Primas, N. (Nicolas)

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    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
    (Elsevier, 2020-11) Fersing, C. (Cyril); Pinault, E. (Emilie); Malzert-Fréon, A. (Aurélie); Wyllie, S. (Susan); Since, M. (Marc); Verhaeghe, P. (Pierre); Vanelle, P. (Patrice); Fairlamb, A.H. (Alan H.); Pedron, J. (Julien); Destere, A. (Alexandre); Bourgeade-Delmas, S. (Sandra); Castera-Ducros, C. (Caroline); Muruzábal, D. (Damián); Hutter, S. (Sébastien); Kabri, Y. (Youssef); Azas, N. (Nadine); Corvaisier, S. (Sophie); Boudot, C. (Clotilde); Courtioux, B. (Bertrand); Sournia-Saquet, A. (Alix); Di-Giorgio, C. (Carole); Valentin, A. (Alexis); Primas, N. (Nicolas); Rathelot, P. (Pascal); Azqueta, A. (Amaya); Paoli-Lombardo, R. (Romain)
    To 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.
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    2-Phenoxy-3-Trichloromethylquinoxalines are antiplasmodial derivatives with activity against the Apicoplast of Plasmodium falciparum
    (MDPI, 2021) Amrane, D. (Dyhia); Arnol, C.S. (Christophe-Sébastien); Hutter, S. (Sébastien); Sanz-Serrano, J. (Julen); Collia, M. (Miguel); Azqueta, A. (Amaya); Paloque, L. (Lucie); Cohen, A. (Anita); Amanzougaghene, N. (Nadia); Tajeri, S. (Shahin); Franetich, J.F. (Jean-François); Mazier, D. (Dominique); Benoit-Vical, F. (Françoise); Verhaeghe, P. (Pierre); Azas, N. (Nadine); Vanelle, P. (Patrice); Botté, C. (Cyrille); Primas, N. (Nicolas)
    The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism of action. Based on the previous antiplasmodial hit-molecules identified in the 2-trichloromethylquinoxaline series, we report herein a structure–activity relationship (SAR) study at position two of the quinoxaline ring by synthesizing 20 new compounds. The biological evaluation highlighted a hit compound (3i) with a potent PfK1 EC50 value of 0.2 µM and a HepG2 CC50 value of 32 µM (Selectivity index = 160). Nitro-containing (3i) was not genotoxic, both in the Ames test and in vitro comet assay. Activity cliffs were observed when the 2-CCl3 group was replaced, showing that it played a key role in the antiplasmodial activity. Investigation of the mechanism of action showed that 3i presents a drug response by targeting the apicoplast and a quick-killing mechanism acting on another target site.