Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis, and Biological Evaluation

The design, synthesis, and biological evaluation of 18 ferrocenyl derivatives (4A–12A and 4B–12B) of the most well-known drug against schistosomiasis, namely praziquantel (PZQ), are reported. These compounds, which have been all isolated as racemates, were unambiguously characterized by 1H and 13C NMR spectroscopy, mass spectrometry, and elemental analysis as well as by X-ray crystallography for 4A, 5A, and 7A. Cytotoxicity studies revealed that the complexes were moderately toxic toward a cervical cancer cell line (HeLa) and, importantly, significantly less active toward a noncancerous cell line (MRC-5). The in vitro anthelmintic activity of the 18 ferrocenyl PZQ derivatives was tested against adult Schistosoma mansoni, and values in the micromolar range (26–68 μM) were determined for the four most active compounds. It was also demonstrated using two compounds of the series as models (8A and 8B) that the complexes were stable when incubated for 24 h at 37 °C in human plasma.

本文报道了针对血吸虫病的一线临床药物吡喹酮（praziquantel, PZQ）的18个二茂铁衍生物（ferrocenyl derivatives，4A–12A及4B–12B）的设计、合成与生物学评价。所有目标化合物均以消旋体形式分离得到，并通过1H及13C核磁共振波谱法、质谱法、元素分析法完成了明确的结构表征；其中化合物4A、5A与7A还通过X射线单晶衍射（X-ray crystallography）进行了结构确证。细胞毒性实验结果显示，该系列衍生物对宫颈癌细胞系（HeLa）具有中等毒性，而尤为关键的是，其对正常细胞系MRC-5的活性显著更低。针对这18个二茂铁修饰的吡喹酮衍生物，本研究开展了体外抗曼氏血吸虫（Schistosoma mansoni）成虫的驱虫活性测试，其中活性最优的4个化合物的活性值处于26–68 μM的微摩尔区间。本研究还以该系列中的8A与8B作为模型化合物进行验证，结果表明该类衍生物在37 ℃的人血浆中孵育24小时后仍保持稳定。