title: A small-molecule cell-based screen led to the identification of biphenylimidazoazines with highly potent and broad-spectrum anti-apicomplexan activity.
abstract: An in vitro screening of the anti-apicomplexan activity of 51 compounds, stemming from our chemical library and from chemical synthesis, was performed. As a study model, we used Toxoplasma gondii (T. gondii), expressing β-galactosidase for the colorimetric assessment of drug activity on parasites cultivated in vitro. This approach allowed the validation of a new series of molecules with a biphenylimidazoazine scaffold as inhibitors of T. gondii growth in vitro. Hence, 8 molecules significantly inhibited intracellular replication of T. gondii in vitro, with EC50 < 1 μM, while being non-toxic for human fibroblasts at these concentrations. Most attractive candidates were then selected for further biological investigations on other apicomplexan parasites (Neospora caninum, Besnoitia besnoiti, Eimeria tenella and Plasmodium falciparum). Finally, two compounds were able to inhibit growth of four different apicomplexans with EC50 in the submicromolar to nanomolar range, for each parasite. These data, including the broad anti-parasite spectrum of these inhibitors, define a new generation of potential anti-parasite compounds of wide interest, including for veterinary application. Studies realized on E. tenella suggest that these molecules act during the intracellular development steps of the parasite. Further experiments should be done to identify the molecular target(s) of these compounds.
authors.affiliation: UMR INRA 1282 Infectiologie et Santé Publique, Recherche et Innovation en Chimie Médicinale, University François Rabelais of Tours, F-37200 Tours, France; UMR INRA 1282 Infectiologie et Santé Publique, Immunologie Parasitaire, Vaccinologie et Bio-thérapie Anti-infectieuse, University François Rabelais of Tours, F-37200 Tours, France.
authors.forename: Espérance
authors.initials: E
authors.lastname: Moine
authors.affiliation: UMR INRA 1282 Infectiologie et Santé Publique, Recherche et Innovation en Chimie Médicinale, University François Rabelais of Tours, F-37200 Tours, France. Electronic address: caroline.sabourin@univ-tours.fr.
authors.forename: Caroline
authors.initials: C
authors.lastname: Denevault-Sabourin
authors.affiliation: UMR INRA 1282 Infectiologie et Santé Publique, Immunologie Parasitaire, Vaccinologie et Bio-thérapie Anti-infectieuse, University François Rabelais of Tours, F-37200 Tours, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Debierre-Grockiego
authors.affiliation: UMR INRA 1282 Infectiologie et Santé Publique, Recherche et Innovation en Chimie Médicinale, University François Rabelais of Tours, F-37200 Tours, France; UMR INRA 1282 Infectiologie et Santé Publique, Apicomplexes et Immunité des Muqueuses, INRA, F-37380 Nouzilly, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Silpa
authors.affiliation: Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, Département de Parasitologie et de Mycologie, F-75015 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gorgette
authors.affiliation: Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, Département de Parasitologie et de Mycologie, F-75015 Paris, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Barale
authors.affiliation: UMR 1225 INRA-National Veterinary School of Toulouse, Interactions hôtes-agents pathogènes, F-31076 Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jacquiet
authors.affiliation: UMR INRA 1282 Infectiologie et Santé Publique, Apicomplexes et Immunité des Muqueuses, INRA, F-37380 Nouzilly, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Brossier
authors.affiliation: UMR INRA 1282 Infectiologie et Santé Publique, Recherche et Innovation en Chimie Médicinale, University François Rabelais of Tours, F-37200 Tours, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Gueiffier
authors.affiliation: UMR INRA 1282 Infectiologie et Santé Publique, Immunologie Parasitaire, Vaccinologie et Bio-thérapie Anti-infectieuse, University François Rabelais of Tours, F-37200 Tours, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dimier-Poisson
authors.affiliation: UMR INRA 1282 Infectiologie et Santé Publique, Recherche et Innovation en Chimie Médicinale, University François Rabelais of Tours, F-37200 Tours, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Enguehard-Gueiffier
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016782:Apicomplexa / Q000187:drug effects* / Q000254:growth & development; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015394:Molecular Structure; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000187:drug effects / Q000254:growth & development
chemical_list: D000981:Antiprotozoal Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011724:Pyridazines; D011725:Pyridines; D054852:Small Molecule Libraries
keywords: Anti-apicomplexan; Besnoitia besnoiti; Eimeria tenella; Imidazo[1,2-a]pyridine; Imidazo[1,2-b]pyridazine; Neospora caninum; Plasmodium falciparum; Toxoplasma gondii