title: Development of new highly potent imidazo[1,2-b]pyridazines targeting Toxoplasma gondii calcium-dependent protein kinase 1.
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.
authors.affiliation: Université François-Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, F-37000 Tours, France; INRA, UMR1282 Infectiologie et Santé Publique, F-37380 Nouzilly, France.
authors.forename: Espérance
authors.initials: E
authors.lastname: Moine
authors.affiliation: Université François-Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, F-37000 Tours, France; INRA, UMR1282 Infectiologie et Santé Publique, F-37380 Nouzilly, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dimier-Poisson
authors.affiliation: Université François-Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, F-37000 Tours, France; INRA, UMR1282 Infectiologie et Santé Publique, F-37380 Nouzilly, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Enguehard-Gueiffier
authors.affiliation: Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICiMed-EA 1155, UFR de Sciences Pharmaceutiques et Biologiques, F-44035 Nantes, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Logé
authors.affiliation: Université François-Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, F-37000 Tours, France; INRA, UMR1282 Infectiologie et Santé Publique, F-37380 Nouzilly, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Pénichon
authors.affiliation: Université François-Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, F-37000 Tours, France; INRA, UMR1282 Infectiologie et Santé Publique, F-37380 Nouzilly, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Moiré
authors.affiliation: USR3151 CNRS/UPMC, Plate-forme de Criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, F-29688 Roscoff, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Delehouzé
authors.affiliation: USR3151 CNRS/UPMC, Plate-forme de Criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, F-29688 Roscoff, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Foll-Josselin
authors.affiliation: USR3151 CNRS/UPMC, Plate-forme de Criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, F-29688 Roscoff, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ruchaud
authors.affiliation: USR3151 CNRS/UPMC, Plate-forme de Criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, F-29688 Roscoff, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bach
authors.affiliation: Université François-Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, F-37000 Tours, France; INRA, UMR1282 Infectiologie et Santé Publique, F-37380 Nouzilly, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Gueiffier
authors.affiliation: Université François-Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, F-37000 Tours, France; INRA, UMR1282 Infectiologie et Santé Publique, F-37380 Nouzilly, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Debierre-Grockiego
authors.affiliation: Université François-Rabelais de Tours, UMR1282 Infectiologie et Santé Publique, F-37000 Tours, France; INRA, UMR1282 Infectiologie et Santé Publique, F-37380 Nouzilly, France. Electronic address: caroline.sabourin@univ-tours.fr.
authors.forename: Caroline
authors.initials: C
authors.lastname: Denevault-Sabourin
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine; D014122:Toxoplasma / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development
chemical_list: D000981:Antiprotozoal Agents; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011494:Protein Kinases; D002118:Calcium
keywords: Anti-apicomplexan; Imidazo[1,2-b]pyridazine; Toxoplasma gondii; Toxoplasma gondii calcium-dependent protein kinase 1