Chemical and Antiplasmodial Investigations on <i>Carapa</i>-Derived Gedunin Derivatives and Semisynthetic 6- and 7‑Substituted Gedunin Analogues from the Brazilian Amazon.

Abstract

The aim of this work was to explore structure-antiplasmodial activity relationships among 6- and 7-acyloxy and hydroxy substituted gedunin derivatives. 7-Deacetyl-7-oxogedunin (cedrolide, <b>1</b>) and 6α-acetoxygedunin (<b>12</b>)known antiplasmodial limonoids from the seeds of <i>Carapa guianensis</i> Aublet (Meliaceae)were targeted for isolation at scale and used as starting materials for the preparation of a small, semisynthetic compound library that included gedunin (<b>4</b>), 7α- or 7β-acyloxy substituted 7-deacetylgedunins (<b>5</b>-<b>9</b>), and 6α-acyloxy substituted 7-deacetylgedunin derivatives (<b>13</b>-<b>15</b>). The concentrations of these compounds that inhibit 50% of the in vitro growth (IC₅₀) of the multidrug-resistant K1 strain of the human malaria parasite, <i>Plasmodium falciparum</i>, were determined. Also, these compounds were screened for toxicity to MRC-5 human fibroblasts. The most antiplasmodial compounds featured a 7α-acetoxy or a 7β-acetoxy moiety (IC₅₀ = 2.3-4.4 μM). Lower antiplasmodial activity was observed for gedunin derivatives exhibiting a 7α- or 7β-hydroxy, <i>O</i>-butanoyl, or <i>O</i>-pentanoyl moiety (and a C6 substituent). This study highlights the antiplasmodial effects, low toxicity to fibroblasts, and good selectivity (SI > 37) of 7-<i>epi</i>-gedunin (<b>5</b>), a compound that is available only through semisynthesis and whose antiplasmodial activity is reported for the first time.