Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Ciudad deBuenos Aires, Argentina.
Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Ciudad de Buenos Aires, Argentina.
Molecules. 2019 Aug 30;24(17):3168. doi: 10.3390/molecules24173168.
The current chemotherapy of Chagas disease needs to be urgently improved. With this aim, a series of 16 hybrids of 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 In particular, eight out of 16 hybrids presented an IC ≤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 (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 and were the most trypanocidal hybrids against Y strain trypomastigotes, with IC 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 and induced a significant reduction in intracellular amastigotes and on the release of trypomastigotes from infected cells.
目前对恰加斯病的化疗需要紧急改进。为此，通过 Barton-Zard 脱羧反应，用 norcholane 取代基的自由基攻击在喹啉核的 C-2 位进行功能化，合成了一系列 16 种生物碱和胆酸的杂种。杂种的抗锥虫活性在不同阶段和株系的 Trypanosoma cruzi 上进行了测试。特别是，16 种杂种中的 8 种对 CL Brener 株的锥虫体具有 IC ≤1 μg/mL 的活性，并且/或者选择性指数高于 10。当对 RA 株的 Trypomastigotes 进行测试时，这些有前途的杂种产生了类似的结果（离散分型单位-DTU-VI）。令人惊讶的是，Y 株（DTU II）的锥虫体对苯并咪唑和大多数杂种的抗性比对 CL Brener 和 RA 株的抗性更强。然而，辛可宁/鹅去氧胆酸结合物的乙酰化和非乙酰化形式 和 是针对 Y 株锥虫体最具杀锥虫活性的杂种，IC 值分别为 0.5 和 0.65 μg/mL。更重要的是，在使用 Y 株的入侵试验中观察到了有希望的结果，杂种 和 诱导了细胞内无鞭毛体的显著减少以及感染细胞中锥虫体的释放。
