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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.


Synthesis of 4-nitroimidazoles 13a-g and 14a-f. i) benzyl or alkyl bromide, K2CO3, DMF, rt → μW 80 °C, 7–98%; ii) HNO3, H2SO4, 60 °C, 64%; iii) NH2OH, MeOH, 60 °C, 37%; iv) 1 M NaOH, THF: MeOH (1:1), rt, 37%; v) oxalyl chloride, cat. DMF, DCM, 0 °C → rt; vi) NH2NH2•H2O, DCM, 0 °C, 65%.
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sch3: Synthesis of 4-nitroimidazoles 13a-g and 14a-f. i) benzyl or alkyl bromide, K2CO3, DMF, rt → μW 80 °C, 7–98%; ii) HNO3, H2SO4, 60 °C, 64%; iii) NH2OH, MeOH, 60 °C, 37%; iv) 1 M NaOH, THF: MeOH (1:1), rt, 37%; v) oxalyl chloride, cat. DMF, DCM, 0 °C → rt; vi) NH2NH2•H2O, DCM, 0 °C, 65%.

Mentions: The novel 4-nitroimidazoles 13a-g and 14a-c were synthesised from the respective 1H-imidazole carboxamides 12g, 12l, 12m and 12p by alkylation with benzyl or alkyl halides under basic conditions (K2CO3) (Scheme 3). The hydroxamic acid 14d was prepared by treatment of the ester 14c with hydroxylamine in methanol at 60 °C. The hydrazide 14e was prepared from 14f via an acid chloride intermediate and hydrazine. The title compounds 13a-g and 14a-e were purified by chromatography or recrystallisation and characterised as described for 8a-k.


Nitroimidazole carboxamides as antiparasitic agents targeting Giardia lamblia , Entamoeba histolytica and Trichomonas vaginalis
Synthesis of 4-nitroimidazoles 13a-g and 14a-f. i) benzyl or alkyl bromide, K2CO3, DMF, rt → μW 80 °C, 7–98%; ii) HNO3, H2SO4, 60 °C, 64%; iii) NH2OH, MeOH, 60 °C, 37%; iv) 1 M NaOH, THF: MeOH (1:1), rt, 37%; v) oxalyl chloride, cat. DMF, DCM, 0 °C → rt; vi) NH2NH2•H2O, DCM, 0 °C, 65%.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4920673&req=5

sch3: Synthesis of 4-nitroimidazoles 13a-g and 14a-f. i) benzyl or alkyl bromide, K2CO3, DMF, rt → μW 80 °C, 7–98%; ii) HNO3, H2SO4, 60 °C, 64%; iii) NH2OH, MeOH, 60 °C, 37%; iv) 1 M NaOH, THF: MeOH (1:1), rt, 37%; v) oxalyl chloride, cat. DMF, DCM, 0 °C → rt; vi) NH2NH2•H2O, DCM, 0 °C, 65%.
Mentions: The novel 4-nitroimidazoles 13a-g and 14a-c were synthesised from the respective 1H-imidazole carboxamides 12g, 12l, 12m and 12p by alkylation with benzyl or alkyl halides under basic conditions (K2CO3) (Scheme 3). The hydroxamic acid 14d was prepared by treatment of the ester 14c with hydroxylamine in methanol at 60 °C. The hydrazide 14e was prepared from 14f via an acid chloride intermediate and hydrazine. The title compounds 13a-g and 14a-e were purified by chromatography or recrystallisation 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.