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

Abstract

1,5-Di(4-amidinophenoxy)pentane (pentamidine) and 38 analogs of pentamidine were screened for in vitro activity against the enteric protozoan Giardia lamblia WB (ATCC 30957). All compounds were active against G. lamblia as measured by a [methyl-3H]thymidine incorporation assay. Antigiardial activity varied widely, with 50% inhibitory concentrations (IC50s) ranging from 0.51 +/- 0.13 microM (mean +/- standard deviation) for the most active compound to over 100.0 microM for the least active compounds. The IC50 of the most potent antigiardial agent, 1,3-di(4-amidino-2-methoxyphenoxy)propane compared favorably with the IC50s of the compounds currently used to treat giardiasis, i.e., furazolidone (1.0 +/- 0.03 microM), metronidazole (2.1 +/- 0.80 microM), quinacrine HCl (0.03 +/- 0.02 microM), and tinidazole (0.78 +/- 0.48 microM). A mode of antigiardial activity for these compounds was suggested by the correlation observed between antigiardial activity and the binding of the compounds to calf thymus DNA and poly(dA).poly(dT).