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

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

  • Eur J Med Chem. 2020 Sep 15;202:112558. doi: 10.1016/j.ejmech.2020.112558.
Cyril Fersing 1,  Clotilde Boudot 2,  Caroline Castera-Ducros 1,  Emilie Pinault 3,  Sébastien Hutter 4,  Romain Paoli-Lombardo 1,  Nicolas Primas 1,  Julien Pedron 5,  Line Seguy 5,  Sandra Bourgeade-Delmas 6,  Alix Sournia-Saquet 5,  Jean-Luc Stigliani 5,  Jean-Yves Brossas 7,  Luc Paris 7,  Alexis Valentin 6,  Susan Wyllie 8,  Alan H Fairlamb 8,  Élisa Boutet-Robinet 9,  Sophie Corvaisier 10,  Marc Since 10,  Aurélie Malzert-Fréon 10,  Alexandre Destere 11,  Dominique Mazier 12,  Pascal Rathelot 1,  Bertrand Courtioux 2,  Nadine Azas 4,  Pierre Verhaeghe 13,  Patrice Vanelle 1
Affiliations

Affiliations

  • 1 Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS30064, 13385, Marseille Cedex 05, France.
  • 2 Université de Limoges, UMR Inserm 1094, Neuroépidémiologie Tropicale, Faculté de Pharmacie, 2 rue du Dr Marcland, 87025, Limoges, France.
  • 3 Université de Limoges, BISCEm Mass Spectrometry Platform, CBRS, 2 rue du Pr. Descottes, F-87025, Limoges, France.
  • 4 Aix Marseille Univ, IHU Méditerranée Infection, UMR VITROME, Tropical Eukaryotic Pathogens, 19-21 Boulevard Jean Moulin, 13005, Marseille, France.
  • 5 LCC-CNRS Université de Toulouse, CNRS, UPS, Toulouse, France.
  • 6 UMR 152 PHARMA-DEV, Université de Toulouse, IRD, UPS, Toulouse, France.
  • 7 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Parasitologie Mycologie, Paris, France.
  • 8 University of Dundee, School of Life Sciences, Division of Biological Chemistry and Drug Discovery, Dow Street, Dundee, DD1 5EH, Scotland, United Kingdom.
  • 9 Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.
  • 10 Normandie Univ, UNICAEN, CERMN, 14000, Caen, France.
  • 11 Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, INSERM, UMR 1248, University of Limoges, Limoges, France.
  • 12 CIMI-Paris, Sorbonne Université 91 boulevard de l'Hôpital, 75013, Paris, France.
  • 13 LCC-CNRS Université de Toulouse, CNRS, UPS, Toulouse, France. Electronic address: pierre.verhaeghe@lcc-toulouse.fr.
PMID: 32652409 DOI: 10.1016/j.ejmech.2020.112558
Abstract

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.

Keywords

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

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