Identification of potential biological target for trypanocidal sesquiterpene lactones derivatives.

Sesquiterpene lactones are natural products of the Asteraceae family that have shown trypanocidal activity against Trypanosoma cruzi, even exceeding the effectiveness of drugs used in the treatment of American trypanosomiasis. However, there is no agreement on their mechanism of action and their specificity to interact with parasite proteins. For this reason, we aimed to find biological targets that can interact with these compounds by reverse virtual screening with ligand pharmacophores and putative binding sites and the use of bioinformatic databases. Therefore, 41 possible biological targets were found, and four of them (with crystallized proteins), interfering directly or indirectly in the trypanosomatid redox system, were studied in detail. As a first approach, we focused on the study of trypanothione reductase, and protein-ligand interaction fingerprint analyses were performed to find binding site determinants that promote a possible inhibition of the enzyme. This study contributes to the understanding of one of the putative mechanisms of action of sesquiterpene lactones on one of the numerous suggested targets.Communicated by Ramaswamy H. Sarma.

Psilostachyins as trypanocidal compounds: Bioguided fractionation of Ambrosia tenuifolia chemically modified extract.

This work focusses on the chemical diversification of an Ambrosia tenuifolia extract and its bioguided fractionation, aiming to unveil the chemical entity responsible for the trypanocidal activity. Besides, a revision of the phytochemical study of this species, based on previous reports of the antiparasitic psilostachyins A and C as main compounds, was conducted. To improve the biological properties of a plant extract through a simple chemical reaction, the oxidative diversification of the dichloromethane extract of this plant species was carried out. A bioguided fractionation of a chemically modified extract was performed by evaluating the inhibitory activity against Trypanosoma cruzi trypomastigotes. This experiment led to the isolation of one of the most active compounds. In general terms, epoxidized metabolites were obtained as a result of the oxidation of the major metabolite of the species. The trypanocidal activity of some tested metabolites overperformed the reference drug, benznidazole, displaying no cytotoxicity at trypanocidal concentrations. Key structure-activity relationships were obtained for designing previously undescribed antiparasitic sesquiterpene lactones.