Nitroimidazole carboxamides as antiparasitic agents targeting Giardia lamblia , Entamoeba histolytica and Trichomonas vaginalis
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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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sch2: Synthesis of 4(5)-nitroimidazoles 12a-o. Amide groups a-k are as defined in Scheme 1. i) HNO3, H2SO4, 80 °C, 54%; ii) oxalyl chloride, cat. DMF, DCM, 0 °C → rt; iii) amine, PyBOP, DIPEA, 6–75% iv) amine, TEA, DCM, 0 °C → rt, 12–93%. Mentions: To examine the corresponding 4(5)-nitroimidazole carboxamide series of 8a-k (i.e no N-methyl substitution) we prepared the analogous series of novel compounds 12a-k. In addition, four alternative novel carboxamides 12l-o were prepared, as shown in Scheme 2. Imidazole-2-carboxylic acid 9 was readily nitrated with conc. HNO3/H2SO4 to give 4(5)-nitroimidazole carboxylic acid 10. Carboxamides 12a-o were subsequently prepared by activation of acid 10 (oxalyl chloride/catalytic DMF or PyBOP/DIPEA) followed by coupling of the requisite amine. Amidation via intermediate 11 was the preferred route due to the difficulty of removing the HOBt and tripyrrolidinophosphine oxide by-products formed during the PyBOP mediated coupling. The primary amide 12l was prepared by quenching the acid chloride 11 with concentrated ammonium hydroxide solution. The title compounds 12a-o were all purified and characterised as described for 8a-k. |
View Article: PubMed Central - PubMed
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.