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  3. Nitroimidazole carboxamides as antiparasitic agents targeting Giardia lamblia, Entamoeba histolytica and Trichomonas vaginalis

Nitroimidazole carboxamides as antiparasitic agents targeting Giardia lamblia, Entamoeba histolytica and Trichomonas vaginalis

  • Eur J Med Chem. 2016 Sep 14:120:353-62. doi: 10.1016/j.ejmech.2016.04.064.
A M Jarrad 1,  A Debnath 2,  Y Miyamoto 3,  K A Hansford 1,  R Pelingon 1,  M S Butler 1,  T Bains 2,  T Karoli 1,  M A T Blaskovich 1,  L Eckmann 3,  M A Cooper 4
Affiliations

Affiliations

  • 1 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
  • 2 Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
  • 3 Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
  • 4 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia. Electronic address: [email protected].
PMID: 27236016 DOI: 10.1016/j.ejmech.2016.04.064
Abstract

Diarrhoeal diseases caused by the intestinal parasites Giardia lamblia and Entamoeba histolytica constitute a major global health burden. Nitroimidazoles are first-line drugs for the treatment of giardiasis and amebiasis, with metronidazole 1 being the most commonly used drug worldwide. However, treatment failures in giardiasis occur in up to 20% of cases and development of resistance to metronidazole is of concern. We have re-examined 'old' nitroimidazoles as a foundation for the systematic development of next-generation derivatives. Using this approach, derivatisation of the nitroimidazole carboxamide scaffold provided improved antiparasitic agents. Thirty-three novel nitroimidazole carboxamides were synthesised and evaluated for activity against G. lamblia and E. histolytica. Several of the new compounds exhibited potent activity against G. lamblia strains, including metronidazole-resistant strains of G. lamblia (EC50 = 0.1-2.5 μM cf. metronidazole EC50 = 6.1-18 μM). Other compounds showed improved activity against E. histolytica (EC50 = 1.7-5.1 μM cf. metronidazole EC50 = 5.0 μM), potent activity against Trichomonas vaginalis (EC50 = 0.6-1.4 μM cf. metronidazole EC50 = 0.8 μM) and moderate activity against the intestinal Bacterial pathogen Clostridium difficile (0.5-2 μg/mL, cf. metronidazole = 0.5 μg/mL). The new compounds had low toxicity against mammalian kidney and liver cells (CC50 > 100 μM), and selected antiparasitic hits were assessed for human plasma protein binding and metabolic stability in liver microsomes to demonstrate their therapeutic potential.

Keywords

Antiparasitic agent; Entamoeba histolytica; Giardia lamblia; Metabolism; Nitroimidazole; Plasma protein binding.

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