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Synthesis and activity of azaterphenyl diamidines againstTrypanosoma brucei rhodesienseandPlasmodium falciparum

Authors
Journal
Bioorganic & Medicinal Chemistry
0968-0896
Publisher
Elsevier
Publication Date
Volume
17
Issue
18
Identifiers
DOI: 10.1016/j.bmc.2009.07.080
Keywords
  • Diamidines
  • Antiprotozoal Agents
  • Dna Binding Affinity
  • Azaterphenyl

Abstract

Abstract A series of azaterphenyl diamidines has been synthesized and evaluated for in vitro antiprotozoal activity against both Trypanosoma brucei rhodesiense ( T. b. r.) and Plasmodium falciparum ( P. f.) and in vivo efficacy in the STIB900 acute mouse model for T. b. r. Six of the 13 compounds showed IC 50 values less than 7 nM against T. b. r. Twelve of those exhibited IC 50 values less than 6 nM against P. f. and six of those showed IC 50 values ⩽0.6 nM, which are more than 25-fold as potent as furamidine. Moreover, two of them showed more than 40-fold selectivity for P. f. versus T. b. r. Three compounds 15b, 19d and 19e exhibited in vivo efficacy against T. b. r. much superior to furamidine, and equivalent to or better than azafuramidine. The antiparasitic activity of these diamidines depends on the ring nitrogen atom(s) location relative to the amidine groups and generally correlates with DNA binding affinity.

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