European Journal of Medicinal Chemistry 2015-11-13

Development of new highly potent imidazo[1,2-b]pyridazines targeting Toxoplasma gondii calcium-dependent protein kinase 1.

Espérance Moine, Isabelle Dimier-Poisson, Cécile Enguehard-Gueiffier, Cédric Logé, Mélanie Pénichon, Nathalie Moiré, Claire Delehouzé, Béatrice Foll-Josselin, Sandrine Ruchaud, Stéphane Bach, Alain Gueiffier, Françoise Debierre-Grockiego, Caroline Denevault-Sabourin

文献索引：Eur. J. Med. Chem. 105 , 80-105, (2015)

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摘要

Using a structure-based design approach, we have developed a new series of imidazo[1,2-b]pyridazines, targeting the calcium-dependent protein kinase-1 (CDPK1) from Toxoplasma gondii. Twenty derivatives were thus synthesized. Structure-activity relationships and docking studies confirmed the binding mode of these inhibitors within the ATP binding pocket of TgCDPK1. Two lead compounds (16a and 16f) were then identified, which were able to block TgCDPK1 enzymatic activity at low nanomolar concentrations, with a good selectivity profile against a panel of mammalian kinases. The potential of these inhibitors was confirmed in vitro on T. gondii growth, with EC50 values of 100 nM and 70 nM, respectively. These best candidates also displayed low toxicity to mammalian cells and were selected for further in vivo investigations on murine model of acute toxoplasmosis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.