Microwave assisted synthesis of 4-phenylquinazolin-2(1H)-one derivatives that inhibit vasopressor tonus in rat thoracic aorta

Article abstract of DOI:10.3390/molecules25061467

Quinazolinones have pharmacological effects on vascular reactivity through different mechanisms. We synthesized 4-phenylquinazolin-2(1H)-one derivatives under microwave irradiation and tested them on the rat thoracic aorta. The prepared compounds 2a-2f were obtained in about 1 h with suitable yields (31-92%). All derivatives produced vasorelaxant effects with IC₅₀ values ranging from 3.41 ± 0.65 μM to 39.72 ± 6.77 μM. Compounds 2c, 2e and 2f demonstrated the highest potency in endothelium-intact aorta rings (IC₅₀ 4.31 ± 0.90 μM, 4.94 ± 1.21 μM and 3.41 ± 0.65 μM respectively), and they achieved around 90% relaxation (30 μM). In aorta rings without an endothelium, the effect of compound 2f was abolished. Using the MTT assay to test for cell viability, only compound 2b induced cytotoxicity at the maximum concentration employed (30 μM). The results show that vasorelaxation by 4-phenylquinazolin-2(1H)-one derivatives might depend on the activation of a signalling pathway triggered by endothelium-derived factors.

Full text of DOI:10.3390/molecules25061467

molecules
Communication
Microwave Assisted Synthesis of
4-Phenylquinazolin-2(1H)-one Derivatives that
Inhibit Vasopressor Tonus in Rat Thoracic Aorta
Rafaela Teixeira 1,
*
, Talita Menengat 2, Gabriel Andrade 3, Bruno Cotrim 3, Cristiano Ponte 2,
Wilson C. Santos 1 and Gabriel Resende 3
1
Programa de Pós-Graduação em Ciências Aplicadas a Produtos para a Saúde, Faculdade de Farmácia,
Universidade Federal Fluminense, Niterói 24241-000, RJ, Brazil; wsantos@id.uff.br
Núcleo de Ciência Biomédicas Aplicadas, Instituto Federal do Rio de Janeiro, Rio de Janeiro 20270-021, RJ,
2
Brazil; talymenengat@yahoo.com.br (T.M.); cristiano.ponte@ifrj.edu.br (C.P.)
Núcleo de Ciências Químicas, Instituto Federal do Rio de Janeiro, Rio de Janeiro 20270-021, RJ, Brazil;
3
gfa.ifrj@gmail.com (G.A.); bruno.cotrim@ifrj.edu.br (B.C.); gabriel.resende@ifrj.edu.br (G.R.)
*
Correspondence: rafaelagomes@id.uff.br; Tel.: +55-(21)-983974444
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 12 February 2020; Accepted: 14 March 2020; Published: 24 March 2020
Abstract: Quinazolinones have pharmacological effects on vascular reactivity through different
mechanisms. We synthesized 4-phenylquinazolin-2(1H)-one derivatives under microwave irradiation
and tested them on the rat thoracic aorta. The prepared compounds 2a–2f were obtained in about 1 h
with suitable yields (31–92%). All derivatives produced vasorelaxant effects with IC50 values ranging
from 3.41
endothelium-intact aorta rings (IC50 4.31
and they achieved around 90% relaxation (30
compound 2f was abolished. Using the MTT assay to test for cell viability, only compound 2b induced
cytotoxicity at the maximum concentration employed (30 M). The results show that vasorelaxation
±
0.65
µM to 39.72
±
6.77
µ
M. Compounds 2c, 2e and 2f demonstrated the highest potency in
0.90 M, 4.94 1.21 M and 3.41 0.65 M respectively),
M). In aorta rings without an endothelium, the effect of
±
µ
±
µ
±
µ
µ
µ
by 4-phenylquinazolin-2(1H)-one derivatives might depend on the activation of a signalling pathway
triggered by endothelium-derived factors.
Keywords: microwave irradiation; 4-phenylquinazolin-2(1H)-one; vasorelaxation; endothelium; rat
thoracic aorta
1. Introduction
Heterocyclic drugs make up over 60% of major retail medicines for the pharmaceutical market [
Considering the heterocyclic quinazolines and quinazolinone-containing compounds, they have already
shown pharmacological relevance with broad therapeutic potential [ ]. Hence, several quinazoline
and quinazolinones have been applied in the chemical and pharmaceutical fields, and many of them
have already been approved as medicines [ ]. Quinazolinones are heterocyclic chemical compounds
1,2].
3
4
with two structural isomers, namely quinazolin-2(1H)-one and quinazolin-4(3H)-one (Figure 1); the
latter is the most investigated in the literature [5].
Molecules 2020, 25, 1467; doi:10.3390/molecules25061467
www.mdpi.com/journal/molecules

Molecules 2020, 25, 1467
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H
N
N
O
N
O
N
N
NH
Quinazolin-2(1H)-one
Quinazolin-4(3H)-one
Quinazoline
Figure 1. Quinazoline and quinazolinone structures.
Quinazoline derivatives have also demonstrated antihypertensive effects, such as the class of
the alpha 1-adrenergic ( 1) receptor antagonists used in the treatment of hypertension [ ]. Drugs
α
6,7
such as prazosin or terazosin act on vascular smooth muscle receptors, leading to vasodilation and a
consequent reduction in peripheral vascular resistance; these medications are used for the treatment of
benign prostatic hyperplasia (BPH) [
shown activity on vascular reactivity through different mechanisms such as the modulation of T-type
calcium channels [ ], angiotensin converting enzyme (ACE) [10] and phosphodiesterase-5 (PDE-5) [11].
Indeed, several therapeutic activities of quinazolines and their derivatives have been reported in the
literature, including antimicrobial [12], antitumor [13 14] and anticonvulsant [15]. In addition, interest
8]. Concerning their antihypertensive effects, quinazolines have
9
,
in the synthesis and biological activity of quinazolinones and quinazolines has contributed to the
growing number of new patents for such molecules in recent years [4].
Thereby, considering all this knowledge, the existence of several reports on vascular activity
attributed to quinazolines and, notably, few studies that focus on the biological effects of the isomer
quinazolin-2(1H)-one, we decided to investigate the putative effects of its derivatives on the rat
thoracic aorta. In the present investigation, we synthesized 4-phenylquinazolin-2(1H)-one derivatives
synthetized under microwave irradiation and tested them for their vasorelaxation properties using
experimental protocols on the rat thoracic aorta.
2. Results and Discussion
2.1. Chemistry
Several methodologies for the 4-phenylquinazolin-2(1H)-one scaffold have been described in
the literature; however, they require prolonged reaction times [16,17] or expensive reagents [18–21].
Most of the time heating using microwave radiation allows one to drastically reduce times and increase
the yield of reactions. Microwave radiation provides more efficient heating since it is generated
internally by direct absorption of microwave radiation by polar molecules present in the reaction
mixture (for example solvents, reagents and catalysts) [22,23]. In order to improve the existing synthesis
protocol, a series of 4-phenylquinazolin-2(1H)-one derivatives were synthetized using a conventional
methodology and microwave (MW) irradiation with urea and substituted 2-aminobenzophenones as
the preliminary compounds (Scheme 1). The results are recorded in Table 1.
Table 1 shows that the methodology using microwave heating provided higher yields and required
less reaction time compared with the traditional methodology. The compounds 2a–f, except compound
2b, were obtained in less than 1 h and obtained with good yields (63–92%). Compound 2b, which has
an electron withdrawing group (nitro group), had very poor yield with the traditional methodology
(16%), but this was increased using the microwave methodology (31%).

Molecules 2020, 25, 1467
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O
R3
R3
NH
O
R2
O
N
N
R2
CH3COOH
NH2
H2N
Termal heating
or MW
+
R1
a: R1= H; R2= H; R3= H
b: R1= NO2; R2= H; R3= H
c: R1= Cl; R2= Me; R3= H
d: R1= Cl; R2= F; R3= H
e: R1= Br; R2= H; R3= H
f: R1= Cl; R2= H; R3= Me
R1
1a-f
2 a-f
Scheme 1. Synthesis of 4-phenylquinazolin-2(1H)-one derivatives.
Table 1. Optimization of reaction conditions for the synthesis of compounds 2a–f.
Compound
Method
Conventional
MW
Yield (%)
Time
18 h
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2f
78
92
16
31
67
89
78
80
68
63
85
88
30 min
30 h
Conventional
MW
45 min
24 h
Conventional
MW
30 min
22 h
Conventional
MW
30 min
24 h
Conventional
MW
30 min
28 h
Conventional
MW
2f
30 min
2.2. Biological Evaluation
All tested compounds induced concentration-dependent relaxation (IC50 ranging from
3.41 ± 0.65 µM to 39.72 6.77 M) in endothelium-intact aorta arterial rings pre-contracted with
Phe 1 M (Table 2, Figures 2 and 3). The cumulative addition of increasing concentrations of the
studied compounds potentiated the observed vasorelaxant effect. Compound 2f was found to be the
most potent in endothelium-intact vessels (IC50 = 3.41 0.65 M), while compounds 2a 2b and 2d
showed the lowest potency in the endothelium-intact aorta at the concentrations employed in the
±
µ
µ
±
µ
,
present study. Additionally, compounds 2c
of 4.31 ± 0.90 µM, 4.94 ± 1.21 µM and 3.41
relaxation at the highest concentration of 30
,
2e and 2f demonstrated the highest potency with an IC50
0.65 M, respectively, and they achieved around 90%
M in endothelium-intact aorta rings. Thus, we decided to
±
µ
µ
test compound 2f at lower concentrations (30–300 nM) in endothelium-intact and endothelium-denuded
aorta rings.

Molecules 2020, 25, 1467
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Table 2. Compounds identification (ID), molecular weight and IC50 vasorelaxation response in
endothelium-intact (E+) aorta arterial vessels.
Compound ID
R1
H
R2
H
R3
H
MW (g/mol)
222.24
IC50 (µM)
39.72 ± 6.77
16.39 ± 3.50
4.31 ± 0.90
26.53 ± 8.98
4.94 ± 1.21
3.41 ± 0.65
2a
2b
2c
2d
2e
2f
NO2
Cl
H
H
267.24
Me
F
H
270.71
Cl
H
274.68
Br
H
H
301.13
Cl
H
Me
270.71
O
R3
N
N
R2
R1
2 a-f
Figure 2. Structure of 4-phenylquinazolin-2(1H)-one derivatives.
Figure 3. Concentration-response curves for compounds 2a
endothelium aortic rings pre-contracted with Phe 1 M. Cumulative concentrations (1
and 30 M) were added to the Phe contraction plateau. DMSO was employed at the same volume
used to dissolve the compound stock solution (maximum final concentration at 0.3%). All data are
expressed as mean standard error of the mean (SEM) (n = 4–5). (* P < 0.05; *** P < 0.001; **** P < 0.0001
–f
and control (vehicle: DMSO) in intact
µ
µ
M, 3 M, 10
µ
µM
µ
±
compound vs. control).
Preliminarily, we decided to investigate the effect of compound 2f, as the most effective in the
series, in an experimental model without the endothelium to assess its possible involvement on the
observed vasorelaxation. A representative record of cumulative concentrations of compound 2f (1
M, 10 M and 30 M) on aortic rings endothelium-intact and endothelium-denuded pre-contracted
with Phe 1 M are shown in Figure 4. Phe induced a steady tone in both preparations that were greater
µM,
3
µ
µ
µ
µ

Molecules 2020, 25, 1467
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in endothelium denuded rings. The results demonstrate that vasorelaxation was abolished in the
absence of the endothelium.
Figure 4. Concentration-response curves of compound 2f in endothelium-intact (E+) and
endothelium-denuded (E
(30 nM, 100 nM, 300 nM, 1
) Representative record of vasorelaxation induced by the cumulative addition (1
and 30 M) of compound 2f in endothelium-intact (E+) aortic rings pre-contracted with Phe 1
) Representative record of vasorelaxation induced by the cumulative addition (1 M, 3 M, 10
and 30 M) of compound 2f in endothelium-denuded (E ) aortic rings pre-contracted with Phe 1
All data are expressed as mean standard error of the mean (SEM) (n = 4). (**** P < 0.0001 E+ vs. E
−
) aortic rings pre-contracted with Phe 1
M, 3 M, 10 M and 30 M) were added to the Phe contraction plateau.
M, 3 M, 10
µM. (a) Cumulative concentrations
µ
µ
µ
µ
(
b
µ
µ
µM
µ
µM.
(
c
µ
µ
µM
µ
−
µ
M.
).
±
−
Based on the results of the MTT assay (Figure 5), it was observed that none of the compounds
induced a significant difference in the percentage of cell viability at the lowest concentrations used
(0.3–10
µM). Although all six compounds (2a–2f) showed a significant difference at the highest
concentration of 30
µM, it is important to note that the percentage of living cells in this case was above
70%, except for compound 2b (69.05%). According to ISO 10993: 5 (2009), samples that reduce cell
viability values below 70% should be considered cytotoxic. Therefore, only compound 2b could be
considered cytotoxic at the concentration of 30
µM. In addition, we highlight that these compounds in
general had IC50 values below 30 µM.
The main findings show that compounds 2a
–
2f were able to relax the aorta. Furthermore, the
results indicate an effect directly related to the presence of the endothelium for the 2f analogue.
Therefore, it is possible that vasorelaxation is dependent on the modulation of some signalling pathway
triggered by endothelium-derived factors (EDFs) [24]. It is noteworthy that nitric oxide (NO) is one of
the principle vasodilators related to tone control in most vessels, so our results with the 2f derivative
suggest the possibility of the involvement of NO in the observed vasorelaxation [25]. However, other
physiological mechanisms that play a role in the activity of the vascular smooth muscle contractile
machinery cannot be disregarded [26
,27]. Consequently, some other protocols must be tested to study
the influence of other pathways on the observed response.

Molecules 2020, 25, 1467
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Figure 5. Cell viability assessed by the MTT method on the VERO cell line after 48 h of exposure to the
compounds. The cells were exposed to different concentrations of the compounds (0.3 M, 1 M, 3 M,
10 M and 30 M). All data are expressed as mean standard error of the mean (SEM) (n = 22–25).
µ
µ
µ
µ
µ
±
(DMSO maximum final concentration at 0.3%) (* P < 0.05, compound vs. control).
As is broadly known, endothelial dysfunction is one of the relevant features in the pathophysiology
of hypertensive disorders such as hypertension [28]. Therefore, substances that directly affect
endothelial functional regulation such as the quinazoline derivatives studied in the present paper may
have significant potential in the treatment of circulation diseases [29].
3. Materials and Methods
3.1. General Information
The reactions were carried out in a 300-W CEM Discover focused microwave reactor (CEM
Microwave Technology Ltd., Buckingham, UK). Reagents were purchased from Sigma-Aldrich Brazil
(São Paulo, SP, Brazil) or donated by Nortec Química S/A (2-aminobenzophenones 1b–f) and were
used without further purification. Column chromatography was performed with silica gel 60
(Merck 70–230 mesh, RJ, Brazil). Analytical thin-layer chromatography (TLC) was performed with
silica gel plates (Merck, TLC silica gel 60 F254), and the plots were visualized using UV light or
aqueous solutions of ammonium sulphate. Yields refer to chromatographically and spectroscopically
homogeneous materials.
3.2. Chemistry
3.2.1. General Procedure for the Preparation of 2a–f
Conventional
A mixture of 2-aminobenzophenone 1a–f (1 mmol) and urea (15 mmol) in glacial acetic acid (10 mL)
was stirred at 140 ◦C and the progress of the reaction was monitored by TLC. After completion of the
reaction, the reaction mixture was filtered, and the precipitate was washed with water. The physical
and spectroscopic data were previously reported in the literature for 2a
2c [18].
, 2e and 2f [30]; 2b and 2d [31];

Molecules 2020, 25, 1467
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Microwave Irradiation
A mixture of 2-aminobenzophenone 1a
–
f
(1mmol) and urea (15 mmol) in glacial acetic acid (10 mL)
was irradiated in a sealed tube at 140 ◦C (200 w) for 30–45 min in a CEM Discover microwave reactor.
The reaction mixture was filtered, and the precipitate was washed with water.
3.3. Sample Preparation
All compounds were dissolved with DMSO 100% to obtain a stock solution of 10 mM. In all
experiments, the stock solution was employed to obtain a final concentration diluted in Krebs Henseleit
solution (vascular reactivity assay) and DMEM supplemented with 10% FBS (cytotoxicity assay).
3.4. Animals
Male Wistar normotensive rats (Rattus norvegicus) weighing between 200 and 300 grams were
supplied by the Central Animal Facility of Fluminense Federal University (NAL-UFF) (Rio de Jane◦iro,
Brazil). The animals were kept in standard environmental conditions of temperature (22
±
1 C)
and 12 h light/dark cycle, with free access to food (Purina, Brazil) and water. All experiments were
conducted in accordance to the guidelines established by National Council for Animal Experimentation
Control (CONCEA, Brazil). This study was approved by the Ethics Committee in the Use of Animals
of the Fluminense Federal University (CEUA-UFF), certificate under protocol number: 795/2017.
3.5. Compounds and Solution
L-phenylephrine hydrochloride (Phe), acetylcholine chloride (Ach) and dimethyl sulfoxide (DMSO)
were purchased from Sigma-Aldrich (São Paulo, Brazil). Reagents employed in the preparation of
Krebs Henseleit solution were all obtained from Merck (Rio de Janeiro, Brazil).
3.6. Vascular Reactivity
Animals were anesthetized by isoflurane (1% mg/kg) inhalation and, after the loss of motor
control, rats were euthanized by cervical dislocation. Subsequently, the thoracic aorta was dissected
and cleaned of connective tissue to obtain rings 4 mm in length that were suspended in a 15 mL organ
bath (Panlab four chamber organ bath, AD-Instruments, Sydney, Australia). Tissues were kept in
Krebs Henseleit solution at 37 ◦C with the following composition (mM): NaCl 120; KCl 5.0; MgCl2
1.1; CaCl2 2.5; NaH2PO4 1.2; N-[2-hydroxyethyl] piperazine-N’-[2-ethane-sulfonic acid] (HEPES) 10;
NaHCO3 15; and glucose 11, bubbled constantly with a gas mixture of 95% O2 and 5% CO2 (pH 7.4).
Each arterial segment was suspended between two steel hooks connected to an isometric transducer to
measure tension through a data acquisition system (PowerLab 8 and LabChart Pro, AD-Instruments,
Australia). After a stabilization period of 60 min at a rest tension of 1.0 g with periodic changes of
solution (every 15 min), a stable contraction was achieved with 1
µM Phe. Functional endothelial
integrity was assessed by the ability of 10
with 1 µM Phe.
µM ACh to induce
≥
70% relaxation in vessels pre-contracted
3.7. Cytotoxicity
A 3-[4,5-dimehyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazoliumbromide (MTT) assay was employed
to assess the general cytotoxicity for 4-phenylquinazolin-2(1H)-one derivatives. VERO cells (African
Green monkey (Cercopithecus aethiops) kidney cell line) were used and obtained from the Rio de Janeiro
Cell Bank (PABCAM, Federal University, Rio de Janeiro, Brazil) and grown in Roswell Park Memorial
Institute medium (Sigma-Aldrich, St. Louis, MO, USA) supplemented with 10% heat-inactivated fetal
bovine serum (FBS; Gibco BRL, Gaithersburg, MD, USA), without antibiotics. Cells were plated in
plastic Petri dishes and incubated at 37 ◦C under a 95% O2/5% CO2 atmosphere. Cell culture was
maintained up to 15 days until cells reached 90% confluence.

Molecules 2020, 25, 1467
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The MTT cell viability assay investigates the number of viable cells by measuring the
mitochondrial-dependent reduction of water-soluble tetrazolium into an insoluble formazan product.
The absorbance obtained is directly proportional to the activity of functional mitochondria and
represents the number of viable cells. Briefly, VERO cells were seeded at a density of 1
per well in 96-well plates containing 200 L of DMEM culture medium supplemented with 10% FBS
and incubated at 37 ◦C and 5% CO2 atmosphere. After the first 24 h, either vehicle only (control) or
compounds (0.3, 1, 3, 10 and 30 M) were added to the culture medium and VERO cells were incubated
×
104 cells
µ
µ
for an additional 48 h. At the end of the treatment period, the medium was replaced with complete
fresh medium containing 5 mg/mL tetrazolium dye (MTT) and incubated for 3 h; then, the medium was
removed and 100 µL of DMSO was added. Absorbance was measured with a plate reader (SpectraMax
190, CA, USA) at a wavelength of 550 nm and expressed as a percentage of the control (vehicle).
3.8. Expression of Data and Statistical Analysis
Values are expressed as mean
±
standard error of mean (SEM). A P-value less than 0.05 was
termed statistically significant. The IC50 values (defined as the concentration of the test compound that
reduced 50% of the maximal contraction) were obtained by actual concentration-response curve fitting
using GraphPad Prism 6.0 software (GraphPad Software, San Diego, CA). Statistical significance was
determined using Bonferroni
´s multiple comparison for vascular reactivity experiments and using
Turkey s multiple comparison for cytotoxicity evaluation following two-way analysis of variance
´
(ANOVA).
4. Conclusions
All tested compounds were obtained through simple synthetic reactions using simple
methodologies. The reaction methodology using microwave irradiation provided better yields
and lower reactional times when compared with the traditional methodology. In vitro screening for
a relaxant effect on aorta rings isolated from rats showed that compounds 2a–f exhibited significant
concentration-dependent effects that were dependent on the presence of an intact endothelium,
suggesting a mechanism of action mediated by endothelium-derived factors (EDFs). Additionally, only
one of the active compounds exhibited significant cytotoxicity at the highest concentration employed,
suggesting low toxicity. Nevertheless, further toxicity investigations are required to ensure these
findings. In conclusion, this series of molecules displayed the potential to serve as templates for the
development of new drugs for diseases involving vascular smooth muscle, especially in disorders in
which endothelial dysfunction is a relevant pathophysiological feature.
Author Contributions: R.T.: experimental design, in vitro experiments, data analysis, interpretation and writing –
original draft preparation. T.M.: cytotoxicity evaluation. G.A.: compound synthesis. B.C.: compound synthesis,
data analysis and data interpretation. C.P.: cytotoxicity evaluation, data interpretation, data analysis and
supervision. W.C.S.: experimental design, data analysis, data interpretation, supervision, manuscript drafting and
editing. G.R.: compound synthesis, data analysis, data interpretation and manuscript writing. All authors have
read and agreed to the published version of the manuscript.
Funding: FAPERJ (Brazil), CAPES (Brazil), Fundaci
ó
n Carolina (España), Instituto Nacional de Ci
ê
ncia e
Tecnologia (INCT REDOXOMA, CNPq) and Instituto Federal do Rio de Janeiro.
Acknowledgments: We would like to thank Faculdade de Farm
á
cia of Universidade Federal Fluminense, N
ú
cleo
de Ci
ê
ncias Biom
é
dicas Aplicadas and N
ú
cleo de Ci
ê
ncias Qu
í
micas of Instituto Federal do Rio de Janeiro on
mica S/A for donation of benzophenones 1b-f.
research facility support. We would like to acknowledge Nortec Qu
í
Conflicts of Interest: The authors declare no conflict of interest.

Molecules 2020, 25, 1467
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