Synthesis and activity of azaterphenyl diamidines against Trypanosoma brucei rhodesiense

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• 作者：Laixing Hu ; Reem K. Arafa ; Mohamed A. Ismail ; Alpa Patel ; Manoj Munde ; W. David Wilson ; Tanja Wenzler ; Reto Brun ; David W. Boykin
• 关键词：Diamidines ; Antiprotozoal agents ; DNA binding affinity ; Azaterphenyl
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2009
• 出版时间：15 September 2009
• 年：2009
• 卷：17
• 期：18
• 页码：6651-6658
• 全文大小：473 K

文摘

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 IC₅₀ values less than 7 nM against T. b. r. Twelve of those exhibited IC₅₀ values less than 6 nM against P. f. and six of those showed IC₅₀ 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.