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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.


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%.
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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.


Nitroimidazole carboxamides as antiparasitic agents targeting Giardia lamblia , Entamoeba histolytica and Trichomonas vaginalis
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%.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4920673&req=5

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

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.