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J Med Chem. 2015 Jun 11;58(11):4483-93. doi: 10.1021/jm5017895. Epub 2015 Jun 2.

Pyrimethamine Derivatives: Insight into Binding Mechanism and Improved Enhancement of Mutant β-N-acetylhexosaminidase Activity.

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†Genetics and Genome Biology, SickKids, PGCRL 686 Bay Street, Toronto, Ontario M5G 0A4, Canada.
‡Department of Chemistry, University of British Columbia, 2036 Main Mall Vancouver, British Columbia V6T 1Z1, Canada.
§Department of Laboratory Medicine and Pathology, University of Toronto, Medical Science Building, 1 King's College Circle, 6th Floor, Toronto, Ontario M5S 1A8, Canada.


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.

[Indexed for MEDLINE]

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