| Summary: | <i>Background and objectives:</i> <i>Leishmania</i> species is the causative agent of leishmaniasis, a broad-spectrum clinical condition that can even be life-threatening when neglected. Current therapeutic strategies, despite beings highly cost-effective, have been increasingly associated with the appearance of drug-resistant microorganisms. Thus, an increasing number of thorough studies are needed towards upcoming drug discovery. This study aims to reveal the anti-protozoa activity of <i>Lavandula luisieri</i> and <i>Lavandula viridis</i> essential oils (EO) and their main components (1,8-cineole, linalool, and borneol). <i>Materials and Methods:</i> <i>L. luisieri</i> and <i>L. viridis</i> EO and their main components’ leishmanicidal effects were tested in vitro against <i>Leishmania infantum, Leishmania major</i>, and <i>Leishmania tropica</i> strains. Cell viability effects were estimated by using the tetrazolium-dye (MTT) colorimetric method, morphological changes were assessed by scanning electron microscopy (SEM) and ultrastructural investigation by transmission electronic microscopy (TEM). Phosphatidylserine externalization, mitochondrial membrane potential (MMP), and cathepsin D activity assessment were also carried out. Finally, cytotoxic activity of the studied matrices was also determined in mammalian cells. <i>Results:</i> Plant-studied EO exhibited prominent anti-<i>Leishmania</i> effects (IC<sub>50</sub> = 31−263 µg/mL), with <i>L. luisieri</i> being the most active one. At concentrations corresponding to IC<sub>50</sub> values, EO-exposed <i>L. infantum</i> promastigotes suffered marked ultrastructural modifications. The presence of aberrant-shaped cells, mitochondrial and kinetoplast swelling, and autophagosomal structures were the most common evidenced changes. <i>L. luisieri</i> EO exerted its leishmanicidal activity through different mechanisms, but mainly through unleashing apoptosis. Phosphatidylserine externalization, mitochondrial membrane potential loss, and cell-cycle arrest at G(0)/G(1) phase were the most remarkable apoptosis-mediated aspects. Inhibition of cathepsin D activity was also observed. No toxic effects were found on macrophage cells. <i>Conclusions:</i> <i>L. luisieri</i> seems to be an upcoming source of bioactive molecules for leishmaniasis control and to find leading molecules for new drugs formulation against <i>Leishmania</i> infections.
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