Dihydropyrimidinone/1,2,3-triazole hybrid molecules: Synthesis and anti-varicella-zoster virus (VZV) evaluation

Article abstract of DOI:10.1016/j.ejmech.2018.06.028

By combining the structural features of dihydropyrimidinone and 1,2,3-triazole heterocycles, novel hybrid compounds were synthesized using a simple and convenient method. A series of novel mono and bis 1,2,3-triazole was synthesized via copper-catalyzed Huisgen azide-alkyne cycloadditions (CuAAC) under microwave irradiation. The newly synthesized compounds were evaluated for their antiviral activity against varicella-zoster virus (VZV). Compounds 6aa, 7ab, 6ba and 6da showed valuable antiviral activities, with EC₅₀ values ranging from 3.6 to 11.3 μM against TK+ and TK- VZV and without measurable cell-growth inhibition.

Full text of DOI:10.1016/j.ejmech.2018.06.028

Accepted Manuscript
Dihydropyrimidinone/1,2,3-triazole hybrid molecules: Synthesis and anti-varicella-
zoster virus (VZV) evaluation
Hanane Kaoukabi, Youssef Kabri, Christophe Curti, Moha Taourirte, Juan C.
Rodriguez-Ubis, Robert Snoeck, Graciela Andrei, Patrice Vanelle, Hassan B. Lazrek
PII:
S0223-5234(18)30519-1
10.1016/j.ejmech.2018.06.028
EJMECH 10498
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 2 May 2018
Revised Date: 28 May 2018
Accepted Date: 11 June 2018
Please cite this article as: H. Kaoukabi, Y. Kabri, C. Curti, M. Taourirte, J.C. Rodriguez-Ubis, R. Snoeck,
G. Andrei, P. Vanelle, H.B. Lazrek, Dihydropyrimidinone/1,2,3-triazole hybrid molecules: Synthesis
and anti-varicella-zoster virus (VZV) evaluation, European Journal of Medicinal Chemistry (2018), doi:
10.1016/j.ejmech.2018.06.028.
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ACCEPTED MANUSCRIPT
Dihydropyrimidinone/1,2,3-triazole hybrid molecules synthesis and anti-
varicella-zoster virus (VZV) evaluation
Hanane Kaoukabi1,2, Youssef Kabri3, Christophe Curti3, Moha Taourirte1, Juan C. Rodriguez-
Ubis4, Robert Snoeck5, Graciela Andrei5, Patrice Vanelle*3, Hassan B. Lazrek*2
E-Mail : patrice.vanelle@univ-amu.fr

ACCEPTED MANUSCRIPT
Dihydropyrimidinone/1,2,3-triazole hybrid molecules: synthesis and anti-
varicella-zoster virus (VZV) evaluation
Hanane Kaoukabi1,2, Youssef Kabri3, Christophe Curti3, Moha Taourirte1, Juan C. Rodriguez-
Ubis4, Robert Snoeck5, Graciela Andrei5, Patrice Vanelle*3, Hassan B. Lazrek*2
1 Laboratory of Bioorganic and Macromolecular Chemistry, Department of Chemistry, Faculty of Sciences and Technology
Gueliz (FSTG), Marrakesh, Morocco.
2 Laboratory of Biomolecular and Medicinal Chemistry, Department of Chemistry, Faculty of Sciences Semlalia (FSSM),
Marrakesh, Morocco.
3Aix Marseille University, Institut de Chimie Radicalaire ICR, UMR CNRS 7273, Laboratoire de Pharmaco-Chimie
Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin-CS 30064,13385 Marseille CEDEX 05, France.
4 Laboratory Organic-Inorganic Solids and Luminiscent Probes (M01-L207), Department of Organic Chemistry, Faculty of
Sciences, University Autonoma, Madrid, Spain.
5 Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
E-Mail : patrice.vanelle@univ-amu.fr, hblazrek@uca.ac.ma
O
N
N
N
O
N
O
N
H3C
H3C
N
N
NO2
H3C
H3C
NH
N
N
O
N
O
N
N
N
N
N
8a
7d
NO2
EC50 TK+ VZV = 3.62 µM
EC50 TK- VZV = 7.85 µM
CC50 HEL > 100 µM
EC50 TK+ VZV = 11.33 µM
EC50 TK- VZV = 10.79 µM
CC50 HEL > 100 µM
Abstract: By combining the structural features of dihydropyrimidinone and 1,2,3-triazole
heterocycles, novel hybrid compounds were synthesized using a simple and convenient method. A
series of novel mono and bis 1,2,3-triazole was synthesized via copper-catalyzed Huisgen azide-
alkyne cycloadditions (CuAAC) under microwave irradiation. The newly synthesized compounds
were evaluated for their antiviral activity against varicella-zoster virus (VZV). Compounds 6aa, 7ab,
6ba and 6da showed valuable antiviral activities, with EC50 values ranging from 3.6 to 11.3 µM
against TK+ and TK- VZV and without measurable cell-growth inhibition.
Keywords: Biginelli reaction; 1,3-dipolar cycloaddition; 1,2,3 triazole; microwave; hybrid molecules;
anti-VZV.
Introduction
The prevalence of Herpesviruses in the developed world is a major source of disease. Infection with
varicella-zoster virus (VZV) results in varicella (chickenpox), which usually takes a mild course in
children but may be more severe in adults. However, reactivation of the virus is a serious threat in
immunocompromised individuals, e.g. recipients of solid-organ and hematopoietic stem cell
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transplants, patients under aggressive chemotherapy or individuals with acquired immunodeficiency
syndrome (AIDS). Under these circumstances, efficacious antiviral drugs are crucial [1-3].
Recent trends in medicinal chemistry illustrate the popularity of molecular hybridization for drug
design and development. This is based on combining pharmacophoric moieties of different bioactive
substances to make a new hybrid molecule with enhanced affinity and efficacy, compared to the parent
drug [4-6].
One strategy for producing high potency drug molecules is to combine two bioactive molecules
belonging to a particular therapeutic category. For instance, the 1,2,3-triazole based heterocycles have
been well exploited for the generation of many medicinal scaffolds exhibiting antiviral activities (anti-
HIV, anti VZV, …) [7]. On the other hand, the multi-functionalized pyrimidinone scaffold represents
a class of heterocyclic compounds with significant pharmacological efficiency, including anti-viral
activity [8]. These findings suggest that it would be useful to synthesize novel hybrid molecules with
increased activity and/or decreased toxicity
In an attempt to correlate structure with antiviral activity, herein we report the synthesis and antiviral
evaluation against varicella-zoster virus (VZV) in human embryonic lung (HEL) cells and against
cytomegalovirus in human embryonic lung (HEL) cells.
Results and Discussion
Chemistry
The general route to the synthesis of the target pyrimidine–triazole hybrids is depicted in Scheme 1.
The starting materials 5-Acetyl-6-methyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones 1a-d were
synthesized by multi-component reaction from aryl aldehyde, acetylacetone and urea, using Biginelli
reaction conditions [9]. The literature contains several reports on catalytic methods to improve the
yields and scope of this reaction often using Brønsted or Lewis acid catalysis [10, 11, 12].
First, reactions were launched at room temperature. Under these conditions, compounds 1a-d were
obtained in moderate yields (49-55%) in 3-5 h. Yields were dramatically increased under microwave
irradiation (Scheme 1) and reaction times were moreover highly reduced.
Scheme 1: 5-Acetyl-6-methyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones (1a-d).
In the next step, compounds 1a-c reacted with propargyl halide to give N-alkylated
dihydropyrimidinones (Scheme 2). To determine the optimum reaction conditions, the type and the
number of equivalents of base (t-BuOK, NaH) were investigated (Table 1). As expected, yields
obtained with propargyl bromide (Entries 3-12) were higher than those obtained with propargyl
chloride (Entries 1-2). Moreover, the N1-monoalkylated product was obtained as the major product
using t-BuOK as base and the N1, N3-bisalkyled product was obtained as the major product using NaH
as base.
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Scheme 2: N-alkylation of dihydropyrimidin-2(1H)-one derivatives 1a-c
Table 1: Optimization of reaction conditions
Entry Product
Propargyl
Base (equiv)
Reaction
Temperature
Products (Yields %)a
halide (equiv)
time (min)
2a-c
3a-c
1
-Cl (1.0)
-Cl (2.2)
-Br (2.2)
-Br (2.2)
-Br (2.2)
-Br (2.2)
-Br (2.2)
-Br (2.2)
-Br (2.2)
-Br (2.2)
-Br (2.2)
-Br (2.2)
t-BuOK (1.0)
t-BuOK (2.2)
t-BuOK (2.2)
t-BuOK (2.2)
t-BuOK (2.2)
NaH (2.2)
60
60
60
60
5
25 °C
25 °C
2b (40)
2b (53)
2b (80)
2b (83)
2b (85)
2b (5)
3b (5)
1b
2
3b (5)
1b
3
25 °C
3b (10)
3b (10)
3b (10)
3b (95)
3b (80)
3b (98)
3a (15)
3a (99)
3c (10)
3c (98)
1b
4
50 °C
1b
5
100 °Cb
25 °C
1b
6
60
60
1
1b
7c
NaH (2.2)
25 °C
2b (15)
2b (2)
1b
8
NaH (2.2)
100 °Cb
100 °Cb
100 °Cb
100 °Cb
100 °Cb
1b
9
t-BuOK (2.2)
NaH (2.2)
5
2a (80)
2a (1)
1a
10
1
1a
11
t-BuOK (2.2)
NaH (2.2)
5
2c (85)
2c (2)
1c
12
1
1c
a.
b. Reaction launched under microwave irradiation.
c. THF was used as solvent.
Yield of isolated product based on the corresponding pyrimidinone.
1
The position of N-alkylation was determined using H, 13C NMR and confirmed as N1- alkylated
dihydropyrimidinone by single-crystal X-ray diffraction (XRD) for compounds 2a and 2b. It should be
noted that during the process of single-crystal formation from the racemic mixture of compound 2a
and 2b, only the R-isomer was crystallized out (Scheme 3). This is known as “chiral amnesia” [13,
14].
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ACCEPTED MANUSCRIPT
2a
2b
Scheme 3: Single-crystal X-ray diffraction structure of compound 2a and 2b (R-isomer).
With this convenient base-dependent protocol, three alkylated isomers (2d, 3d, 4d) were also
synthesized with good yields (Scheme 4). In line with NMR spectras, propargylation began on the
phenol moiety, then N1 and finally N3 were propargylated. As reported, increasing the strength of the
base increased the rate of propargylation and consequently increased yields of tripropargylated
derivative 4d.
Scheme 4: Synthesis of mono- di- and tripropargylated derivatives (2d, 3d, 4d)
Then, 1,3-dipolar cycloadditions [15, 16] were performed by one-pot three-component reactions under
microwave irradiation. These reactions were performed in water/acetonitrile mixture with 3
equivalents of sodium azide, 3 equivalents of alkyl halide, 1.5 equivalent of trimethylamine and 0.1
equiv of CuI as catalyst. Under these conditions, dihydropyrimidinone hybrid molecules 5a-c, 6a-c
substituted on N1 with one 1,2,3-triazole were obtained in almost quantitative yields (Scheme 5).
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ACCEPTED MANUSCRIPT
Scheme 5: Synthesis of dihydropyrimidinone hybrid molecules 5a-c, 6a-c
Finally, these reaction conditions were applied to oxypropargylated 2d, bis-propargylated 3a-d and
tripropargylated 4d dihydropyrimidinones (Scheme 6) to obtain a wide variety of hybrid molecules N
and/or O-substituted with one, two or three 1,2,3-triazoles. Yields are reported in Table 2.
Scheme 6: Synthesis of dihydropyrimidinone hybrid molecules mono- bi- and trisubstituted with
1,2,3-triazoles
Table 2: Extension of the synthesis of dihydropyrimidinone-1,2,3-triazole hybrid molecules
Entry Starting
material
R1
R2
R3
R4
Product
obtained
Yields
(%)a
1b
-H
-H
-H
-H
-H
4-NO2
-H
99
97
96
2d
5d
6d
7a
2b
2d
3c
-H
3a
4c
-H
4-NO2
-H
95
98
96
97
94
99
99
95
96
3a
8a
7b
8b
7c
5c
2,5-OCH3
2,5-OCH3
4-N(CH3)2
4-N(CH3)2
3b
6c
4-NO2
-H
3b
7c
3c
8c
4-NO2
-H
3c
8c
9c
-H
-H
3d
7d
8d
9d
10d
10c
4-NO2
-H
3d
11c
4d
12c
4-NO2
4d
a.
b. NaN3: 3 equiv, alkyl halide: 3 equiv.
c. NaN3: 5 equiv, alkyl halide: 5 equiv.
Yield of isolated product based on the corresponding pyrimidinone.
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Antiviral activity
All the eighteen synthesized compounds, 5a-d, 6a-d, 7a-d, 8a-d, 9d and 10d, were tested for their
antiviral activities against the human varicella-zoster virus (VZV), both wild type and thymidine
kinase deficient (TK-). Nine derivatives of the tested compounds showed moderate to good antiviral
activities (Table 3) and compounds 7a, 8a, 7b and 7d emerged as the most active derivatives (Scheme
7). The nine other compounds did not show measurable activity against VZV. We assume that cell-
growth inhibition was only studied for the four compounds that exhibited an antiviral activity lower
than 20 µM.
Table 3: Antiviral activity against varicella-zoster virus (VZV) in HEL cell cultures and cell growth
inhibition for compounds 5b, 6a-b, 7a-d, 8a, 10d.
Antiviral activity EC50 (µM)
TK+ VZV strain
(OKA)
TK- VZV strain
(07-1)
Cell
Growth Inhibition CC50 (µM)
NDa
48.90
50.17
5b
6a
6b
7a
48.90
44.72
8.38b
42.65
48.12
6.08b
NDa
NDa
7.02
3.62b
9.85b
7.85b
8.87b
>100
>100
NDa
8a
7b
23.15
11.33b
69.93
2.35b
17.03
10.79b
>20
7c
>100
NDa
7d
10d
Acyclovir
133.30b
104.28b
>440
>300
Brivudin
0.025b
a. Not determined
b. Mean value of two experiments
The antiviral activities of synthesized dihydropyrimidinone-1,2,3-triazole hybrid molecules were
lower than the antiviral activities of reference compounds acyclovir and brivudin against the TK+
VZV strain, but were better than that those of the reference compounds against the TK- VZV strain.
Moreover, when antiviral activities against TK+ and TK- strains were compared, only a slight
decrease in antiviral activities was observed for each active hybrid molecule, suggesting a class effect.
As the TK- VZV strain is known for its resistance to conventional antiviral drugs,
dihydropyrimidinone-1,2,3-triazole hybrid molecules appear to be a useful alternative as a second-line
treatment.
Except for molecule 7a, none of the dihydropyrimidinone-1,2,3-triazole hybrid molecules showed
quantifiable cell-growth inhibition.
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Scheme 7: Dihydropyrimidinone-1,2,3-triazole hybrid molecules with antiviral activity
Compounds bearing two substituted triazolylmethyl moieties showed higher activities than those
bearing one or three substituent moieties. Molecule 8a had the highest antiviral activity, with an EC50
of 3.6 µM against TK+ VZV strain, decreasing to an EC50 of 7.8 µM against TK- strain. Interestingly,
molecule 7d, substituted on nitrogen and oxygen by triazole rings, displayed similar antiviral activities
against TK+ and TK- VZV strains (with respective EC50 of 11.3 and 10.8 µM). This could suggest that
N,O-triazole substitution on dihydropyrimidinone leads to molecules whose antiviral activities are
unaffected by the degree of thymidine kinase resistance. Moreover, for the active compounds, the
replacement of the benzyl group (7a) by 4-nitrobenzyl (8a) improved the antiviral activities against
TK+ VZV strains and decreased considerably the cell-growth inhibition. Unfortunately, molecule 8d
bearing 4-NO2 (like 8a) and N,O-triazole substituted (like 7d) displayed no antiviral activity.
All compounds were also tested against cytomegalovirus in human embryonic lung (HEL) cells
(HCMV) [AD-169 and Davis strain]. None of the tested compounds exhibited measurable antiviral
activity against HCMV. These negative results, correlated to the activity found against VZV could
suggest a selectivity of dihydropyrimidinone/1,2,3-triazole hybrid molecules into the herpesviridae
family against VZV. This phenomenon was already described for other antiviral molecules, such as
the bicyclic furanopyrimidine nucleosides FV-100 [17]. To confirm these promising results,
investigations on dihydropyrimidinone/1,2,3-triazole hybrid molecules are actually in progress.
Conclusion
New dihydropyrimidinone derivatives have been synthesized and evaluated for their activity against
varicella-zoster virus. Four out of the tested compounds showed interesting antiviral activities against
VZV TK+ strains at EC50 as low as 3.6 µM without measurable cell-growth inhibition. However, only
slight decreases in antiviral activities against VZV TK- strains were observed. The easy and
economical synthetic protocol described herein offers a new approach to developing this new class of
hybrid molecules as novel anti varicella-zoster virus agents.
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Experimental
Chemistry
General
1
Melting points were determined on Büchi B-540 and are uncorrected. 300 MHz H NMR spectra
13
(reference CDCl3 δ = 7.26, DMSO-d6 δ = 2.50) and 75 MHz C NMR spectra (reference CDCl3 δ =
77.0, DMSO-d6 δ = 39.7) were recorded on a Bruker ARX at the Faculty of Sciences, University
Autonoma, Madrid, Spain. The following adsorbent was used for column chromatography: silica gel
60 (Merck, particle size 0.063-0.200 mm, 70-230 mesh ASTM). TLC was performed on 5 cm x 10 cm
aluminium plates coated with silica gel 60F-254 (Merck) in an appropriate eluent. HRMS was carried
out at the Spectropole, Faculté des Sciences et Techniques de Saint-Jérôme, Marseille. HRMS spectra
were recorded on a QStar Elite (Applied Biosystems SCIEX) spectrometer. PEG was a matrix for
HRMS. Microwave reactions were performed with a Biotage® Initiator Microwave oven using 10-20
mL sealed vials; temperatures were measured with an IR-sensor and reaction times are given as hold
times.
General procedure for the synthesis of the 5-acetyl-3,4-dihydro-6-methyl-4-arylpyrimidin-2(1H)-ones 1a-d
To a mixture of 1.50 g (15 mmol) of acetylacetone, 0.90 g (15 mmol) of urea and of substituted benzaldehyde
(15 mmol) in ethanol (20 mL), four drops of HCl (37%) were added as catalyst. The mixture was irradiated in
the microwave oven for 10 to 15 min at 100 °C. The crude product precipitated after cooling was filtered,
washed with ethanol (50%), and then recrystallized in ethanol.
5-Acetyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one 1a:
1
Yield 64%, white solid, mp 235 °C. H NMR (DMSO-d6, 300 MHz) δ = 9.14 (s, 1H, NH), 7.77 (s, 1H, NH),
7.11 (m, 5H, 5 HAr), 5.19 (d, 1H, J = 4.0 Hz, CH), 2.24 (s, 3H, CH3), 2.06 (s, 3H, CH3) ppm. 13C NMR (DMSO-
d6, 75 MHz) δ = 194.3, 152.1, 148.1, 144.2, 128.5, 128.5, 127.3, 126.5, 126.5, 109.5, 53.7, 30.2, 18.8 ppm.
HRMS: calcd. for C13H14N2O2 [M + H+] 230.1102; found 230.1105.
5-Acetyl-4-(2,5-dimethoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one 1b:
1
Yield 79%, white solid, mp 251 °C. H NMR (DMSO-d6, 300 MHz) δ = 9.14 (s, 1H, NH), 7.34 (s, 1H, NH),
6.92-6.97 (m, 1H, HAr), 6.79-6.84 (m,1H, HAr), 6.57 (d, 1H, J = 3.0 Hz, HAr), 5.52 (d, 1H, J = 3.2 Hz, CH), 3.77
(s, 3H, OCH3), 3.65 (s, 3H, OCH3), 2.28 (s, 3H, CH3), 2.03 (s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz)
δ = 194.6, 153.3, 152.3, 150.5, 148.2, 132.5, 113.9, 112.4, 112.3, 108.0, 56.1, 55.4, 49.0, 29.8, 18.7 ppm.
HRMS: calcd. for C15H18N2O4 [M + H+] 290.1261; Found 290.1271.
5-Acetyl-4-(4-dimethylaminophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one 1c:
1
Yield 70%, white solid, mp 213 °C. H NMR (DMSO-d6, 300 MHz) δ = 9.10 (s, 1H, NH), 7.69 (s, 1H, NH),
7.06 (d, 2H, J = 8.2 Hz, 2 HAr), 6.78 (br, 2H, 2 HAr), 5.14 (d, 1H, J = 3.0 Hz, CH), 2.88 (s, 6H, N(CH3)2), 2.26 (s,
3H, CH3), 2.05 (s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ = 194.5, 156.7, 154.3, 152.1, 149.8, 147.4,
131.9, 127.2, 112.3, 109.5, 102.1, 53.6, 30.7, 30.7, 18.7 ppm. Anal. Calcd. for C15H19N3O2: C 65.91; H 7.01; N
15.37. Found: C 65.85; H 7.11; N 15.48.
5-Acetyl-4-(4-hydroxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one 1d:
1
Yield 94%, white solid, mp 232 °C. H NMR (DMSO-d6, 300 MHz) δ = 9.35 (s, 1H, OH), 9.09 (s, 1H, NH),
7.69 (s, 1H, NH), 7.67 (d, 2H, J = 8.4 Hz, 2 HAr), 7.01 (d, 2H, J = 8.4 Hz, 2 HAr), 5.12 (d, 1H, J = 4.0 Hz, CH),
2.25 (s, 3H, CH3), 2.04 (s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ = 194.5, 156.6, 152.1, 147.5, 134.7,
127.6, 127.6, 115.1, 115.1, 109.6, 53.5, 30.0, 18.8 ppm. Anal. Calcd. for C13H14N2O3: C 63.41; H 5.69; N 11.38.
Found: C 63.50; H 5.68; N 11.35. HRMS: Calcd. for C13H14N2O3 [M + H+] 246.1004; Found 246.1018.
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General procedure for the synthesis of the mono- and dialkylated 5-acetyl-3,4-dihydro-6-methyl-4-aryl
pyrimidin-2(1H)-ones 2a-d and dialkylated 3d respectively.
5-Acetyl-3,4-dihydro-6-methyl-4-arylpyrimidin-2(1H)-ones 1a-d (1 mmol) and tBuOK (2.2 equiv, 2.2 mmol,
247 mg) were dissolved in dry DMF (2.5 mL). The mixture was stirred for 15 min at room temperature and
propargyl bromide (2.2 equiv, 2.2 mmol, 0.17 mL) was added dropwise. The mixture was irradiated in the
microwave oven at 100 °C for 10 min. The reaction mixture was diluted with water (20 mL) and extracted with
ethyl acetate (3 × 20 mL). The organic phase was dried over Na2SO4, evaporated under vacuum and the crude
product was purified by column chromatography using hexane/acetate (90:10, v/v) as eluent.
5-Acetyl-6-methyl-4-phenyl-1-(prop-2-yn-1-yl)-3,4-dihydropyrimidin-2(1H)-one 2a:
Yield 80%, yellow solid, mp 151 °C. 1H NMR (DMSO-d6, 300 MHz) δ = 8.13 (s, 1H, NH), 7.27-7.32 (m, 5H, 5
HAr), 5.22 (s, 1H, CH), 4.39-4.62 (m, 2H, CH2), 3.26 (s, 1H, CH), 2.53 (s, 3H, CH3), 2.09 (s, 3H, CH3) ppm. 13
C
NMR (DMSO-d6, 75 MHz) δ = 196.1, 151.9, 147.3, 143.0, 128.6, 128.6, 127.7, 126.5, 126.5, 113.2, 80.3, 74.3,
53.0, 31.7, 30.3, 16.1. HRMS: Calcd. for C16H16N2O2 [M + H+] 269.1285 found 269.1285.
5-Acetyl-4-(2,5-dimethoxyphenyl)-6-methyl-1-(prop-2-yn-1-yl)-3,4-dihydropyrimidin-2(1H)-one 2b:
Yield 85%, white solid, mp 98-100 °C. 1H NMR (DMSO-d6, 300 MHz) δ = 7.80 (s, 1H, NH), 6.65-6.97 (m, 2H,
2 HAr), 6.62-6.64 (s, 1H, HAr), 5.49 (s, 1H, CH), 4.34-4.67 (m, 2H, CH2), 3.75 (s, 3H, OCH3), 3.65 (s, 3H,
OCH3), 3.28 (s, 1H, CH), 2.50 (s, 3H, CH3), 2.08 (s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ = 196.3,
153.2, 152.3, 150.1, 146.4, 131.2, 113.3, 112.4, 112.1, 111.9, 80.7, 74.1, 55.8, 55.3, 47.7, 31.4, 29.6, 15.7.
HRMS: Calcd. for C18H20N2O4 [M + H+ + Na+] 351.1315 found 351.1315.
5-Acetyl-4-(4-dimethylaminophenyl)-6-methyl-1-(prop-2-yn-1-yl)-3,4-dihydropyrimidin-2(1H)-one 2c:
Yield 85%, yellow solid, mp 91 °C. 1H NMR (DMSO-d6, 300 MHz) δ = 7.99 (d, 1H, J = 3.2 Hz, NH), 7.06 (d,
2H, J = 8.5 Hz, 2 HAr), 6.63 (d, 2H, J = 8.5 Hz, 2 HAr), 5.08 (d, 1H, J = 3.0 Hz, CH), 4.43-4.57 (m, 2H, CH2),
3.29 (s, 1H, CH), 2.85 (s, 6H , N(CH3)2), 2.52 (s, 3H, CH3), 2.05 (s, 3H ,CH3) ppm. 13C NMR (DMSO-d6, 75
MHz) δ = 196.3, 151.9, 149.9, 146.6, 130.4, 127.4, 127.4, 113.3, 112.3, 112.3, 80.4, 74.3, 52.8, 41.3, 41.3, 31.5,
30.1, 15.9 ppm. HRMS: Calcd. for C18H21N3O2 [M + H+] 312.1707 found 312.1707.
5-Acetyl-6-methyl-4-[4-(prop-2-yn-1-yloxy)phenyl]-3,4-dihydropyrimidin-2(1H)-one 2d:
1
Yield 55%, white solid, mp 143 °C. H NMR (DMSO-d6, 300 MHz) δ = 9.14 (s, 1H, NH), 7.75 (s, 1H, NH),
7.16 (d, 2H, J = 7.0 Hz, 2 HAr), 6.92 (d, 2H, J = 7.1 Hz, 2 HAr), 5.19 (s, 1H, CH), 4.74 (s, 2H, CH2), 3.53 (s, 1H,
CH), 2.26 (s, 3H, CH3), 2.07 (s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ = 194.3, 156.4, 152.0, 147.8,
137.1, 127.6, 127.6, 114.8, 114.8, 109.6, 79.3, 78.1, 55.4, 53.3, 30.2, 18.8. HRMS: Calcd. for C16H16N2O3 [M +
H+] 285.1234 found 285.1235.
5-Acetyl-6-methyl-1-(prop-2-yn-1-yl)-4-[4-(prop-2-yn-1-yloxy)phenyl]-3,4-dihydropyrimidin-2(1H)-one
3d.
1
Yield 35%, yellow solid, mp 125 °C. H NMR (DMSO-d6, 300 MHz) δ = 8.11 (s, 1H, NH), 7.18 (d, 2H, J = 7.9
Hz, 2 HAr), 6.91 (d, 2H, J = 8.1 Hz, 2 HAr), 5.17 (s, 1H, CH), 4.76 (s, 2H, CH2), 4.40-4.60 (m, 2H, CH2), 3.53 (s,
1H, CH), 3.28 (s, 1H, CH), 2.53 (s, 3H, CH3), 2.08 (s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ = 196.1,
156.7, 151.9, 147.2, 135.9, 127.8, 127.8, 114.9, 114.9, 113.3, 80.4, 79.2, 78.2, 74.3, 55.4, 52.5, 30.7, 30.3, 16.0
ppm. HRMS: Calcd. for C19H18N2O3 [M + H+] 323.1390 found 323.1388.
General procedure for the synthesis of the di- and trialkylated 5-acetyl-3,4-dihydro-6-methyl-4-aryl
pyrimidin-2(1H)-ones 3a-c and trialkylated 4d respectively.
5-Acetyl-3,4-dihydro-6-methyl-4-aryl-2(1H)-pyrimidinones 1a-d (1 mmol) were dissolved in dry DMF (2.5 mL)
at 0 °C and NaH (2.2 equiv, 2.2 mmol, 53 mg) was added and stirred for 15 min at room temperature.
Afterwards, propargyl bromide (2.2 equiv, 2.2 mmol, 0.17 mL) was added dropwise and the mixture was
irradiated in the microwave oven at 100 °C for 5 min. The reaction mixture was diluted with water (20 mL),
extracted with ethyl acetate (3 × 20 mL) and the organic layer was dried over Na2SO4 and evaporated under
vacuum. The crude product was purified by column chromatography using hexane/acetate (90:10, v/v) as eluent.
5-Acetyl-6-methyl-4-phenyl-1,3-di(prop-2-yn-1-yl)-3,4-dihydropyrimidin-2(1H)-one 3a:
Yield 99%, yellow solid, mp 81 °C. 1H NMR (CDCl3, 300 MHz) δ = 7.30 (s, 5H, 5 HAr), 5.61 (s, 1H, CH), 4.72-
4.87 (m, 2H, CH2), 4.41-4.49 (m, 1H, CH), 3.47-3.55 (m, 1H, CH), 2.59 (s, 3H, CH3), 2.34-2.37 (m, 2H, CH2),
9

ACCEPTED MANUSCRIPT
2.20 (s, 3H, CH3) ppm. 13C NMR (CDCl3, 75 MHz) δ = 196.3, 151.8, 146.1, 138.3, 129.0, 129.0, 128.6, 127.3,
127.3, 114.6, 79.0, 77.7, 73.6, 72.5, 57.4, 34.8, 33.2, 30.6, 16.6 ppm. HRMS: Calcd. for C19H18N2O2 [M + H+]
307.1441 found 307.1441.
5-Acetyl-4-(2,5-dimethoxyphenyl)-6-methyl-1,3-di(prop-2-yn-1-yl)-3,4-dihydropyrimidin-2(1H)-one 3b:
Yield 98%, brown solid, mp 159 °C. 1H NMR (CDCl3, 300 MHz) δ = 6.75-6.81 (m, 3H, HAr), 5.96 (s, 1H, CH),
4.66-4.82 (m, 2H, CH2), 4.35-4.45 (m, 1H, CH), 3.82 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.61 (d, 1H, J = 2.4
Hz, CH), 2.54 (s, 3H, CH3), 2.22-2.32 (m, 2H, CH2), 2.18 (s, 3H, CH3) ppm. 13C NMR (CDCl3, 75 MHz) δ =
197.1, 154.1, 153.8, 150.7, 145.6, 128.0, 114.5, 114.1, 114.0, 111.7, 79.4, 78.8, 72.5, 71.8, 55.8, 55.8, 51.9, 35.5,
33.1, 29.7, 16.2 ppm. HRMS: Calcd. for C21H22N2O4 [M + H+] 367.1652 found 367.1653.
5-Acetyl-4-[4-(dimethylamino)phenyl]-6-methyl-1,3-di(prop-2-yn-1-yl)-3,4-dihydropyrimidin-2(1H)-one
3c:
1
Yield 98%, yellow solid, mp 161 °C. H NMR (CDCl3, 300 MHz) δ = 7.25-7.28 (m, 2H, 2 HAr), 6.72-6.78 (m,
2H, 2 HAr), 5.58 (s, 1H, CH), 4.84-4.96 (m, 2H, CH2), 4.57 (d, 1H, J = 2.2 Hz, CH), 3.59-3.65 (m, 1H, CH), 3.04
(s, 6H, N(CH3)2), 2.70 (s, 3H, CH3), 2.46 (d, 2H, J = 1.3 Hz, CH2), 2.27 (s, 3H, CH3) ppm. 13C NMR (CDCl3, 75
MHz) δ = 196.8, 151.9, 150.7, 145.5, 128.5, 128.5, 125.5, 114.6, 112.5, 112.5, 79.3, 78.2, 73.3, 72.4, 57.2, 40.4,
40.4, 34.47, 33.1, 30.4, 16.5 ppm. HRMS: Calcd. for C21H23N3O2 [M + H+] 350.1863 found 350.1861.
5-Acetyl-6-methyl-1,3-di(prop-2-yn-1-yl)-4-[4-(prop-2-ynyloxy)phenyl]-3,4-dihydropyrimidin-2(1H)-one
4d:
1
Yield 70%, yellow solid, mp 61 °C. H NMR (CDCl3, 300 MHz) δ = 7.22-7.27 (m, 2H, 2 HAr), 6.89-6.98 (m,
2H, 2 HAr), 5.56 (s, 1H, CH), 4.71-4.85 (m, 2H, CH2), 4.66 (d, 2H, J = 2.3 Hz, CH2), 4.38-4.48 (m, 1H, CH),
3.45-3.55 (m, 1H, CH), 2.59 (s, 3H, CH3), 2.52 (s, 1H, CH), 2.36 (br, 2H, CH2), 2.19 (s, 3H, CH3) ppm. 13C
NMR (CDCl3, 75 MHz) δ = 196.3, 162.5, 157.7, 151.8, 145.9, 131.4, 128.7, 128.7, 115.3, 115.3, 114.7, 79.1,
78.3, 75.9, 73.7, 72.6, 56.9, 55.8, 36.5, 31.4, 30.5, 16.6 ppm. HRMS: Calcd. for C22H20N2O3 [M + H+] 361.1547
found 361.1547.
General procedure for the synthesis of the mono-1, 2, 3-triazole analogues of DHPMs 5a-d, 6a-d:
A solution of propargylated compounds 2a-d (1 mmol), sodium azide (3 equiv, 3 mmol, 200 mg), alkyl halide (3
equiv, 3 mmol), Et3N (1.5 equiv, 1.5 mmol, 0.2 mL), CuI (0.1 equiv, 0.1 mmol, 19 mg) in water/acetonitrile
mixture (10 mL, v/v), was irradiated in the microwave oven at 100 °C for 3 min. The reaction mixture was
diluted with 25 mL of water at 0 °C and extracted with ethyl acetate (3 x 30 mL). The combined organic layers
were dried with Na2SO4, concentrated and the crude product was purified by column chromatography using
CH2Cl2/MeOH mixture (99:1, v/v) as eluent.
5-Acetyl-[1-(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one
5a:
1
Yield 98%, yellow solid, mp 191 °C. H NMR (DMSO-d6, 300 MHz) δ = 8.06 (s,1H, HAr), 7.86 (s, 1H, NH),
7.19-7.34 (m, 10H, 10 HAr), 5.55 (s, 2H, CH2), 5.19 (s, 1H, CH), 4.84-5.00 (m, 2H, CH2), 2.49 (s, 3H, CH3), 2.07
(s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ = 197.6, 153.0, 148.7, 143.2, 136.0, 129.3, 129.3, 129.1,
129.1, 128.9, 128.9, 128.4, 128.4, 128.3, 126.8, 126.8, 123.8, 113.7, 53.4, 51.8, 37.1, 30.7, 17.1 ppm. HRMS:
Calcd. for C23H23N5O2 [M + H+] 402.1925; found 402.1924.
5-Acetyl-6-methyl-1-{[1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-4-phenyl-3,4-dihydropyrimidin-
2(1H)-one 6a:
1
Yield 97%, yellow solid, mp 153 °C. H NMR (DMSO-d6, 300 MHz) δ = 8.21 (d, 2H, J = 8.4 Hz, 2 HAr), 8.08
(d, 1H, J = 2.7 Hz, HAr), 7.97 (s, 1H, NH), 7.52 (d, 2H, J = 8.3 Hz, HAr), 7.20 (m, 5H, 5 HAr), 5.74 (s, 2H, CH2),
5.20 (s, 1H, CH), 4.81-5.01 (m, 2H, CH2), 2.53 (s, 3H, CH3), 2.07 (s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75
MHz) δ = 196.6, 152.8, 148.5, 147.7, 145.1, 143.8, 143.8, 129.6, 129.6, 129.6, 129.0, 129.0, 128.0, 127.0, 127.0,
124.4, 124.4, 113.3, 53.6, 52.3, 38.0, 30.9, 17.1 ppm. HRMS: Calcd. for C23H22N6O4 [M + H+] 447.1773; found
447.1773.
5-Acetyl-1-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-4-(2,5-dimethoxyphenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one 5b:
10

ACCEPTED MANUSCRIPT
1
Yield 98%, yellow solid, mp 119 °C. H NMR (DMSO-d6, 300 MHz) δ = 7.91 (s, 1H, HAr), 7.67 (s, 1H, NH),
7.27-7.36 (m, 5H, 5 HAr), 6.90 (d, 1H, J = 2.9 Hz, HAr), 6.78 (d, 1H, J = 2.9 Hz, HAr), 6.55 (d, 1H, J = 2.9 Hz,
HAr), 5.54 (s, 2H, CH2), 5.48 (s, 1H, CH), 4.79-5.01 (m, 2H, CH2), 3.70 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 2.47
(s, 3H, CH3), 2.04 (s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ = 197.5, 161.8, 152.9, 151.2, 147.0,
135.4, 131.1, 129.1, 129.1, 129.1, 128.7, 128.7, 128.7, 128.2, 128.2, 113.0, 112.2, 112.0, 55.7, 55.4, 52.9, 47.8,
37.2, 29.5, 16.2 ppm. HRMS: Calcd. for C25H27N5O4 [M + H+] 462.2136; found 462.2136.
5-Acetyl-1-[(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl]-4-(2,5-dimethoxyphenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one 6b:
Yield 98%, yellow solid, mp 95 °C. 1H NMR (DMSO-d6, 300 MHz) δ = 8.20 (d, 2H, J = 8.5 Hz, 2 HAr), 8.02 (s,
1H, HAr), 7.70 (d, 1H, J = 3.0 Hz, NH), 7.48 (d, 2H, J = 8.4 Hz, 2 HAr), 6.90 (d, 1H, J = 8.9 Hz, HAr), 6.77 (d,
1H, J = 2.9 Hz, HAr), 6.54 (d, 1H, J = 2.9 Hz, HAr), 5.73-5.75 (d, 2H, J = 3.5 Hz, CH2), 5.48 (s, 1H, CH), 4.81-
4.98 (m, 2H, CH2), 3.71 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 2.49 (s, 3H, CH3), 2.07 (s, 3H, CH3) ppm. 13C NMR
(DMSO-d6, 75 MHz) δ = 197.4, 152.9, 152.9, 150.1, 147.2, 142.9, 130.9, 128.9, 128.9, 128.9, 128.9, 123.8,
123.8, 123.8, 123.8, 113.0, 112.2, 112.0, 55.7, 55.2, 52.0, 47.9, 37.2, 29.5, 16.3. HRMS: Calcd. for C25H26N6O6
[M + H+] 507.1987 found 507.1988.
5-Acetyl-1-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-4-[4-(dimethylamino)phenyl]-6-methyl-3,4-
dihydropyrimidin-2(1H)-one 5c:
1
Yield 96%, yellow solid, mp 101 °C. H NMR (DMSO-d6, 300 MHz) δ = 7.92 (s, 1H, HAr), 7.83 (s, 1H, NH),
7.28-7.33 (m, 5H, 5 HAr ), 6.99 (d, 2H, J = 8.4 Hz, 2 HAr), 6.57 (d, 2H, J = 8.6 Hz, 2 HAr), 5.56 (s, 2H, CH2), 5.07
(s, 1H, CH), 4.78-4.98 (m, 2H, CH2), 2.84 (s, 6H, N(CH3)2), 2.49 (s, 3H, CH3), 2.03 (s, 3H, CH3) ppm. 13C NMR
(DMSO-d6, 75 MHz) δ = 196.9, 152.9, 150.4, 147.8, 145.1, 136.5, 131.2, 129.2, 129.2, 128.6, 128.3, 128.3,
127.9, 126.7, 123.9, 113.4, 112.7, 112.7, 53.3, 53.2, 40.6, 40.6, 37.2, 31.2, 16.9 ppm. HRMS: Calcd. for
C25H28N6O2 [M + H+] 445.2347; found 445.2347.
5-Acetyl-1-[(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl]methyl]-4-[4-(dimethylamino)phenyl]-6-methyl-3,4-
dihydropyrimidin-2(1H)-one 6a:
1
Yield 95%, yellow solid, mp 105 °C. H NMR (DMSO-d6, 300 MHz) δ = 8.25 (d, 1H, J = 8.6 Hz, HAr), 8.20 (d,
2H, J = 7.7 Hz, 2 HAr), 8.05-8.08 (m, 1H, NH), 7.91 (d, 2H, J = 7.7 Hz, 2 HAr), 7.47 (d, 2H, J = 7.7 Hz, 2 HAr),
6.97 (d, 1H, J = 7.7 Hz, HAr), 6.56 (d, 1H, J = 7.7 Hz, HAr), 5.72 (s, 2H, CH2), 5.05 (s, 1H, CH), 4.79-4.97 (m,
2H, CH2), 2.80 (s, 6H, N(CH3)2), 2.47 (s, 3H, CH3), 2.00 (s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ =
197.4, 152.9, 150.4, 147.9, 145.0, 136.3, 131.0, 129.3, 129.3, 129.3, 128.7, 128.3, 128.3, 128.3, 127.8, 123.8,
113.6, 112.7, 53.3, 53.2, 40.5, 40.5, 31.1, 30.5, 16.9 ppm. HRMS: Calcd. for C25H27N7O4 [M + H+] 512.2017
found 512.2034.
5-Acetyl-4-{4-[(1-benzyl-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-6-methyl-3,4-dihydropyrimidin-2(1H)-one
5d:
Yield 99%, white solid, mp 215 °C. 1H NMR (DMSO-d6, 300 MHz) δ = 9.15 (s, 1H, NH), 8.28 (s, 1H, HAr), 7.77
(s, 1H, NH), 7.29-7.39 (m, 5H, 5 HAr), 7.15 (d, 2H, J = 8.6 Hz, 2 HAr), 6.97 (d, 2H, J = 8.6 Hz, 2 HAr), 5.61 (s,
2H, CH2), 5.21 (d, 1H, J = 3.2 Hz, CH), 5.11 (s, 2H, CH2), 2.28 (s, 3H, CH3), 2.08 (s, 3H, CH3) ppm. 13C NMR
(DMSO-d6, 75 MHz) δ = 195.5, 157.7, 152.7, 148.5, 143.5, 137.0, 136.2, 129.3, 129.3, 129.3, 128.8, 128.4,
128.4, 128.4, 128.1, 125.1, 115.1, 110.2, 61.4, 53.7, 53.4, 30.6, 19.3 ppm. HRMS: Calcd. for C23H23N5O3 [M +
H+] 418.1874; found 418.1873.
5-Acetyl-4-{4-[(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl]methoxy)phenyl}-6-methyl-3,4-dihydropyrimidin-
2(1H)-one 6d:
1
Yield 97%, yellow Solid, mp 181 °C. H NMR (DMSO-d6, 300 MHz) δ = 9.14 (s, 1H, NH), 8.35 (s, 1H, HAr),
8.22 (d, 2H, J = 8.8 Hz, 2 HAr), 7.76 (s, 1H, NH), 7.52 (d, 2H, J = 8.8 Hz, 2 HAr), 7.14 (d, 2H, J = 8.6 Hz, 2 HAr),
6.96 (d, 2H, J = 8.6 Hz, 2 HAr), 5.79 (s, 2H, CH2), 5.19 (s, 1H, CH), 5.12 (s, 2H, CH2), 2.27 (s, 3H, CH3), 2.07 (s,
3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ = 194.8, 157.7, 152.6, 148.4, 147.8, 143.9, 143.7, 137.3, 129.6,
129.6, 128.1, 128.1, 125.5, 124.4, 124.4, 115.1, 115.1, 110.1, 61.5, 53.7, 52.4, 31.2, 19.3 ppm. HRMS: Calcd.
for C23H22N6O5 [M + H+] 463.1724 found 463.1724.
General procedure for the synthesis of the bis-1, 2, 3-triazole analogues of DHPMs 7a-d, 8a-d:
11

ACCEPTED MANUSCRIPT
A solution of bis-propargylated compounds 3a-d (1 equiv), sodium azide (5 equiv, 5 mmol, 325 mg), alkyl
halide (5 equiv), Et3N (1.5 equiv, 1.5 mmol, 0.2 mL), CuI (0.1 equiv, 0.1 mmol, 19 mg) in water/acetonitrile
mixture (10 mL, v/v) was irradiated in the microwave oven at 100 °C for 5 min. The reaction mixture was
diluted with 25 mL of water at 0 °C and extracted with ethyl acetate (3 x 25 mL). The combined organic layers
were dried with Na2SO4, concentrated and the crude product was purified by column chromatography using
CH2Cl2/MeOH mixture (99:1, v/v) as eluent.
5-Acetyl-1,3-bis[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-
one 7a:
1
Yield 96%, yellow Solid, mp 59 °C. H NMR (DMSO-d6, 300 MHz) δ = 8.02 (s, 1H, HAr), 7.99 (s, 1H, HAr),
7.15-7.35 (m, 15H, 15 HAr), 5.57 (s, 2H, CH2), 5.54 (s, 2H, CH2), 5.31 (s, 1H, CH), 5.15 (d, 1H, J = 15.2 Hz,
CH2), 4.83-4.96 (m, 2H, CH2), 3.97 (d, 1H, J = 15.2 Hz, CH2), 2.49 (s, 3H, CH3), 2.03 (s, 3H, CH3) ppm. 13C
NMR (DMSO-d6, 75 MHz) δ = 196.2, 166.4, 156.4, 152.6, 150.8, 147.5, 144.5, 143.5, 142.9, 140.5, 139.1,
136.4, 134.7, 129.4, 129.2, 129.2, 128.5, 128.5, 128.3, 128.3, 127.4, 124.4, 124.2, 122.7, 121.9, 114.5, 58.0,
53.3, 53.3, 41.0, 39.1, 30.1, 17.3 ppm. HRMS: Calcd. for C33H32N8O2 [M + H+] 573.2721 found 573.2719.
5-Acetyl-6-methyl-1,3-bis{[1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-4-phenyl-3,4-
dihydropyrimidin-2(1H)-one 8a:
Yield 95, yellow solid, mp 80 °C. 1H NMR (CDCl3, 300 MHz) δ = 7.96-8.10 (m, 4H, 4 HAr), 7.38 (s, 1H, HAr),
7.21-7.28 (m, 5H, 5 HAr), 7.14 (s, 1H, HAr), 7.07 (m, 4H, 4 HAr), 5.45 (s, 4H, 2 CH2), 5.29 (s, 1H, CH), 4.83-499
(m, 3H, CH2, H-CH2), 4.11 (d, 1H, J = 15.3 Hz, CH2), 2.43 (s, 3H, CH3), 1.99 (s, 3H, CH3) ppm. 13C NMR
(CDCl3, 75 MHz) δ = 196.3, 153.1, 147.8, 146.6, 145.4, 145.1, 141.5, 139.9, 128.9, 128.9, 128.9, 128.6, 128.6
128.6 128.6, 127.3, 127.3, 127.3, 124.3, 124.3, 124.3, 124.3, 124.3, 123.7, 122.9, 114.8, 59.0, 53.2, 53.2, 41.2,
39.2, 30.8, 17.4 ppm. HRMS: Calcd. for C33H30N10O6 [M + H+] 663.2423 found 663.2421.
5-Acetyl-1,3-bis[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-4-(2,5-dimethoxyphenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one 7b:
Yield 98, yellow Solid, mp 99 °C. 1H NMR (DMSO-d6, 300 MHz) δ = 7.99 (s, 1H, HAr), 7.95 (s, 1H, HAr), 7.25-
7.36 (m, 10H, 10 HAr), 6.78-6.89 (m, 2H, 2 HAr), 6.52 (s, 1H, HAr), 5.62 (s, 1H, CH), 5.55 (s, 4H, 2 CH2), 4.06-
5.11 (d, 1H, J = 16.1 Hz, CH2), 4.81-4.99 (m, 2H, CH2), 3.94-3.99 (d, 1H, J = 15.3 Hz, CH2), 3.60 (s, 3H,
OCH3), 3.56 (s, 3H, OCH3), 2.39 (s, 3H, CH3), 1.92 (s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ =
196.1, 153.4, 152.2, 150.0, 145.4, 136.1, 128.9, 128.7, 128.7, 128.7, 128.7, 128.7, 127.9, 127.9, 127.9, 127.9,
127.8, 127.8, 127.8, 127.8, 123.8, 123.5, 113.6, 113.4, 112.8, 112.4, 55.7, 55.2, 52.7, 52.7, 52.0, 40.5, 38.4, 29.3,
16.2 ppm. HRMS: Calcd. for C35H36N8O4 [M + H+] 633.2932 found 633.2933.
5-Acetyl-4-(2,5-dimethoxyphenyl)-6-methyl-1,3-bis{[1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-3,4-
dihydropyrimidin-2(1H)-one 8b:
1
Yield 96, yellow solid, mp 113 °C. H NMR (DMSO-d6, 300 MHz) δ = 8.20-8.23 (m, 4H, 4 HAr), 8.09 (s, 1H,
HAr), 8.02 (s, 1H, HAr), 7.46-7.52 (m, 4H, 4 HAr), 6.87 (dd, 1H, J = 2.7, 8.9 Hz, HAr), 6.76-6.80 (m, 1H, HAr),
6.52 (d, 1H, J = 2.5 Hz, HAr), 5.74 (s, 4H, 2 CH2), 5.67 (s, 1H, CH), 5.09 (d, 1H, J = 16.0 Hz, CH2), 4.85-4.99
(m, 2H, CH2), 4.02 (d, 1H, J = 15.2 Hz, CH2), 3.65 (s, 3H, OCH3), 3.57 (s, 3H, OCH3), 2.41 (s, 3H, CH3), 2.07
(s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ = 197.3, 153.1, 152.4, 149.9, 147.1, 147.1, 145.6, 142.9,
142.9, 128.9, 128.9, 128.9, 128.9, 128.9, 128.9, 128.9, 128.6, 123.7, 123.7, 123.7, 123.7, 123.7, 123.7, 113.8,
113.1, 112.4, 55.6, 55.1, 52.6, 52.1, 51.9, 40.8, 38.1, 30.5, 16.2 ppm. HRMS: Calcd. for C35H34N10O8 [M + H+]
723.2634 found 723.2631.
5-Acetyl-1,3-bis[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-4-[4-(dimethylamino)phenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one 7c:
1
Yield 97%, yellow solid, mp 113 °C. H NMR (DMSO-d6, 300 MHz) δ = 1.96 (s, 3H, CH3), 2.07 (s, 1H, CH2),
2.49 (s, 3H, CH3), 2.84 (s, 6H, N(CH3)2), 3.93 (d, 1H, J = 14.9 Hz, CH2), 4.82-4.94 (m, 2H, CH2), 5.16 (s, 1H,
CH), 5.55 (s, 2H, CH2), 5.58 (s, 2H, CH2), 6.52 (d, 2H, J = 8.5 Hz, 2 HAr), 7.00 (d, 2H, J = 8.4 Hz, 2 HAr), 7.25-
7.35 (m, 10H, 10 HAr), 8.00 (s, 1H, HAr), 8.05 (s, 1H, HAr) ppm. 13C NMR (DMSO-d6, 75 MHz) δ = 196.4,
152.6, 150.6, 146.7, 136.5, 136.4, 129.3, 129.2, 129.2, 129.2, 129.2, 129.2, 129.2, 128.7, 128.6, 128.6, 128.5,
128.4, 128.4, 128.4, 128.3, 128.3, 128.2, 127.4, 114.3, 112.6, 112.5, 111.5, 57.8, 53.3, 53.3, 40.4, 39.2, 31.2,
17.1. HRMS: Calcd. for C35H37N9O2 [M + H+] 616.3143 found 616.3146.
5-Acetyl-4-[4-(dimethylamino)phenyl]-6-methyl-1,3-bis{[1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-
3,4-dihydropyrimidin-2(1H)-one 8c:
12

ACCEPTED MANUSCRIPT
Yield 94%, yellow solid, mp 121 °C. 1H NMR (CDCl3, 300 MHz) δ = 8.28 (d, 2H, J = 8.6 Hz, 2 HAr), 8.18-8.22
(m, 3H, 3 HAr), 7.96 (d, 2H, J = 8.6 Hz, 2 HAr), 7.53 (s, 1H, HAr), 7.32-7.36 (m, 2H, 2 HAr), 7.05 (d, 2H, J = 8.3
Hz, 2 HAr), 6.58 (d, 2H, J = 8.3 Hz, 2 HAr), 5.57 (s, 4H, 2 CH2), 5.25 (s, 1H, CH), 4.85-5.00 (m, 3H, H-(CH2),
4.27 (d, 1H, J = 14.9 Hz, CH2), CH2), 2.89 (s, 6H , N(CH3)2), 2.25 (s, 3H, CH3), 2.05 (s, 3H, CH3) ppm. 13C
NMR (CDCl3, 75 MHz) δ = 195.8, 166.0, 152.0, 147.1, 145.0, 140.5, 138.3, 138.1, 138.1, 127.6, 127.6, 127.6,
127.6, 127.6, 126.6, 123.3, 123.3, 123.3, 123.3, 122.9, 122.9, 122.9, 122.9, 122.9, 113.1, 113.1, 60.9, 57.9, 52.1,
52.1, 40.1, 39.4, 38.1, 21.7, 16.2 ppm. HRMS: Calcd. for C35H35N11O6 [M + H+] 706.2845 found 706.2850.
5-Acetyl-4-{4-[(1-benzyl-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-1-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-
6-methyl-3,4-dihydropyrimidin-2(1H)-one 7d:
1
Yield 99, yellow Solid, mp 169 °C. H NMR (DMSO-d6, 300 MHz) δ = 8.26 (s, 1H, HAr), 8.00 (d, 1H, J = 3.4
Hz, 1 HAr), 7.87 (s, 1H, NH), 7.25-7.36 (m, 10H, 10 HAr), 7.10 (d, 2H, J = 8.6 Hz, 2 HAr), 6.87-6.90 (d, 2H, J =
8.6 Hz, 2 HAr), 5.60 (s, 2H, CH2), 5.55 (s, 2H, CH2), 5.14 (d, 1H, J = 3.1 Hz, CH), 5.08 (s, 2H, CH2), 4.78-5.02
(m, 2H, CH2), 2.51 (s, 3H, CH3), 2.04 (s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ = 197.3, 157.8, 152.9,
148.4, 144.9, 143.5, 136.2, 136.2, 136.0, 129.3, 129.3, 129.3, 129.3, 129.3, 128.8, 128.8, 128.4, 128.4, 128.3,
128.3, 128.3, 128.3, 125.1, 123.8, 115.2, 113.5, 61.3, 60.5, 53.3, 52.9, 38,4, 31.1, 17.1 ppm. HRMS: Calcd. for
C33H32N8O3 [M + H+] 589.2670 found 589.2670.
5-Acetyl-4-{4-[(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-1-{[1-(4-nitrobenzyl)-1H-1,2,3-
triazol-4-yl]methyl}-6-methyl-3,4-dihydropyrimidin-2(1H)-one 8d:
Yield 99%, yellow Solid, mp 139 °C. 1H NMR (DMSO-d6, 300 MHz) δ = 8.33 (s, 1H, HAr), 8.19-8.24 (m, 4H, 4
HAr), 8.01 (d, 1H, J = 3.4 Hz, HAr), 7.99 (s, 1H, NH), 7.48-7.54 (m, 4H, 4 HAr), 7.11 (d, 2H, J = 8.6 Hz, 2 HAr),
6.88 (d, 2H, J = 8.6 Hz, 2 HAr), 5.79 (s, 2H, CH2), 5.75 (s, 2H, CH2), 5.15 (d, 1H, J = 3.1 Hz, CH), 5.10 (s, 2H,
CH2), 4.82-5.04 (m, 2H, CH2), 2.52 (s, 3H, CH3), 2.05 (s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ =
196.6, 157.9, 152.8, 148.2, 147.7, 145.1, 143.8, 143.6, 136.3, 129.5, 129.5, 129.5, 129.5, 129.5, 129.5, 128.4,
128.4, 125.5, 124.4, 124.4, 124.4, 124.4, 124.4, 124.4, 115.1, 113.3, 61.6, 55.4, 53.1, 52.4, 38.2, 31.2, 17.1
HRMS: Calcd. for C33H30N10O7 [M + H+] 679.2372 found 679.2371.
General procedure for the synthesis of tri-1,2,3-triazole analogues of DHPMs 9d and 10d
A mixture of O-N-1,N-3-tri-propargylated compound 4d (1 mmol), sodium azide (5 equiv, 5 mmol, 325 mg),
alkyl halide (5 equiv), Et3N (1.5 equiv, 1.5 mmol, 0.2 mL), CuI (0.1 equiv, 0.1 mmon, 19 mg) in 10 mL of
water/acetonitrile mixture (v/v) was irradiated in the microwave oven at 100 °C for 5 min. The reaction mixture
was diluted with 25 mL of water, and extracted with ethyl acetate (3 x 25 mL). The organic layer was dried over
Na2SO4, evaporated under vacuum and the crude product was purified by column chromatography using
CH2Cl2/MeOH mixture (99:1, v/v) as eluent.
5-Acetyl-4-{4-[(1-benzyl-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-1,3-bis[(1-benzyl-1H-1,2,3-triazol-4-
yl)methyl]-6-methyl-3,4-dihydropyrimidin-2(1H)-one 9d:
1
Yield 95%, yellow Solid, mp 81 °C. H NMR (DMSO-d6, 300 MHz) δ = 8.27 (s, 1H, HAr), 8.05 (s, 1H, HAr),
8.01 (s, 1H, HAr), 7.24-7.34 (m, 15H, 15 HAr), 7.11 (d, 2H, J = 8.2 Hz, 2 HAr), 6.83 (d, 2H, J = 8.2 Hz, 2 HAr),
5.61 (s, 2H, CH2), 5.57 (s, 2H, CH2), 5.55 (s, 2H, CH2), 5.25 (s, 1H, CH), 5.11 (d, 1H, J = 15.2 Hz, CH2), 5.08
(s, 2H, CH2), 4.83-4.95 (m, 2H, CH2), 3.95 (d, 1H, J = 15.2 Hz, CH2), 2.49 (s, 3H, CH3), 2.00 (s, 3H, CH3) ppm.
13C NMR (DMSO-d6, 75 MHz) δ = 196.1, 158.2, 152.8, 152.6, 147.7, 147.7, 147.1, 144.1, 143.8, 143.8, 143.8,
143.6, 133.0, 129.5, 129.5, 129.5, 129.5, 129.5, 129.3, 129.3, 129.3, 129.3, 129.0, 129.0, 125.0, 124.8, 124.4,
124.4, 124.4, 124.4, 124.4, 124.4, 115.2, 114.5, 61.5, 57.6, 55.4, 52.4, 52.4, 39.9, 39.7, 31.2, 17.3 ppm. HRMS:
Calcd. for C43H41N11O3 [M + H+] 760.3467 found 760.3469.
5-Acetyl-6-methyl-4-{4-[(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-1,3-bis{[1-(4-
nitrobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-3,4-dihydropyrimidin-2(1H)-one 10d:
Yield 96%, yellow solid, mp 119 °C. 1H NMR (DMSO-d6, 300 MHz) δ = 8.32 (s, 1H, HAr), 8.22-8.26 (m, 6H, 6
HAr), 8.19 (s, 1H, HAr), 8.11 (s, 1H, HAr), 7.45-7.56 (m, 6H, 6 HAr), 7.12 (d, 2H, J = 7.6 Hz, 2 HAr), 6.86 (d, 2H, J
= 7.8 Hz, 2 HAr), 5.79 (s, 2H, CH2), 5.76 (s, 2H, CH2), 5.74 (s, 2H, CH2), 5.28 (s, 1H, CH), 5.14-5.20 (d, 1H, J =
15.2 Hz, CH2), 5.10 (s, 2H, CH2), 4.87-4.95 (m, 2H, CH2), 4.00 (d, 1H, J = 15.2 Hz, CH2), 2.49 (s, 3H, CH3),
2.02 (s, 3H, CH3) ppm. 13C NMR (DMSO-d6, 75 MHz) δ = 195.5, 157.7, 152.1, 147.2, 147.2, 147.2, 147.1,
144.2,
13

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143.4, 143.3, 143.3, 143.3, 143.1, 132.5, 129.0, 129.0, 129.0, 129.0, 129.0, 128.8, 128.8, 128.8, 128.8, 128.5,
124.5, 124.3, 123.9, 123.9, 123.9, 123.9, 123.9, 123.8, 114.6, 113.9, 61.1, 57.1, 54.9, 51.9, 51.9, 39.7, 39.5, 30.7,
16.7 ppm. HRMS: Calcd. for C43H38N14O9 [M + H+] 895.3019 found 895.3021.
Antiviral activity assays
The antiviral assays were based on inhibition of virus-induced cytopathicity or plaque formation in human
embryonic lung (HEL) cells against varicella-zoster virus (VZV) (thymidine kinase wild-type (TK+) (Oka strain)
and TK-deficient (TK─) (07-1 strain) and against human cytomegalovirus (HCMV) AD-169 and Davis strains.
Confluent cell cultures in microtiter 96-well plates were infected with 100 (for human cytomegalovirus, HCMV)
or with 20 plates forming units (PFU) for VZV.
After 2 h adsorption, the viral inoculum was removed and the cell cultures were incubated with fresh medium in
the presence of varying concentrations of the test compounds. Viral plaque formation for VZV or viral
cytopathic effect (for HCMV) was recorded after, respectively, 5 and 7 days post-infection. Antiviral activity
was expressed as the EC50 or compound concentration required to reduce viral cytopathic effect (HCMV) or viral
plaque formation (VZV) by 50%.
Alternatively, the cytostatic activity of the test compounds was measured based on inhibition of cell growth.
HEL cells were seeded at a rate of 5 x 103 cells/well into 96-well microtiter plates and allowed to proliferate for
24 h. Then, medium containing different concentrations of the test compounds was added. After 3 days of
incubation at 37 °C, the cell number was determined with a Coulter counter. The cytostatic concentration was
calculated as the CC50, or the compound concentration required to reduce cell proliferation by 50% relative to the
number of cells in the untreated controls.
Acknowledgements
H. Kaoukabi is grateful to the ERASMUS program (University Autonoma, laboratory Organic-Inorganic Solids
and Luminiscent Probes (M01-L207), Madrid, Spain) for financial support in the form of a fellowship. We
gratefully acknowledge the invaluable technical help received from the staff of the CAC (center for analysis and
characterization) at Cadi Ayyad University. We are also grateful to Ellen De Waegenaere for assisting with the
biological assays.
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Highlights:
-
-
Synthesis of new dihydropyrimidinone derivatives with valuable antiviral activities
Synthesis of dihydropyrimidinone derivatives using Biginelli and 1,3-dipolar
cycloadditions reactions.
-
-
Interesting antiviral activities against VZV TK+ and VZV TK- strains were observed
No measurable cell-growth inhibition for the active compounds