title: Lowering the pKa of a bisimidazoline lead with halogen atoms results in improved activity and selectivity against Trypanosoma brucei in vitro.
abstract: Diphenyl-based bis(2-iminoimidazolidines) are promising antiprotozoal agents that are curative in mouse models of stage 1 trypanosomiasis but devoid of activity in the late-stage disease, possibly due to poor brain penetration caused by their dicationic nature. We present here a strategy consisting in reducing the pKa of the basic 2-iminoimidazolidine groups though the introduction of chlorophenyl, fluorophenyl and pyridyl ring in the structure of the trypanocidal lead 4-(imidazolidin-2-ylideneamino)-N-(4-(imidazolidin-2-ylideneamino)phenyl)benzamide (1). The new compounds showed reduced pKa values (in the range 1-3 pKa units) for the imidazolidine group linked to the substituted phenyl ring. In vitro activities (EC50) against wild type and resistant strains of T. b. brucei (s427 and B48, respectively) were in the submicromolar range with four compounds being more active and selective than 1 (SI > 340). In particular, the two most potent compounds (3b and 5a) acted approximately 6-times faster than 1 to kill trypanosomes in vitro. No cross-resistance with the diamidine and melaminophenyl class of trypanocides was observed indicating that these compounds represent interesting leads for further in vivo studies.
authors.affiliation: Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Ríos Martínez
authors.affiliation: Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: J Jonathan
authors.initials: JJ
authors.lastname: Nué Martínez
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Godwin U
authors.initials: GU
authors.lastname: Ebiloma
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Harry P
authors.initials: HP
authors.lastname: de Koning
authors.affiliation: Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Ibon
authors.initials: I
authors.lastname: Alkorta
authors.affiliation: Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain. Electronic address: dardonville@iqm.csic.es.
authors.forename: Christophe
authors.initials: C
authors.lastname: Dardonville
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006219:Halogens / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D048288:Imidazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D006219:Halogens; D048288:Imidazolines; D014344:Trypanocidal Agents
keywords: Dibasic compound; Halogen scan; Imidazoline; T. brucei; pK(a)