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Activity of and initial mechanistic studies on a novel antileishmanial agent identified through in silico pharmacophore development and database searching.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2006 Jul 13; Vol. 49 (14), pp. 4196-207. - Publication Year :
- 2006
-
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.
- Subjects :
- Aniline Compounds chemistry
Aniline Compounds pharmacology
Animals
Cell Line
Leishmania ultrastructure
Leishmania donovani drug effects
Leishmania donovani ultrastructure
Leishmania mexicana drug effects
Leishmania mexicana ultrastructure
Macrophages drug effects
Macrophages parasitology
Membrane Potentials drug effects
Mice
Microscopy, Electron, Transmission
Microscopy, Fluorescence
Mitochondria drug effects
Mitochondria physiology
Mitochondria ultrastructure
Models, Molecular
Nitro Compounds chemistry
Nitro Compounds pharmacology
Nitrobenzenes chemistry
Nitrobenzenes pharmacology
Structure-Activity Relationship
Sulfides chemistry
Sulfides pharmacology
Sulfonamides chemistry
Sulfonamides pharmacology
Trypanocidal Agents chemistry
Trypanocidal Agents pharmacology
Aniline Compounds chemical synthesis
Leishmania drug effects
Nitro Compounds chemical synthesis
Nitrobenzenes chemical synthesis
Sulfides chemical synthesis
Sulfonamides chemical synthesis
Trypanocidal Agents chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 49
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16821779
- Full Text :
- https://doi.org/10.1021/jm060156v