To date, a limited number of drug candidates are available for fighting Leishmania, and there is an urgent need for efficient medical treatments. Within a wider research project aimed at discovering new bioactive compounds from plant kingdom, we focused on Eremurus persicus roots. As a result of our investigation, we isolated (R)-Aloesaponol III 8-methyl ether (R)-ASME, showing a remarkable antiprotozoal effect against L. infantum with an IC50 of 73 μg/Ml and not significant toxicity in a macrophage cell line. The potential of such compound against Leishmania infections will lead us to get further insight into the mechanisms of actions studying its behavior in cells. Basing on the obtained results, we can state that (R)-ASME is a interesting hit compound and it constituted the starting point of the herein presented work. Of note, the hit is poorly soluble in water and in aqueous buffers, as a consequence the biological assays are difficult to perform and the results difficult to compare. Accordingly, we designed new water-soluble (R)-ASMEderivatives. To improve the hit physicochemical properties, different molecular modification strategies of (R)-ASME have been planned, taking into account its structural features and molecular reactivity. The investigated approaches consisted in the conjugation of (R)-ASME with either amino acid (AA), since it is considered a useful method for increase compound water solubility or with an hydrophilic moiety. The latter approach allowed us to obtain a stable and water soluble salt. The in vivo assays of this ASME-derivative are still in progress. Moreover, to improve the cellular uptake, and following a drug targeting approach, ongoing efforts will be addressed to prepare a biotin-conjugated (R)-ASME derivative. Results will be presented in due course.
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