8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi

Cyril Fersing, Clotilde Boudot, Caroline Castera-Ducros, Emilie Pinault, Sébastien Hutter, Romain Paoli-Lombardo, Nicolas Primas, Julien Pedron, Line Seguy, Sandra Bourgeade-Delmas, Alix Sournia-Saquet, Jean Luc Stigliani, Jean Yves Brossas, Luc Paris, Alexis Valentin, Susan Wyllie, Alan H. Fairlamb, Élisa Boutet-Robinet, Sophie Corvaisier, Marc SinceAurélie Malzert-Fréon, Alexandre Destere, Dominique Mazier, Pascal Rathelot, Bertrand Courtioux, Nadine Azas, Pierre Verhaeghe, Patrice Vanelle

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12 Citations (Scopus)
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An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC50 blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs. Among these hit molecules, compound 19 also showed the same level of activity against T. cruzi (EC50 amastigotes = 1.2 μM) as benznidazole and fexinidazole. An in vitro comet assay showed that nitroaromatic derivative 19 was not genotoxic. It displayed a low redox potential value (−0.68 V/NHE) and was shown to be bioactivated by type 1 nitroreductases both in Leishmania and Trypanosoma. The SAR study indicated that an alcohol function improved aqueous solubility while maintaining good activity and low cytotoxicity when the hydroxyl group was at position beta of the alkyne triple bond. Hit-compound 19 was also evaluated regarding in vitro pharmacokinetic data: 19 is BBB permeable (PAMPA assay), has a 16 min microsomal half-life and a high albumin binding (98.5%). Moreover, compound 19 was orally absorbed and was well tolerated in mouse after both single and repeated administrations at 100 mg/kg. Its mouse plasma half-life (10 h) is also quite encouraging, paving the way toward further efficacy evaluations in parasitized mouse models, looking for a novel antitrypanosomal lead compound.

Original languageEnglish
Article number112558
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Early online date8 Jul 2020
Publication statusPublished - 15 Sept 2020


  • Comet assay
  • Imidazo[1,2-a]pyridine
  • Kinetoplastids
  • Nitroaromatic
  • Nitroreductases
  • SARs

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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