title: Quinolone Amides as Antitrypanosomal Lead Compounds with In Vivo Activity.
abstract: Human African trypanosomiasis (HAT) is a major tropical disease for which few drugs for treatment are available, driving the need for novel active compounds. Recently, morpholino-substituted benzyl amides of the fluoroquinolone-type antibiotics were identified to be compounds highly active against Trypanosoma brucei brucei Since the lead compound GHQ168 was challenged by poor water solubility in previous trials, the aim of this study was to introduce structural variations to GHQ168 as well as to formulate GHQ168 with the ultimate goal to increase its aqueous solubility while maintaining its in vitro antitrypanosomal activity. The pharmacokinetic parameters of spray-dried GHQ168 and the newly synthesized compounds GHQ242 and GHQ243 in mice were characterized by elimination half-lives ranging from 1.5 to 3.5 h after intraperitoneal administration (4 mice/compound), moderate to strong human serum albumin binding for GHQ168 (80%) and GHQ243 (45%), and very high human serum albumin binding (>99%) for GHQ242. For the lead compound, GHQ168, the apparent clearance was 112 ml/h and the apparent volume of distribution was 14 liters/kg of body weight (BW). Mice infected with T. b. rhodesiense (STIB900) were treated in a stringent study scheme (2 daily applications between days 3 and 6 postinfection). Exposure to spray-dried GHQ168 in contrast to the control treatment resulted in mean survival durations of 17 versus 9 days, respectively, a difference that was statistically significant. Results that were statistically insignificantly different were obtained between the control and the GHQ242 and GHQ243 treatments. Therefore, GHQ168 was further profiled in an early-treatment scheme (2 daily applications at days 1 to 4 postinfection), and the results were compared with those obtained with a control treatment. The result was statistically significant mean survival times exceeding 32 days (end of the observation period) versus 7 days for the GHQ168 and control treatments, respectively. Spray-dried GHQ168 demonstrated exciting antitrypanosomal efficacy.
authors.affiliation: Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Würzburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Hiltensperger
authors.affiliation: Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Würzburg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Hecht
authors.affiliation: Swiss Tropical and Public Health Institute, Parasite Chemotherapy, Basel, Switzerland Universität Basel, Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Würzburg, Germany.
authors.forename: Jens-Christoph
authors.initials: JC
authors.lastname: Rybak
authors.affiliation: Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Würzburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoerst
authors.affiliation: Universität Würzburg, Institut für Anorganische Chemie, Würzburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Dannenbauer
authors.affiliation: Universität Würzburg, Institut für Anorganische Chemie, Würzburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller-Buschbaum
authors.affiliation: Universität Würzburg, Institut für Molekulare Infektionsbiologie, Würzburg, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Bruhn
authors.affiliation: Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Würzburg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Esch
authors.affiliation: Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Würzburg, Germany.
authors.forename: Leane
authors.initials: L
authors.lastname: Lehmann
authors.affiliation: Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Würzburg, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Meinel
authors.affiliation: Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Würzburg, Germany ulrike.holzgrabe@uni-wuerzburg.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
mesh_terms: D000577:Amides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000472:pathogenicity; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects / Q000472:pathogenicity
chemical_list: D000577:Amides; D015363:Quinolones; D014344:Trypanocidal Agents