A small-molecule cell-based screen led to the identification of biphenylimidazoazines with highly potent and broad-spectrum anti-apicomplexan activity
2015
Moine, Espérance | Denevault-Sabourin, Caroline | Debierre-Grockiego, Françoise | Silpa, Laurence | Gorgette, Olivier | Barale, Jean-Christophe | Jacquiet, Philippe | Brossier, Fabien | Gueiffier, Alain | Dimier-Poisson, Isabelle | Enguehard-Gueiffier, Cécile | Infectiologie et Santé Publique (UMR ISP) ; Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT) | Université de Tours (UT) | Immunologie moléculaire des parasites ; Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS) | Interactions hôtes-agents pathogènes [Toulouse] (IHAP) ; Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT) ; Institut National Polytechnique (Toulouse) (Toulouse INP) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP) ; Université de Toulouse (UT)-Université de Toulouse (UT) | Niche, Nutrition, Cancer et métabolisme oxydatif (N2Cox) ; Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Показать больше [+] Меньше [-]Английский. 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.
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