Synthesis and structure-activity relationships of new quinolone-type molecules against Trypanosoma brucei

Hiltensperger, G. and Jones, N. G. and Niedermeier, S. and Stich, A. and Kaiser, M. and Jung, J. and Puhl, S. and Damme, A. and Braunschweig, H. and Meinel, L. and Engstler, M. and Holzgrabe, U.. (2012) Synthesis and structure-activity relationships of new quinolone-type molecules against Trypanosoma brucei. Journal of medicinal chemistry, 55 (6). pp. 2538-2548.

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Official URL: http://edoc.unibas.ch/dok/A6094398

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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's 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-activity 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 (IC(50) = 47 nM) and T. b. rhodesiense (IC(50) = 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
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:05 Dec 2017 10:11
Deposited On:19 Jul 2013 07:40

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