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Modification of Triclosan Scaffold in Search of Improved Inhibitors for Enoyl-Acyl Carrier Protein (ACP) Reductase inToxoplasma gondii
- Source :
- ChemMedChem. 8:1138-1160
- Publication Year :
- 2013
- Publisher :
- Wiley, 2013.
-
Abstract
- Through our focused effort to discover new and effective agents against toxoplasmosis, a structure-based drug design approach was used to develop a series of potent inhibitors of the enoyl-acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4' of the well-known ENR inhibitor triclosan afforded a series of 29 new analogues. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16 a and 16 c have IC50 values of 250 nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against recombinant TgENR were found to be 43 and 26 nM, respectively. Additionally, 11 other analogues in this series had IC50 values ranging from 17 to 130 nM in the enzyme-based assay. With respect to their excellent in vitro activity as well as improved drug-like properties, the lead compounds 16 a and 16 c are deemed to be excellent starting points for the development of new medicines to effectively treat Toxoplasma gondii infections.
- Subjects :
- Models, Molecular
Plasmodium falciparum
Antiprotozoal Agents
Reductase
Biochemistry
Permeability
Article
law.invention
Microbiology
Mice
Structure-Activity Relationship
chemistry.chemical_compound
Parasitic Sensitivity Tests
law
parasitic diseases
Drug Discovery
Animals
Humans
Potency
Structure–activity relationship
Enzyme Inhibitors
General Pharmacology, Toxicology and Pharmaceutics
Pharmacology
chemistry.chemical_classification
Dose-Response Relationship, Drug
Molecular Structure
biology
Organic Chemistry
Toxoplasma gondii
biology.organism_classification
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
Triclosan
Disease Models, Animal
Acyl carrier protein
Enzyme
chemistry
Recombinant DNA
biology.protein
Molecular Medicine
Caco-2 Cells
Toxoplasma
Toxoplasmosis
Subjects
Details
- ISSN :
- 18607179
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- ChemMedChem
- Accession number :
- edsair.doi.dedup.....7bed39988fc78dba60012565483b42e2
- Full Text :
- https://doi.org/10.1002/cmdc.201300050