Synthesis and antiprotozoal activities of dicationic bis(phenoxymethyl)benzenes, bis(phenoxymethyl)naphthalenes, and bis(benzyloxy)naphthalenes

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• 作者：Donald A. Patrick ; Stanislav A. Bakunov ; Svetlana M. Bakunova ; E.V.K. Suresh Kumar ; Heidi Chen ; Susan Kilgore Jones ; Tanja Wenzler ; Todd Barzcz ; Karl A. Werbovetz ; Reto Brun ; Richard R. Tidwell
• 关键词：Diamidines ; Xylene derivatives ; Naphthalene derivatives ; Antiprotozoal ; Antitrypanosomal ; Antiplasmodial ; Antileishmanial
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：September 2009
• 年：2009
• 卷：44
• 期：9
• 页码：3543-3551
• 全文大小：259 K

文摘

A series of 37 dicationically substituted bis(phenoxymethyl)benzene bis(phenoxymethyl)naphthalene, and bis(benzyloxy)naphthalene analogues of pentamidine was prepared and evaluated for antiprotozoal activities and cytotoxicity in in vitro. 1,3-Bis(4-amidinophenoxymethyl)benzene (1) was the most active against Trypanosoma brucei rhodesiense (IC₅₀ = 2.1 nM). 1,3-Bis[4-(N-isopropylamidino)phenoxymethyl]benzene (2) was most active against Plasmodium falciparum (IC₅₀ = 3.6 nM) and displayed a selectivity index more than 50 times greater than that of pentamidine. Several other compounds displayed lower antiplasmodial IC₅₀ values and higher selectivity indices relative to pentamidine. 1,4-Bis(4-amidinophenoxymethyl)benzene (14) was the most active against Leishmania donovani (IC₅₀ = 1.3 μM). Compound 2 displayed the greatest activity against T. b. rhodesiense in vivo, curing three of four infected mice dosed intraperitoneally at 5 mg/kg × 4 days.