Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France.
CNRS, LCC (Laboratoire de Chimie de Coordination), Université de Toulouse, UPS, INPT, 205 Route de Narbonne, BP 44099, 31077 Toulouse, France and Département Sciences de la Matière, Faculté des Sciences Exactes, Université Larbi Ben M'hidi, BP 358, Route de Constantine, 04000 Oum El Bouaghi, Algeria.
Dalton Trans. 2020 May 26;49(20):6616-6626. doi: 10.1039/d0dt01107j.
Helminthiases, a group of neglected tropical diseases, affect more than one billion people mainly in tropical and subtropical regions. Moreover, major intestinal protozoa have a significant impact on global public health. Albendazole (ABZ) is a broad-spectrum anthelmintic recommended by the World Health Organisation (WHO). However, drug resistance is emerging due to its widespread use. In order to tackle this problem, taking into account the spectacular results obtained with ferroquine, an organometallic derivatization of the antimalarial drug chloroquine, we have prepared, in this study, a series of new ferrocenyl and ruthenocenyl derivatives of the organic drug ABZ and assessed their activity against different helminths and protozoans, namely Trichuris muris, Heligmosomoides polygygrus, Schistosoma mansoni, Giardia lamblia, Haemonchus contortus and Toxoplasma gondii. The ferrocene-containing ABZ analogue 2d exhibited over 70% activity against T. muris adults in vitro at 200 μM and no toxicity to mammalian cells (IC50 >100 μM). H. polygyrus adults were not affected by any of the derivatives tested. Against T. gondii, the ferrocene-containing ABZ analogues 1a and 2d showed better in vitro activity than ABZ and low toxicity to the host cells. The activity of the analogous ruthenocenyl compound 2b against S. mansoni and T. gondii in vitro might be attributed to its toxicity towards the host cells rather than a specific antiparasitic activity. These results demonstrate that the derivatives show a species specific in vitro activity and the choice of the organometallic moieties attached to the organic drug is playing a very important role. Two of our organometallic compounds, namely 1b and 2d, were tested in T. muris infected mice. At a 400 mg kg-1 dose, the compounds showed moderate worm burden reductions but low worm expulsion rates. Overall, this work, which is one of the first studies reporting the potential of organometallic compounds on a very broad range of parasitic helminths and protozoan, is a clear confirmation of the potential of organometallic complexes against parasites of medical and veterinary importance.
蠕虫病是一组被忽视的热带病，主要影响热带和亚热带地区的 10 多亿人。此外，主要的肠道原生动物对全球公共卫生有重大影响。阿苯达唑（ABZ）是世界卫生组织（WHO）推荐的广谱驱虫药。然而，由于其广泛使用，耐药性正在出现。考虑到铁喹酮（抗疟药物氯喹的有机金属衍生物）取得的显著效果，我们在这项研究中制备了一系列新的有机药物 ABZ 的二茂铁基和钌基衍生物，并评估了它们对不同蠕虫和原生动物的活性，即旋毛虫、多房棘球绦虫、曼氏血吸虫、蓝氏贾第鞭毛虫、捻转血矛线虫和刚地弓形虫。含二茂铁的 ABZ 类似物 2d 在 200μM 时对体外培养的 T. muris 成虫表现出超过 70%的活性，对哺乳动物细胞无毒性（IC50>100μM）。没有一种测试的衍生物对 H. polygyrus 成虫有影响。对 T. gondii，含二茂铁的 ABZ 类似物 1a 和 2d 表现出比 ABZ 更好的体外活性和对宿主细胞的低毒性。类似的钌基化合物 2b 对 S. mansoni 和 T. gondii 的体外活性可能归因于其对宿主细胞的毒性，而不是特定的抗寄生虫活性。这些结果表明，衍生物表现出物种特异性的体外活性，并且与有机药物连接的金属有机部分的选择起着非常重要的作用。我们的两种金属有机化合物，即 1b 和 2d，在 T. muris 感染的小鼠中进行了测试。在 400mgkg-1 剂量下，化合物显示出中等的蠕虫负担减少，但蠕虫排出率低。总的来说，这项工作是首次报道金属有机化合物对广泛的寄生蠕虫和原生动物的潜在作用的研究之一，清楚地证实了金属有机配合物对医学和兽医重要寄生虫的潜在作用。
