Institute of Anatomy II, University Hospital Jena, Teichgraben 7, 07743 Jena, Germany.
Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Heinrich Buff Ring 26-32, 35392 Giessen, Germany.
Nat Commun. 2017 Feb 17;8:14478. doi: 10.1038/ncomms14478.
In search of antiparasitic agents, we here identify arylmethylamino steroids as potent compounds and characterize more than 60 derivatives. The lead compound 1o is fast acting and highly active against intraerythrocytic stages of chloroquine-sensitive and resistant Plasmodium falciparum parasites (IC 1-5 nM) as well as against gametocytes. In P. berghei-infected mice, oral administration of 1o drastically reduces parasitaemia and cures the animals. Furthermore, 1o efficiently blocks parasite transmission from mice to mosquitoes. The steroid compounds show low cytotoxicity in mammalian cells and do not induce acute toxicity symptoms in mice. Moreover, 1o has a remarkable activity against the blood-feeding trematode parasite Schistosoma mansoni. The steroid and the hydroxyarylmethylamino moieties are essential for antimalarial activity supporting a chelate-based quinone methide mechanism involving metal or haem bioactivation. This study identifies chemical scaffolds that are rapidly internalized into blood-feeding parasites.
在寻找抗寄生虫药物的过程中，我们发现芳基甲氨基甾体类化合物是一种有效的化合物，并对 60 多种衍生物进行了鉴定。先导化合物 1o 对氯喹敏感和耐药的恶性疟原虫（IC 1-5nM）的红内期和配子体均具有快速而高效的作用。在感染伯氏疟原虫的小鼠中，口服给予 1o 可显著降低寄生虫血症并治愈动物。此外，1o 能够有效地阻止寄生虫从小鼠传播到蚊子。甾体化合物在哺乳动物细胞中显示出低细胞毒性，并且不会在小鼠中引起急性毒性症状。此外，1o 对吸血性吸虫寄生虫曼氏血吸虫具有显著的活性。甾体和羟芳基甲氨基部分对于抗疟活性是必需的，支持涉及金属或血红素生物激活的螯合醌亚甲化合物机制。本研究确定了可快速进入吸血寄生虫的化学支架。
