Hybrids of Cinchona Alkaloids and Bile Acids as Antiparasitic Agents Against Trypanosoma cruzi

Molecules

卷:24

Gabriel Ferri¹  Daniel Musikant²  Diana Bernal²  MartinM. Edreira²  JorgeA. Palermo³  Aurélie Leverrier³ 

[1] CONICET-Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), 1428 Ciudad de Buenos Aires, Argentina;

[2] Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Ciudad deBuenos Aires, Argentina;

[3] Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Ciudad de Buenos Aires, Argentina;

关键词: Cinchona alkaloids;    bile acids;    hybrids;    Trypanosoma cruzi;    amastigotes;    antiparasitic activity;   

DOI  :  10.3390/molecules24173168

来源: DOAJ

【 摘 要 】

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 IC₅₀ ≤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 IC₅₀ 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.

【 授权许可】

Unknown