| Summary: | <i>Plasmodium falciparum</i> and <i>Leishmania</i> sp. resistance to antiparasitic drugs has become a major concern in malaria and leishmaniasis control. These diseases are public health problems with significant socioeconomic impacts, and mostly affect disadvantaged populations living in remote tropical areas. This challenge emphasizes the need to search for new chemical scaffolds that preferably possess novel modes of action to contribute to antimalarial and antileishmanial research programs. This study aimed to investigate the antimalarial and antileishmanial properties of a methanol extract (<b>KS</b>-<b>MeOH</b>) of the stem bark of the Cameroonian medicinal plant <i>Khaya senegalensis</i> and its isolated compounds. The purification of <b>KS</b>-<b>MeOH</b> led to the isolation of a new ordered limonoid derivative, 21<i>β</i>-hydroxybourjotinolone A (<b>1a</b>), together with 15 known compounds (<b>1bc</b>–<b>14</b>) using a repeated column chromatography. Compound <b>1a</b> was obtained in an epimeric mixture of 21<i>α</i>-melianodiol (<b>1b</b>) and 21<i>β</i>-melianodiol (<b>1c</b>). Structural characterization of the isolated compounds was achieved with HRMS, and 1D- and 2D-NMR analyses. The extracts and compounds were screened using pre-established in vitro methods against synchronized ring stage cultures of the multidrug-resistant Dd2 and chloroquine-sensitive/sulfadoxine-resistant 3D7 strains of <i>Plasmodium falciparum</i> and the promastigote form of <i>Leishmania donovani</i> (1S(MHOM/SD/62/1S). In addition, the samples were tested for cytotoxicity against RAW 264.7 macrophages. Positive controls consisted of artemisinin and chloroquine for <i>P. falciparum</i>, amphotericin B for <i>L. donovani</i>, and podophyllotoxin for cytotoxicity against RAW 264.7 cells. The extract and fractions exhibited moderate to potent antileishmanial activity with 50% inhibitory concentrations (IC<sub>50</sub>) ranging from 5.99 ± 0.77 to 2.68 ± 0.42 μg/mL, while compounds displayed IC<sub>50</sub> values ranging from 81.73 ± 0.12 to 6.43 ± 0.06 μg/mL. They were weakly active against the chloroquine-sensitive/sulfadoxine-resistant <i>Pf</i>3D7 strain but highly potent toward the multidrug-resistant <i>Pf</i>Dd2 (extracts, IC<sub>50</sub> 2.50 ± 0.12 to 4.78 ± 0.36 μg/mL; compounds IC<sub>50</sub> 2.93 ± 0.02 to 50.97 ± 0.37 μg/mL) with selectivity indices greater than 10 (SI<sub>Dd2</sub> > 10) for the extract and fractions and most of the derived compounds. Of note, the limonoid mixture [21<i>β</i>-hydroxylbourjotinolone A (<b>1a</b>) + 21<i>α</i>-melianodiol (<b>1b</b>) + 21<i>β</i>-melianodiol (<b>1c</b>)] exhibited moderate activity against <i>P. falciparum</i> and <i>L. donovani.</i> This novel antiplasmodial and antileishmanial chemical scaffold qualifies as a promising starting point for further medicinal chemistry-driven development of a dually active agent against two major infectious diseases affecting humans in Africa.
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