|Title||Pyrimethamine Derivatives: Insight into Binding Mechanism and Improved Enhancement of Mutant beta-N-acetylhexosaminidase Activity|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Tropak, MB, Zhang, J, Yonekawa, S, Rigat, BA, Aulakh, VS, Smith, MR, Hwang, H-J, Ciufolini, MA, Mahuran, DJ|
|Journal||JOURNAL OF MEDICINAL CHEMISTRY|
|Date Published||JUN 11|
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.