title: Inhibition by Dications of in vitro growth of Leishmania major and Leishmania tropica: causative agents of old world cutaneous leishmaniasis.
abstract: Old World cutaneous leishmaniasis is caused by infection with Leishmania major and Leishmania tropica. Pentamidine and related dications exhibit broad spectrum antiprotozoal activity. Based on the previously reported efficacy of these compounds against related organisms, 18 structural analogs of pentamidine were evaluated for in vitro antileishmanial activity, using pentamidine as the standard reference drug for comparison. Furan analogs and reversed amidine compounds were examined for activity against L. major and L. tropica promastigotes. The most active compounds against both Leishmania species were in the reversed amidine series. DB745 and DB746 exhibited the highest activity against L. major and DB745 was the most active compound against L. tropica. Both of these compounds exhibited 50% inhibitory concentrations (IC50) below 1 nM for L. major. Ten reversed amidines were also tested for their ability to inhibit growth in an axenic amastigote model. Nine of 10 reversed amidine analogs were active at concentrations below 1 nM. These results justify further study of dicationic compounds as potential new agents for treating cutaneous leishmaniasis.
authors.affiliation: School of Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Alexa C
authors.initials: AC
authors.lastname: Rosypal
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
authors.forename: Manar
authors.initials: M
authors.lastname: Salem
authors.forename: Chad E
authors.initials: CE
authors.lastname: Stephens
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.forename: James E
authors.initials: JE
authors.lastname: Hall
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
mesh_terms: D000578:Amidines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000633:toxicity; D002478:Cells, Cultured; D005663:Furans / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D020128:Inhibitory Concentration 50; D018320:Leishmania major / Q000187:drug effects* / Q000254:growth & development; D007895:Leishmania tropica / Q000187:drug effects* / Q000254:growth & development; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D032446:Myoblasts / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000494:pharmacology; D051381:Rats
chemical_list: D000578:Amidines; D000981:Antiprotozoal Agents; D005663:Furans; D010419:Pentamidine