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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.

Author information

1
†Genetics and Genome Biology, SickKids, PGCRL 686 Bay Street, Toronto, Ontario M5G 0A4, Canada.
2
‡Department of Chemistry, University of British Columbia, 2036 Main Mall Vancouver, British Columbia V6T 1Z1, Canada.
3
§Department of Laboratory Medicine and Pathology, University of Toronto, Medical Science Building, 1 King's College Circle, 6th Floor, Toronto, Ontario M5S 1A8, Canada.

Abstract

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.

PMID:
25984755
DOI:
10.1021/jm5017895
[Indexed for MEDLINE]

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