Trypanocidal activity of 5,6-dihydropyran-2-ones against free trypomastigotes forms of Trypanosoma cruzi

Sixteen 5,6-dihydro-2H-pyran-2-ones were evaluated in in vitro assay against trypomastigotes forms of Trypanosoma cruzi, the causative agent of Chagas' disease. A structure–activity relationship study (SAR) allowed us to establish the relevant structural features for the trypanocidal activity of goniothalamin analogues against T. cruzi. In fact, non-natural form of goniothalamin (ent-1) was threefold more potent than the natural one (1). In addition, we have identified analogues 9 and 10 (both displaying S configuration) as the highest potent compounds against T. cruzi with IC50 = 0.12 and 0.09 mM (IC50 value for crystal violet was 0.08 mM) whereas significantly lower toxicities were observed when these compounds were evaluated under LLC-MK2 lineage cells (1.38 and 4.89 mM, respectively). In addition, epoxides derivatives 12 and ent-12 were shown to be more potent than the corresponding stereoisomers 2 and ent-2 and non-natural argentilactone (ent-3, IC50 = 0.47 mM) was twofold more potent than natural argentilactone (3, IC50 = 0.94 mM).

Dihydropyranones 9 and 10 (both displaying S configuration) were found to be the most potent compounds against the trypomastigotes form of T. cruzi (IC50 = 0.12 and 0.09 mM, respectively) among 16 compounds investigated. (S)-goniothalamin (1), the parent compound in this series, displayed reduced trypanocidal activity (IC50 0.35 mM) but was shown to be threefold more potent than its natural form (R)-1 (IC50 1.30 mM). Significantly lower toxicities against LLC-MK2 lineage cells were determined for dihydropyranones 9 and 10 (1.38 and 4.89 mM, respectively).Figure optionsDownload as PowerPoint slide