Establishment of a Structure鈥揂ctivity Relationship of 1H-Imidazo[4,5-c]quinoline-Based Kinase Inhibitor NVP-BEZ235 as a Lead for African Sleeping Sickness
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- 作者：Jo茫o D. Seixas ; Sandra A. Luengo-Arratta ; Rosario Diaz ; Manuel Saldivia ; Domingo I. Rojas-Barros ; Pilar Manzano ; Silvia Gonzalez ; Manuela Berlanga ; Terry K. Smith ; Miguel Navarro ; Michael P. Pollastri
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：June 12, 2014
- 年：2014
- 卷：57
- 期：11
- 页码：4834-4848
- 全文大小：586K
- 年卷期：v.57,no.11(June 12, 2014)
- ISSN：1520-4804
文摘
Compound NVP-BEZ235 (1) is a potent inhibitor of human phospoinositide-3-kinases and mammalian target of rapamycin (mTOR) that also showed high inhibitory potency against Trypanosoma brucei cultures. With an eye toward using 1 as a starting point for anti-trypanosomal drug discovery, we report efforts to reduce host cell toxicity, to improve the physicochemical properties, and to improve the selectivity profile over human kinases. In this work, we have developed structure鈥揳ctivity relationships for analogues of 1 and have prepared analogues of 1 with improved solubility properties and good predicted central nervous system exposure. In this way, we have identified 4e, 9, 16e, and 16g as the most promising leads to date. We also report cell phenotype and phospholipidomic studies that suggest that these compounds exert their anti-trypanosomal effects, at least in part, by inhibition of lipid kinases.