title: Antileishmanial activities of several classes of aromatic dications.
abstract: Aromatic dicationic molecules possess impressive activity against a broad spectrum of microbial pathogens, including Pneumocystis carinii, Cryptosporidium parvum, and Candida albicans. In this work, 58 aromatic cations were examined for inhibitory activity against axenic amastigote-like Leishmania donovani parasites. In general, the most potent of the compounds were substituted diphenyl furan and thiophene dications. 2,5-Bis-(4-amidinophenyl)thiophene was the most active compound. This agent displayed a 50% inhibitory concentration (IC50) of 0.42 +/- 0.08 microM against L. donovani and an in vitro antileishmanial potency 6.2-fold greater than that of the clinical antileishmanial dication pentamidine and was 155-fold more toxic to the parasites than to a mouse macrophage cell line. 2,4-Bis-(4-amidinopheny)furan was twice as active as pentamidine (IC50), 1.30 +/- 0.21 microM), while 2,5-bis-(4-amidinopheny)furan and pentamidine were essentially equipotent in our in vitro antileishmanial assay. Carbazoles, dibenzofurans, dibenzothiophenes, and benzimidazoles containing amidine or substituted amidine groups were generally less active than the diphenyl furans and thiophenes. In all cases, aromatic dications possessing strong antileishmanial activity were severalfold more toxic to the parasites than to a cultured mouse macrophage cell line. These structure-activity relationships demonstrate the potent antileishmanial activity of several aromatic dications and provide valuable information for the future design and synthesis of more potent antiparasitic agents.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Brendle
authors.forename: Abram
authors.initials: A
authors.lastname: Outlaw
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.forename: Donald A
authors.initials: DA
authors.lastname: Patrick
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
mesh_terms: D000328:Adult; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D002227:Carbazoles / Q000138:chemical synthesis / Q000494:pharmacology; D002412:Cations; D002455:Cell Division / Q000187:drug effects; D005663:Furans / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development; D007894:Leishmania mexicana / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000469:parasitology; D051379:Mice; D010419:Pentamidine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000981:Antiprotozoal Agents; D001562:Benzimidazoles; D002227:Carbazoles; D002412:Cations; D005663:Furans; D007202:Indicators and Reagents; D013876:Thiophenes; D010419:Pentamidine