Synthesis and in vitro study of antiproliferative benzyloxy dihydropyrimidinones

Article abstract of DOI:10.1002/ardp.202000466

In this study, we report on antiproliferative benzyloxy dihydropyrimidinones (DHPMs) produced by the Biginelli reaction of benzyloxy benzaldehyde, urea, and diverse 1,3-diones. The reaction was catalyzed by lanthanum triflate and completed within 1–1.5 h,

Full text of DOI:10.1002/ardp.202000466

Received: 22 December 2020
DOI: 10.1002/ardp.202000466
Revised: 15 January 2021
Accepted: 21 January 2021
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F U L L P A P E R
Synthesis and in vitro study of antiproliferative benzyloxy
dihydropyrimidinones
Ruturajsinh M. Vala1
Adrián Puerta2
Ramesh L. Gardas3
| Mayank G. Sharma1
| José M. Padrón2 | Venkatachalam Ramkumar3
| Hitendra M. Patel1
| Divyang M. Patel1
|
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1Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, Gujarat, India
2BioLab, Instituto Universitario de Bio‐Orgánica Antonio González (IUBO‐AG), Universidad de La Laguna, La Laguna, Spain
3Department of Chemistry, Indian Institute of Technology–Madras, Chennai, Tamil Nadu, India
Correspondence
Hitendra M. Patel, Department of Chemistry,
Sardar Patel University, Vallabh Vidyanagar,
Gujarat 388120, India.
Abstract
In this study, we report on antiproliferative benzyloxy dihydropyrimidinones
(DHPMs) produced by the Biginelli reaction of benzyloxy benzaldehyde, urea, and
diverse 1,3‐diones. The reaction was catalyzed by lanthanum triflate and completed
within 1–1.5 h, with 74–97% yield. The antiproliferative assay was carried out for all
synthesized dihydropyrimidinones against six human solid tumor cell lines. Six
compounds showed good antiproliferative activity with GI50 values below 5 μM.
Among all the synthesized compounds, the most potent derivative showed good
antiproliferative activity against all cell lines with GI50 values in the range of
1.1–3.1 μM. These DHPMs comply with druglikeness. Furthermore, ADMET pre-
diction and the effect of P‐glycoprotein on the antiproliferative activity were also
studied. Overall, our method allows eco‐friendly access to benzyloxy DHPMs as
potential anticancer drugs.
Email hm_patel@spuvvn.edu
Funding information
University Grants Commission,
Grant/Award Number: 1–14/2002‐2016(NS/
PE); Ministerio de Ciencia, Innovación y
Universidades, Grant/Award Numbers:
PGC2018‐094503‐B‐C22 (MCIU/AEI/FEDER,
UE); European Social Fund,
Grant/Award Number: TESIS2020010055;
Science and Engineering Research Board,
Grant/Award Number: EEQ/2016/000376
K E Y W O R D S
antiproliferative activity, dihydropyrimidinones, lanthanum triflate, Lipinski's rule of five
microtubules of the mitotic spindle.[11] The members of the kinesin
superfamily are engaged in intracellular transport and cell
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1
INTRODUCTION
Pharmaceutically relevant dihydropyrimidinones (DHPMs) produced
via the Biginelli reaction have attracted the attention of researchers
for many years. They possess a wide range of biological applications,
and they act as acetylcholinesterase inhibitors,[1] HIV‐1 replication
inhibitors,[2] urease inhibitors,[3] calcium channel blockers,[4] anti-
microbial agents,[5] antioxidant agents,[6] nonsteroidal RORα agonists,[7]
and antitubercular agents.[8] From this family of compounds, the Eg5
inhibitor monastrol[9] emerged as a lead compound.[10]
division.[12] Eg5 motors slide in microtubules during cell division
using energy produced by ATP hydrolysis.[13] This kinesin‐5 motor
activity is required to establish and maintain the bipolar spindle.[14]
In addition, it is also required for the accurate segregation of re-
plicated chromosomes during cell division.[15] In 1999, Mayer et al.[9]
identified monastrol as a mitotic inhibitor of Xenopus replication
through binding reversibly to Eg5. Monastrol perturbs the bipolar
mitotic spindle apparatus. Thus, cell division is arrested midway
through mitosis with a characteristically malformed spindle. As
compounds that lead to mitotic arrest have antitumor activity in
Eg5, a member of the kinesin‐5 subclass of kinesins, is a plus‐
end‐directed kinesin‐related motor protein that associates with
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Arch Pharm. 2021;e2000466.
wileyonlinelibrary.com/journal/ardp © 2021 Deutsche Pharmazeutische Gesellschaft
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https://doi.org/10.1002/ardp.202000466

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VALA ET AL.
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humans, monastrol may serve as a lead for the development of new
anticancer drugs. In 2004, Russowosky et al.[16] reported the anti-
proliferative activity of monastrol and its derivatives against seven
cancer cell lines (I in Figure 1). This result led other groups to de-
velop various DHPMs, which showed antiproliferative activity
against different human solid tumor cell lines (Figure 1).[17]
Inspired by these studies, we synthesized benzyloxy derivatives
of DHPM in continuation of our interest in obtaining new bioactive
compounds.[18] We produced these derivatives via the Biginelli reaction
of benzyloxy benzaldehyde, 1,3‐dione, and urea. A wide variety of cata-
lysts was reported for the Biginelli reaction.[19] Most of them were Lewis
acids, salts, or ionic liquids. We selected lanthanum triflate as Lewis acid
in this study, which gave better product yields in shorter reaction times.
All synthesized DHPMs were evaluated for their antiproliferative activity
in vitro against six different human solid tumor cell lines. We also as-
sessed the drug‐like properties and P‐glycoprotein (P‐gp) effect of the
two most potent compounds.
Using the aforementioned protocol, we synthesized 20 different
DHPMs 4a–t from various substrates (Table 2). All the synthesized
compounds were characterized by 1H nuclear magnetic resonance
(NMR), 13C{1H} attached proton test (APT), and either high‐
resolution mass spectra (HRMS) or liquid chromatography–mass
spectrometry (LCMS) analysis. We also developed a single crystal of
4a and it was analyzed by single‐crystal X‐ray diffraction (XRD). The
analysis results confirmed the structure of 4a and proved that 4a
crystallizes in the monoclinic crystal system with a P 1 21/c 1 space
group. Unit cell constants of the monoclinic crystal system are as
follows: a = 10.6226(5) Å, b = 15.3077(7) Å, c = 10.7256(4) Å, α = 90°,
β = 99.7636(19)°, γ = 90°, and volume = 1718.80(13) Å3, which are
based upon the refinement of the XYZ‐centroids of 4190 reflections
above 20 σ(I) with 4.683° < 2θ < 48.14°. The ORTEP view of the
crystal, generated from ORTEP3 software, is shown in Figure 2. XRD
data were deposited online to Cambridge Crystallographic Data
Centre (CCDC). CCDC deposition number 1971557 contains the
Supporting Information crystallographic data for this paper.
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2
RESULTS AND DISCUSSION
Chemistry
|
2.2
In vitro antiproliferative activity
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2.1
After successfully synthesizing all compounds, they were evaluated
for antiproliferative activity in vitro against six different human solid
tumor cell lines: A549 and SW1573 (non‐small cell lung), HBL100
and T‐47D (breast), HeLa (cervix), and WiDr (colon). We followed our
implementation of the NCI protocol[20] and used the standard an-
ticancer drug cisplatin (CDDP) as a reference compound. The results
of the assay given in GI50 (molar concentration of the compound that
inhibits 50% net cell growth) are shown in Table 3. Most of the
compounds show inhibition in all cell lines, denoting that the DHPM
scaffold is a privileged structure for the development of pharmaco-
logically active substances. Some of the compounds showed a better
antiproliferative activity than the anticancer drug cisplatin. Out of
20, 7 DHPMs, namely 4d, 4f, 4o–s, displayed GI50 values below
10 μM. Among all DHPMs, 4q is the most potent compound. It shows
a good antiproliferative activity against all six solid tumor cell lines.
Dubernet et al.[7] also screened this most potent 4q for binding re-
action with nonsteroidal RORα. The report showed that 4q did not
work as an agonist for nonsteroidal RORα.[7]
Benzyloxy derivatives of DHPM were synthesized from the multi-
component reaction of benzyloxy benzaldehydes 1a–c, 1,3‐diones 2a–g,
and urea 3 (Scheme 1). This reaction was catalyzed by 10 mol% lantha-
num triflate La(OTf)3. The desired products were obtained in good‐to‐
excellent yields after heating the reaction mixture at 100°C for 1–1.5 h.
Initially, we screened the reaction outcome under a solvent‐free
condition as well as with various solvents like ethanol, acetonitrile,
ethylene dichloride, tetrahydrofuran, dimethylformamide, and water
(Table 1). Ethanol gave better result with an excellent product yield.
The amount of solvent notably affects the reaction time. If the re-
action was carried out in more amount of solvent (2–3 ml), the re-
action completion was achieved in 3.5 h under reflux. However, when
the reaction was carried out with a small amount of ethanol (0.5 ml)
at 100°C, the reaction mixture solidified within 35 min, but the re-
action remained slightly incomplete. So, 0.5 ml more ethanol was
added and the reaction mixture was further stirred for more 25 min.
After the workup process, 97% yield of product was obtained.
FIGURE 1 Some antiproliferative dihydropyrimidinones and their potency against human tumor cell lines

VALA ET AL.
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SCHEME 1 Multicomponent synthesis of
dihydropyrimidinones from benzyloxy
benzaldehydes 1a–c, 1,3‐diones 2a–g, and urea 3
_
_
_
1a c
2a g
4a t
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2.2.1
Structure–activity relationship
cell culture assay. Compounds 4p and 4q were selected for this test.
Thus, we determined the GI50 values after 48 h of exposure to 4p
and 4q in wild‐type and P‐gp‐overexpressing SW1573 cells, and in
the presence of the P‐gp transport inhibitor verapamil (at a fixed
concentration of 10 μM). The standard microtubule‐interacting drugs
colchicine, vincristine, vinblastine, and paclitaxel were used
for comparison purposes. The results are shown in Table 4. For
better comparison of the data, we defined resistance factor (Rf) for a
given compound as the ratio of GI50 values against the P‐gp‐
overexpressing and the wild‐type cell lines, respectively. Overall, the
results indicate that the activity of 4p and 4q is not affected by the
overexpression of P‐gp.
The antiproliferative activity data allow us to compare the inhibition
potential of compounds related to their structure. We used a
color pattern to facilitate the overall comparison of the data re-
ported in Table 3. Overall, the inhibition potential of DHPMs due
to the benzyloxy scaffold has the following order: o‐benzyloxy <
m‐benzyloxy < p‐benzyloxy. Five p‐benzyloxy DHPMs (4o–s) dis-
played GI50 values below 10 μM. Thus, the presence of the
p‐benzyloxy phenyl group at the pyrimidinone ring increases the
antiproliferative activity. Furthermore, DHPMs with an acetyl group
at position 5 of the pyrimidinone ring disfavor the activity. In con-
trast, the substitution with an alkyloxy or amide functional group
increases the activity. Moreover, superior antiproliferative activity
was observed in the presence of an i‐butoxy group.
TABLE 2 Synthesis of benzyloxy DHPMs by the
multicomponent reaction of 1 mmol benzyloxy benzaldehydes
(1a–c), 1.1 mmol 1,3‐diones (2a–g), and 1.2 mmol urea (3)
|
2.3
P‐gp assay
Entry
1
OBn
R
Product
4a
4b
4c
Time (h)
Yield (%)a
o‐OBn
o‐OBn
o‐OBn
o‐OBn
o‐OBn
o‐OBn
o‐OBn
m‐OBn
m‐OBn
m‐OBn
m‐OBn
m‐OBn
m‐OBn
p‐OBn
p‐OBn
p‐OBn
p‐OBn
p‐OBn
p‐OBn
p‐OBn
Me
1
84
P‐gp is a transmembrane glycoprotein that extrudes cytotoxic drugs
from cells. The overexpression of P‐gp confers drug resistance to
cells. To test if our compounds could suffer P‐gp extrusion, we used a
2
OMe
OEt
1
87
3
1
85
4
Oi‐Bu
Ot‐Bu
OBn
NHPh
Me
4d
4e
4f
1.5
1.5
1
78
TABLE 1 Effect of solvent on the reactiona
5
74
6
85
Conversion relative to
Entry Solvent
Temp
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
100°C
Time
3 h
aldehydeb
7
4g
4h
4i
1.5
1
86
1
2
3
4
5
6
7
8
9
CH3CNc
DCEc
100%
8
83
4 h
Incomplete
Incomplete
Mixture of products
Incomplete
100%
9
OMe
OEt
1
89
THFc
4 h
10
11
12
13
14
15
16
17
18
19
20
4j
1
87
DMFc
2 h
Oi‐Bu
Ot‐Bu
OBn
Me
4k
4l
1.5
1.5
1
76
Waterc
Ethanolc
Ethanold
4 h
75
3.5 h
1 h
4m
4n
4o
4p
4q
4r
88
100%
1
95
Solvent‐free 100°C
Solvent‐free 130°C
30 min
30 min
Incomplete
Mixture of products
OMe
OEt
1
96
1
97
Abbreviations: DCE, 1,2‐dichloroethane; DMF, dimethylformamide;
TLC, thin‐layer chromatography; THF, tetrahydrofuran.
aReaction condition: 1 mmol p‐benzyloxy benzaldehyde 1c, 1.1 mmol
ethyl acetoacetate 2c, 1.2 mmol urea 3, and 0.1 mmol La(OTf)3.
bObserved from TLC analysis.
c3 ml solvent.
Oi‐Bu
Ot‐Bu
OBn
NHPh
1.5
1.5
1
88
77
4s
94
4t
1.5
95
d0.5 ml solvent.
aIsolated yield.

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and cytotoxicity against HepG‐2 cells. Here, AMES test is a common
way to assess a chemical's mutagenicity and hERG codes for a po-
tassium ion channel involved in the normal cardiac repolarization
activity of the heart. Drug‐induced blockade of hERG function can
cause long QT syndrome, which may result in arrhythmia and death.
Cytochrome P450 inhibition prediction for five main drug‐
metabolizing CYPs shows that the target compounds are only
Cyp3A4 inhibitors.
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3
CONCLUSION
We successfully synthesized benzyloxy derivatives of DHPM by
the multicomponent reaction of benzyloxy benzaldehydes, urea,
and 1,3‐diones. Lanthanum triflate catalyzed the reaction and gave
good‐to‐excellent yields within 1–1.5 h. In an antiproliferative
assay against six human solid tumor cell lines, the majority
showed inhibitory activity in the low micromolar range. Among
them, seven compounds exhibited a good activity (GI50 < 10 μM).
The two most potent compounds, 4p and 4q, were evaluated for
drug‐like properties, which comply with recommended drug
properties. P‐gp does not affect the antiproliferative activity of
potent 4p and 4q. Further biological studies, outside the scope of
this study, should shed light on the potential of these compounds
in the treatment of cancer.
FIGURE 2 The ORTEP view of compound 4a with displacement
ellipsoids drawn at 40%. H atoms are shown as small spheres of
arbitrary radii
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2.4
Druglikeness
“Drug‐like properties” is a term that relates to several structural,
physicochemical, and biological properties, and pharmacokinetics/
toxicity of investigational compounds in drug discovery processes.
The fastest method for evaluating the drug‐like properties of a
compound is to apply “rules.” Rules are a set of guidelines for the
structural properties of compounds that have a higher probability of
being well absorbed after oral dosing. These guidelines are not ab-
solute and they are also not intended to form strict cut‐off values for
which property values are drug‐like and which are not drug‐like.
Table 5 shows the threshold values for the parameters covered by
the most widely used rules for evaluating drug‐like properties, that
is, Lipinski's,[21] Ghose's,[22] and Veber's rules.[23] Our lead com-
pounds 4p and 4q comply with these rules.
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4
EXPERIMENTAL
Chemistry
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4.1
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4.1.1
General
All chemical reagents for synthesis were purchased from HiMedia
Laboratories, Sigma‐Aldrich, and Sisco Research Laboratories Pvt.
Ltd. They were used without further purification. Chemical reactions
were monitored by thin‐layer chromatography (TLC) on F254 silica
gel 60 TLC plates. Melting points were determined by the open ca-
pillary tube method and were uncorrected. HRMS were recorded on
an Agilent QTOF 6530 micromass spectrometer. The LCMS analysis
was collected on an MS–Agilent 6120 quadrupole. 1H NMR and 13C
{1H} APT spectral analyses were recorded with a BRUKER AVANCE
II 400 NMR spectrometer using CDCl3 and dimethyl sulfoxide
(DMSO)‐d6 as the solvent and tetramethylsilane as an internal
standard. Splitting patterns of an apparent multiplet associated with
an averaged coupling constant were designated as follows: s, singlet;
d, doublet; t, triplet; q, quartet; quint., quintet; dd, double doublet; td,
triple doublet; ddd, double of double doublet; br, broad signal; and m,
multiplet. Chemical shifts are expressed in parts per million and
coupling constants (J) are provided in Hertz.
|
2.5
ADMET (absorption, distribution,
metabolism, excretion, and toxicity) prediction
ADMET properties of the drug candidate are important for their
efficacy and toxicity. We targeted seven potent DHPMs, namely 4d,
4f, 4o–s, for ADMET prediction. vNN web server was utilized for the
ADMET prediction, which constructed 15 ADMET prediction mod-
els.[24] Tabulated results, expressed in Table 6, show that all the
targeted compounds are not P‐gp substrates, but they are P‐gp in-
hibitors. In addition, they exhibit a negative prediction for AMES test,
mitochondrial toxicity (mitochondrial membrane potential [MMP]
distribution), hERG (human ether‐à‐go‐go‐related gene) blockade,
The original spectra of the investigated compounds and their
InChI codes, together with some biological activity data, are provided
as Supporting Information.

VALA ET AL.
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TABLE 3 Antiproliferative activity (GI50 [μM]) against human solid tumor cell linesa
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4.1.2
General procedure for the synthesis of
round bottom flask with 0.5 ml ethanol and 0.1 mmol (10 mol %)
lanthanum triflate. It was stirred at 100°C for 35 min. Within this
time, the reaction mixture solidified or became sticky (except
those that contain tert‐butyl acetoacetate 2e), and then 0.5 ml
more ethanol was added and stirred for the required time, as
benzyloxy derivatives of DHPMs (4a–t)
A mixture of 1 mmol benzyloxy benzaldehydes (1a–c), 1.1 mmol
1,3‐diones (2a–g), and 1.2 mmol urea (3) was added to a 50‐ml
TABLE 4 P‐gp test in SW1573 and SW1573/P‐gp cell linesa
Without verapamil
SW1573
With verapamil
SW1573
SW1573/P‐gp
26 13
Rfb
3.3
2.3
566
36
SW1573/P‐gp
Rfb
9.1
2.8
0.7
5.2
2.5
1.8
4p
7.9
1
11 2.2
>100
4q
3.6 0.49
8.1 1.9
2.9 0.43
8.2 1
Paclitaxel
Colchicine
Vincristine
Vinblastine
0.00053 0.00022
0.067 0.015
0.3 0.11
0.00046 0.00021
0.029 0.012
0.0006 0.00011
0.00055 0.00011
0.00031 0.00015
0.15 0.029
2.4 0.94
0.0039 0.0015
0.00094 0.00035
0.086 0.015
0.016 0.0047
22
0.0015 0.00018
0.001 0.00045
17
aValues are given in µM and represent mean values of at least three independent experiments SD.
bRf represents the ratio between GI50 SW1573/P‐gp and SW1573.

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TABLE 5 Drug‐like propertiesa
Entry
Parameter
Threshold
Lipinski's rules
MW
logP
HBA
HBD
logP
MW
MR
<500
366.41
4.11
6
394.46
4.75
6
<5
<10
<5
2
2
Ghose's rules (CMC‐80)
−0.4 < log P < 5.6
160 < MW < 480
40 < MR < 130
20 < TNA < 70
≤10
4.11
366.41
108.76
49
4.75
394.46
118.37
55
TNA
RB
Veber's rules
7
8
PSA
THB
≤140
76.66
8
76.66
8
≤12
Abbreviations: HBA, hydrogen bond acceptors; HBD, hydrogen bond donors; log P, lipophilicity; MR, molar refractivity; MW, molecular weight; PSA, polar
surface area; RB, rotational bond; THB, total hydrogen bonds; TNA, total number of atoms.
ahttps://mcule.com/apps/property-calculator/.
mentioned in Table 2. Next, 5 ml more ethanol was added and
cooled to room temperature. The progress of the reaction was
monitored by TLC. After completion of the reaction, the reaction
mixture was poured slowly into 20 ml ice‐cold water with
stirring and kept still until the precipitation of the product was
completed. The crude product was filtered and washed with
20% aqueous solution of ethanol (5 ml × 3). Products were
recrystallized from 6 ml ethanol.
5‐Acetyl‐4‐[2‐(benzyloxy)phenyl]‐6‐methyl‐3,4‐dihydropyrimidin‐
2(1H)‐one (4a)
White solid (0.283 g, 84%), mp: 200–202°C (lit[3] mp: 192–194°C);
1H NMR (400 MHz, DMSO‐d6) δ: 2.00 (s, 3H), 2.28 (s, 3H), 5.20 (s,
2H), 5.69 (d, J = 3.2 Hz, 1H), 6.90 (t, J = 7.2 Hz, 1H), 7.05 (d, J = 7.6 Hz,
1H), 7.09 (dd, J = 2.0, 7.6 Hz, 1H), 7.22 (td, J = 1.6, 7.8 Hz, 1H),
7.32–7.42 (m, 4H), 7.54 (d, J = 7.2 Hz, 2H) 9.16 (s, 1H); 13C{1H} APT
(100 MHz, DMSO‐d6) δ: 18.7, 29.7, 48.7, 69.3, 108.0, 112.6, 120.7,
TABLE 6 ADMET predictions of benzyloxy DHPMs by vNN method
P‐gp
Compound DILI Cytotoxicity HLM 1A2 3A4 2D6 2C9 2C19 BBB inhibitor
P‐gp
substates
hERG
MRTD
Liver toxicity
Cyp Inhibitors for
blocker
MMP AMES (mg/day)
4d
4f
No
No
No
No
No
No
No
No
No
Yes
No
No
No
No
No
No
No
No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
40
227
53
4o
4p
4q
4r
4s
Yes No
Yes No
Yes Yes
Yes Yes
Yes Yes
Yes Yes
Yes Yes
19
No
Yes No
No No
No
40
216
222
Abbreviations: ADMET, absorption, distribution, metabolism, excretion, and toxicity; BBB, blood–brain barrier; DHPM, dihydropyrimidinone; DILI, drug‐
induced liver Injury, hERG, human ether‐à‐go‐go‐related gene; HLM, human liver microsomal; MMP, mitochondrial membrane potential;
MRTD, maximum recommended therapeutic dose; P‐gp, P‐glycoprotein, vNN, variable nearest neighbor.

VALA ET AL.
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127.2, 127.4, 127.7, 128.4, 128.8, 131.6, 137.3, 148.0, 152.0, 155.0,
194.4; HRMS (electrospray ionization time‐of‐flight [ESI‐TOF]) m/z
calcd. for C20H21N2O3 (M+H)+: 337.1552, found: 337.1548.
Benzyl 4‐[2‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,4‐
tetrahydropyrimidine‐5‐carboxylate (4f)
White solid (0.363 g, 85%), mp: 112–114°C; 1H NMR (400 MHz,
CDCl3) δ: 2.41 (s, 3H), 5.00–5.04 (m, 2H), 5.08–5.12 (m, 2H), 5.65 (s,
1H), 5.85 (s, 1H), 6.90–7.03 (m, 4H), 7.11 (d, J = 6.8 Hz, 1H), 7.23 (t,
J = 6.2 Hz, 4H), 7.37 (s, 5H), 8.06 (br, 1H); 13C{1H} APT (100 MHz,
CDCl3) δ: 18.6, 50.2, 65.5, 70.3, 97.9, 112.0, 121.1, 127.1, 127.5,
127.5, 127.7, 128.2, 128.3, 128.7, 129.2, 130.3, 136.3, 136.6, 149.0,
153.1, 156.0, 165.4; HRMS (ESI‐TOF) m/z calcd. for C26H25N2O4 (M
+H)+: 429.1814, found: 429.1811.
Methyl 4‐[2‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,
4‐tetrahydropyrimidine‐5‐carboxylate (4b)
White solid (0.305 g, 87%), mp: 206–208°C (lit[25] mp: 205–207°C);
1H NMR (400 MHz, DMSO‐d6) δ: 2.28 (s, 3H), 3.45 (s, 3H), 5.18 (d,
J = 4.0 Hz, 2H), 5.62 (s, 1H), 6.89 (t, J = 7.2 Hz, 1H), 7.01 (d, J = 8.4 Hz,
1H), 7.10 (d, J = 7.6 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.29–7.30 (m,
1H), 7.33 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 7.4 Hz, 2H), 7.52 (d, J = 7.2 Hz,
2H), 9.18 (s, 1H); 13C{1H} APT (100 MHz, CDCl3) δ: 18.5, 50.2, 51.2,
70.2, 98.0, 112.0, 121.0, 126.9, 127.5, 128.2, 128.8, 129.1, 130.1,
136.6, 148.8, 153.7, 156.0, 166.3; HRMS (ESI‐TOF) m/z calcd. for
4‐[2‐(Benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐N‐phenyl‐1,2,3,
4‐tetrahydropyrimidine‐5‐carboxamide (4g)
White solid (0.354 g, 86%), mp: 190–192°C; 1H NMR (400 MHz,
CDCl3) δ: 2.34 (s, 3H), 5.16 (s, 2H), 5.71 (s, 1H, NH), 5.73 (s, 1H, CH),
7.06 (t, J = 4.0 Hz, 3H, Ar–H), 7.09 (s, 1H, NH), 7.23 (d, J = 5.2 Hz, 4H),
7.33–7.41 (m, 7H), 7.77 (s, 1H); 13C{1H} APT (100 MHz, CDCl3) δ:
18.3, 50.4, 70.8, 102.3, 112.9, 120.3, 122.0, 124.2, 127.8, 128.0,
128.5, 128.9, 128.9, 129.1, 130.4, 136.0, 137.8, 143.5, 153.2, 155.5,
164.4; MS (MMES + APCI) m/z calcd. for C25H24N3O3 (M+H)+:
414.18, found: 414.00.
C
20H21N2O4 (M+H)+: 353.1501, found: 353.1499.
Ethyl 4‐[2‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,
4‐tetrahydropyrimidine‐5‐carboxylate (4c)
White solid (0.312 mg, 85%), mp: 190–192°C; 1H NMR (400 MHz,
CDCl3) δ: 1.12 (t, J = 7.2 Hz, 3H), 2.39 (s, 3H), 4.07 (q, J = 7.2 Hz, 2H),
5.14 (s, 2H), 5.73 (s, 1H), 5.80 (s, 1H), 6.89–6.97 (m, 2H), 7.10 (d,
J = 6.8 Hz, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.36–7.46 (m, 5H), 8.37 (s, 1H);
13C{1H} APT (100 MHz, CDCl3) δ: 14.2, 18.5, 50.4, 59.8, 70.1, 98.2,
112.0, 120.9, 127.0, 127.5, 128.2, 128.7, 129.1, 130.2, 136.6, 148.3,
153.6, 156.0, 165.9; HRMS (ESI‐TOF) m/z calcd. for C21H23N2O4 (M
+H)+: 367.1658, found: 367.1656.
5‐Acetyl‐4‐[3‐(benzyloxy)phenyl]‐6‐methyl‐3,4‐dihydropyrimidin‐
2(1H)‐one (4h)
White solid (0.278 g, 83%), mp: 168–170°C (lit[3] mp: 204–209°C);
1H NMR (400 MHz, CDCl3) δ: 2.10 (s, 3H), 2.33 (s, 3H), 5.04 (s, 2H),
5.40 (s, 1H), 5.86 (s, 1H), 6.90 (s, 3H), 7.32–7.41 (m, 6H), 8.00 (s, 1H);
13C{1H} APT (100 MHz, CDCl3) δ: 19.8, 30.3, 56.0, 70.1, 110.4, 113.5,
114.3, 119.1, 127.6, 128.1, 128.6, 130.2, 136.8, 144.2, 145.6, 152.9,
159.4, 195.4; MS (MMES + APCI) m/z calcd. for C20H21N2O3 (M+H)+:
337.16, found: 336.85.
Isobutyl 4‐[2‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,
4‐tetrahydropyrimidine‐5‐carboxylate (4d)
White solid (0.306 g, 78%), mp: 166–168°C; 1H NMR (400 MHz,
DMSO‐d6) δ: 0.63 (dd, J = 2.0, 6.8 Hz, 6H), 1.63 (quint., J = 6.4 Hz, 1H),
2.32 (s, 3H), 3.65 (ddd, J = 6.4, 10.8, 32.0 Hz, 2H), 5.16 (dd, J = 12.8,
27.2 Hz, 2H), 5.68 (d, J = 2.8 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 7.02 (d,
J = 8.0 Hz, 1H), 7.11 (d, J = 1.2, 7.6 Hz, 1H), 7.18–7.22 (m, 1H), 7.28 (s,
1H), 7.33 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.4 Hz, 2H), 7.53 (d, J = 7.2 Hz,
2H), 9.16 (s, 1H); 13C{1H} APT (100 MHz, DMSO‐d6) δ: 17.6, 18.6,
18.6, 27.2, 48.5, 69.0, 69.2, 97.5, 112.2, 120.5, 127.0, 127.3, 127.6,
128.3, 128.6, 131.9, 137.4, 149.3, 152.1, 155.2, 165.2; HRMS (ESI‐
Methyl 4‐[3‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,
4‐tetrahydropyrimidine‐5‐carboxylate (4i)
White solid (0.315 g, 89%), mp: 200–202°C (lit[25] mp: 173–175°C);
1H NMR (400 MHz, CDCl3) δ: 2.35 (s, 3H), 3.63 (s, 3H), 5.05 (s, 2H),
5.37 (s, 1H), 5.86 (s, 1H), 6.88–6.94 (m, 3H), 7.25 (t, J = 7.8 Hz, 1H),
7.32–7.45 (m, 5H), 8.25 (br, 1H); 13C{1H} APT (100 MHz, CDCl3) δ:
18.8, 51.2, 55.5, 70.6, 101.0, 113.4, 114.0, 119.1, 127.6, 128.0, 128.6,
129.9, 136.9, 145.1, 146.6, 153.3, 159.1, 166.0; MS (MMES + APCI)
m/z calcd. for C20H21N2O4 (M+H)+: 353.15, found: 353.00.
TOF) m/z calcd. for
C
23H27N2O4 (M+H)+: 395.1971, found:
395.1963.
tert‐Butyl 4‐[2‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,
4‐tetrahydropyrimidine‐5‐carboxylate (4e)
Ethyl 4‐[3‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,
White solid (0.291 g, 74%), mp: 184–186°C; 1H NMR (400 MHz,
DMSO‐d6) δ: 1.18 (s, 9H), 2.26 (s, 2H), 5.15 (d, J = 4.8 Hz, 2H), 5.59 (d,
J = 2.0 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 7.10
(dd, J = 1.2, 7.6 Hz, 1H), 7.18–7.22 (m, 2H), 7.33 (d, J = 7.2 Hz, 1H),
7.39 (t, J = 7.4 Hz, 2H), 7.53 (d, J = 7.2 Hz, 2H), 9.00 (s, 1H); 13C{1H}
APT (100 MHz, DMSO‐d6) δ: 17.5, 27.7, 49.0, 69.1, 78.7, 98.9, 112.1,
120.3, 127.2, 127.3, 127.6, 128.3, 128.4, 132.2, 137.4, 147.7, 152.0,
155.3, 164.8; HRMS (ESI‐TOF) m/z calcd. for C23H27N2O4 (M+H)+:
395.1971, found: 395.1969.
4‐tetrahydropyrimidine‐5‐carboxylate (4j)
White solid (0.319 g, 87%), mp: 174–176°C; 1H NMR (400 MHz,
CDCl3) δ: 1.18 (d, J = 6.8 Hz, 3H), 2.33 (s, 3H), 4.08 (d, J = 6.0 Hz, 2H),
5.04 (s, 2H), 5.38 (s, 1H), 6.20 (s, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.93 (d,
J = 13.2 Hz, 2H), 7.23 (t, J = 6.8 Hz, 1H), 7.34–7.42 (m, 5H), 8.65 (s,
1H); 13C{1H} APT (100 MHz, CDCl3) δ: 14.2, 18.6, 55.5, 60.0, 70.0,
101.1, 113.4, 114.0, 119.2, 127.6, 128.0, 128.6, 129.8, 136.9, 145.3,
146.2, 153.8, 159.1, 165.7; MS (MMES + APCI) m/z calcd. for
C
21H23N2O4 (M+H)+: 367.17, found: 367.00.

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VALA ET AL.
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Isobutyl 4‐[3‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,
(100 MHz, CDCl3) δ: 18.8, 51.2, 55.1, 70.1, 101.5, 115.0, 127.5,
127.8, 128.0, 128.6, 136.2, 136.9, 146.2, 153.3, 158.5, 166.2; HRMS
(ESI‐TOF) m/z calcd. for C20H21N2O4 (M+H)+: 353.1501, found:
353.1494.
4‐tetrahydropyrimidine‐5‐carboxylate (4k)
White solid (0.299 g, 76%), mp: 116–118°C; 1H NMR (400 MHz,
DMSO‐d6) δ: 0.75 (dd, J = 2.8, 6.8 Hz, 6H), 1.75 (quint., J = 6.4 Hz, 1H),
2.28 (s, 3H), 3.73 (dd, J = 6.4, 10.0 Hz, 2H), 5.06 (s, 2H), 5.12 (d,
J = 3.2 Hz, 1H), 6.84 (t, J = 7.2 Hz, 2H), 6.90 (dd, J = 2.0, 8.0 Hz, 1H),
7.24 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.37–7.44 (m, 4H),
7.73 (s, 1H), 9.21 (s, 1H); 13C{1H} APT (100 MHz, DMSO‐d6) δ: 17.8,
18.8, 27.2, 53.8, 69.2, 69.3, 98.7, 113.0, 113.2, 118.5, 127.6, 127.8,
128.4, 129.5, 137.0, 146.2, 148.8, 152.0, 158.4, 165.3; MS (MMES +
APCI) m/z calcd. for C23H27N2O4 (M+H)+ 395.20, found: 395.00.
Ethyl 4‐[4‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,4‐
tetrahydropyrimidine‐5‐carboxylate (4p)
White solid (0.354 g, 97%), mp: 178–180°C (lit[27] mp: 183–185°C,
lit[7] mp: 188–189°C); 1H NMR (400 MHz, CDCl3) δ: 1.19 (t,
J = 7.2 Hz, 3H), 2.36 (s, 3H), 4.07–4.10 (m, 2H), 5.06 (s, 2H), 5.37 (s,
1H), 5.76 (s, 1H), 6.93 (dd, J = 2.0, 6.8 Hz, 2H), 7.24–7.28 (m, 2H),
7.34–7.36 (m, 2H), 7.40–7.43 (m, 4H), 8.05 (s, 1H); 13C{1H} APT
(100 MHz, CDCl3) δ: 14.2, 18.7, 55.2, 60.1, 70.0, 101.8, 115.0, 127.5,
127.9, 128.0, 128.6, 136.2, 136.9, 145.8, 153.3, 158.5, 165.6; HRMS
(ESI‐TOF) m/z calcd. for C21H23N2O4 (M+H)+: 367.1658, found:
367.1654.
tert‐Butyl 4‐[3‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,
4‐tetrahydropyrimidine‐5‐carboxylate (4l)
White solid (0.295 g, 75%), mp: 140–142°C; 1H NMR (400 MHz,
CDCl3) δ: 1.35 (s, 9H), 2.31 (s, 1H), 5.05 (s, 2H), 5.32 (d, J = 2.0 Hz,
1H), 6.00 (s, 1H), 6.86–6.89 (m, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.95 (d,
J = 1.6 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.31–7.44 (m, 5H), 8.38 (s, 1H);
13C{1H} APT (100 MHz, CDCl3) δ: 18.4, 28.2, 55.9, 70.0, 80.4, 102.2,
113.4, 114.0, 119.2, 127.5, 128.0, 128.6, 129.7, 136.6, 136.9, 145.4,
153.5, 159.1, 165.0; MS (MMES+APCI) m/z calcd. for C23H27N2O4
(M+H)+: 395.20, found: 395.00.
Isobutyl 4‐[4‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,
4‐tetrahydropyrimidine‐5‐carboxylate (4q)
White solid (0.348 g, 88%), mp: 166–168°C; 1H NMR (400 MHz,
DMSO‐d6) δ: 0.76 (dd, J = 4.0, 6.8 Hz, 6H), 1.76 (quint., J = 6.6 Hz,
1H), 2.27 (s, 3H), 3.73 (ddd, J = 6.4, 10.4, 20 Hz, 2H), 5.08 (s, 2H,
benzylic CH2), 5.9 (s, 1H, CH), 6.96 (d, J = 8.8 Hz, 2H), 7.14
(d, J = 8.8 Hz, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.36–7.44 (m, 4H), 7.65
(d, J = 2.0 Hz, 1H), 9.16 (s, 1H); 13C{1H} APT (100 MHz, DMSO‐d6)
δ: 17.8, 18.9, 27.2, 53.3, 69.2, 69.2, 99.2, 114.6, 127.4, 127.5,
127.7, 128.4, 131.9, 137.1, 148.4, 152.0, 157.5, 165.3; HRMS
(ESI‐TOF) m/z calcd. for C23H27N2O4 (M+H)+: 395.1971, found:
395.1963.
Benzyl 4‐[3‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,
4‐tetrahydropyrimidine‐5‐carboxylate (4m)
White solid (0.376 g, 88%), mp: 140–142°C; 1H NMR (400 MHz,
DMSO‐d6) δ: 2.28 (s, 3H), 5.00 (d, J = 0.8 Hz, 2H), 5.04 (d, J = 8.0 Hz,
1H), 5.16 (d, J = 3.2 Hz, 1H), 6.81–6.83 (m, 2H), 6.91 (d, J = 9.2 Hz,
1H), 7.17–7.78 (m, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.25–7.28 (m, 3H),
7.33–7.44 (m, 5H); 7.75 (s, 1H), 9.27 (s, 1H); 13C{1H} APT (100 MHz,
DMSO‐d6) δ: 17.8, 53.7, 64.8, 69.2, 98.5, 113.1, 113.2, 118.6, 127.5,
127.7, 127.7, 127.8, 128.2, 128.4, 129.6, 136.5, 136.9, 146.2, 149.4,
152.0, 158.4, 165.0; MS (MMES+APCI) m/z calcd. for C26H25N2O4
(M+H)+: 429.18, found: 428.85.
tert‐Butyl 4‐[4‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,
4‐tetrahydropyrimidine‐5‐carboxylate (4r)
White solid (0.303 g, 77%), mp: 174–176°C (lit[27] mp: 174–176°C);
1H NMR (400 MHz, DMSO‐d6) δ: 1.29 (s, 9H), 2.21 (s, 3H), 5.03 (d,
J = 3.2 Hz, 1H), 5.08 (s, 2H), 6.98 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.4 Hz,
2H), 7.33 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.4 Hz, 2H), 7.42–7.44 (m,
2H), 7.59 (d, J = 2.4 Hz, 1H), 9.03 (s, 1H); 13C{1H} APT (100 MHz,
DMSO‐d6) δ: 17.6, 27.8, 53.7, 69.1, 79.0, 100.8, 114.5, 127.4, 127.6,
127.7, 128.4, 137.1, 137.4, 147.0, 152.1, 157.4, 164.8; HRMS
(ESI‐TOF) m/z calcd. for C23H27N2O4 (M+H)+: 395.1971, found:
395.1965.
5‐Acetyl‐4‐[4‐(benzyloxy)phenyl]‐6‐methyl‐3,4‐dihydropyrimidin‐
2(1H)‐one (4n)
White solid (0.318 g, 95%), mp: 188–190°C (lit[3] mp: 187–189°C,
lit[26] mp: 221°C); 1H NMR (400 MHz, DMSO‐d6) δ: 2.08 (s, 3H), 2.28
(s, 3H), 5.08 (s, 2H), 5.21 (d, J = 3.2 Hz, 1H), 6.96–6.98 (m, 2H), 7.17
(d, J = 8.4 Hz, 2H), 7.33 (d, J = 7.2 Hz, 1H), 7.37–7.41 (m, 2H),
7.43–7.45 (m, 2H), 7.76 (d, J = 2.8 Hz, 1H), 9.15 (s, 1H); 13C{1H} APT
(100 MHz, DMSO‐d6) δ: 18.7, 30.1, 53.3, 69.2, 109.6, 114.7, 127.6,
127.6, 127.8, 128.4, 136.6, 137.1, 147.8, 152.1, 157.6, 194.3; HRMS
(ESI‐TOF) m/z calcd. for C20H21N2O3 (M+H)+: 337.1552, found:
337.1547.
Benzyl 4‐[4‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,
4‐tetrahydropyrimidine‐5‐carboxylate (4s)
White solid (0.402 g, 94%), mp: 166–168°C; 1H NMR (400 MHz,
DMSO‐d6) δ: 2.27 (s, 3H), 5.03 (d, J = 11.2 Hz, 2H), 5.09 (s, 2H), 5.13
(d, J = 3.2 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 7.11–7.16 (m, 4H), 7.28 (t,
J = 3.2 Hz, 3H), 7.34 (d, J = 7.2 Hz, 1H), 7.38–7.46 (m, 4H), 7.70 (s,
1H), 9.24 (d, J = 1.2 Hz, 1H); 13C{1H} APT (100 MHz, DMSO‐d6) δ:
17.8, 53.3, 64.7, 69.1, 99.0, 114.6, 127.5, 127.5, 127.6, 127.7, 127.8,
128.2, 128.4, 136.5, 137.08, 137.10, 148.8, 151.9, 157.6, 165.1;
HRMS (ESI‐TOF) m/z calcd. for C26H25N2O4 (M+H)+: 429.1814,
found: 429.1807.
Methyl 4‐[4‐(benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐1,2,3,4‐
tetrahydropyrimidine‐5‐carboxylate (4o)
White solid (0.338 g, 96%), mp: 190–192°C; 1H NMR (400 MHz,
CDCl3) δ: 2.40 (s, 3H), 3.64 (s, 3H), 5.05 (s, 2H), 5.36 (d, J = 2.4 Hz,
1H), 5.75 (s, 1H), 6.91–6.95 (m, 2H), 7.25 (dd, J = 2.0, 6.8 Hz, 2H),
7.34–7.36 (m, 1H), 7.80–7.45 (m, 4H), 8.13 (s, 1H); 13C{1H} APT

VALA ET AL.
9 of 10
|
4‐[4‐(Benzyloxy)phenyl]‐6‐methyl‐2‐oxo‐N‐phenyl‐1,2,3,4‐
tetrahydropyrimidine‐5‐carboxamide (4t)
are also thankful to SERB, New Delhi, India, for providing
financial assistance from the major research project (file no.
EEQ/2016/000376, dated 07/02/2017). They thank UGC, New
Delhi, for UGC‐CPEPA Phase‐II program sponsored under award
letter no. F. No.1–14/2002‐2016(NS/PE), dated April 28, 2016,
for the assistance in general and NMR facility in particular.
White solid (0.392 g, 95%), mp: 210–212°C (lit[28] mp: 218–220°C,
lit[29] mp: 214°C); 1H NMR (400 MHz, DMSO‐d6) δ: 2.04 (s, 3H), 5.06
(s, 2H), 5.36 (s, 1H), 6.95–6.99 (m, 3H), 7.19–7.24 (m, 4H), 7.31–7.41
(m, 5H), 7.54 (d, J = 7.6 Hz, 3H), 8.70 (s, 1H), 9.52 (s, 1H); 13C{1H} APT
(100 MHz, DMSO‐d6) δ: 17.0, 54.5, 69.1, 105.6, 114.6, 119.5, 123.0,
127.5, 127.6, 127.8, 128.4, 128.5, 136.7, 137.1, 138.2, 139.2, 152.5,
157.6, 165.3; MS (MMES+APCI) m/z: calcd. for C25H24N3O3 (M+H)+:
414.18, found: 414.00.
CONFLICTS OF INTERESTS
The authors declare that there are no conflicts of interests.
ORCID
Ruturajsinh M. Vala
Mayank G. Sharma
Divyang M. Patel
http://orcid.org/0000-0002-9829-1816
http://orcid.org/0000-0002-9375-7728
http://orcid.org/0000-0002-4579-6423
|
4.2
Antiproliferative activity
The antiproliferative activity was tested in vitro against human
cancer cells using the protocol of the National Cancer Institute (NCI)
of the United States, with minor modifications. The following den-
sities (cells per well) were used: 2500 (A549, HBL‐100, HeLa, and
SW1573), 5000 (T‐47D and WiDr). Stock solutions of compounds
4 a–t were prepared in DMSO at 40 mM, that is, 400 times the
maximum test concentration. The cells were exposed to serial deci-
mal dilutions in the range of 1–100 μM for a period of 48 h. Cisplatin
was used as a reference drug. For each product, GI50 values were
calculated according to the NCI formulas.[20]
Adrián Puerta
http://orcid.org/0000-0002-7975-1960
http://orcid.org/0000-0001-6268-6552
José M. Padrón
Venkatachalam Ramkumar
http://orcid.org/0000-0001-7088-5797
Ramesh L. Gardas
Hitendra M. Patel
http://orcid.org/0000-0002-6185-5825
http://orcid.org/0000-0003-4740-7329
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Drug‐like properties
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4.4
ADMET prediction
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ACKNOWLEDGMENTS
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The authors are thankful to Manoj Mangukiya, Associate
Analytical Scientist, Aether Industries Ltd., Surat, for the LCMS
experiments. Mayank G. Sharma is thankful to SERB, New Delhi,
for SRF. Adrián Puerta and José M. Padrón ackowledge the
Spanish Government for financial support through project
PGC2018‐094503‐B‐C22 (MCIU/AEI/FEDER, UE) and Adrián
Puerta thanks the EU Social Fund (FSE) and Canary Islands
ACIISI for a predoctoral grant TESIS2020010055. The authors

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How to cite this article: Vala RM, Sharma MG, Patel DM,
et al. Synthesis and in vitro study of antiproliferative
benzyloxy dihydropyrimidinones. Arch Pharm.
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