title: Identification of new antileishmanial leads from hits obtained by high-throughput screening.
abstract: A previous screen of ~200,000 compounds from the PubChem database identified 70 compounds possessing 50% effective concentrations (EC(50)s) below 1 μM against Leishmania major promastigotes that were not toxic to mammalian epithelial cancer cells at this concentration (E. Sharlow et al., PLoS Negl. Trop. Dis. 3:e540, 2009). Based on availability and chemical exclusion criteria, 31 of these compounds were purchased from commercial suppliers and evaluated for in vitro activity against intracellular L. donovani and L. amazonensis parasites. Benzothiazole cyanine compounds (PubChem 16196319 and 16196223) displayed potent activity against intracellular amastigotes, prompting a search for commercially available compounds that were structurally related. Pubchem 123859 (the cyanine dye thiazole orange) showed exceptionally potent activity against intracellular L. donovani in vitro (50% inhibitory concentration [IC(50)] = 21 ± 12 nM) and low cytotoxicity against Vero cells (IC(50) = 7,800 ± 200 nM). Administration of 123859 and 16196319 at a dose of 1 mg/kg of body weight intraperitoneally (i.p.) daily for 5 days resulted in 44% ± 4% and 42% ± 3% suppression of liver parasitemia in L. donovani-infected BALB/c mice, respectively, compared to the untreated control group (the reductions in liver parasitemia were 30% ± 5% and 27% ± 4%, respectively, compared to the (2-hydroxypropyl)-β-cyclodextrin solution (HPβCD) vehicle control, which itself displayed some antileishmanial activity). Benzothiazole-containing cyanine dyes are thus potential lead compounds for the discovery of novel antileishmanial agents.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhu
authors.forename: Trupti
authors.initials: T
authors.lastname: Pandharkar
authors.forename: Karl
authors.initials: K
authors.lastname: Werbovetz
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology*; D002232:Carbocyanines / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D016208:Databases, Factual; D005260:Female; D057166:High-Throughput Screening Assays; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development; D007893:Leishmania donovani / Q000187:drug effects / Q000254:growth & development; D008099:Liver / Q000187:drug effects / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: C478828:BEBO cyanine dye; D052160:Benzothiazoles; D002232:Carbocyanines; D014344:Trypanocidal Agents