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.

Recent advances in Entamoeba biology: RNA interference, drug discovery, and gut microbiome

“…Currently, metronidazole is the drug of choice and is used worldwide to treat invasive amoebiasis in both adults and children 68– 71 . In addition, the luminal amoebicide paramomycin is administered to eradicate cysts from the colon 69, 70 .…”

Synthesis and characterization of microwave‐assisted biologically active triazole silanes

“…Intestinal protozoan parasites are a major global health burden; giardiasis is an important parasitic cause and is accompanied by diarrhea …”

2,4‐Disubstituted 5‐Nitroimidazoles Potent against Clostridium difficile

“…Nitroimidazoles are known for their antibacterial and antiparasitic properties. There have been several pharmacomodulation attempts to improve metronidazole activity on parasites such as Giardia intestinalis or Trichomonas vaginalis , and on anaerobic bacteria of the Clostridium and Bacteroïdes species . Previously, we synthesized a 2‐substituted 5‐nitroimidazole by unimolecular radical nucleophilic substitution (S RN 1), RP 57967, which was shown to be fivefold more active than metronidazole against Clostridium perfringens with higher mutagenicity (Figure ) .…”