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Title

Lowering the pK<inf>a</inf> of a bisimidazoline lead with halogen atoms results in improved activity and selectivity against Trypanosoma brucei in vitro

AuthorsRíos Martínez, Carlos H. ; Nué Martínez, J. Jonathan; Godwin U. Ebiloma; de Koning, Harry P.; Alkorta, Ibon ; Dardonville, Christophe
Issue Date2015
PublisherElsevier
CitationEuropean Journal of Medicinal Chemistry 101: 806-817 (2015)
AbstractDiphenyl-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 pK<inf>a</inf> 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 pK<inf>a</inf> values (in the range 1-3 pK<inf>a</inf> units) for the imidazolidine group linked to the substituted phenyl ring. In vitro activities (EC<inf>50</inf>) 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.
Publisher version (URL)http://dx.doi.org/10.1016/j.ejmech.2015.07.013
URIhttp://hdl.handle.net/10261/125960
DOI10.1016/j.ejmech.2015.07.013
Identifiersdoi: 10.1016/j.ejmech.2015.07.013
issn: 1768-3254
e-issn: 1768-3254
Appears in Collections:(IQM) Artículos
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