Synthesis and antiviral evaluation of 1,3-dimethyl-6-(1H-1,2,3-triazol-1- YL)pyrimidine-2,4(1H,3H)-dione derivatives

Article abstract of DOI:10.1007/s10593-010-0633-8

Some 6-(1H-1,2,3-triazol-1-yl)pyrimidine-2,4(1H,3H)-dione derivatives were synthesized via the reaction of 6-azido-1,3-dimethyluracil with ethyl acetoacetate in the presence of sodium ethoxide. The antiviral activities of these compounds against Hepatitis A virus (HAV, MBB-cell culture adapted strain) and Herpes simples virus type-1 (HSV-1) were tested.

Full text of DOI:10.1007/s10593-010-0633-8

Chemistry of Heterocyclic Compounds, Vol. 46, No. 9, 2010
SYNTHESIS AND ANTIVIRAL EVALUATION OF
1,3-DIMETHYL-6-(1H-1,2,3-TRIAZOL-1-YL)PYRIMIDINE-
2,4(1H,3H)-DIONE DERIVATIVES
A. Sh. El-Etrawy1 and A. A.-H. Abdel-Rahman2*
Some 6-(1H-1,2,3-triazol-1-yl)pyrimidine-2,4(1H,3H)-dione derivatives were synthesized via the
reaction of 6-azido-1,3-dimethyluracil with ethyl acetoacetate in the presence of sodium ethoxide. The
antiviral activities of these compounds against Hepatitis A virus (HAV, MBB-cell culture adapted
strain) and Herpes simples virus type-1 (HSV-1) were tested.
Keywords: pyrimidine derivatives, 1,2,3-triazoles, anti hepatitis A virus, cycloaddition.
The chemistry of azides has attracted the attention of many chemists, since many of these compounds
play an important role in organic chemistry [1–3]. One of the more useful synthetic applications of azides is the
preparation of 1,2,3-triazoles via cycloaddition reactions [4–6]. 1,2,3-Triazoles have also received much
attention because of their chemotherapeutic value [7]. Moreover, 1,2,3-triazole derivatives show significant
Scheme 1
O
EtOH
O
O
conc. H2SO4
reflux
Me
Me
O
Me
O
N
MeCOCH2CO2Et
N
N
N
N
EtOH/EtONa/reflux
O
N
N
N
N
N3
N
Me
2
N
N
Me
Me
1
Me
COOEt
Me
COOH
O
3
Me
N
.
NH2NH2 H2O
N
EtOH/reflux
O
N
N
N
Me
Me
CONHNH2
4
_______
* To whom correspondence should be addressed, e-mail: adelnassar63@hotmail.com.
1Department of Organic Chemistry, College of Pharmacy, Misr University for Science and Technology, 6th
October City, Egypt.
2Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1372-1375, September, 2010. Original
article received December 02, 2009.
0009-3122/10/4609-1105©2010 Springer Science+Business Media, Inc.
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antimicrobial, cytostatic, virostatic, and anti-inflamatory activities [8-10]. The versatile biological properties of
pyrimidine derivatives and 1,2,3-triazoles prompted us to investigate the synthesis and antiviral activity of
modified pyrimidine with the 1,2,3-triazolyl moiety at the 6-position of the pyrimidine.
In this investigation, reaction of 6-azido-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (1) [11] with ethyl
acetoacetate in the presence of sodium ethoxide under reflux afforded 6-(4-carboxy-5-methyl-1H-1,2,3-triazol-
1-yl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (2) in 80% yield. Esterification of compound 2 with ethanol in
the presence of conc. H2SO4 at reflux temperature afforded 6-(4-ethoxycarbonyl-5-methyl-1H-1,2,3-triazol-1-yl)-
1,3-dimethylpyrimidine-2,4(1H,3H)-dione (3) in 95% yield. The acid hydrazide derivative 4 was obtained in
93% yield by boiling compound 3 with hydrazine hydrate in ethanol (Scheme 1).
Refluxing of the acid hydrazide 4 with dibromochalcone derivatives 5a-f [12] in dry pyridine gave the
substituted pyrazole derivatives 6a-f in 77–88% yields (Scheme 2).
Scheme 2
O
Me
N
O
Br
dry pyridine
reflux
N
O
N
N
4 +
Ar
N
N
Ph
Ar
Me
Br
Me
N
O
Ph
5a–f
6a–f
5, 6 a Ar = phenyl, b Ar = 2-bromophenyl, c Ar = 4-bromophenyl,
d Ar = 2,4-dibromophenyl, e Ar = 2-fluorophenyl, f Ar = 3-nitrophenyl
1
1
The structures of compounds 26 were confirmed by H NMR and mass spectrometry. In the H NMR
spectra of the synthesized compounds we observed all proton signals of the aromatic ring, heterocyclic ring, and
methyl group.
Plaque infectivity assay [13] was carried out to test the prepared compounds for antiviral activity. The
test was performed to include three possibilities for antiviral activity  virucidal effect, virus adsorption, and
effect on virus replication for both Hepatitis A virus (HAV-27) and Herpes simples virus type 1 (HSV-1).
For the antiviral activity against HAV-27 it was noticed that, at both concentrations 10 and 20 µg/105
cells, compounds 6a,c revealed the highest antiviral activity in this series of compounds, and compounds 6e,f
revealed high activity at 10 µg/105 cells using Amantadine (maximum concentration) as a control. Compound 2
showed moderate activity, while at a concentration of 20 µg/105 cells, compound 3 revealed little antiviral
activities.
For the antiviral activity against HSV-1, the results revealed that compounds 2 and 6af showed the
highest effect on HSV-1 at concentration 10 µg/105 cells, while compounds 3 and 4 showed moderate activity.
In conclusion, new 6-(1,2,3-triazol-1-yl)pyrimidine derivatives were synthesized in order to increase the
number of tested compounds screened for antiviral activity. Some of them displayed promising activities.
EXPERIMENTAL
Melting points were determined using a Büchi apparatus. 1H NMR spectra were recorded with a Varian
Gemini spectrometer at 200 (compounds 24) and 300 MHz (compounds 6a-f) in DMSO-d6 with TMS as
internal standard. The microanalyses were performed at the microanalytical unit, Tokyo University, Japan. The
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progress of the reactions was monitored by TLC using aluminum silica gel plates 60 F245. EI-mass spectra were
recorded with a HP D5988 A 1000 MHz instrument (Hewlett-Packard, Palo Alto, CA, USA).
6-(4-Carboxy-5-methyl-1H-1,2,3-triazol-1-yl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (2). 6-Azido-
1,3-dimethyluracil 1 [11] (5.43 g, 30 mmol) in absolute ethanol (20 ml) was treated with sodium ethoxide in
ethanol (0.15 M, 10 ml) with stirring at room temperature. Ethyl acetoacetate (4.55 g, 35 mmol) was added to
the reaction mixture, which was then refluxed for 6 h. The reaction mixture was left to cool and then neutralized
with Amberlite IR-120(H+) resin and filtered, and the resin was washed with ethanol. The combined filtrates
were evaporated under reduced pressure, and the residue was recrystallized from ethanol to afford compound 2
(6.36 g, 80%) as a pale-yellow powder; mp 270-272ºC. 1H NMR spectrum, , ppm: 2.33 (3H, s, CH3); 3.20 (3H,
s, CH3); 3.39 (3H, s, CH3); 6.66 (1H, s, H-5); 11.04 (1H, br. s, OH). Mass spectrum, m/z (I, %): 265 [M+] (45).
Found, %: C 45.11; H 4.05; N 26.33. C10H11N5O4. Calculated, %: C 45.28; H 4.18; N 26.41.
6-(4-Ethoxycarbonyl-5-methyl-1H-1,2,3-triazol-1-yl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione
(3). Acid derivative 2 (2.65 g, 10 mmol) in absolute ethanol (30 ml) was treated, carefully dropwise, with conc.
H2SO4 (5 ml) with stirring at room temperature. The reaction mixture was refluxed for 1 h and then cooled to
room temperature. The solvent was concentrated and cooled to afford a pale-yellow crystals (2.78 g, 95%); mp
1
211-213ºC. H NMR spectrum, , ppm (J, Hz): 1.30 (3H, t, J = 6.5, CH3CH2); 2.37 (3H, s, CH3); 3.17 (3H, s,
CH3); 3.40 (3H, s, CH3); 4.20 (2H, q, J = 6.5, CH3CH2); 6.61 (1H, s, H-5). Mass spectrum, m/z (I, %): 293 [M+]
(32). Found, %: C 48.98; H 5.02; N 23.79. C12H15N5O4. Calculated, %: C 49.14; H 5.16; N 23.88.
6-(4-Carbohydrazide-5-methyl-1H-1,2,3-triazol-1-yl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione
(4). Compound 3 (2.93 g, 10 mmol) in absolute ethanol (20 ml) was treated with hydrazine hydrate (5 ml) with
stirring under reflux for 3 h and then cooled to room temperature. The solid was filtered off and dried to give 4
(2.59 g, 93%); mp 245-247ºC. 1H NMR spectrum, , ppm: 2.11 (2H, br. s, NH2); 2.34 (3H, s, CH3); 3.19 (3H, s,
CH3); 3.37 (3H, s, CH3); 6.65 (1H, s, H-5); 8.00 (1H, br. s, NH). Mass spectrum, m/z (I, %): 279 [M+] (24).
Found, %: C 42.88; H 4.55; N 34.90. C10H13N7O3. Calculated, %: C 43.01; H 4.69; N 35.11.
Preparation of the Pyrazole Derivatives 6a-f (General Method). A mixture of compound 4 (0.279 g,
1 mmol) and dibromochalcone derivatives 5a-f [12] (1 mmol) in dry pyridine (15 ml) was refluxed for 7-10 h.
The solvent was evaporated under reduced pressure and coevaporated with toluene (45 ml). The residue was
recrystallized from ethanol to afford 6a-f in 77-88% yields as pale-yellow powders.
6-[4-(3,5-Diphenyl-1H-pyrazole-1-carbonyl)-5-methyl-1H-1,2,3-triazol-1-yl]-1,3-dimethylpyrimidine-
2,4(1H,3H)-dione (6a). Yield 0.41 g (88%); mp 195-197ºC. 1H NMR spectrum, , ppm: 2.30 (3H, s, CH3); 3.18
(3H, s, CH3); 3.28 (3H, s, CH3); 6.60 (1H, s, H-5); 7.10 (1H, s, H-4 pyrazole); 7.41-7.79 (8H, m, H Ar);
8.00-8.15 (2H, m, H Ar). Mass spectrum, m/z (I, %): 467 [M+] (15). Found, %: C 64.07; H 4.44; N 20.72.
C25H21N7O3. Calculated, %: C 64.23; H 4.53; N 20.97.
6-{4-[5-(2-Bromophenyl)-3-phenyl-1H-pyrazole-1-carbonyl]-5-methyl-1H-1,2,3-triazol-1-yl}-1,3-di-
1
methylpyrimidine-2,4(1H,3H)-dione (6b). Yield 0.43 g (80%); mp 205-207ºC. H NMR spectrum, , ppm:
2.33 (3H, s, CH3); 3.16 (3H, s, CH3); 3.29 (3H, s, CH3); 6.66 (1H, s, H-5); 7.13 (1H, s, H-4 pyrazole); 7.30-7.62
(7H, m, H Ar); 8.018.07 (2H, m, H Ar). Mass spectrum, m/z (I, %): 545/547 [M+] (12). Found, %: C 54.80;
H 3.50; N 17.77. C25H20BrN7O3. Calculated, %: C 54.96; H 3.69; N 17.94.
6-{4-[5-(4-Bromophenyl)-3-phenyl-1H-pyrazole-1-carbonyl]-5-methyl-1H-1,2,3-triazol-1-yl}-1,3-di-
1
methylpyrimidine-2,4(1H,3H)-dione (6c). Yield 0.44 g (82%); mp 219221ºC. H NMR spectrum, , ppm:
2.30 (3H, s, CH3); 3.19 (3H, s, CH3); 3.32 (3H, s, CH3), 6.62 (1H, s, H-5), 7.10 (1H, s, H-4 pyrazole), 7.50-7.80
(7H, m, H Ar); 8.03-8.09 (2H, m, H Ar). Mass spectrum, m/z (I, %): 545/547 [M+] (17). Found, %: C 54.77;
H 3.47; N 17.79. C25H20BrN7O3. Calculated, %: C 54.96; H 3.69; N 17.94.
6-{4-[5-(2,4-Dibromophenyl)-3-phenyl-1H-pyrazole-1-carbonyl]-5-methyl-1H-1,2,3-triazol-1-yl}-
1
1,3-dimethylpyrimidine-2,4(1H,3H)-dione (6d). Yield 0.48 g (78%); mp 228-230ºC. H NMR spectrum, ,
ppm: 2.32 (3H, s, CH3); 3.17 (3H, s, CH3); 3.30 (3H, s, CH3); 6.64 (1H, s, H-5); 7.13 (1H, s, H-4 pyrazole);
7.527.70 (5H, m, H Ar); 8.03-8.07 (3H, m, H Ar). Mass spectrum, m/z (I, %): 624/626 [M+] (7).
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6-{4-[5-(2-Fluorophenyl)-3-phenyl-1H-pyrazole-1-carbonyl]-5-methyl-1H-1,2,3-triazol-1-yl}-1,3-di-
1
methylpyrimidine-2,4(1H,3H)-dione (6e). Yield 0.38 g (80%); mp 210-212ºC. H NMR spectrum, , ppm:
2.28 (3H, s, CH3); 3.16 (3H, s, CH3); 3.29 (3H, s, CH3); 6.66 (1H, s, H-5); 7.14 (1H, s, H-4 pyrazole); 7.28-7.77
(7H, m, H Ar); 8.008.05 (2H, m, H Ar). Mass spectrum, m/z (I, %): 485 [M+] (21). Found, %: C 61.66; H 4.10;
N 20.07. C25H20FN7O3. Calculated, %: C 61.85; H 4.15; N 20.20.
1,3-Dimethyl-6-{5-methyl-4-[5-(3-nitrophenyl)-3-phenyl-1H-pyrazole-1-carbonyl]-1H-1,2,3-triazol-
1-yl}-pyrimidine-2,4(1H,3H)-dione (6f). Yield 0.39 g (77%); mp 233-235ºC. 1H NMR spectrum, , ppm: 2.31
(3H, s, CH3); 3.19 (3H, s, CH3); 3.32 (3H, s, CH3); 6.64 (1H, s, H-5); 7.12 (1H, s, H-4 pyrazole); 7.41-7.75 (4H,
m, H Ar); 8.09-8.45 (5H, m, H Ar). Mass spectrum, m/z (I, %): 512 [M+] (8). Found, %: C 58.44; H 3.77;
N 21.68. C25H20N8O5. Calculated, %: C 58.59; H 3.93; N 21.87.
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