Abstract / Summary
Chagas disease and leishmaniasis, caused by the protozoan Trypanosoma cruzi and different Leishmania species, respectively, remain public health problems in developing regions due to high prevalence and the limited efficacy and safety of current treatments. Plant-derived natural products are emerging as a promising source of safer antikinetoplastid agents. The present work explores Argyranthemum frutescens as a source of antiparasitic compounds to identify new therapeutic candidates. To address this aim, a bioassay-guided fractionation of the ethanolic root extract from cultivated A. frutescens was carried out against kinetoplastids, including T. cruzi, L. amazonensis, and L. donovani. Polyacetylenes with leishmanicidal and trypanocidal activity were identified using this approach. Among them, compound 1 showed greater activity than the reference drug miltefosine against L. amazonensis and T. cruzi. Compound 1 showed activity against the amastigote stages of both parasites, surpassing the activity of the leishmanicidal reference drug. Notably, compound 1 showed a good selectivity index against the mammalian cell line. The findings indicated that the nature of the chemical group present at the propargyl–benzyl position plays a role in compound bioactivity. Subsequent assays revealed that this compound induces programmed cell death-related processes in T. cruzi and L. amazonensis, including ATP depletion, chromatin condensation, plasma membrane damage, accumulation of reactive oxygen species (ROS), and alterations in mitochondrial membrane potential (ΔΨm). Collectively, these findings highlight the potential of polyacetylenes as promising antikinetoplastid lead compounds and identify A. frutescens as a valuable natural source for the development of therapeutic agents against Chagas disease and leishmaniasis.