Facile synthetic approach towards vasorelaxant active 4-hydroxyquinazoline-4-carboxamides

Article abstract of DOI:10.1039/c9ra04321g

A Facile synthetic approach is reported towards 4-hydroxyquinazoline-4-carboxamides 13a-i through ring expansion of 2,3-dioxoindoline-1-carboxamides 10a-c during secondary amine 11a-d nucleophilic reaction. Single crystal X-ray studies of 10c and 13d supp

Full text of DOI:10.1039/c9ra04321g

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Facile synthetic approach towards vasorelaxant
active 4-hydroxyquinazoline-4-carboxamides†
Cite this: RSC Adv., 2019, 9, 28534
b
c
Marian N. Aziz,a Siva S. Panda,
ElSayed M. Shalaby,
Nehmedo G. Fawzya
a
*
and Adel S. Girgis
A Facile synthetic approach is reported towards 4-hydroxyquinazoline-4-carboxamides 13a–i through
ring expansion of 2,3-dioxoindoline-1-carboxamides 10a–c during secondary amine 11a–
d nucleophilic reaction. Single crystal X-ray studies of 10c and 13d support the structures. Some of
the synthesized quinazolinecarboxamides 13 show promising vasorelaxant properties with potency
higher than that of Doxazosin through the pre-contracted (norepinephrine hydrochloride) rat aorta
standard bioassay. Good molecular models (2D-QSAR, pharmacophore) describe the biological
observations.
Received 9th June 2019
Accepted 4th September 2019
DOI: 10.1039/c9ra04321g
rsc.li/rsc-advances
globally (approximately 17.9 millions representing 31% of
global deaths in 2016 according to WHO “World Health
Organization”19,20). Heart attack and stroke are usually asso-
Introduction
Quinazoline is an important heterocyclic system that
occupies a striking position in medicinal chemistry due to
the diverse biological and/or pharmacological properties
associated with its derivatives.1–6 For example, Getinib
(Iressa) 1 is a drug clinically approved by the FDA for treat-
ment of non-small cell lung cancer (NSCLC, on May 5, 2003)
(Fig. 1). It is a tyrosine kinase inhibitor accessible for patients
with metastatic NSCLC.7,8 Erlotinib (Tarceva) 2 is also
a kinase inhibitor approved by the FDA (Nov. 18, 2004) for
locally advanced or metastatic NSCLC and pancreatic
cancers.9,10 Lapatinib (Tykerb) 3 is approved by the FDA (Mar.
13, 2007) for treatment of advanced or metastatic breast
cancer.11,12 However, due to the drug resistance observed by
the targeted rst generation reversible EGFR (epidermal
growth factor receptor) drugs 1–3, by many patients, the
second generation irreversible EGFR inhibitors were devel-
oped.13 Of which, Afatinib (Gilotrif) 4 and Dacomitinib
(Vizimpro) 5 were approved for treatment of metastatic
NSCLC (FDA on July 12, 2013 and Sept. 27, 2018,
respectively).14–17
ciated with hypertension.21 Many a1-adrenergic receptor (a1-
AR) antagonists are clinically useful drugs for vascular
smooth muscle relaxation (vasodilator) such as Doxazosin 6
and Terazosin 7 but associate with severe side effects.22 The
high mortality factor of hypertension and serious side effects
of the clinically known drugs dimensioned their applica-
tions, directed the research efforts for developing novel
effective hits/leads. The recent publications describing
diverse biological properties of quinazoline containing-
compounds as antibacterial,23 antiviral,24 antifungal,25 anti-
plasmodial,26 anti-inammatory,27 cholinesterase,28,29 and
monoamine oxidase inhibitors30 also prompted the present
work.
The present study is directed towards construction of
novel quinazoline-based analogues and investigation their
vasorelaxant properties. The amino group located at the 4-
position of the antihypertensive active drugs 6 and 7 were
replaced by a hydroxy group due to the common chemical
properties of the two functions. The alicyclic-amino ring is
also attached to the quinazolinyl C-4 forming an amidic
linkage (Scheme 1). Many synthetic pathways were developed
for construction of quinazoline-containing compounds
including m-chloroperbenzoic acid oxidative rearrangement
of 4-imino-(1H,4H)-3,1-benzoxazin-2-ones and reaction of
isatins with arylamines in the presence of hydrogen peroxide
as an oxidant.31 Previous publications described the ring
opening of isatins under the effect of water, alcohols,
amines,32,33 urea,34 hydrazines33,35 and guanidine.34,36 The
present study describes a facile synthetic approach via ring
expansion of isatin-1-carboxamides during secondary amine
nucleophilic attack.
Additionally, Doxazosin 6 and Terazosin 7 are well known
drugs for hypertension.18 Hypertension is one of the cardio-
vascular diseases which are the rst cause of human death
aDepartment of Pesticide Chemistry, National Research Centre, Dokki, Giza 12622,
Egypt. E-mail: girgisas10@yahoo.com
bDepartment of Chemistry & Physics, Augusta University, Augusta, GA 30912, USA
cX-Ray Crystallography Lab, Physics Division, National Research Centre, Dokki, Giza
12622, Egypt
† Electronic supplementary information (ESI) available: Copy of IR, 1H- and
13C-NMR spectra, biological curves, computational tables/gures. CCDC
1913146 and 1913147. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c9ra04321g
28534 | RSC Adv., 2019, 9, 28534–28540
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Advances
Fig. 1 Quinazoline-based antitumor and antihypertensive drugs.
purication. N-Ethyl-2,3-dioxoindoline-1-carboxamide (10c)
could be isolated in good microcrystallized form accessible
for single crystal X-ray studies, which add good support for
the structure (Fig. 2).
Reaction of 10a–c with secondary amines 11a–d in dry
THF led to ring expansion affording directly the 4-
hydroxyquinazoline-4-carboxamides 13a–i and not the ex-
pected 3-hydroxy-2-oxoindoline-1-carboxamides 12. IR
Results and discussion
Chemistry
Isocyanates 9a,b were subjected to reaction with isatins 8a,b
in dry tetrahydrofuran (THF) in the presence of sufficient
amount of triethylamine at 0 ꢀC affording the corresponding
2,3-dioxoindoline-1-carboxamides 10a–c in good yields
which were used in the next reaction without any further
Scheme 1 Synthetic route towards 4-hydroxyquinazoline-4-carboxamides 13a–i.
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 28534–28540 | 28535

View Article Online
RSC Advances
Paper
Fig. 2 ORTEP views of compounds 10c (left) and 13d (right) with the atom-numbering scheme. H atoms are shown as small spheres of arbitrary
radii.
spectrum of 13a (an example of the synthesized analogues)
reveals the carbonyl groups as a broad signal at n ¼
Vasodilation studies
The standard pre-contracted (norepinephrine hydrochloride) rat
aorta technique was utilized for determination the vasodilation
properties of the synthesized compounds 10c, 13a–i and compared
with Doxazosin (a1-AR antagonist).38 From the exhibited data
(Table 1, ESI Fig. S33 and S34†) it can be concluded that, many of
the synthesized quinazolines are vasorelaxant active agents with
efficacy comparable to that of Doxazosin. Compound 13h seems
superior among all the tested analogues with 2.2 folds potency
relative to the standard reference (IC50 ¼ 158, 348 mM for 13h and
Doxazosin, respectively). Compounds 13e also shows remarkable
vasorelaxant properties (about 139% potency of Doxazosin with
IC50 ¼ 250 mM). Promising smooth muscle relaxation is also
shown by compounds 13a,d,f,g (IC50 ¼ 298–332 mM). N-Ethyl-2,3-
dioxoindoline-1-carboxamide (10c) is also a promising vaso-
relaxant active agent (1.47 folds efficacy relative to the standard
drug).
Based on the observed vasodilation properties few SAR
(structure–activity relationship) rules can be stated. The chlo-
rine substituent attached at the quinazolinyl C-6 is an impor-
tant factor for enhancing the biological properties observed as
exhibited in pairs 13b/13c, 13d/13e and 13g/13h. The alicyclic-
amino ring of the amidic function is also a controlling param-
eter for biological activity. The importance of the amino ring for
1
1670 cmꢁ1. H-NMR spectrum of 13a reveals the triplet and
quartet signals of the ethyl groups at dH ¼ 1.03 and
2.74 ppm, respectively, which are also well observed at dC
¼
10.8, 18.5; 41.1, 56.0, respectively in the 13C-NMR spectrum.
The quinazolinyl C-2 and amidic carbonyls are shown at dC
¼ 151.9, 172.4 ppm, respectively. Meanwhile, the charac-
teristic quinazolinyl C-4 is exhibited at dC ¼ 87.1 ppm
(spectral charts are exhibited in ESI Fig. S1–S30,† over-
lapping of few carbon signals in the 13C-NMR spectral data
of compounds 13g,h is observed). Single crystal X-ray
studies of 13d support the chemical/stereochemical struc-
ture assigned (Fig. 2). The reaction is assumed to take place
through amine 11 nucleophilic attack at the indolyl C-2
giving rise to ve-membered ring opening followed by re-
cyclization with ring expansion to the six-membered qui-
nazoline heterocycle (Scheme 1).
X-ray studies
ORTEP views of compounds 10c and 13d are revealed in Fig. 2.
Compound 10c is crystallized in the monoclinic space group C2/
c while, compound 13d is crystallized in the monoclinic space
group P21/n (ESI Table S1†). The main constituent of 10c is the
indolyl heterocycle and the main constituents of 13d are qui-
nazolinyl, piperidinyl and phenyl rings. Compound 10c exhibits
one molecule per asymmetric unit cell and four molecules per
unit cell. However, compound 13d shows two molecules per
asymmetric unit cell and eight molecules per unit cell. In 10c,
the ethyl group is nearly perpendicular to the plane containing
the main constituent. Meanwhile, the piperidinyl ring of
compound 13d exhibits a chair conformation and the phenyl as
well as quinazolinyl heterocycle are nearly planar. Generally, the
geometrical parameters of compounds 10c and 13d (ESI Tables
S2 and S3†) are comparable to structures having similar
constituents.37 Different sets of intermolecular hydrogen-
bonding interactions stabilize the crystal structure of the
studied compounds and led to the formation of supramolecular
assemblies (ESI Table S4, Fig. S31 and S32†).
Table 1 Vasorelaxant properties of 10c, 13a–i and Doxazosin
Entry
Compd.
R
R1
NR2/R3
IC50, mM
1
10c
H
H
H
Cl
H
Cl
H
H
Cl
H
—
Et
—
NEt2
236
302
415
392
332
250
305
298
158
416
348
2
13a
Ph
Ph
Ph
Ph
Ph
Et
Ph
Ph
Et
3
13b
Pyrrolidinyl
Pyrrolidinyl
Piperidinyl
Piperidinyl
Piperidinyl
Morpholinyl
Morpholinyl
Morpholinyl
—
4
13c
5
13d
6
13e
7
13f
8
13g
9
10
11
13h
13i
Doxazosin
—
28536 | RSC Adv., 2019, 9, 28534–28540
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Advances
vasodilation properties enhancement can be arranged in the experimental biological properties support the goodness of
following order morpholinyl
>
piperidinyl
>
pyrrolidinyl the 3D-pharmacophoric model.
(compound 13f is an exception).
Conclusions
Molecular modeling studies
4-Hydroxyquinazoline-4-carboxamides 13a–i are synthesized in
a facile synthetic approach (yield 68–85%) via reaction of 2,3-
dioxoindoline-1-carboxamides 10a–c with secondary amines
11a–d in dry THF. Single crystal X-ray studies of 10c and 13d
support the chemical structures. Some of the synthesized qui-
nazolines reveal vasorelaxant properties with efficacy compa-
rable to that of Doxazosin especially, compound 13h that
exhibits 2.2 folds potency relative to the standard reference. 2D-
QSAR model describes the biological observations (N ¼ 9, n ¼ 2,
R2 ¼ 0.970). Also, the 3D-pharmacophoric model supports the
elements of design for the present study.
2D-QSAR study. QSAR (quantitative structure–activity rela-
tionship) study is a widely used computational technique for
explaining the biological observations and better under-
standing the parameters optimizing properties.39 Two
descriptor QSAR model was obtained by CODESSA-Pro for the
vasorelaxant quinazoline-4-carboxamides 13a–i (R2 ¼ 0.970, ESI
Table S5†). Explanation/calculation of the QSAR descriptors was
mentioned in the ESI.† Goodness of the QSAR model is sup-
ported by the leave one-out and leave many-out (up to 20% of
the compounds used in the study) coefficient values relative to
the original QSAR coefficient value (R2 ¼ 0.970, R2cvOO ¼ 0.905,
R2cvMO ¼ 0.937). The predicted IC50 values relative to the
experimental are also supporting evidence for the robust of
computational model (Fig. 3).
Experimental
Chemistry
3D-Pharmacophore study. Three chemical features (two
hydrophobics “H-1, H-2” and one hydrogen bonding donor
“HBD”, ESI Fig. S35 and S36†) are shown by the 3D-
pharmacophoric model (Discovery Studio 2.5 soware) for
the vasorelaxant active quinazoline-4-carboxamides 13a–i.40
All the synthesized compounds reveal alignment of the
hydroxyl group with the HBD and the amino residue/ring of
the amidic linkage with one of the hydrophobic in variable
tness affording diverse estimated biological properties (ESI
Table S8†). These observations support the elements of
design for the present study and also the assigned SAR
mentioned. The high correlations between the estimated and
Melting points were determined on a capillary point apparatus
(Stuart SMP3) equipped with a digital thermometer. IR spectra
(KBr) were recorded on a Shimadzu FT-IR 8400S spectropho-
tometer. Reactions were monitored using thin layer chroma-
tography (TLC) on 0.2 mm silica gel F254 plates (Merck)
utilizing various solvents for elution. The chemical structures of
the synthesized compounds were characterized by nuclear
magnetic resonance spectra (1H-NMR, 13C-NMR) and deter-
mined on a Bruker NMR spectrometer (500 MHz, 125 MHz). 13C-
NMR spectra are fully decoupled. Chemical shis were reported
in parts per million (ppm) using the deuterated solvent peak or
tetramethylsilane as an internal standard.
Reaction of 8a,b with isocyanates 9a,b
A solution of the corresponding isocyanate 9a,b (5 mmol) in dry
THF (5 ml) was added dropwise to a mixture of the appropriate
8a,b (5 mmol) in dry THF (20 ml) containing triethylamine (5.5
mmol), at 0 ꢀC. The reaction was magnetically stirred at the
same temperature for 10 h then, stored in the fridge overnight.
The separated solid was collected and washed with benzene
affording 10a,b which was used without any more purications.
In case of the reaction of 8a and 9b, the separated solid was
crystallized from benzene affording 10c as orange
microcrystals.
N-Ethyl-2,3-dioxoindoline-1-carboxamide (10c). It was ob-
tained from the reaction of 8a and 9b (reaction time 10 h) as
orange microcrystals from benzene with mp 159–161 ꢀC and
yield 73% (0.80 g). IR: nmax/cmꢁ1 3337, 1756, 1740, 1701, 1612.
1H-NMR (DMSO-d6) d (ppm): 1.15 (t, J ¼ 7.2 Hz, 3H, CH3CH2),
3.30–3.35 (m, 2H, CH3CH2), 7.28 (t, J ¼ 7.5 Hz, 1H, arom. H),
7.67 (d, J ¼ 7.5 Hz, 1H, arom. H), 7.71 (t, J ¼ 7.9 Hz, 1H, arom.
H), 8.17 (d, J ¼ 8.2 Hz, 1H, arom. H), 8.22 (t, J ¼ 5.3 Hz, 1H, NH).
13C-NMR (DMSO-d6) d (ppm): 14.7 (CH2CH3), 34.4 (NCH2CH3),
116.5, 118.9, 124.3, 124.6, 137.5, 148.2 (arom. C), 150.4 (urea
CO), 158.9 (indolyl C-2), 180.4 (indolyl C-3). Anal. calcd for
Fig.
3 BMLR-QSAR model plot of correlation representing the
observed versus predicted [log(IC50, mM)] values for the synthesized
vasorelaxant quinazoline (13a–i).
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 28534–28540 | 28537

View Article Online
RSC Advances
Paper
C11H10N2O3 (218.21): C, 60.55; H, 4.62; N, 12.84. Found: C, (carboxamide CO). Anal. calcd for C19H18ClN3O3 (371.82): C,
60.76; H, 4.77; N, 12.93.
61.38; H, 4.88; N, 11.30. Found: C, 61.57; H, 5.00; N, 11.38.
4-Hydroxy-3-phenyl-4-(piperidine-1-carbonyl)-3,4-dihy-
droquinazolin-2(1H)-one (13d). It was obtained from the
reaction of 10a and 11c (reaction time 6 h) as colorless
Reaction of 10a–c with secondary amines 11a–d
The appropriate secondary amine 11a–d (5.5 mmol) was added microcrystals from ethanol with mp 176–178 ꢀC and yield
dropwise to the magnetically stirred solution of 10a–c (5 mmol) 77% (1.35 g). IR: nmax/cmꢁ1 3387, 1682, 1636, 1605, 1501. 1H-
in dry THF (20 ml) at room temperature (20–25 ꢀC) for the NMR (DMSO-d6) d (ppm): 0.62 (br s, 1H, piperidinyl H), 1.12–
appropriate time. The separated solid was collected and crys- 1.46 (m, 5H, piperidinyl H), 2.64 (t, J ¼ 10.9 Hz, 1H, piper-
tallized from a suitable solvent affording the corresponding idinyl H), 3.12 (t, J ¼ 11.8 Hz, 1H, piperidinyl H), 3.49 (d, J ¼
13a,c,d,g–i. In case of 13b, 13e, and 13f the reaction mixture was 12.8 Hz, 1H, piperidinyl H), 3.94 (d, J ¼ 12.3 Hz, 1H, piper-
evaporated till dryness under reduced pressure. The remaining idinyl H), 6.75 (s, 1H, NH), 6.93–7.00 (m, 3H, arom. H), 7.30–
material was triturated with methanol (5 ml). The separated 7.34 (m, 6H, arom. H), 10.22 (s, 1H, OH). 13C-NMR (DMSO-
solid was collected and crystallized from a suitable solvent.
d6) d (ppm): 23.3, 24.0, 25.1 (piperidinyl C-3/4/5), 44.3, 46.9
N,N-Diethyl-4-hydroxy-2-oxo-3-phenyl-1,2,3,4-tetrahydroquinazoline-
(piperidinyl C-2/6), 85.4 (quinazolinyl C-4), 114.2, 120.6,
4-carboxamide (13a). It was obtained from the reaction of 10a and 11a 121.7, 125.6, 127.5, 128.3, 129.5, 129.7, 135.0, 137.8 (arom.
(reaction time 8 h) as colorless microcrystals from methanol with mp C), 150.7 (quinazolinyl C-2), 166.2 (carboxamide CO). Anal.
145–147 C and yield 71% (1.20 g). IR: nmax/cmꢁ1 3202, 3059, 1670, calcd for C20H21N3O3 (351.41): C, 68.36; H, 6.02; N, 11.96.
ꢀ
1609, 1497, 1412. 1H-NMR (DMSO-d6) d (ppm): 1.03 (t, J ¼ 6.9 Hz, 6H, 2 Found: C, 68.14; H, 5.84; N, 12.16.
CH2CH3), 2.74 (q, J ¼ 6.4 Hz, 4H, 2 CH2CH3), 6.41 (br s, 1H, NH), 6.80–
6-Chloro-4-hydroxy-3-phenyl-4-(piperidine-1-carbonyl)-3,4-
6.85 (m, 2H, arom. H), 7.05 (d, J ¼ 7.4 Hz, 1H, arom. H), 7.14 (t, J ¼ dihydroquinazolin-2(1H)-one (13e). It was obtained from the
7.3 Hz, 1H, arom. H), 7.22–7.27 (m, 5H, arom. H), 9.62 (br s, 1H, OH). reaction of 10b and 11c (reaction time 12 h) as colorless
13C-NMR (DMSO-d6) d (ppm): 10.8 (CH2CH3), 18.5 (CH2CH3), 41.1 microcrystals from n-butanol of mp 180–182 C and yield 68%
ꢀ
1
(NCH2CH3), 56.0 (NCH2CH3), 87.1 (quinazolinyl C-4), 113.0, 120.5, (1.30 g). IR: nmax/cmꢁ1 3314, 3210, 1682, 1643, 1605, 1493. H-
124.0, 125.7, 126.5, 127.6, 128.1, 130.7, 136.0, 139.3 (arom. C), 151.9 NMR (DMSO-d6) d (ppm): 0.65–0.77 (m, 1H, piperidinyl H),
(quinazolinyl C-2), 172.4 (carboxamide CO). Anal. calcd for C19H21N3O3 1.22–1.53 (m, 5H, piperidinyl H), 2.69 (t, J ¼ 11.0 Hz, 1H,
(339.40): C, 67.24; H, 6.24; N, 12.38. Found: C, 67.38; H, 6.30; N, 12.42. piperidinyl H), 3.16 (t, J ¼ 11.4 Hz, 1H, piperidinyl H), 3.48 (d, J
4-Hydroxy-3-phenyl-4-(pyrrolidine-1-carbonyl)-3,4-dihy-
droquinazolin-2(1H)-one (13b). It was obtained from the reac- idinyl H), 6.90 (br s, 2H, NH + arom. H), 7.01 (d, J ¼ 8.6 Hz, 1H,
¼ 13.4 Hz, 1H, piperidinyl H), 3.93 (d, J ¼ 12.5 Hz, 1H, piper-
tion of 10a and 11b (reaction time 10 h) as colorless microcrystals arom. H), 7.30–7.42 (m, 6H, arom. H), 10.45 (s, 1H, OH). 13C-
from methanol with mp 184–186 ꢀC and yield 74% (1.25 g). IR: nmax
/
NMR (DMSO-d6) d (ppm): 23.2, 24.1, 25.1 (piperidinyl C-3/4/5),
cmꢁ1 3503, 3402, 1678, 1636, 1605, 1504. 1H-NMR (DMSO-d6) 44.1, 46.7 (piperidinyl C-2/6), 85.1 (quinazolinyl C-4), 116.0,
d (ppm): 1.59–1.76 (m, 3H, pyrrolidinyl H), 2.53–2.56 (m, 1H, pyr- 122.3, 124.86, 124.94, 127.4, 128.2, 129.3, 129.6, 134.0, 137.5
rolidinyl H), 3.01 (quintet, J ¼ 7.0 Hz, 1H, pyrrolidinyl H), 3.18 (d, J ¼ (arom. C), 150.4 (quinazolinyl C-2), 165.5 (carboxamide CO).
4.8 Hz, 1H, pyrrolidinyl H), 3.35–3.38 (m, 1H, pyrrolidinyl H), 3.48– Anal. calcd for C20H20ClN3O3 (385.85): C, 62.26; H, 5.22; N,
3.53 (m, 1H, pyrrolidinyl H), 6.70 (s, 1H, NH), 6.93–7.00 (m, 3H, 10.89. Found: C, 62.44; H, 5.03; N, 10.73.
arom. H), 7.24 (d, J ¼ 7.4 Hz, 2H, arom. H), 7.30–7.38 (m, 4H, arom.
3-Ethyl-4-hydroxy-4-(piperidine-1-carbonyl)-3,4-dihy-
H), 10.22 (s, 1H, OH). 13C-NMR (DMSO-d6) d (ppm): 22.7, 25.8 droquinazolin-2(1H)-one (13f). It was obtained from the
(pyrrolidinyl C-3/4), 46.5, 47.5 (pyrrolidinyl C-2/5), 85.9 (quinazolinyl reaction of 10c and 11c (reaction time 24 h) as colorless
C-4), 113.8, 119.8, 121.7, 125.5, 127.3, 128.2, 129.4, 129.5, 135.8, microcrystals from benzene with mp 165–167 ꢀC and yield
137.6 (arom. C), 150.9 (quinazolinyl C-2), 166.2 (carboxamide CO). 73% (1.10 g). IR: nmax/cmꢁ1 3318, 3198, 3121, 1667, 1636,
Anal. calcd for C19H19N3O3 (337.38): C, 67.64; H, 5.68; N, 12.46. 1609, 1504. 1H-NMR (DMSO-d6) d (ppm): 0.61 (br s, 1H,
Found: C, 67.81; H, 5.59; N, 12.57.
piperidinyl H), 1.10 (t, J ¼ 7.0 Hz, 4H, CH3CH2 + piperidinyl
6-Chloro-4-hydroxy-3-phenyl-4-(pyrrolidine-1-carbonyl)-3,4-
H), 1.37–1.53 (m, 4H, piperidinyl H), 3.00–3.33 (m, 5H,
dihydroquinazolin-2(1H)-one (13c). It was obtained from the CH3CH2 + 3 piperidinyl H), 3.96 (br s, 1H, piperidinyl H),
reaction of 10b and 11b (reaction time 6 h) as colorless micro- 6.75 (s, 1H, NH), 6.86 (d, J ¼ 8.1 Hz, 1H, arom. H), 6.90–6.96
crystals from n-butanol with mp 208–210 ꢀC and yield 85% (1.58 (m, 2H, arom. H), 7.25 (t, J ¼ 7.6 Hz, 1H, arom. H), 9.96 (s,
g). IR: nmax/cmꢁ1 3564, 3345, 3210, 1682, 1643, 1605, 1489. H- 1H, OH). 13C-NMR (DMSO-d6) d (ppm): 14.3 (CH3CH2), 23.2,
1
NMR (DMSO-d6) d (ppm): 1.59–1.74 (m, 4H, pyrrolidinyl H), 24.1, 25.1 (piperidinyl C-3/4/5), 37.8 (CH3CH2), 44.5, 46.5
2.57–2.62 (m, 1H, pyrrolidinyl H), 3.01 (quintet, J ¼ 6.7 Hz, 1H, (piperidinyl C-2/6), 84.6 (quinazolinyl C-4), 113.6, 119.6,
pyrrolidinyl H), 3.33–3.52 (m, 2H, pyrrolidinyl H), 6.91 (s, 1H, 121.3, 125.7, 129.5, 135.0 (arom. C), 150.3 (quinazolinyl C-
NH), 6.92 (d, J ¼ 2.1 Hz, 1H, arom. H), 6.98 (d, J ¼ 8.7 Hz, 1H, 2), 167.5 (carboxamide CO). Anal. calcd for C16H21N3O3
arom. H), 7.22 (d, J ¼ 7.4 Hz, 2H, arom. H), 7.31–7.39 (m, 4H, (303.36): C, 63.35; H, 6.98; N, 13.85. Found: C, 63.22; H,
arom. H), 10.25 (s, 1H, OH). 13C-NMR (DMSO-d6) d (ppm): 22.6, 6.87; N, 13.79.
25.9 (pyrrolidinyl C-3/4), 46.6, 47.6 (pyrrolidinyl C-2/5), 86.0
4-Hydroxy-4-(morpholine-4-carbonyl)-3-phenyl-3,4-dihy-
(quinazolinyl C-4), 115.8, 122.0, 124.9, 125.1, 127.4, 128.2, 129.5, droquinazolin-2(1H)-one (13g). It was obtained from the reaction
129.6, 134.8, 137.4 (arom. C), 150.6 (quinazolinyl C-2), 165.8 of 10a and 11d (reaction time 20 h) as colorless microcrystals from
28538 | RSC Adv., 2019, 9, 28534–28540
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Advances
ethanol with mp 173–175 ꢀC and yield 71% (1.25 g). IR: nmax/cmꢁ1
3618, 3526, 3345, 3198, 1682, 1639, 1609. 1H-NMR (DMSO-d6)
d (ppm): 2.83 (t, J ¼ 8.9 Hz, 1H, morpholinyl H), 2.96 (t, J ¼ 9.5 Hz,
1H, morpholinyl H), 3.20–3.45 (m, 5H, morpholinyl H), 3.65–3.72
(m, 1H, morpholinyl H), 6.79 (s, 1H, NH), 6.96–7.03 (m, 3H, arom.
H), 7.29–7.35 (m, 6H, arom. H), 10.28 (s, 1H, OH). 13C-NMR (DMSO-
d6) d (ppm): 43.4, 46.7 (morpholinyl NCH2), 64.6, 65.7 (morpholinyl
OCH2), 85.8 (quinazolinyl C-4), 114.2, 118.7, 120.7, 121.6, 125.3,
127.2, 128.1, 128.7, 129.2, 129.6, 135.0, 137.9 (arom. C), 150.8 (qui-
nazolinyl C-2), 166.5 (carboxamide CO). Anal. calcd for C19H19N3O4
(353.38): C, 64.58; H, 5.42; N, 11.89. Found: C, 64.64; H, 5.56; N,
11.76.
Molecular modeling studies
Experimental procedures for the molecular modeling studies
are mentioned in the ESI.†
Conflicts of interest
The authors have declared no conict of interest.
Acknowledgements
This work was supported nancially by National Research
Centre, Egypt, project ID: 11010341.
6-Chloro-4-hydroxy-4-(morpholine-4-carbonyl)-3-phenyl-3,4-
dihydroquinazolin-2(1H)-one (13h). It was obtained from the
reaction of 10b and 11d (reaction time 6 h) as colorless micro-
crystals from n-butanol with mp 189–191 ꢀC and yield 75% (1.45
g). IR: nmax/cmꢁ1 3352, 3213, 1686, 1643, 1609. 1H-NMR (DMSO-
d6) d (ppm): 2.82–2.86 (m, 1H, morpholinyl H), 2.99 (t, J ¼
9.1 Hz, 1H, morpholinyl H), 3.23–3.43 (m, 5H, morpholinyl H),
3.64 (br d, J ¼ 10.1 Hz, 1H, morpholinyl H), 6.95–7.02 (m, 3H,
NH + 2 arom. H), 7.31–7.41 (m, 6H, arom. H), 10.42 (s, 1H, OH).
13C-NMR (DMSO-d6) d (ppm): 43.4, 46.7 (morpholinyl NCH2),
64.8, 65.8 (morpholinyl OCH2), 85.8 (quinazolinyl C-4), 116.1,
124.6, 125.0, 127.3, 128.2, 129.2, 129.6, 134.1, 137.7 (arom. C),
150.5 (quinazolinyl C-2), 166.0 (carboxamide CO). Anal. calcd
for C19H18ClN3O4 (387.82): C, 58.84; H, 4.68; N, 10.84. Found: C,
58.96; H, 4.78; N, 11.04.
Notes and references
1 D. Das and J. Hong, Recent advancements of 4-
aminoquinazoline derivatives as kinase inhibitors and
their applications in medicinal chemistry, Eur. J. Med.
Chem., 2019, 170, 55–72.
2 V. Alagarsamy, K. Chitra, G. Saravanan, V. R. Solomon,
M. T. Sulthana and B. Narendhar, An overview of
quinazolines: pharmacological signicance and recent
developments, Eur. J. Med. Chem., 2018, 151, 628–685.
3 I. Khan, S. Zaib, S. Batool, N. Abbas, Z. Ashraf, J. Iqbal and
A. Saeed, Quinazolines and quinazolinones as ubiquitous
structural fragments in medicinal chemistry: an update on
3-Ethyl-4-hydroxy-4-(morpholine-4-carbonyl)-3,4-dihy-
the
development
of
synthetic
methods
and
droquinazolin-2(1H)-one (13i). It was obtained from the reac-
tion of 10c and 11d (reaction time 10 h) as colorless
microcrystals from benzene with mp 161–163 ꢀC and yield
77% (1.17 g). IR: nmax/cmꢁ1 3310, 3267, 3210, 1748, 1655,
1609. 1H-NMR (CDCl3) d (ppm): 1.33 (t, J ¼ 7.0 Hz, 3H,
CH3CH2), 2.94 (br t, J ¼ 9.8 Hz, 1H, morpholinyl H), 3.11 (br
d, J ¼ 13.7 Hz, 1H, morpholinyl H), 3.23–3.27 (m, 1H, mor-
pholinyl H), 3.34–3.55 (m, 4H, CH3CH2 + 2 morpholinyl H),
3.61 (t, J ¼ 9.8 Hz, 1H, morpholinyl H), 3.78 (br d, J ¼ 11.9 Hz,
1H, morpholinyl H), 4.01 (br d, J ¼ 13.3 Hz, 1H, morpholinyl
H), 6.65 (s, 1H, NH), 6.87 (d, J ¼ 8.1 Hz, 1H, arom. H), 7.03 (t, J
¼ 7.4 Hz, 1H, arom. H), 7.06 (t, J ¼ 6.5 Hz, 1H, arom. H), 7.31
(d, J ¼ 8.3 Hz, 1H, arom. H), 9.57 (s, 1H, OH). 13C-NMR
(CDCl3) d (ppm): 14.7 (CH3CH2), 38.8 (CH3CH2), 44.6, 46.9
(morpholinyl NCH2), 65.3, 66.4 (morpholinyl OCH2), 85.0
(quinazolinyl C-4), 114.4, 119.1, 122.6, 125.9, 130.3, 134.5
(arom. C), 152.0 (quinazolinyl C-2), 169.1 (carboxamide CO).
Anal. calcd for C15H19N3O4 (305.33): C, 59.01; H, 6.27; N,
13.76. Found: C, 59.08; H, 6.36; N, 13.89.
pharmacological diversication, Bioorg. Med. Chem., 2016,
24, 2361–2381.
4 I. Khan, A. Ibrar, W. Ahmed and A. Saeed, Synthetic
approaches, functionalization and therapeutic potential of
quinazoline and quinazolinone skeletons: the advances
continue, Eur. J. Med. Chem., 2015, 90, 124–169.
5 S. Ravez, O. Castillo-Aguilera, P. Depreux and L. Goossens,
Quinazoline derivatives as anticancer drugs:
a patent
review (2011 - present), Expert Opin. Ther. Pat., 2015, 25,
789–804.
6 I. Khan, A. Ibrar, N. Abbas and A. Saeed, Recent advances in
the structural library of functionalized quinazoline and
quinazolinone scaffolds: synthetic approaches and
multifarious applications, Eur. J. Med. Chem., 2014, 76,
193–244.
7 https://www.drugs.com/history/iressa.html.
8 https://www.cancer.gov/about-cancer/treatment/drugs/
getinib.
9 https://www.drugs.com/history/tarceva.html.
10 https://www.cancer.gov/about-cancer/treatment/drugs/
erlotinibhydrochloride.
Single crystal X-ray studies
11 https://www.drugs.com/history/tykerb.html.
Experimental procedure for the single X-ray studies of 12 https://www.cancer.gov/about-cancer/treatment/drugs/
compounds 10c and 13d is mentioned in the ESI.†
lapatinibditosylate.
13 Y. Zhang, L. Chen, H. Xu, X. Li, L. Zhao, W. Wang, B. Li and
X. Zhang, 6,7-Dimorpholinoalkoxy quinazoline derivatives
as potent EGFR inhibitors with enhanced antiproliferative
activities against tumor cells, Eur. J. Med. Chem., 2018, 147,
77–89.
Vasodilation studies
Experimental procedure utilized for vasodilation studies is
mentioned in the ESI.†
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 28534–28540 | 28539

View Article Online
RSC Advances
Paper
14 https://www.drugs.com/history/gilotrif.html.
15 https://www.cancer.gov/about-cancer/treatment/drugs/
afatinibdimaleate.
N1-substituted derivatives of 2,3-dihydroquinazolin-4(1H)-
one as inhibitors of cholinesterases, Bioorg. Chem., 2017,
72, 256–267.
16 https://www.drugs.com/history/vizimpro.html.
17 https://www.cancer.gov/about-cancer/treatment/drugs/
dacomitinib.
29 M. Sarfraz, N. Sultana, U. Rashid, M. S. Akram, A. Sadiq and
M. I. Tariq, Synthesis, biological evaluation and docking
studies of 2,3-dihydroquinazolin-4(1H)-one derivatives as
inhibitors of cholinesterases, Bioorg. Chem., 2017, 70, 237–
244.
`
18 G. Romeo, L. Materia, G. Marucci, M. Modica, V. Pittala,
L. Salerno, M. A. Siracusa, M. Buccioni, P. Angeli and
K. P. Minneman, New pyrimido[5,4-b]indoles and [1] 30 M. A. Qhobosheane, A. Petzer, J. P. Petzer and L. J. Legoabe,
benzothieno[3,2-d]pyrimidines: high affinity ligands for the
a1-adrenoceptor subtypes, Bioorg. Med. Chem. Lett., 2006,
16, 6200–6203.
Synthesis and evaluation of 2-substituted 4(3H)-
quinazolinone thioether derivatives as monoamine oxidase
inhibitors, Bioorg. Med. Chem., 2018, 26, 5531–5537.
31 G. Shi, X. He, Y. Shang, C. Yang and L. Xiang, Oxidative
rearrangement of isatins with arylamines using H2O2 as
oxidant: a facile synthesis of quinazoline-2,4-diones and
evaluation of their antibacterial activity, Chin. J. Chem.,
2017, 35, 1835–1843.
19 https://www.who.int/cardiovascular_diseases/en/.
20 https://www.who.int/cardiovascular_diseases/world-heart-
day/en/.
21 K. S. Jain, J. B. Bariwal, M. K. Kathiravan, M. S. Phoujdar,
R. S. Sahne, B. S. Chauhan, A. K. Shah and M. R. Yadav,
Recent advances in selective a1-adrenoreceptor antagonists 32 S. Petersen, H. Helmut and L. Born, Isatin-N-
¨
as antihypertensive agents, Bioorg. Med. Chem., 2008, 16,
4759–4800.
carbonsaureamide und ihre Reaktionen, Justus Liebigs Ann.
Chem., 1974, 12, 2003–2014.
´
˜
22 J. Munın, E. Quezada, A. Cuinas, M. Campos-Toimil, 33 L. Capuano and K. Benz, Spirocyclisierungen, Chem. Ber.,
˜
E. Uriarte, L. Santana and D. Vina, Synthesis, biological
1977, 110, 3849–3861.
evaluation and structure–activity relationships of new 34 M. Yamagishi, K.- i. Ozaki, H. Ohmizu, Y. Yamada and
phthalazinedione derivatives with vasorelaxant activity,
Eur. J. Med. Chem., 2014, 82, 407–417.
M. Suzuki, Quinazolin-2-ones having a spirohydantoin
ring. I. Synthesis of spiro[1,2,3,4-tetrahydroquinazoline-
23 S. Gatadi, T. V. Lakshmi and S. Nanduri, 4(3H)-
Quinazolinone derivatives: Promising antibacterial drug
leads, Eur. J. Med. Chem., 2019, 170, 157–172.
4,4'-imidazolidine]-2,2',5'-trione
carbamoylisatin with urea or guanidine, Chem. Pharm.
Bull., 1990, 38, 2926–2928.
by
reaction
of
1-
24 D. Xie, J. Shi, A. Zhang, Z. Lei, G. Zu, Y. Fu, X. Gan, L. Yin, 35 S. Petersen, Dyestuffs and heterocycles inters- ie 3-substd 2-
B. Song and D. Hu, Syntheses, antiviral activities and
induced resistance mechanisms of novel quinazoline
keto-4-hydroxy-1,2,3,4-tetra hydro quinazoline-4-carboxylic
acid hydrazides, Ger. Patent, DE2314242A1, 1973.
derivatives containing a dithioacetal moiety, Bioorg. Chem., 36 D. C. Palmer, e-EROS Encyclopedia of Reagents for Organic
2018, 80, 433–443. Synthesis, 2001, pp. 1–4.
25 J. Zhang, J. Liu, Y. Ma, D. Ren, P. Cheng, J. Zhao, F. Zhang 37 A. F. Mabied, A. S. Girgis, E. M. Shalaby, R. F. George,
and Y. Yao, One-pot synthesis and antifungal activity
against plant pathogens of quinazolinone derivatives
containing an amide moiety, Bioorg. Med. Chem. Lett.,
2016, 26, 2273–2277.
B. E. M. El-Gendy and F. N. Baselious, Stereoselective
synthesis, structural and spectroscopic study of 4,5,11-
triazatricyclo[6.2.1.0*2,6*]undec-5-ene, J. Heterocycl. Chem.,
2016, 53, 1074–1080.
26 A. Bouchut, D. Rotili, C. Pierrot, S. Valente, S. Latte, 38 E. M. Shalaby, A. S. Girgis, H. Farag, A. F. Mabied and
J. Schultz, U. Hoglund, R. Mazzone, A. Lucidi, G. Fabrizi,
D. Pechalrieu, P. B. Arimondo, T. S. Skinner-Adams,
M. J. Chua, K. T. Andrews, A. Mai and J. Khalife,
A. N. Fitch, Synthesis, X-ray powder diffraction and DFT
calculations of vasorelaxant active 3-(arylmethylidene)
pyrrolidine-2,5-diones, RSC Adv., 2016, 6, 112950–112959.
Identication of novel quinazoline derivatives as potent 39 A. M. Srour, S. S. Panda, A. M. M. Salman, M. A. El-
antiplasmodial agents, Eur. J. Med. Chem., 2019, 161, 277–
291.
27 K. P. Rakesh, H. M. Manukumar and D. C. Gowda, Schiff's
bases of quinazolinone derivatives: synthesis and SAR
Manawaty, R. F. George, E. M. Shalaby, A. N. Fitch,
N. G. Fawzy and A. S. Girgis, Synthesis and molecular
modeling studies of bronchodilatory active indole-pyridine
conjugates, Future Med. Chem., 2018, 10, 1787–1804.
studies of a novel series of potential anti-inammatory and 40 S. S. Panda, O. S. Detistov, A. S. Girgis, P. P. Mohapatra,
antioxidants, Bioorg. Med. Chem. Lett., 2015, 25, 1072–1077.
28 N. Sultana, M. Sarfraz, S. T. Tanoli, M. S. Akram, A. Sadiq,
U. Rashid and M. I. Tariq, Synthesis, crystal structure
determination, biological screening and docking studies of
A. Samir and A. R. Katritzky, Synthesis and molecular
modeling of antimicrobial active uoroquinolone-pyrazine
conjugates with amino acid linkers, Bioorg. Med. Chem.
Lett., 2016, 26, 2198–2205.
28540 | RSC Adv., 2019, 9, 28534–28540
This journal is © The Royal Society of Chemistry 2019