Lowering the pKa of a bisimidazoline lead with halogen atoms results in improved activity and selectivity against Trypanosoma brucei in vitro

Ríos Martínez, C. H., Nué Martínez, J. J., Ebiloma, G. U., De Koning, H. P. , Alkorta, I. and Dardonville, C. (2015) Lowering the pKa of a bisimidazoline lead with halogen atoms results in improved activity and selectivity against Trypanosoma brucei in vitro. European Journal of Medicinal Chemistry, 101, pp. 806-817. (doi: 10.1016/j.ejmech.2015.07.013) (PMID:26231081)

Full text not currently available from Enlighten.

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:De Koning, Professor Harry
Authors: Ríos Martínez, C. H., Nué Martínez, J. J., Ebiloma, G. U., De Koning, H. P., Alkorta, I., and Dardonville, C.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:European Journal of Medicinal Chemistry
Publisher:Elsevier
ISSN:0223-5234
ISSN (Online):1768-3254
Published Online:10 July 2015

University Staff: Request a correction | Enlighten Editors: Update this record