The current chemotherapy of Chagas disease needs to be urgently improved. With this aim, a series of 16 hybrids of
Cinchona alkaloids and bile acids were prepared by functionalization at position C-2 of the quinoline nucleus by a radical attack of a norcholane
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The current chemotherapy of Chagas disease needs to be urgently improved. With this aim, a series of 16 hybrids of
Cinchona alkaloids and bile acids were prepared by functionalization at position C-2 of the quinoline nucleus by a radical attack of a norcholane substituent via a Barton–Zard decarboxylation reaction. The antitrypanosomal activity of the hybrids was tested on different stages and strains of
T. cruzi. In particular, eight out of 16 hybrids presented an IC
50 ≤1 μg/mL against trypomastigotes of the CL Brener strain and/or a selectivity index higher than 10. These promising hybrids yielded similar results when tested on trypomastigotes from the RA strain of
T. cruzi (discrete typing unit—DTU—VI). Surprisingly, trypomastigotes of the Y strain (DTU II) were more resistant to benznidazole and to most of the hybrids than those of the CL Brener and RA strains. However, the peracetylated and non-acetylated forms of the cinchonine/chenodeoxycholic bile acid conjugate
4f and
5f were the most trypanocidal hybrids against Y strain trypomastigotes, with IC
50 values of 0.5 and 0.65 μg/mL, respectively. More importantly, promising results were observed in invasion assays using the Y strain, where hybrids
5f and
4f induced a significant reduction in intracellular amastigotes and on the release of trypomastigotes from infected cells.
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