105104-81-2Relevant articles and documents
Pyrimethamine Derivatives: Insight into Binding Mechanism and Improved Enhancement of Mutant β- N -acetylhexosaminidase Activity
Tropak, Michael B.,Zhang, Jianmin,Yonekawa, Sayuri,Rigat, Brigitte A.,Aulakh, Virender S.,Smith, Matthew R.,Hwang, Hee-Jong,Ciufolini, Marco A.,Mahuran, Don J.
, p. 4483 - 4493 (2015/06/23)
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.
