Synthesis and Structure鈥揂ctivity Relationships of New Quinolone-Type Molecules against Trypanosoma brucei

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• 作者：Georg Hiltensperger ; Nicola G. Jones ; Sabine Niedermeier ; August Stich ; Marcel Kaiser ; Jamin Jung ; Sebastian Puhl ; Alexander Damme ; Holger Braunschweig ; Lorenz Meinel ; Markus Engstler ; Ulrike Holzgrabe
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 22, 2012
• 年：2012
• 卷：55
• 期：6
• 页码：2538-2548
• 全文大小：427K
• 年卷期：v.55,no.6(March 22, 2012)
• ISSN：1520-4804

文摘

Human African trypanosomiasis (HAT) or sleeping sickness is caused by two subspecies of Trypanosoma brucei, Trypanosoma brucei gambiense, and Trypanosoma brucei rhodesiense and is one of Africa鈥檚 old plagues. It causes a huge number of infections and cases of death per year because, apart from limited access to health services, only inefficient chemotherapy is available. Since it was reported that quinolones such as ciprofloxacin show antitrypanosomal activity, a novel quinolone-type library was synthesized and tested. The biological evaluation illustrated that 4-quinolones with a benzylamide function in position 3 and cyclic or acyclic amines in position 7 exhibit high antitrypanosomal activity. Structure鈥揳ctivity relationships (SAR) are established to identify essential structural elements. This analysis led to lead structure 29, which exhibits promising in vitro activity against T. b. brucei (IC₅₀ = 47 nM) and T. b. rhodesiense (IC₅₀ = 9 nM) combined with low cytotoxicity against macrophages J774.1. Screening for morphological changes of trypanosomes treated with compounds 19 and 29 suggested differences in the morphology of mitochondria of treated cells compared to those of untreated cells. Segregation of the kinetoplast is hampered in trypanosomes treated with these compounds; however, topoisomerase II is probably not the main drug target.