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.
Highlights
Diarrhoeal diseases caused by intestinal protozoan parasites are a major global health burden
Given the core 5-nitroimidazole group in the nitroimidazole carboxamides is similar to metronidazole, we hypothesised that these compounds could have therapeutic potential against enteric parasites, including G. lamblia and E. histolytica
MtzS G. lamblia WB, with EC50 values ranging from 1.6 mM to 4.9 mM
Summary
Diarrhoeal diseases caused by intestinal protozoan parasites are a major global health burden. Two of the most common intestinal parasites, Giardia lamblia and Entamoeba histolytica, are responsible for ~280 million and ~50 million annual infections, respectively [1,2]. Transmission of these parasites occurs by the faecal-oral route through ingestion of cysts in contaminated water or food, or by direct person-to-person contact. G. lamblia may have animal reservoirs, making the infection a potential zoonotic disease [3]. Abbreviation: MtzS, metronidazole sensitive; MtzR, metronidazole resistant; MIC, minimum inhibition concentration
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