An efficient microwave-assisted synthesis and biological properties of polysubstituted pyrimidinyl- and 1,3,5-triazinylphosphonic acids

Abstract

a b s t r a c tPolysubstituted pyrimidinylphosphonic and 1,3,5-triazinylphosphonic acids with potential biological properties were prepared in high yields by the microwave-assisted MichaeliseArbuzov reaction of trialkyl phosphite with the corresponding halopyrimidines and halo-1,3,5-triazines, respectively, followed by the standard deprotection of the phosphonate group using TMSBr in acetonitrile. 4,6-Diamino-5chloropyrimidin-2-ylphosphonic acid (7a) was found to exhibit a weak to moderate anti-influenza activity (28e50 mM) and may represent a novel hit for further SAR studies and antiviral improvement.

5-Substituted 2-amino-4,6-dihydroxypyrimidines and 2-amino-4,6-dichloropyrimidines: synthesis and inhibitory effects on immune-activated nitric oxide production

“…There is a large class of pharmacologically important pyrimidine derivatives that act as dihydrofolate reductase (DHFR) inhibitors (Hitchings, 1989), as well as compounds with anti-HIV (Holý, 2003;De Clercq and Holý, 2005), anti-adenovirus (Naesens et al, 2005), and anti-HBV activities (Ying et al, 2005), inhibitors of tetrahydrobiopterin synthesis Kolinsky and Gross, 2004), regulators of pain sensitivity and persistence (Tegeder et al, 2006), antidepressants (Arvanitis et al, 1999), compounds which suppress accumulation of cytokine-induced NF-jB (Ikemoto et al, 2008), inhibitors of EGFR and Her-2 tyrosine kinases (Suzuki et al, 2012) and cyclin-dependent kinases as potential drug candidates for cancer therapy (Beattie et al, 2003;Breault et al, 2003). Substitution at position 5 of the pyrimidine moiety has been used in the past to improve the biological property of several pharmacologically interesting pyrimidine derivatives with anti-HIV (Hocková et al, 2003(Hocková et al, , 2004 or anti-influenza activity (Jansa et al, 2012), with inhibitory activity against human thymidine phosphorylase (Nencka et al, 2007) or with antioxidative activity (Procházková et al, 2012a, b).…”

Optimization and a Kinetic Study on the Acidic Hydrolysis of Dialkyl α-Hydroxybenzylphosphonates

“…Most often, the hydrolyses were performed under acidic conditions [ 1 , 2 , 3 , 4 ], but the application of NaOH or KOH is also common [ 5 , 6 , 7 , 8 ]. An additional possibility is the fission of the P-O-C unit by the effect of Me 3 SiBr [ 9 , 10 , 11 ]. Usually, the acid- or base-catalyzed hydrolyses were carried out routinely, under “excessive” (unoptimized) conditions applying the acid or base catalysts in a larger quantity than required, and allowing longer reaction times.…”

Synthesis of 3(2)-phosphonylated thiazolo[3,2-a]oxopyrimidines

“…Despite the wide variety of thiazolopyrimidines reported to date, phosphonylated analogues of compounds of this series are unknown. Of special interest is the design of molecules containing practically significant heteroaromatic rings and a biologically active and hydrolysis-resistant phosphonate group, as it has been reported that the combination of several pharmacophore fragments in one molecule can lead to a synergistic increase in biological activity or an additional variety of the latter [22][23][24][25][26][27][28].…”