title: In vitro and in vivo evaluation of 28DAP010, a novel diamidine for treatment of second-stage African sleeping sickness.
abstract: African sleeping sickness is a neglected tropical disease transmitted by tsetse flies. New and better drugs are still needed especially for its second stage, which is fatal if untreated. 28DAP010, a dipyridylbenzene analogue of DB829, is the second simple diamidine found to cure mice with central nervous system infections by a parenteral route of administration. 28DAP010 showed efficacy similar to that of DB829 in dose-response studies in mouse models of first- and second-stage African sleeping sickness. The in vitro time to kill, determined by microcalorimetry, and the parasite clearance time in mice were shorter for 28DAP010 than for DB829. No cross-resistance was observed between 28DAP010 and pentamidine on the tested Trypanosoma brucei gambiense isolates from melarsoprol-refractory patients. 28DAP010 is the second promising preclinical candidate among the diamidines for the treatment of second-stage African sleeping sickness.
authors.affiliation: Medical Parasitology & Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland Tanja.Wenzler@unibas.ch.
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas, USA.
authors.forename: Sihyung
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Patrick
authors.affiliation: University of Basel, Basel, Switzerland Department of Urology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Braissant
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ismail
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas, USA.
authors.forename: Michael Zhuo
authors.initials: MZ
authors.lastname: Wang
authors.affiliation: Medical Parasitology & Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008549:Melarsoprol / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D010419:Pentamidine / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D014347:Trypanosoma brucei gambiense / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D000578:Amidines; C555517:CPD 0801; C000600960:CPD0905; D011725:Pyridines; D014344:Trypanocidal Agents; D010419:Pentamidine; D008549:Melarsoprol