@article { ISI:000356316600006,
	title = {Pyrimethamine Derivatives: Insight into Binding Mechanism and Improved Enhancement of Mutant beta-N-acetylhexosaminidase Activity},
	journal = {JOURNAL OF MEDICINAL CHEMISTRY},
	volume = {58},
	number = {11},
	year = {2015},
	month = {JUN 11},
	pages = {4483-4493},
	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 beta-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 mu M, while showing less toxicity. These findings demonstrate the importance of the phenyl group in modulating the chaperoning efficacy and toxicity profile of the derivatives.},
	issn = {0022-2623},
	doi = {10.1021/pn5017895},
	author = {Tropak, Michael B. and Zhang, Jianmin and Yonekawa, Sayuri and Rigat, Brigitte A. and Aulakh, Virender S. and Smith, Matthew R. and Hwang, Hee-Jong and Ciufolini, Marco A. and Mahuran, Don J.}
}
