Synthesis and Antiprotozoal Activity of Dicationic m-Terphenyl and 1,3-Dipyridylbenzene Derivatives

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• 作者：Donald A. Patrick ; Mohamed A. Ismail ; Reem K. Arafa ; Tanja Wenzler ; Xiaohua Zhu ; Trupti Pandharkar ; Susan Kilgore Jones ; Karl A. Werbovetz ; Reto Brun ; David W. Boykin ; Richard R. Tidwell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 11, 2013
• 年：2013
• 卷：56
• 期：13
• 页码：5473-5494
• 全文大小：670K
• 年卷期：v.56,no.13(July 11, 2013)
• ISSN：1520-4804

文摘

4,4鈥?Diamidino-m-terphenyl (1) and 36 analogues were prepared and assayed in vitro against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Plasmodium falciparum, and Leishmania amazonensis. Twenty-three compounds were highly active against T. b. rhodesiense or P. falciparum. Most noteworthy were amidines 1, 10, and 11 with IC₅₀ of 4 nM against T. b. rhodesiense, and dimethyltetrahydropyrimidinyl analogues 4 and 9 with IC₅₀ values of 鈮?3 nM against P. falciparum. Bis-pyridylimidamide derivative 31 was 25 times more potent than benznidazole against T. cruzi and slightly more potent than amphotericin B against L. amazonensis. Terphenyldiamidine 1 and dipyridylbenzene analogues 23 and 25 each cured 4/4 mice infected with T. b. rhodesiense STIB900 with four daily 5 mg/kg intraperitoneal doses, as well as with single doses of 鈮?0 mg/kg. Derivatives 5 and 28 (prodrugs of 1 and 25) each cured 3/4 mice with four daily 25 mg/kg oral doses.