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dc.creatorFersing, C. (Cyril)-
dc.creatorBoudot, C. (Clotilde)-
dc.creatorPaoli-Lombardo, R. (Romain)-
dc.creatorPrimas, N. (Nicolas)-
dc.creatorPinault, E. (Emilie)-
dc.creatorHutter, S. (Sébastien)-
dc.creatorCastera-Ducros, C. (Caroline)-
dc.creatorKabri, Y. (Youssef)-
dc.creatorPedron, J. (Julien)-
dc.creatorBourgeade-Delmas, S. (Sandra)-
dc.creatorSournia-Saquet, A. (Alix)-
dc.creatorValentin, A. (Alexis)-
dc.creatorAzqueta, A. (Amaya)-
dc.creatorMuruzábal, D. (Damián)-
dc.creatorDestere, A. (Alexandre)-
dc.creatorWyllie, S. (Susan)-
dc.creatorFairlamb, A.H. (Alan H.)-
dc.creatorCorvaisier, S. (Sophie)-
dc.creatorSince, M. (Marc)-
dc.creatorMalzert-Fréon, A. (Aurélie)-
dc.creatorDi-Giorgio, C. (Carole)-
dc.creatorRathelot, P. (Pascal)-
dc.creatorAzas, N. (Nadine)-
dc.creatorCourtioux, B. (Bertrand)-
dc.creatorVanelle, P. (Patrice)-
dc.creatorVerhaeghe, P. (Pierre)-
dc.identifier.citationFersing C, Boudot C, Paoli-Lombardo R, Primas N, Pinault E, Hutter S, Castera-Ducros C, Kabri Y, Pedron J, Bourgeade-Delmas S, Sournia-Saquet A, Stigliani JL, Valentin A, Azqueta A, Muruzabal D, Destere A, Wyllie S, Fairlamb AH, Corvaisier S, Since M, Malzert-Fréon A, Di Giorgio C, Rathelot P, Azas N, Courtioux B, Vanelle P, Verhaeghe P. Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties. Eur J Med Chem. 2020 Nov 15;206:112668. doi: 10.1016/j.ejmech.2020.112668.es_ES
dc.description.abstractTo study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program.es_ES
dc.description.sponsorshipThis work is supported by Aix-Marseille Université, the Université de Toulouse and the CNRS. A. Fairlamb and S. Wyllie are supported by funding from the Wellcome Trust (WT105021). C. Fersing thanks the Assistance Publique - Hôpitaux de Marseille (AP-HM) for hospital appointment. J. Pedron thanks the Université Paul Sabatier and the Conseil Régional Occitanie for PhD funding. The authors thank Dr Vincent Remusat for the NMR spectra recording, Dr Christophe Chendo and Dr Valérie Monnier for the HRMS analyses. Catherine Piveteau and Alexandre Biela from Institut Pasteur de Lille are also acknowledged for their contribution in determining in vitro PK parameters. We thank Dr Jean-Baptiste Woillard for the in vivo pharmacokinetic analysis and Mr François-Ludovic Sauvage for his help in mass spectrometry analysis. Dr. Amaya Azqueta thanks the ’Ramon y Cajal’ programme (RYC-2013-14370) of the Spanish Government.es_ES
dc.subjectRedox potentialses_ES
dc.titleAntikinetoplastid SAR study in 3-nitroimidazopyridine series: identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic propertieses_ES
dadun.citation.publicationNameEuropean Journal of Medicinal Chemistryes_ES

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