title: Characterization of a melamino nitroheterocycle as a potential lead for the treatment of human african trypanosomiasis.
abstract: This paper reports an evaluation of a melamino nitroheterocycle, a potential lead for further development as an agent against human African trypanosomiasis (HAT). Studies on its efficacy, physicochemical and biopharmaceutical properties, and potential for toxicity are described. The compound previously had been shown to possess exceptional activity against Trypanosoma brucei in in vitro assays comparable to that of melarsoprol. Here, we demonstrate that the compound also was curative in the stringent acute mouse model T. brucei rhodesiense STIB 900 when given intraperitoneally at 40 mg/kg of body weight. Nevertheless, activity was only moderate when the oral route was used, and no cure was obtained when the compound was tested in a stage 2 rodent model of infection. Genotoxic profiling revealed that the compound induces DNA damage by a mechanism apparently independent from nitroreduction and involving the introduction of base pair substitutions (Ames test), possibly caused by oxidative damage of the DNA (comet test). No significant genotoxicity was observed at the chromosome level (micronucleus assay). The lack of suitable properties for oral and central nervous system uptake and the genotoxic liabilities prevent the progression of this melamine nitroheterocycle as a drug candidate for HAT. Further modification of the compound is required to improve the pharmacokinetic properties of the molecule and to separate the trypanocidal activity from the toxic potential.
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Parma, Parco Area delle Scienze, Parma, Italy Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Federica
authors.initials: F
authors.lastname: Giordani
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Parma, Parco Area delle Scienze, Parma, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Buschini
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, United Kingdom.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Baliani
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.affiliation: Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Barrett
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Parma, Parco Area delle Scienze, Parma, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pellacani
authors.affiliation: Dipartimento di Bioscienze, Università degli Studi di Parma, Parco Area delle Scienze, Parma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Poli
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, United Kingdom i.h.gilbert@dundee.ac.uk.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D021261:Parasitic Sensitivity Tests; D014344:Trypanocidal Agents / Q000627:therapeutic use*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000472:pathogenicity*; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D014344:Trypanocidal Agents