855377-91-2Relevant academic research and scientific papers
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.
MESOMERIC ANIONS. X. METHYLATION OF ALKALI-METAL DERIVATIVES OF SOME 1,3-KETONITRILES
Emelina, E. E.,Ershov, B. A.
, p. 692 - 696 (2007/10/02)
The effect of polar factors on the relative nucleophilicity of the oxygen and carbon reaction centers in the alkali-metal derivatives of 2-(X-benzoyl)acetonitriles, 2-(X-benzoyl)propionitriles, and 2-(X-phenyl)acetylacetonitriles was investigated.During methylation with methyl iodide and methyl p-toluenesulfonate in DMFA the ratio of the C- and O-methylation products for all the investigated compounds decreases with increase in the accepting power of the substituent X.It was shown that the sensitivity of the C-reaction center to the effect of the substituent X is greater than that of the O-center.
