Synergistic Antileishmanial Activity of Erythrodiol, Uvaol, and Oleanolic Acid Isolated from Olive Leaves of cv. Chemlali

This is an accepted version of the following published document: Lafi O, Essid R, Lachaud L, et al (2023) Synergistic antileishmanial activity of erythrodiol, uvaol, and oleanolic acid isolated from olive leaves of cv. Chemlali. 3 Biotech 13:395. https://doi.org/10.1007/s13205-023-03825-3. This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s13205-023-03825-3.[Abstract] This study aimed to assess the antileishmanial activity of biomolecules obtained from Olea europaea L. leaves and twigs recovered from eight Tunisian cultivars. The extraction was first carried out with 80% methanol, and then the obtained extract was fractionated using three solvents of increasing polarity: cyclohexane (CHX), dichloromethane (DCM) and ethyl acetate (EtOAc). The antileishmanial activity was determined against leishmanial strains responsible for cutaneous, visceral, and mucocutaneous leishmaniasis. The cyclohexane fraction of the leaves of cv. Chemlali from the region of Sidi-Bouzid exhibited the strongest leishmanicidal activity against all the tested leishmanial strains. The inhibition concentrations (IC50) were 16.5, 14.5, and 7.4 μg mL−1 for Leishmania mexicana (cutaneous), Leishmania braziliensis (mucocutaneous), and Leishmania donovani (visceral), respectively. Interestingly, low cytotoxicity was observed on THP-1 cells with selective indexes (SI) ranging from 22.8 to 50.5. HPLC-HRMS and full-house NMR analysis allowed the identification of three triterpenic compounds, oleanolic acid (IC50 = 64.1 μg mL−1), erythrodiol (IC50 = 52.0 µg mL−1), and uvaol (IC50 = 53.8 μg mL−1). Antileishmanial activity of uvaol and oleanolic acid has been previously reported. However, this work constitutes the first report of the antileishmanial activity of erythrodiol which showed combinatorial interaction with uvaol (IC50 = 26.1 μg mL−1) against Leishmania tropica. The mixture of the three compounds, as major ones, exhibited an enhanced activity against Leishmania tropica (IC50 = 16.3 µg mL−1) compared to erythrodiol alone or the combination of uvaol and erythrodiol. This finding is of great importance and needs further investigation.The research leading to this paper was funded by the Tunisian Ministry of Higher Educatio