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

View Article: PubMed Central - PubMed

ABSTRACT

1: 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 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.

No MeSH data available.


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Compound 12a inhibited Giardia lamblia trophozoites growth A) vehicle (DMSO), B) metronidazole (3 × EC50 = 18 μM) and C) 12a (3 × EC50 = 1.5 μM).
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fig2: Compound 12a inhibited Giardia lamblia trophozoites growth A) vehicle (DMSO), B) metronidazole (3 × EC50 = 18 μM) and C) 12a (3 × EC50 = 1.5 μM).

Mentions: Microscopy was used to visually examine the impact of one of the most potent compounds, the 4(5)-nitroimidazole 12a (R = NHCH2(4-F-Ph)), on G. lamblia trophozoites. Parasite cell growth was similarly inhibited by treatment with 3 × EC50 of either metronidazole (18 μM) or compound 12a (1.5 μM) relative to the vehicle control (which produced a confluent cell layer under the test conditions). The morphology of G. lamblia treated with 12a was altered, while the morphology of the metronidazole-treated cells remained similar to the vehicle control (Fig. 2). A prior study by Tejman-Yarden et al. reported that metronidazole slowed the rate of oscillation of the Giardia flagella, while auranofin, a compound with a proposed different mode of action, caused cell blebbing [24]. The different morphology of the G. lamblia treated with the 4(5)-nitroimidazole carboxamide 12a may indicate an additional mode of action compared to metronidazole.


Nitroimidazole carboxamides as antiparasitic agents targeting Giardia lamblia , Entamoeba histolytica and Trichomonas vaginalis
Compound 12a inhibited Giardia lamblia trophozoites growth A) vehicle (DMSO), B) metronidazole (3 × EC50 = 18 μM) and C) 12a (3 × EC50 = 1.5 μM).
© Copyright Policy - CC BY
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4920673&req=5

fig2: Compound 12a inhibited Giardia lamblia trophozoites growth A) vehicle (DMSO), B) metronidazole (3 × EC50 = 18 μM) and C) 12a (3 × EC50 = 1.5 μM).
Mentions: Microscopy was used to visually examine the impact of one of the most potent compounds, the 4(5)-nitroimidazole 12a (R = NHCH2(4-F-Ph)), on G. lamblia trophozoites. Parasite cell growth was similarly inhibited by treatment with 3 × EC50 of either metronidazole (18 μM) or compound 12a (1.5 μM) relative to the vehicle control (which produced a confluent cell layer under the test conditions). The morphology of G. lamblia treated with 12a was altered, while the morphology of the metronidazole-treated cells remained similar to the vehicle control (Fig. 2). A prior study by Tejman-Yarden et al. reported that metronidazole slowed the rate of oscillation of the Giardia flagella, while auranofin, a compound with a proposed different mode of action, caused cell blebbing [24]. The different morphology of the G. lamblia treated with the 4(5)-nitroimidazole carboxamide 12a may indicate an additional mode of action compared to metronidazole.

View Article: PubMed Central - PubMed

ABSTRACT

1: 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 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.

No MeSH data available.


Related in: MedlinePlus