Structure-activity studies of dicationically substituted bis-benzimidazoles against Giardia lamblia: correlation of antigiardial activity with DNA binding affinity and giardial topoisomerase II inhibition

doi:10.1128/AAC.37.12.2668

Paper

Structure-activity studies of dicationically substituted bis-benzimidazoles against Giardia lamblia: correlation of antigiardial activity with DNA binding affinity and giardial topoisomerase II inhibition

Published Dec 1, 1993 · Constance A. Bell, C. C. Dykstra, N. A. Naiman

Antimicrobial Agents and Chemotherapy

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Abstract

Nine dicationically substituted bis-benzimidazoles were examined for their in vitro activities against Giardia lamblia WB (ATCC 30957). The potential mechanisms of action of these compounds were evaluated by investigating the relationship among in vitro antigiardial activity and the affinity of the molecules for DNA and their ability to inhibit the activity of giardial topoisomerase II. Each compound demonstrated antigiardial activity, as measured by assessing the incorporation of [methyl-3H]thymidine by giardial trophozoites exposed to the test agents. Three compounds exhibited excellent in vitro antigiardial activities, with 50% inhibitory concentrations which compared very favorably with those of two currently used drugs, quinacrine HCl and metronidazole. Putative mechanisms of action for these compounds were suggested by the strong correlation observed among in vitro antigiardial activity and the affinity of the molecules for natural and synthetic DNA and their ability to inhibit the relaxation activity of giardial topoisomerase II. A strong correlation between the DNA binding affinity of these compounds and their inhibition of giardial topoisomerase II activity was also observed.

In Vitro Study

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Study Snapshot

Dicicially substituted bis-benzimidazoles show excellent in vitro antigiardial activities against Giardia lamblia, with strong correlations between their DNA binding affinity and inhibition of giardial topoisomerase II activity.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Structure-activity studies of dicationically substituted bis-benzimidazoles against Giardia lamblia: correlation of antigiardial activity with DNA binding affinity and giardial topoisomerase II inhibition

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References

Activity of cationically substituted bis-benzimidazoles against experimental Pneumocystis carinii pneumonia

1,4-bis[5-(2-imidazolinyl)-2-benzimidazolyl]butane shows more potent and less toxic activity against Pneumocystis carinii pneumonia than pentamidine.

Structure, DNA minor groove binding, and base pair specificity of alkyl- and aryl-linked bis(amidinobenzimidazoles) and bis(amidinoindoles).

Bis(amidinobenzimidazoles) with even methylenes show higher affinity for DNA, while those with odd methylenes show no structurally associated differential in nucleic acid base pair specificity or affinity.

Structure and DNA binding activity of analogues of 1,5-bis(4-amidinophenoxy)pentane (pentamidine)

The shape of the molecules is important for DNA binding, with moderate specificity for AT base pairs and no intercalation.

Structure-activity relationships of pentamidine analogs against Giardia lamblia and correlation of antigiardial activity with DNA-binding affinity

Pentamidine analogs show varied antigiardial activity against Giardia lamblia, with 1,3-di(4-amidino-2-methoxyphenoxy)propane showing potential as a new treatment for giardiasis.

Activity of the anthelmintic benzimidazoles against Giardia lamblia in vitro.

Mebendazole is a highly effective anthelmintic benzimidazole against Giardia lamblia, with lethal activity observed at a concentration fivefold lower than metronidazole, making it an attractive new antigiardial agent.

Citations

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Structurally diverse benzimidazole scaffolds show promising anticancer and antibacterial properties, with apoptosis being the primary mechanism for cancer cell death.

Anti-Protozoal Potential of Heterocyclic Compounds Against Giardiasis

Heterocyclic compounds, including nitroimidazoles and benzimidazoles, show potential anti-protozoal activity against Giardia species, with potential for improved bioavailability and resistance management.

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