| Summary: | The natural triterpene celastrol (<b>CE</b>) is here used as lead compound for the design and synthesis of a panel of eleven <b>CE</b> carboxamides that were tested in vitro for their growth inhibitory activity against <i>Leishmania infantum</i> and <i>L.</i><i>tropica</i> parasites. Among them, in vitro screening identified four basic <b>CE</b> carboxamides endowed with nanomolar leishmanicidal activity, against both the promastigotes and the intramacrophage <i>Leishmania</i> amastigotes forms. These compounds also showed low toxicity toward two human (HMEC-1 and THP-1) and one murine (BMDM) cell lines. Interestingly, the most selective <b>CE</b> analogue (compound <b>3</b>) was also endowed with the ability to inhibit the ATPase activity of the <i>Leishmania</i> protein chaperone Hsp90 as demonstrated by the in vitro assay conducted on a purified, full-length recombinant protein. Preliminary investigations by comparing it with the naturally occurring Hsp90 active site inhibitor Geldanamycin (<b>GA</b>) in two different in vitro experiments were performed. These promising results set the basis for a future biochemical investigation of the mode of interaction of celastrol and <b>CE</b>-inspired compounds with <i>Leishmania</i> Hsp90.
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