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Establishment of a structure-activity relationship of the 1H-imidazo[4,5-c]quinoline-based kinase inhibitor NVP-BEZ235 as a lead for African sleeping sickness

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Date
12/06/2014
Author
Seixas, João D
Luengo-Arratta, Sandra A
Diaz, Rosario
Saldivia, Manuel
Rojas-Barros, Domingo I
Manzano, Pilar
Gonzalez, Silvia
Berlanga, Manuela
Smith, Terry K
Navarro, Miguel
Pollastri, Michael P
Funder
The Wellcome Trust
Grant ID
093228/Z/10/Z
Keywords
African sleeping sickness
Structure-activity relationship
Inhibitors
Phosphoinositol-kinase
QH301 Biology
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Abstract
The compound NVP-BEZ235 (1) is a potent inhibitor of human phospoinositide-3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) that also showed high inhibitory potency against T. brucei cultures. With an eye towards using 1 as a starting point for anti-trypanosomal drug discovery, we report efforts to reduce host cell toxicity, improve the physicochemical properties and improve the selectivity profile over human kinases. In this work we have developed structure-activity relationships (SAR) for analogs of 1 and have prepared analogs of 1 with improved solubility properties and good predicted central nervous system exposure. In that 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.
Citation
Seixas , J D , Luengo-Arratta , S A , Diaz , R , Saldivia , M , Rojas-Barros , D I , Manzano , P , Gonzalez , S , Berlanga , M , Smith , T K , Navarro , M & Pollastri , M P 2014 , ' Establishment of a structure-activity relationship of the 1H-imidazo[4,5-c]quinoline-based kinase inhibitor NVP-BEZ235 as a lead for African sleeping sickness ' , Journal of Medicinal Chemistry , vol. 57 , no. 11 , pp. 4834-4848 . https://doi.org/10.1021/jm500361r
Publication
Journal of Medicinal Chemistry
Status
Peer reviewed
DOI
https://doi.org/10.1021/jm500361r
ISSN
0022-2623
Type
Journal article
Rights
© 2014 American Chemical Society. This is an article distributed in accordance with the terms of the Creative Commons Attribution (CC BY NC 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for noncommercial use, provided the original work is properly cited.
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/5019

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