title: Nitroimidazole carboxamides as antiparasitic agents targeting Giardia lamblia, Entamoeba histolytica and Trichomonas vaginalis.
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.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: Jarrad
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Debnath
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: K A
authors.initials: KA
authors.lastname: Hansford
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Pelingon
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: M S
authors.initials: MS
authors.lastname: Butler
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Bains
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Karoli
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia.
authors.forename: M A T
authors.initials: MA
authors.lastname: Blaskovich
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Eckmann
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia. Electronic address: m.cooper@uq.edu.au.
authors.forename: M A
authors.initials: MA
authors.lastname: Cooper
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004351:Drug Resistance; D004355:Drug Stability; D004748:Entamoeba histolytica / Q000187:drug effects; D016829:Giardia lamblia / Q000187:drug effects; D006801:Humans; D009593:Nitroimidazoles / Q000494:pharmacology*; D010271:Parasites / Q000187:drug effects*; D014246:Trichomonas vaginalis / Q000187:drug effects
chemical_list: D000977:Antiparasitic Agents; D009593:Nitroimidazoles
keywords: Antiparasitic agent; Entamoeba histolytica; Giardia lamblia; Metabolism; Nitroimidazole; Plasma protein binding