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

Jarrad, A. M., Debnath, A., Miyamoto, Y., Hansford, K. A., Pelingon, R., Butler, M. S., Bains, T., Karoli, T., Blaskovich, M. A. T., Eckmann, L. and Cooper, M. A. (2016) Nitroimidazole carboxamides as antiparasitic agents targeting Giardia lamblia, Entamoeba histolytica and Trichomonas vaginalis. European Journal of Medicinal Chemistry, 120 353-362. doi:10.1016/j.ejmech.2016.04.064


Author Jarrad, A. M.
Debnath, A.
Miyamoto, Y.
Hansford, K. A.
Pelingon, R.
Butler, M. S.
Bains, T.
Karoli, T.
Blaskovich, M. A. T.
Eckmann, L.
Cooper, M. A.
Title Nitroimidazole carboxamides as antiparasitic agents targeting Giardia lamblia, Entamoeba histolytica and Trichomonas vaginalis
Formatted title
Nitroimidazole carboxamides as antiparasitic agents targeting Giardia lamblia, Entamoeba histolytica and Trichomonas vaginalis
Journal name European Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 1768-3254
0223-5234
Publication date 2016-09-14
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.ejmech.2016.04.064
Open Access Status DOI
Volume 120
Start page 353
End page 362
Total pages 10
Place of publication Cedex, France
Publisher Elsevier Masson
Collection year 2017
Language eng
Formatted 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.
Keyword Antiparasitic agent
Entamoeba histolytica
Giardia lamblia
Metabolism
Nitroimidazole
Plasma protein binding
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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