Schistosomiasis is a parasitic disease that affects more than 250 million people annually, mostly children in poor, tropical, rural areas. Only one treatment (praziquantel) is available, putting control efforts at risk should resistance occur. In pursuit of treatment alternatives, we derivatized an old antischistosomal agent, oxamniquine (OXA). Four organometallic derivatives of OXA were synthesized and tested against Schistosoma mansoni in vitro and in vivo. Of these, a ferrocenyl derivative, 1, killed larval and adult worms 24 h postexposure in vitro, in contrast to OXA, which lacks in vitro activity against adult worms. A dose of 200 mg/kg of 1 completely eliminated the worm burden in mice. Subsequently, a ruthenocenyl (5) and a benzyl derivative (6) of OXA were synthesized to probe the importance of the ferrocenyl group in 1. Compounds 1, 5, and 6 were lethal to both S. mansoni and S. haematobium adults in vitro. In vivo, at 100 mg/kg, all three compounds revealed S. mansoni worm burden reductions of 76 to 93%, commensurate with OXA. Our findings present three compounds with activity against S. mansoni in vitro, comparable activity in vivo, and high activity against S. haematobium in vitro. These compounds may possess a different binding mode or mode of action compared to OXA and present excellent starting points for further SAR studies.

中文翻译：

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具有对付曼氏血吸虫和血吸虫血吸虫活性的跨物种活性的二茂铁基，钌烯基和苄基氧肟基衍生物

血吸虫病是一种寄生虫病，每年影响超过2.5亿人，其中多数是贫穷，热带和农村地区的儿童。只有一种治疗方法（吡喹酮）可用，如果发生耐药性，控制工作就会面临风险。为了寻求替代治疗方法，我们衍生了一种旧的抗血吸虫病药物奥沙尼喹（OXA）。合成了OXA的四种有机金属衍生物，并在体内和体外针对曼氏血吸虫进行了测试。其中，二茂铁基衍生物1在体外暴露后24小时杀死幼虫和成虫，而OXA则缺乏对成虫的体外活性。200 mg / kg的剂量1完全消除了小鼠体内的蠕虫负担。随后，一个钌烯基（5）和OXA的苄基衍生物（6）进行了合成，以探讨1中二茂铁基的重要性。化合物1，5，和6是致死既曼氏血吸虫和血吸虫体外成人。在体内，三种化合物以100 mg / kg的剂量显示，曼氏沙门氏菌蠕虫的负荷降低了76％至93％，与OXA相当。我们的发现提出了三种具有体外抗曼氏沙门氏菌活性，可比的体内活性以及高抗沙门氏菌活性的化合物体外。与OXA相比，这些化合物可能具有不同的结合模式或作用模式，并为进一步的SAR研究提供了极好的起点。