Establishment of a Structure–Activity Relationship of 1H-Imidazo[4,5-c]quinoline-Based Kinase Inhibitor NVP-BEZ235 as a Lead for African Sleeping Sickness

نویسندگان

  • João 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
چکیده

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-activity 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.

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عنوان ژورنال:

دوره 57  شماره 

صفحات  -

تاریخ انتشار 2014