title: Synthesis and structure-activity relationships of new quinolone-type molecules against Trypanosoma brucei.
abstract: 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.
authors.affiliation: Institut für Pharmazie and Lebensmittelchemie, Universität Wuerzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Hiltensperger
authors.forename: Nicola G
authors.initials: NG
authors.lastname: Jones
authors.forename: Sabine
authors.initials: S
authors.lastname: Niedermeier
authors.forename: August
authors.initials: A
authors.lastname: Stich
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Jamin
authors.initials: J
authors.lastname: Jung
authors.forename: Sebastian
authors.initials: S
authors.lastname: Puhl
authors.forename: Alexander
authors.initials: A
authors.lastname: Damme
authors.forename: Holger
authors.initials: H
authors.lastname: Braunschweig
authors.forename: Lorenz
authors.initials: L
authors.lastname: Meinel
authors.forename: Markus
authors.initials: M
authors.lastname: Engstler
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
mesh_terms: D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D018105:DNA, Kinetoplast / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000648:ultrastructure; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014347:Trypanosoma brucei gambiense / Q000187:drug effects* / Q000648:ultrastructure; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000648:ultrastructure; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D018105:DNA, Kinetoplast; D009025:Morpholines; C573838:N-benzyl-1-butyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-3-carboxamide; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; D014344:Trypanocidal Agents; D004250:DNA Topoisomerases, Type II