RESUMEN
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.