title: Synthesis and activity of azaterphenyl diamidines against Trypanosoma brucei rhodesiense and Plasmodium falciparum.
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.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30303-3083, USA.
authors.forename: Laixing
authors.initials: L
authors.lastname: Hu
authors.forename: Reem K
authors.initials: RK
authors.lastname: Arafa
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ismail
authors.forename: Alpa
authors.initials: A
authors.lastname: Patel
authors.forename: Manoj
authors.initials: M
authors.lastname: Munde
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D000981:Antiprotozoal Agents; D010419:Pentamidine
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