Novel C-6 Fluorinated Acyclic Side Chain Pyrimidine Derivatives:  Synthesis, ¹H and ¹³C NMR Conformational Studies, and Antiviral and Cytostatic Evaluations

Abstract

The synthetic route for introduction of a fluoroalkyl (7-12, 14), fluoroalkenyl (15 and 16), fluorophenylalkyl (17, 19, 20, and 22), and fluorophenylalkenyl (18, 21) side chain at C-6 of the pyrimidine involved the lithiation of the pyrimidine derivatives 3 and 3a and subsequent nucleophilic addition or substitution reactions of the organolithium intermediate thus obtained with various electrophiles. Conformational properties of the novel fluorinated pyrimidine derivatives were assessed by the use of 1D difference NOE enhancements and C-F coupling constants. Compounds 4-22 were evaluated for their antiviral and cytostatic activities. Of all compounds evaluated, the 5-bromopyrimidine derivatives 5 and 6 showed the highest inhibitory activities. Among the series of fluoroalkylated pyrimidines, which is generally more active than the series of fluorophenylalkylated pyrimidines, compounds 8 and 14 displayed moderate cytostatic activities against the tested tumor cell lines. Moreover, compound 8 containing a 2-fluoromethylpropyl side chain expressed some but not highly specific activity against varicella-zoster virus (VZV). From C-6 fluorophenylalkylated pyrimidine derivatives, 17a and 21 showed a slight activity against cytomegalovirus (CMV), VZV, and Coxsackie B4 virus, respectively. Besides, compounds 17a and 21 showed no cytotoxic effect.

A theoretical study on 2-chloro-5-(2-hydroxyethyl)-4-methoxy-6-methylpyrimidine by DFT/ab initio calculations

“…The biological activities shown by 6-substituted uracil derivatives provide a new motivation to explore the chemical and biological activities of these pyrimidine derivatives [2][3][4][5][6][7][8]. Uracil derivatives as well as their nucleosides which have significant status in the field of chemotherapy, are substituted either at C5 or C6 positions.…”

Reaction of 2-R 5-oxo 5-H 6- Ethylcarboxylate 7-phenyl-[1,3,4]thiadiazolo-[3,2-a] pyrimidine with Morpholin and their Properties

“…Keywords: 2-R 5-oxo 5-H 6 -Carbomorpholin 7-phenyl 1,3,4-thiadiazolo-[3,2-a] pyrimidine -2-R 5-Oxo 5-H 6-EthylCarboxilate 7 -phenyl -1, 3, pyrimidine -Morpholin -Synthesis -The reaction.…”

“…The diverse and interesting biological activity of thiadiazoleshas been reported [1][2][3][4] It is well known that these heterocyclesare valuable building blocks. Many methods for preparationof these heterocyclic ring systems and their fused analogues have been described in the literature [5][6] .…”

“…in particular,for the new antibacterial drugs in these homologousseries of compounds, we have synthesized 2-R5-oxo 5-H 6 -Carbomorpholin 7-phenyl 1,3,4-thiadiazolo-[3,2-a] pyrimidine .The structures of the compounds obtained are set NMR, 13 C, IR-spectroscopy.Keywords: 2-R 5-oxo 5-H 6 -Carbomorpholin 7-phenyl 1,3,4-thiadiazolo-[3,2-a] pyrimidine -2-R 5-Oxo 5-H 6-EthylCarboxilate 7 -phenyl -1, 3, pyrimidine -Morpholin -Synthesis -The reaction.and numerous repor tshave appeared in the literature [8][9][10][11][12] …”

Syntheses and Antitumor Evaluation of C(6)‐Isobutyl‐ and C(6)‐Isobutenyl‐Substituted Pyrimidines, and Dihydropyrrolo[1,2‐c]pyrimidine‐1,3‐diones

“…C(6)-Substituted pyrimidines containing the 4-fluorophenyl moiety in the side chain showed pronounced antiproliferative effect on colon (SW620 and HCT116) and lung carcinoma (H460) [21]. The 6-(bromomethyl)-substituted pyrimidine derivatives showed marked cytotoxic activity against all evaluated tumor cell lines, particularly against colon carcinoma (SW620) [22].…”