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Journal Articles European Journal of Medicinal Chemistry Year : 2020

Antikinetoplastid SAR study in 3-nitroimidazopyridine series

Cyril Fersing
Alix Sournia-Saquet
Amaya Azqueta
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Alexandre Destere
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Bertrand Courtioux
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Patrice Vanelle
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Pierre Verhaeghe


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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hal-02920293 , version 1 (24-02-2021)



Cyril Fersing, Clotilde Boudot, Romain Paoli-Lombardo, Nicolas Primas, Emilie Pinault, et al.. 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. European Journal of Medicinal Chemistry, 2020, 206, pp.112668. ⟨10.1016/j.ejmech.2020.112668⟩. ⟨hal-02920293⟩
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