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 Delehouze; Beatrice Foll-Josselin; Sandrine Ruchaud; Stéphane Bach; Alain Gueiffier; Françoise Debierre-Grockiego; Caroline Denevault-Sabourin

doi:10.1016/j.ejmech.2015.10.004

Journal articles

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

Espérance Moine ¹ Isabelle Dimier-Poisson ² Cécile Enguehard-Gueiffier ³ Cédric Logé ⁴ Mélanie Pénichon ⁵ Nathalie Moiré ⁶ Claire Delehouze ⁷ Beatrice Foll-Josselin ⁸ Sandrine Ruchaud ⁷ Stéphane Bach ⁹ Alain Gueiffier ¹⁰ Françoise Debierre-Grockiego ¹¹ Caroline Denevault-Sabourin ¹²

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]

2 UR IASP - Infectiologie Animale et Santé Publique

3 U1069 N2C

4 IICiMed - Cibles et médicaments de l'infection, de l'immunité et du cancer

5 SIMBA - Synthèse et isolement de molécules bio-actives EA 7502

6 UR IASP - UR Infectiologie animale et Santé publique

7 P3H - Phophorylation de protéines et Pathologies Humaines

8 SBR - Station biologique de Roscoff

9 SBR - Station biologique de Roscoff [Roscoff]

10 Université de Tours

11 Institut für Virologie

12 GICC UMR 7292 CNRS - Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017]

Abstract : 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.

Keywords : Imidazo[1,2-b]pyridazine Toxoplasma gondii Toxoplasma gondii calcium-dependent protein kinase 1

Document type :

Journal articles

Domain :

Chemical Sciences / Medicinal Chemistry

Complete list of metadatas

https://hal-univ-tours.archives-ouvertes.fr/hal-02389861
Contributor : Caroline Denevault-Sabourin <>
Submitted on : Monday, December 2, 2019 - 4:50:10 PM
Last modification on : Friday, October 16, 2020 - 3:41:10 AM

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

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

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