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'Clicking' fragment leads to novel dual-binding cholinesterase inhibitors
- Source :
- Bioorganic and Medicinal Chemistry, 42:116269. PERGAMON-ELSEVIER SCIENCE LTD
- Publication Year :
- 2021
- Publisher :
- PERGAMON-ELSEVIER SCIENCE LTD, 2021.
-
Abstract
- Cholinesterase inhibitors are potent therapeutics in the treatment of Alzheimer's disease. Among them, dual binding ligands have recently gained a lot of attention. We discovered novel dual-binding cholinesterase inhibitors, using “clickable” fragments, which bind to either catalytic active site (CAS) or peripheral anionic site (PAS) of the enzyme. Copper(I)-catalyzed azide-alkyne cycloaddition allowed to effectively synthesize a series of final heterodimers, and modeling and kinetic studies confirmed their ability to bind to both CAS and PAS. A potent acetylcholinesterase inhibitor with IC50 = 18 nM (compound 23g) was discovered. A target-guided approach to link fragments by the enzyme itself was tested using butyrylcholinesterase.
- Subjects :
- Stereochemistry
medicine.drug_class
Clinical Biochemistry
Triazole
Pharmaceutical Science
Tryptamine
Hybrid drugs
01 natural sciences
Biochemistry
Combinatorial libraries
chemistry.chemical_compound
Drug Discovery
Tetrahydroisoquinoline
medicine
Animals
Humans
Structure–activity relationship
Horses
Molecular Biology
Butyrylcholinesterase
Cholinesterase
chemistry.chemical_classification
Target-guided synthesis
Dose-Response Relationship, Drug
Molecular Structure
biology
010405 organic chemistry
Galantamine
Organic Chemistry
Active site
Structure-activity relationship
0104 chemical sciences
”click” chemistry
010404 medicinal & biomolecular chemistry
Enzyme
chemistry
Acetylcholinesterase inhibitor
Acetylcholinesterase
biology.protein
Molecular Medicine
Click Chemistry
Cholinesterase Inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 14643391 and 09680896
- Volume :
- 42
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....1874601fd01ef7c4e7ff43b5f87d5732