# Chemical and Antiplasmodial Investigations on Carapa-Derived Gedunin Derivatives and Semisynthetic 6- and 7‑Substituted Gedunin Analogues from the Brazilian Amazon

## TL;DR

This study investigates how chemical changes to a natural compound from the Amazon tree Carapa guianensis affect its ability to fight malaria parasites.

## Contribution

The paper reports the first antiplasmodial activity of 7-epi-gedunin, a semisynthetic compound with high selectivity and low toxicity.

## Key findings

- 7α-acetoxy and 7β-acetoxy substituted compounds showed the highest antiplasmodial activity (IC50 = 2.3–4.4 μM).
- 7-epi-gedunin (5) exhibited strong antiplasmodial effects and a selectivity index greater than 37.
- Compounds with hydroxy or longer acyl groups at position 7 had reduced antiplasmodial activity.

## 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, 1) and
6α-acetoxygedunin (12)known antiplasmodial
limonoids from the seeds of Carapa guianensis 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 (4), 7α-
or 7β-acyloxy substituted 7-deacetylgedunins (5–9), and 6α-acyloxy substituted 7-deacetylgedunin
derivatives (13–15). 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, Plasmodium falciparum, 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, O-butanoyl,
or O-pentanoyl moiety (and a C6 substituent). This
study highlights the antiplasmodial effects, low toxicity to fibroblasts,
and good selectivity (SI > 37) of 7-epi-gedunin
(5), a compound that is available only through semisynthesis
and whose antiplasmodial activity is reported for the first time.