Pyrimethamine Derivatives: Insight into Binding Mechanism and Improved Enhancement of Mutant β-N-acetylhexosaminidase Activity
| Autor: | Brigitte Rigat, Matthew R. Smith, Hee-Jong Hwang, Virender S. Aulakh, Don J. Mahuran, Sayuri Yonekawa, Jianmin Zhang, Marco A. Ciufolini, Michael B. Tropak |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Stereochemistry Mutant Inhibitory postsynaptic potential Structure-Activity Relationship chemistry.chemical_compound Alzheimer Disease Drug Discovery medicine Humans Phenyl group Ethyl group IC50 Cells Cultured Molecular Structure biology Fibroblasts beta-N-Acetylhexosaminidases Enzyme assay 3. Good health Pyrimethamine chemistry Mutation Toxicity biology.protein Molecular Medicine Mutant Proteins medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 58:4483-4493 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | In order to identify structural features of pyrimethamine (5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine) that contribute to its inhibitory activity (IC50 value) and chaperoning efficacy toward β-N-acetylhexosaminidase, derivatives of the compound were synthesized that differ at the positions bearing the amino, ethyl, and chloro groups. Whereas the amino groups proved to be critical to its inhibitory activity, a variety of substitutions at the chloro position only increased its IC50 by 2–3-fold. Replacing the ethyl group at the 6-position with butyl or methyl groups increased IC50 more than 10-fold. Surprisingly, despite its higher IC50, a derivative lacking the chlorine atom in the para-position was found to enhance enzyme activity in live patient cells a further 25% at concentrations >100 μM, while showing less toxicity. These findings demonstrate the importance of the phenyl group in modulating the chaperoning efficacy and toxicity profile of the derivatives. |
| Databáze: | OpenAIRE |
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