27653-49-2

Usage

InChI:InChI=1/C12H14N4/c1-2-9-10(8-6-4-3-5-7-8)11(13)16-12(14)15-9/h3-7H,2H2,1H3,(H4,13,14,15,16)

Upstream product

• 113-00-8 guanidine nitrate 
• 50-01-1 guanidine hydrochloride 
• 78030-29-2 (Z)-3-Ethoxy-2-phenyl-pent-2-enenitrile 
• 6277-02-7 3-oxo-2-phenylpentanenitrile 
• 1326244-85-2 C₁₂H₁₃NO 
• 140-29-4 phenylacetonitrile 
• 141-52-6 sodium ethanolate 
• 186581-53-3 diazomethane 

Downstream Products

• 71552-34-6 6-ethyl-5-(4'-nitrophenyl)-pyrimidine-2,4-diamine 
• 502136-76-7 5-(4'-aminophenyl)-6-ethyl-pyrimidine-2,4-diamine 

Relevant academic research and scientific papers

Pyrimethamine Derivatives: Insight into Binding Mechanism and Improved Enhancement of Mutant β- N -acetylhexosaminidase Activity

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.

COMPOUNDS FOR THE TREATMENT OF LYSOSOMAL STORAGE DISEASES

A method of treating a lysosomal storage disease comprises administering a pyrimethamine derivative to a subject in need thereof.

An expeditious synthesis of 6-alkyl-5-(4′ -amino-phenyl)-pyrimidine-2,4-diamines

A rapid synthesis of a series of 6-alkyl substituted-5-(4′ -amino-phenyl)-pyrimidine-2,4-diamines is described. These analogs were produced in good yields on moderate scale (ca. 8 g) without chromatography. Furthermore, the methodology described herein al

Development of 2,4-diaminopyrimidines as antimalarials based on inhibition of the S108N and C59R+S108N mutants of dihydrofolate reductase from pyrimethamine resistant Plasmodium falciparum

The reduced binding of pyrimethamine to Serl08Asn (S108N) mutants of parasite dihydrofolate reductase (DHFR), which forms the basis of resistance of Plasmodium falciparum to pyrimethamine, is largely due to steric constraint imposed by the bulky side chain of N108 on Cl of the 5-p-Cl-phenyl group. This and other S108 mutants with bulky side chains all showed reduced binding to pyrimethamine and cycloguanil. Less effect on binding to some bulky mutants was observed for trimethoprim, with greater flexibility for the 5-substituent. S108N DHFR also binds poorly with other pyrimethamine derivatives with bulky groups in place of the p-Cl, and the binding was generally progressively poorer for the double (C59R+S108N) mutant. Removal of the p-Cl or replacement with m-Cl led to better binding with the mutant DHFRs. Pyrimethamine analogues with unbranched hydrophobic 6-substituents showed generally good binding with the mutant DHFRs. A number of compounds were identified with high affinities for both wild-type and mutant DHFRs, with very low to no affinity to human DHFR. Some of these compounds show good antimalarial activities against pyrimethamine-resistant P. falciparum containing the mutant DHFRs with low cytotoxicity to three mammalian cell lines.