Author:
Krieg Reimar,Jortzik Esther,Goetz Alice-Anne,Blandin Stéphanie,Wittlin Sergio,Elhabiri Mourad,Rahbari Mahsa,Nuryyeva Selbi,Voigt Kerstin,Dahse Hans-Martin,Brakhage Axel,Beckmann Svenja,Quack Thomas,Grevelding Christoph G.,Pinkerton Anthony B.,Schönecker Bruno,Burrows Jeremy,Davioud-Charvet Elisabeth,Rahlfs Stefan,Becker Katja
Abstract
Abstract
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 (IC50 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Cited by
37 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献