Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina 27599-7525, USA.
J Med Chem. 2010 Jan 14;53(1):254-72. doi: 10.1021/jm901178d.
Novel dicationic triazoles 1-60 were synthesized by the Pinner method from the corresponding dinitriles, prepared via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The type and the placement of cationic moieties as well as the nature of aromatic substituents influenced in vitro antiprotozoal activities of compounds 1-60 against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani and their cytotoxicity for mammalian cells. Eight congeners displayed antitrypanosomal IC(50) values below 10 nM. Thirty-nine dications were more potent against P. falciparum than pentamidine (IC(50) = 58 nM), and eight analogues were more active than artemisinin (IC(50) = 6 nM). Diimidazoline 60 exhibited antiplasmodial IC(50) value of 0.6 nM. Seven congeners administered at 4 x 5 mg/kg by the intraperitoneal route cured at least three out of four animals in the acute mouse model of African trypanosomiasis. At 4 x 1 mg/kg, diamidine 46 displayed better antitrypanosomal efficacy than melarsoprol, curing all infected mice.
新型二价三唑化合物 1-60 是通过 Pinner 法由相应的二腈合成的，这些二腈是通过铜（I）催化的叠氮化物-炔烃环加成（CuAAC）制备的。化合物 1-60 的阳离子部分的类型和位置以及芳基取代基的性质影响了它们对非洲锥虫（Trypanosoma brucei rhodesiense）、疟原虫（Plasmodium falciparum）和利什曼原虫（Leishmania donovani）的体外抗原生动物活性及其对哺乳动物细胞的细胞毒性。有 8 种同系物对锥虫的 IC50 值低于 10 nM。39 种二价阳离子对疟原虫的活性比戊烷脒（IC50 = 58 nM）更强，有 8 种类似物比青蒿素（IC50 = 6 nM）更有效。二咪唑啉 60 对疟原虫的 IC50 值为 0.6 nM。有 7 种同系物以 4 x 5 mg/kg 的剂量通过腹腔途径给药，在非洲锥虫病的急性小鼠模型中，至少有 3/4 的动物被治愈。以 4 x 1 mg/kg 的剂量给药时，二脒 46 的抗锥虫效果优于美拉胂醇，治愈了所有感染的小鼠。
