Patrick Donald A, Bakunov Stanislav A, Bakunova Svetlana M, Kumar E V K Suresh, Chen Heidi, Jones Susan Kilgore, Wenzler Tanja, Barzcz Todd, Werbovetz Karl A, Brun Reto, Tidwell Richard R
Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
Eur J Med Chem. 2009 Sep;44(9):3543-51. doi: 10.1016/j.ejmech.2009.03.014. Epub 2009 Mar 24.
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 (IC(50)=2.1 nM). 1,3-Bis[4-(N-isopropylamidino)phenoxymethyl]benzene (2) was most active against Plasmodium falciparum (IC(50)=3.6 nM) and displayed a selectivity index more than 50 times greater than that of pentamidine. Several other compounds displayed lower antiplasmodial IC(50) values and higher selectivity indices relative to pentamidine. 1,4-Bis(4-amidinophenoxymethyl)benzene (14) was the most active against Leishmania donovani (IC(50)=1.3 microM). Compound 2 displayed the greatest activity against T. b. rhodesiense in vivo, curing three of four infected mice dosed intraperitoneally at 5 mg/kg x 4 days.
制备了一系列37种二脒基取代的双（苯氧基甲基）苯、双（苯氧基甲基）萘以及喷他脒的双（苄氧基）萘类似物，并对其体外抗寄生虫活性和细胞毒性进行了评估。1,3 - 双（4 - 脒基苯氧基甲基）苯（1）对布氏罗得西亚锥虫的活性最强（IC50 = 2.1 nM）。1,3 - 双[4 - （N - 异丙基脒基）苯氧基甲基]苯（2）对恶性疟原虫的活性最强（IC50 = 3.6 nM），且其选择性指数比喷他脒高50倍以上。相对于喷他脒，其他几种化合物显示出较低的抗疟IC50值和较高的选择性指数。1,4 - 双（4 - 脒基苯氧基甲基）苯（14）对杜氏利什曼原虫的活性最强（IC50 = 1.3 microM）。化合物2在体内对布氏罗得西亚锥虫的活性最高，以5 mg/kg×4天的剂量腹腔注射给药，四只感染小鼠中有三只被治愈。
