- Lowering the pKa of a bisimidazoline lead with halogen atoms results in improved activity and selectivity against Trypanosoma brucei in vitro
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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.
- Ríos Martínez, Carlos H.,Nué Martínez, J. Jonathan,Ebiloma, Godwin U.,De Koning, Harry P.,Alkorta, Ibon,Dardonville, Christophe
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- SYNTHESIS AND STRUCTURE OF MONOCHLORO DERIVATIVES OF 2-(4-AMINOPHENYL)-5(6)-AMINOBENZIMIDAZOLE
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Methods for the production of the monochloro derivatives of 2-(4-aminophenyl)-5(6)-aminobenzimidazole from chloronitrobenzanilides or by the condensation of 1,2,4-triaminobenzene with chloroaminobenzoic acid were investigated.It was established that the nitration of o-chlorobenzanilides takes place selectively in a mixture of acetic acid, acetic anhydride, and chloroform, while the nitration of 4(7)- or 5(6)-chlorobenzimidazoles takes place in sulfuric acid.The effect of the chlorine atoms and the nitro (amino) group on the IR and PMR spectra of the benzanilides and benzimidazoles is determined by their mutual position and by the position in relation of the amide bridge or the condensed imidazole ring.Analysis of the PMR spectra of the chlorodiaminophenylbenzimidazoles indicated that the amino group was localized at position 6 of the benzimidazole ring.
- Shchel'tsyn, V. K.,Frolova, T. I.,Grudtsyn, Yu. D.,Vandysheva, E. A.,Kaminskii, A. Ya.,Leonova, V. V.
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p. 2132 - 2142
(2007/10/02)
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