title: Structure-activity studies of dicationically substituted bis-benzimidazoles against Giardia lamblia: correlation of antigiardial activity with DNA binding affinity and giardial topoisomerase II inhibition.
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.
authors.affiliation: Department of Parasitology and Laboratory Practice, University of North Carolina at Chapel Hill 27599.
authors.forename: C A
authors.initials: CA
authors.lastname: Bell
authors.forename: C C
authors.initials: CC
authors.lastname: Dykstra
authors.forename: N A
authors.initials: NA
authors.lastname: Naiman
authors.forename: M
authors.initials: M
authors.lastname: Cory
authors.forename: T A
authors.initials: TA
authors.lastname: Fairley
authors.forename: R R
authors.initials: RR
authors.lastname: Tidwell
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology*; D002412:Cations / Q000378:metabolism / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000302:isolation & purification / Q000378:metabolism; D016054:DNA, Protozoan / Q000187:drug effects* / Q000378:metabolism*; D016829:Giardia lamblia / Q000187:drug effects / Q000201:enzymology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D001562:Benzimidazoles; D002412:Cations; D016054:DNA, Protozoan; D015800:Protozoan Proteins; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II