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Antitrypanosomal lead discovery: identification of a ligand-efficient inhibitor of Trypanosoma cruzi CYP51 and parasite growth.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2013 Mar 28; Vol. 56 (6), pp. 2556-67. Date of Electronic Publication: 2013 Mar 13. - Publication Year :
- 2013
-
Abstract
- Chagas disease is caused by the intracellular protozoan parasite Trypanosomal cruzi , and current drugs are lacking in terms of desired safety and efficacy profiles. Following on a recently reported high-throughput screening campaign, we have explored initial structure-activity relationships around a class of imidazole-based compounds. This profiling has uncovered compounds 4c (NEU321) and 4j (NEU704), which are potent against in vitro cultures of T. cruzi and are greater than 160-fold selective over host cells. We report in vitro drug metabolism and properties profiling of 4c and show that this chemotype inhibits the T. cruzi CYP51 enzyme, an observation confirmed by X-ray crystallographic analysis. We compare the binding orientation of 4c to that of other, previously reported inhibitors. We show that 4c displays a significantly better ligand efficiency and a shorter synthetic route over previously disclosed CYP51 inhibitors, and should therefore be considered a promising lead compound for further optimization.
- Subjects :
- 14-alpha Demethylase Inhibitors chemistry
14-alpha Demethylase Inhibitors metabolism
14-alpha Demethylase Inhibitors pharmacokinetics
Absorption
Biological Availability
Ligands
Models, Molecular
Protein Conformation
Sterol 14-Demethylase chemistry
Structure-Activity Relationship
Trypanocidal Agents chemistry
Trypanocidal Agents metabolism
Trypanocidal Agents pharmacokinetics
Trypanosoma cruzi enzymology
14-alpha Demethylase Inhibitors pharmacology
Drug Discovery
Sterol 14-Demethylase metabolism
Trypanocidal Agents pharmacology
Trypanosoma cruzi drug effects
Trypanosoma cruzi growth & development
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 56
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23448316
- Full Text :
- https://doi.org/10.1021/jm400012e