Antiparasitic Activity of Sesquiterpene γ-Lactones and the Search for New Pharmaceutical Agents.

This study presents a comparative in vitro evaluation of 24 natural sesquiterpene γ-lactones and selected semisynthetic derivatives against three trypanosomatid parasites responsible for neglected tropical diseases: Trypanosoma brucei brucei, Trypanosoma cruzi, and Leishmania amazonensis. The compounds were screened for antiparasitic activity across different parasite life stages, and their cytotoxicity was assessed in mammalian cells. Several compounds demonstrated high inhibitory activity (>95%) at 10 µg/mL, including estafiatin (1), grossheimin (4), cynaropicrin (5), argolide (2) derivatives, and arglabin (23). However, a marked decrease in activity was observed at lower concentrations and in intracellular parasite models, particularly for T. cruzi and L. amazonensis amastigotes. Among the tested compounds, dihydroargolide (3) and pulchellin C (19) exhibited comparatively lower cytotoxicity and were further evaluated, yielding IC50 values of 10.51 ± 1.72 µg/mL and 2.51 ± 1.13 µg/mL against T. b. brucei, respectively. Against L. amazonensis promastigotes, estafiatin (1), 8α-chloroacetoxygrossheimin (12), and arglabin (23) showed IC50 values of 0.16 ± 0.13, 0.35 ± 0.18, and 0.58 ± 0.11 µg/mL, respectively, although their selectivity indices remained limited. Comparative analysis of the dataset indicates that specific structural elements, such as the α-methylene-γ-lactone moiety and selected substituents (e.g., epoxy and acetyl groups), may influence antiparasitic activity in a species-dependent manner. At the same time, the generally low selectivity indices and reduced activity in intracellular models highlight important limitations of these compounds as direct drug leads. Overall, this work provides a systematic comparative dataset and identifies preliminary structure-activity trends that may guide further chemical optimization of sesquiterpene γ-lactones as antiparasitic hit compounds.