Structure-Activity Study of Pentamidine Analogues as Antiprotozoal Agents

被引：54

作者：

Bakunova, Svetlana M. ^{[1
]}

Bakunov, Stanislav A. ^{[1
]}

Patrick, Donald A. ^{[1
]}

Kumar, E. V. K. Suresh ^{[1
]}

Ohemeng, Kwasi A. ^{[1
]}

Bridges, Arlene S. ^{[1
]}

Wenzler, Tanja ^{[3
]}

Barszcz, Todd ^{[2
]}

Jones, Susan Kilgore ^{[1
]}

Werbovetz, Karl A. ^{[2
]}

Brun, Reto ^{[3
]}

Tidwell, Richard R. ^{[1
]}

机构：

[1] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA

[2] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA

[3] Swiss Trop Inst, Dept Med Parasitol & Infect Biol, CH-4002 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 07期

关键词：

PNEUMOCYSTIS-CARINII-PNEUMONIA; HUMAN AFRICAN TRYPANOSOMIASIS; RESEARCH-AND-DEVELOPMENT; DRUG-RESISTANT MALARIA; MINOR-GROOVE BINDERS; VISCERAL LEISHMANIASIS; AROMATIC DIAMIDINES; PLASMODIUM-FALCIPARUM; PANCREATIC KALLIKREIN; ANTIMICROBIAL AGENTS;

D O I：

10.1021/jm801547t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Diamidine 1 (pentamidine) and 65 analogues (2-66) have been tested for in vitro antiprotozoal activities against Trypanosoma brucei rhodesiense, Plasmodium. falciparum, and Leishmania donovani, and for cytotoxicity against mammalian cells. Dications 32, 64, and 66 exhibited antitrypanosomal potencies equal or greater than melarsoprol (IC50 = 4 nM). Nine congeners (2-4, 12, 27, 30, and 64-66) were more active against P. falciparum than artemisinin (IC50 = 6 nM). Eight compounds (12, 32, 33, 44, 59, 62, 64, and 66) exhibited equal or better antileishmanial activities than 1 (IC50 = 1.8 mu M). Several congeners were more active than I in vivo, curing at least 2/4 infected animals in the acute mouse model of trypanosomiasis. The diimidazoline 66 was the most promising compound in the series, showing excellent in vitro activities and high selectivities against T. b. rhodesiense, P. falciparum, and L. donovani combined with high antitrypanosomal efficacy in vivo.

引用

页码：2016 / 2035

页数：20

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