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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.


Activity vs logD of active 4(5)-nitroimidazoles. Compounds were classified as active against G. lamblia and E. histolytica with EC50 < 50 μM and were considered active against T. vaginalis with EC50 < 20 μM. All 4(5)-nitroimidazoles were classified as active against C. difficile (MIC ≤ 16 μg/mL). Metronidazole (black symbols) is shown for comparison.
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fig3: Activity vs logD of active 4(5)-nitroimidazoles. Compounds were classified as active against G. lamblia and E. histolytica with EC50 < 50 μM and were considered active against T. vaginalis with EC50 < 20 μM. All 4(5)-nitroimidazoles were classified as active against C. difficile (MIC ≤ 16 μg/mL). Metronidazole (black symbols) is shown for comparison.

Mentions: To quantify the extent that the variability in activity against each organism was dependent on logD, MW and logS, the coefficient of determination (R2) was next calculated (Fig. 3, Supplementary Figs. 1–3). This analysis supported the correlation between G. lamblia activity and logD, MW and logS properties of the compounds (R2 ranged from 0.67 to 0.86) (Fig. 3, Supplementary Figs. 1–3). No correlation was found for E. histolytica and T. vaginalis activity and compound properties (R2 ranged from 0.15 to 0.28) (Fig. 3, Supplementary Figs. 1–3). In contrast, a weak correlation between C. difficile activity and logD, MW and logS was observed (R2 ranged from 0.47 to 0.56) (Fig. 3, Supplementary Figs. 1–3), demonstrating greater variability in the data that was not accounted for by changes to logD, MW or logS.


Nitroimidazole carboxamides as antiparasitic agents targeting Giardia lamblia , Entamoeba histolytica and Trichomonas vaginalis
Activity vs logD of active 4(5)-nitroimidazoles. Compounds were classified as active against G. lamblia and E. histolytica with EC50 < 50 μM and were considered active against T. vaginalis with EC50 < 20 μM. All 4(5)-nitroimidazoles were classified as active against C. difficile (MIC ≤ 16 μg/mL). Metronidazole (black symbols) is shown for comparison.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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

fig3: Activity vs logD of active 4(5)-nitroimidazoles. Compounds were classified as active against G. lamblia and E. histolytica with EC50 < 50 μM and were considered active against T. vaginalis with EC50 < 20 μM. All 4(5)-nitroimidazoles were classified as active against C. difficile (MIC ≤ 16 μg/mL). Metronidazole (black symbols) is shown for comparison.
Mentions: To quantify the extent that the variability in activity against each organism was dependent on logD, MW and logS, the coefficient of determination (R2) was next calculated (Fig. 3, Supplementary Figs. 1–3). This analysis supported the correlation between G. lamblia activity and logD, MW and logS properties of the compounds (R2 ranged from 0.67 to 0.86) (Fig. 3, Supplementary Figs. 1–3). No correlation was found for E. histolytica and T. vaginalis activity and compound properties (R2 ranged from 0.15 to 0.28) (Fig. 3, Supplementary Figs. 1–3). In contrast, a weak correlation between C. difficile activity and logD, MW and logS was observed (R2 ranged from 0.47 to 0.56) (Fig. 3, Supplementary Figs. 1–3), demonstrating greater variability in the data that was not accounted for by changes to logD, MW or logS.

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 &lsquo;old&rsquo; 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.&nbsp;lamblia and E.&nbsp;histolytica. Several of the new compounds exhibited potent activity against G.&nbsp;lamblia strains, including metronidazole-resistant strains of G.&nbsp;lamblia (EC50&nbsp;=&nbsp;0.1&ndash;2.5&nbsp;&mu;M cf. metronidazole EC50&nbsp;=&nbsp;6.1&ndash;18&nbsp;&mu;M). Other compounds showed improved activity against E.&nbsp;histolytica (EC50&nbsp;=&nbsp;1.7&ndash;5.1&nbsp;&mu;M cf. metronidazole EC50&nbsp;=&nbsp;5.0&nbsp;&mu;M), potent activity against Trichomonas vaginalis (EC50&nbsp;=&nbsp;0.6&ndash;1.4&nbsp;&mu;M cf. metronidazole EC50&nbsp;=&nbsp;0.8&nbsp;&mu;M) and moderate activity against the intestinal bacterial pathogen Clostridium difficile (0.5&ndash;2&nbsp;&mu;g/mL, cf. metronidazole&nbsp;=&nbsp;0.5&nbsp;&mu;g/mL). The new compounds had low toxicity against mammalian kidney and liver cells (CC50&nbsp;&gt;&nbsp;100&nbsp;&mu;M), 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.