Synthesis and antiprotozoal activities of benzyl phenyl ether diamidine derivatives

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• 作者：Donald A. Patrick ; Stanislav A. Bakunov ; Svetlana M. Bakunova ; Susan Kilgore Jones ; Tanja Wenzler ; Todd Barszcz ; Arvind Kumar ; David W. Boykin ; Karl A. Werbovetz ; Reto Brun ; Richard R. Tidwell
• 关键词：Diamidines ; Prodrugs ; Benzyl phenyl ether derivatives ; Antiprotozoal ; Antitrypanosomal ; Antiplasmodial ; Antileishmanial
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：67
• 期：Complete
• 页码：310-324
• 全文大小：1280 K

文摘

Sixty-two cationic benzyl phenyl ether derivatives (36 amidines and 26 prodrugs) were prepared and assayed for activities in?vitro and in?vivo against Trypanosoma brucei rhodesiense (STIB900), and in?vitro against Plasmodium falciparum (K1) and Leishmania donovani axenic amastigotes. 3-Amidinobenzyl 4-amidino-2-iodo-6-methoxyphenyl ether dihydrochloride (55, IC₅₀?=?3.0?nM) and seven other compounds exhibited IC₅₀ values below 10?nM against T.?b. rhodesiense in?vitro. The 2-bromo-4,4¡ä-diamidino analogue 19 (IC₅₀?=?4.0?nM) and 12 other analogues were more potent than pentamidine (IC₅₀?=?46?nM) against P.?falciparum. The 3¡ä,4-diamidino-2,6-diiodo analogue 49 (IC₅₀?=?1.4?¦ÌM) and two other compounds were more effective than pentamidine (IC₅₀?=?1.8?¦ÌM) against L.?donovani. A prodrug, 3¡ä,4-bis(N¡å-methoxy)amidino-2-bromo derivative 38, was the most efficacious against trypanosome infected mice, attaining 4/4 cures in four daily 25?mg/kg oral doses, and the 2-chloro-4,4¡ä-diamidine 18 cured 3/4 mice in four daily 5?mg/kg intraperitoneal doses.