Antileishmanial, antitrypanosomal and anti-coronavirus activities of benzophenanthridine alkaloids and other specialized metabolites isolated from the root bark of Zanthoxylum zanthoxyloides (Lam.) B.Zepernick & Timler

Ba, Abda;Roumy, Vincent;Al Ibrahim, Malak;Hughes, Kristelle;Rivière, Céline;et.al.
(2024) Fitoterapia — Vol. 179, p. 106232 [1-13] (2024)

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Abstract
Strong antileishmanial and antitrypanosomal activities were highlighted for the crude methanolic extract (IC50 = 0.61 and 2.15 μg/mL, respectively) of Zanthoxylum zanthoxyloides (Lam.) B.Zepernick & Timler root bark, as well as for its apolar partitions (cyclohexane: IC50 = 0.66 and 5.17 μg/mL, respectively and dichloromethane: IC50 = 0.07 and 0.22 μg/mL, respectively), with a good selectivity index (SI) towards WI-38 cells. In addition, cyclohexane and dichloromethane extracts exhibited a dose-dependent inhibition of human coronavirus HCoV-229E infection in hepatoma Huh-7 cells expressing or not the cellular protease TMPRSS2 (IC50 values of 5.29 μg/mL and 4.87 μg/mL, respectively). Fractionation of these active extracts led to the isolation of a new racemic benzophenanthridine alkaloid named zanthoxyloithrine (1), together with 13 known compounds. Their structures were elucidated by spectroscopic techniques including IR, UV, HR-MS, 1D and 2D NMR and electronic circular dichroism. In parallel, HR-ESI-MS/MS based dereplication and molecular networking analysis were performed to identify unpurified compounds in cyclohexane and dichloromethane extracts. Zanthoxyloithrine (1) showed strong antileishmanial (IC50 = 0.14 μM, SI = 52.0) and antitrypanosomal (IC50 = 0.36 μM, SI = 20.8) activities. In addition, compound (1) demonstrated a high antiviral activity against HCoV-229E with IC50 value of 6.70 μM in presence of TMPRRS2 and without significant toxicity on Huh-7 cells. Other purified benzo[c]phenanthridine alkaloids also showed anti-coronavirus and antiparasitic activities.
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Ba, A., Roumy, V., Al Ibrahim, M., Hughes, K., Hennebelle, T., Samaillie, J., Sahpaz, S., Beniddir, M. A., Herent, M.-F., Séron, K., Quetin-Leclercq, J., Seck, M., & Rivière, C. (2024). Antileishmanial, antitrypanosomal and anti-coronavirus activities of benzophenanthridine alkaloids and other specialized metabolites isolated from the root bark of Zanthoxylum zanthoxyloides (Lam.) B.Zepernick & Timler. Fitoterapia, 179, 106232 [1-13]. https://doi.org/10.1016/j.fitote.2024.106232 (Original work published 2024)