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

Eur J Med Chem. 2015 Oct 9;105:80-105. doi: 10.1016/j.ejmech.2015.10.004. [Epub ahead of print]

 

Moine E¹, Dimier-Poisson I¹, Enguehard-Gueiffier C¹, Logé C², Pénichon M¹, Moiré N¹, Delehouzé C³, Foll-Josselin B³, Ruchaud S³, Bach S³, Gueiffier A¹, Debierre-Grockiego F¹, Denevault-Sabourin C⁴.

 

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.

KEYWORDS:

Anti-apicomplexan; Imidazo[1,2-b]pyridazine; Toxoplasma gondii; Toxoplasma gondii calcium-dependent protein kinase 1

PMID:

26479029

[PubMed - as supplied by publisher]