activity revealed that lactonization or oxidation enhanced the biological profile, suggesting that the hydrophobic moiety was presumably involved in the activity by increasing the affinity and/or cell membrane permeability. In order to get an insight into the mechanism of action of these compounds, programmed cell death (PCD) experiments were performed, and the obtained results suggest that the reported compounds induced PCD in the treated parasites. These results highlight that sesquiterpenoids and flavonoids from I. viscosa could constitute an interesting scaffold for the development of novel antikinetoplastid agents.