title: Activity of and initial mechanistic studies on a novel antileishmanial agent identified through in silico pharmacophore development and database searching.
abstract: A 3D pharmacophore was generated to describe the antileishmanial activity of dinitroaniline sulfonamides by CATALYST 3D-QSAR methodology, and this pharmacophore was used to search the Maybridge database. Two compounds identified in this search, BTB 06237 and BTB 06256, were highly active with IC(50) values against L. donovani amastigotes of 0.5 +/- 0.2 and 2.3 +/- 0.8 microM, respectively. BTB 06237 also reduced parasite burdens in L. mexicana-infected J774 macrophages at low micromolar concentrations. Unlike the dinitroaniline sulfonamides, the active compounds did not display antimitotic effects against Leishmania. Transmission electron microscopy showed that the single parasite mitochondrion becomes dilated following incubation with BTB 06237, and fluorescence microscopy demonstrated that this organelle fragments into intensely staining spheres when treated with a mitochondrion-specific dye. The mitochondrial membrane potential was also dissipated in BTB 06237-treated parasites. These results indicate that BTB 06237 is an intriguing antileishmanial lead compound that likely interferes with mitochondrial function.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Parks Hall Room 331, 500 West 12th Avenue, Columbus, 43210, USA.
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Delfín
authors.forename: Apurba K
authors.initials: AK
authors.lastname: Bhattacharjee
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Yakovich
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D007891:Leishmania / Q000187:drug effects* / Q000648:ultrastructure; D007893:Leishmania donovani / Q000187:drug effects / Q000648:ultrastructure; D007894:Leishmania mexicana / Q000187:drug effects / Q000648:ultrastructure; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D008958:Models, Molecular; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009578:Nitrobenzenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; C513157:BTB 06237; D009574:Nitro Compounds; D009578:Nitrobenzenes; D013440:Sulfides; D013449:Sulfonamides; D014344:Trypanocidal Agents