Enhancement of Different Biomedical Activities of Newly Synthesized Quinazoline Derivatives

Article abstract of DOI:10.1002/jhet.3147

A series of newly synthesized compounds of quinazolinone by various substituents was screened for its pharmacological activities. These included their action as antibacterial agents against pathogenic bacteria (Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) and as antifungal agents against Aspergillus niger and pathogenic yeast (Candida albicans). The presently investigated compounds were synthesized in higher yields, and the structure features were elucidated on the basis of IR, ¹H-NMR, and mass and elemental analysis data. These compounds were also evaluated as antioxidant agent. The results revealed that six compounds (2a, 11b, 11a, 2b, 13a, and 3c) exhibited higher antimicrobial activity against the tested pathogenic strains. In addition, it was found that compound 6a exhibited a radical scavenging activity higher than other studied compounds.

Full text of DOI:10.1002/jhet.3147

Month 2018
Enhancement of Different Biomedical Activities of Newly Synthesized
Quinazoline Derivatives
a
b
b
a
c
*
Ibrahim F. Zeid, Emad M. Kassem, Neama A. Mohamed, Ahmed A. Salman, and Al Shimaa G. Shalaby
aDepartment of Chemistry, Faculty of Science, Menoufiya University, Shibin Al Kawm, Egypt
bDepartment of Therapeutical Chemistry, National Research Centre, Dokki, Cairo, Egypt
cChemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Division,
National Research Centre, Dokki, Cairo, Egypt
*
E-mail: shimaagamalnrc@gmail.com
Received October 31, 2017
DOI 10.1002/jhet.3147
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of newly synthesized compounds of quinazolinone by various substituents was screened for its
pharmacological activities. These included their action as antibacterial agents against pathogenic bacteria
(Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, and Pseudo-
monas aeruginosa) and as antifungal agents against Aspergillus niger and pathogenic yeast (Candida
albicans). The presently investigated compounds were synthesized in higher yields, and the structure fea-
tures were elucidated on the basis of IR, 1H-NMR, and mass and elemental analysis data. These compounds
were also evaluated as antioxidant agent. The results revealed that six compounds (2a, 11b, 11a, 2b, 13a, and
3c) exhibited higher antimicrobial activity against the tested pathogenic strains. In addition, it was found that
compound 6a exhibited a radical scavenging activity higher than other studied compounds.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
for quinazoline compounds has been characterized by
significant advances. As on date, about 60 clinically used
drugs are quinazoline derivatives, for example,
febrifugine 27 [9], a quinazolinone alkaloid, possessing
antimalarial potential from the Chinese plant Aseru
(Dichroa febrifuga Lour), besides the discovery of
considerable soporific and sedative action of the synthetic
2-methyl-3aryl-4-quinazolone derivatives as afloqualone
28 [10], proquazone 29 (Biarison®) [11], a nonsteroidal
anti-inflammatory drug, prazocin 30 (Minipress®) [8], a
sympatholytic with antihypertensive activity, and
albaconazole 31 (UR-9825) [12], a triazole antifungal.
Quinazolines are a fundamental class of N-heterocyclic
system; it is considered as a base unit in various natural
and synthetic compounds with different biological
activities [1–4]. Quinazoline ring represents a building
block for approximately 150 bioactive naturally occurring
alkaloids [5,6]. Quinazoline derivatives have also emerged
as integral backbones of over 60 existing drugs [7,8].
The most objective result in many researches showed the
effectiveness of quinazolines against various diseases
caused by microorganisms. In the last decades, the search
© 2018 Wiley Periodicals, Inc.

I. F. Zeid, E. M. Kassem, N. A. Mohamed, A. A. Salman, and AL. S. G. Shalaby
Vol 000
with carbon disulfide in dimethylformamide (DMF) and
in the presence of hydrazine hydrate via stirring to
produce compound (7), which was allowed to react
with acetyl acetone/ethyl acetoacetate via heating on
water bath to afford compounds (8) and (9), respectively
(Scheme 1).
Compound (10a) reacted with acetyl/benzoyl chloride
in the presence of pyridine via refluxing to produce
compounds (11a,b), respectively. Compound (10b) can
be reacted with chloroacetic acid in the presence of
absolute ethanol via stirring to afford compound (12).
Compounds (10a,b) [34] can be reacted with ethyl
chloroacetate in the presence of methanol to give
compounds (13a,b). Compounds (14a,b) were
synthesized by the reaction of compounds (13a,b) with
4-chloroaniline in ethanol by refluxing. Compounds
(15a,b) were synthesized by the reaction of compounds
(13a,b) with thiosemicarbazide in DMF via refluxing
(Scheme 2).
Resistance of pathogenic strain against antibiotic still
becoming a potential problem for various diseases and
infections led to the screening of novel synthetic compounds
of quinazoline and its derivatives through substituted
groups. Owing to the broad spectrum of quinazoline, which
possesses pharmacological activities [13–33], therefore,
different biological activities were evaluated for these new
synthetic quinazolines. Anticoagulant and antithrombotic
activities are among the most widely studied properties of
newly synthesized compounds. Thus, the present synthetic
quinazoline derivatives were also examined for their
anticoagulant and fibrinolytic activities.
Evaluation of biological activity depending on structure–
activity relationship. Antimicrobial activity of quinazoline
derivatives. The antimicrobial activity of the investigated
samples was examined against Gram-positive bacteria
(Staphylococcus aureus and Streptococcus pneumoniae)
and Gram-negative bacteria (Escherichia coli ATCC25922,
Klebsiella pneumoniae ATCC13883, and Pseudomonas
aeruginosa ATCC27953) as pathogenic bacteria, Candida
albicans NRRL Y-477 as pathogenic yeast, and Aspergillus
niger as pathogenic fungi. Antimicrobial activity was
expressed as mean diameter of inhibition zone (IZ) (mm).
Table 1 illustrates the diameter of IZ differs according to
the compound used against all studied pathogens. As
shown from the data, there are eight main compounds
appeared more effective than the other. Among all
compounds, 11b has a potent antimicrobial activity on all
the tested pathogens forming a maximum value (IZ) of
24.0 0.2, 22.0 0.5, 22.0 0.5, 20 0.3, 18 0.3,
13 0.2, and 10 0.2 mm against C. albicans, A. niger,
E. coli, K. pneumoniae, P. aeruginosa, S. pneumoniae, and
S. aureus, respectively. Noteworthy is that activity is
The biological activities of quinazoline are related to
their structural features such as the position of branching.
Therefore, the aim of the present study was to examine
the antimicrobial, antioxidant, and fibrinolytic and
anticoagulation activities of synthesis of quinazoline and
their derivatives by modification on structure.
RESULTS AND DISCUSSION
Chemistry.
Compound 2-(pyridin-4-yl)-4H-benzo[d]
[1,3]oxazin-4-one (1) reacted with appropriate sulfa
drugs, namely, sulfamethazine, sulfaguanidine,
sulfamethoxazole, sulfanilamide, sulfapyridine, and
sulfadiazine, in the presence of glacial acetic acid and
anhydrous sodium acetate via refluxing to produce (2a–f),
respectively (Scheme 1). Compound (2d) reacted with
cyanate isothiocyanate derivatives, namely, ethyl
isothiocyanate, cyclohexyl isothiocyanate, and phenyl
isocyanate, in dry acetone via refluxing to give (3a–c),
respectively. Also, compound (1) reacted with p-
phenylenediamine in the presence of pyridine by heating
on sand bath to afford 3-(4-aminophenyl)-2-(pyridin-4-yl)
quinazolin-4(3H)-one (4), which was allowed to react
with appropriate linear sugar, namely, D-mannose and/or
D-arabinose, in absolute ethanol in the presence of drops
of glacial acetic acid via heating at 80°C for 6 h
to produce compounds (5a,b), respectively (Scheme 1).
The latter was allowed to react with thiosalicylic acid in
the presence of dry benzene via refluxing to produce
(6a,b), respectively. Compound (4) can be reacted
arranged
in
the
following
order:
11b > 2a > 2b > 11a > 3c. Compound 13a shows the
highest antimicrobial activity against S. aureus. The other
compounds exhibit a weak antimicrobial activity.
Minimum inhibitory concentration of quinazoline derivatives
(MIC). According to the data in Table 2, the quinazoline
compound as starting compound possesses variable sites at
positions 2 and 3, which improving broad spectrum
antimicrobial activity owing to substitution such as most
active compound 11b by adding phenyl group,
consequently 2a compound by interfering sulfadiazine
group, also 2b compound substitution happened by
addition of sulfaguanidine group, 11a compound addition
of acetyl group make enhancement in antimicrobial
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Biological Evaluation of Quinazoline Derivatives
Scheme 1
activity, respectively, compound 3c changed by interfering
phenyl group.
Modification to quinazoline moiety in case of 13a
presented by addition of ester group showed that greater
antibacterial activity against S. aureus.
The results indicated that the list of the newly
synthesized compounds have antibacterial and antifungal
activities expect 6b, 5b, 2e, and 13b.
Antioxidant activity of quinazoline derivatives. The free-
radical scavenging activity of new derivatives compound of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

I. F. Zeid, E. M. Kassem, N. A. Mohamed, A. A. Salman, and AL. S. G. Shalaby
Vol 000
Scheme 2
quinazoline was evaluated using the DPPH method.
Obviously, structural modifications improve the antioxidant
activity. According to the results in Table 3, a significant
increase concentration of DPPH radical because of the
scavenging ability of soluble solids in compound (6a)
exhibited the highest antioxidant activity of 65%.
quinazoline exhibited relatively higher antimicrobial and
antioxidant action, they were subjected to further biological
evaluation by determining their fibrinolytic and
anticoagulant activities. The results of Table 4 indicates that
the “four compounds (6b, 5b, 2b, and 4)” were
characterized by their relatively higher fibrinolytic activities
(80% lysis of plasma clot) as compared with those of the
“remaining compounds” (50–75% lysis of plasma clot) and
Fibrinolytic and anticoagulant activity of quinazoline
derivatives.
As the newly synthesized compounds of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Biological Evaluation of Quinazoline Derivatives
Table 1
Antimicrobial activity of newly synthesized quinazoline derivatives that was expressed as mean diameter of inhibition zone (mm).
Mean diameter of inhibition zone (mm)
Gram-positive bacteria
Gram-negative bacteria
Yeast
Fungi
Compound
no.
Staphylococcus
Streptococcus
pneumoniae
Escherichia
coli
Pseudomonas
aeruginosa
Klebsiella
pneumoniae
Candida
albicans
Aspergillus
niger
aureus
2a
2b
2c
2e
2f
3c
4
5a
15.0 0.1
10.0 0.2
17.0 0.2
12.0 0.2
20.0 0.2
20.0 0.5
22.0 0.3
À
18.0 0.5
20.0 0.5
20.0 0.2
À
20.0 0.2
18.0 0.5
18.0 0.2
À
22.0 0.3
12.0 0.2
15.0 0.1
18.0 0.2
14.0 0.5
17.0 0.3
10.0 0.2
12.0 0.1
12.0 0.5
18.0 0.3
À
À
À
À
À
À
15.0 0.2
15.0 0.2
15.0 0.2
20.0 0.2
À
10.0 0.5
12.0 0.5
À
12.0 0.2
14.0 0.5
À
À
12.0 0.2
10.0 0.5
10.0
À
À
22.0
À
À
À
À
À
À
5b
6a
6b
À
À
12.0 0.2
À
À
À
À
À
À
À
10.0 0.1
À
12.0 0.2
À
12.0 0.1
À
12.0 0.2
12.0 0.3
À
À
À
11a
11b
13a
13b
14a
14b
15a
15b
Control
10.0 0.3
15.0 0.2
13.0 0.2
20.0 0.3
À
18.0 0.2
22.0 0.5
12.0 0.2
À
15.0 0.2
18.0 0.3
15.0 0.5
À
20.0 0.5
20.0 0.3
16.0 0.2
À
17.0 0.1
13.0 0.2
22.0 0.5
18.0 0.3
10.0 0.1
12.0 0.1
12.0 0.1
15.0 0.2
À
10.0 0.2
25.0 0.2
24.0 0.5
18.0 0.2
À
À
À
12
15.0 0.5
25.0 0.3
12.0 0.1
16.0 0.2
22.0
10.0 0.2
22.0 0.5
15.0 0.1
10.0 0.2
20.0
12.0 0.2
22.0 0.2
15.0 0.2
10.0 0.1
20.0
À
À
À
À
À
À
À
À
10.0 0.2
20.0
À
22.0
25.0
22.0
Control: Imipenem 10 μg for bacteria and griseofulvin 10 μg for fungi and yeast.
Table 2
MIC of newly synthesized quinazoline on indicator pathogens.
MIC (μg/mL)
Gram-positive bacteria
Gram-negative bacteria
Yeast
Fungi
Compound
no.
Staphylococcus
Streptococcus
pneumoniae
Escherichia
coli
Pseudomonas
aeruginosa
Klebsiella
pneumoniae
Candida
albicans
Aspergillus
niger
aureus
2a
2b
2c
2e
2f
3c
4
5a
100
100
À
100
100
À
50
100
50
100
100
100
À
100
100
100
À
50
100
100
À
100
150
100
10
À
À
À
100
100
À
100
100
À
100
100
À
100
100
À
100
100
À
À
200
100
200
À
100
200
À
À
À
À
À
À
5b
6a
6b
À
À
À
À
À
À
À
À
200
À
200
À
200
À
200
À
200
À
200
À
À
11a
11b
13a
13b
14a
14b
15a
15b
Control
100
100
25
À
100
100
50
À
100
50
100
50
100
50
100
50
100
À
100
100
100
100
100
200
200
À
100
À
100
À
100
À
À
50
À
150
100
100
100
50
100
100
100
100
50
100
100
100
100
50
À
À
À
À
À
À
À
100
50
À
50
50
50
The MIC value was expressed as the lowest concentration of the antibacterial and antifungal agents.
MIC, minimum inhibitory concentration.
Journal of Heterocyclic Chemistry
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I. F. Zeid, E. M. Kassem, N. A. Mohamed, A. A. Salman, and AL. S. G. Shalaby
Vol 000
Table 3
“Heparin” preparation. The variation in fibrinolytic and
anticoagulant activities of the synthesized compounds can
be attributed to the position of branching and structure
differences (structure–activity relationship).
Antioxidant activity of newly synthesized quinazoline.
Compound no.
TAC %
2a
32
46
31
26
34
54
58
12
29
65
13
34
36
32.5
26.5
28
24
33
29
96
2b
2c
2e
2f
3c
4
5a
5b
6a
6b
11a
11b
13a
13b
14a
14b
MATERIAL AND METHODS
Chemistry.
All melting points are uncorrected and
measured by the use of an electrothermal capillary
melting point apparatus. Infrared spectra were acquired
with a Jasco FT/IR-6100 using KBr discs. 1H-NMR
spectra were acquired with Joel 270-MHz and Jeol sx
500-MHz spectrometers, using tetramethylsilane as
internal standard. Mass spectra were acquired with a Jeol
JMS-AX 500. All reactions were followed and checked
by thin-layer chromatography (aluminum-backed plates)
with chloroform–methanol 9:1 (v/v) as mobile phase. For
detection, the plates were sprayed with iodine.
15a
15b
Ascorbic acid
General procedure for preparation of compounds 2a–f.
A mixture solution of 1 (0.01 mol) and (0.01 mol) of the
appropriate sulfa drug, namely, sulfamethazine,
TAC, total antioxidant activity/content.
Table 4
sulfaguanidine,
sulfamethoxazole,
sulfanilamide,
sulfapyridine, and sulfadiazine, in (20 mL) glacial acetic
acid containing (0.02 mol) sodium acetate anhydrous was
refluxed for 15 h. Upon pouring on crushed ice/water,
white crystals were obtained, filtered, washed with water,
and recrystallized from proper solvent.
N-(4,6-Dimethylpyrimidin-2-yl)-4-(4-oxo-2-(pyridin-4-yl)
quinazolin-3(4H)-yl)benzene sulfonamide (2a). Crystallized
Fibrinolytic and anticoagulation activities of newly synthesized
quinazoline.
Anticoagulation
activity (clotting
Fibrinolytic
activity
time)
Compound no.
(lysis %)
min
s
2a
2b
2c
2e
2f
3c
4
5a
5b
6a
6b
11a
11b
13a
13b
14a
75
>75
50
<50
75
75
>75
50
>75
75
>75
75
50
50
50
<50
75
50
75
—
75
—
4
7
30
30
4
8
11
9
5
13
5
3
30
7
6
30
7
6
30
2
57
20
18
18
12
45
12
53
55
10
36
30
15
35
20
15
49
55
18
30
—
—
from ethanol/petroleum ether, mp 290°C, yield 70%.
Analysis: for C25H20N6O3S, MW 484.53, calcd: C:
61.97, H: 4.16, N: 17.34. Found: C: 61.86, H: 3.98, N:
17.29. IR (KBr; cmˉ ): 3377 (NH), 1680 (C═O), 1620
(C═N), 1340 (SO2NH). H-NMR (DMSO, δ ppm): 2.30
(s, 6H, 2CH3), 6.68–7.80 (m, 13H, Ar–H, CH of
diazine), 10.25 (s, 1H, NH exchangeable with D2O). MS:
(m/z) ~484 (20.61%).
N-Carbamimidoyl-4-(4-oxo-2-(pyridin-4-yl)quinazolin-3(4H)-
yl)benzene sulfonamide (2b).
Crystallized from ethanol,
mp 254°C, yield 71%. Analysis: for C20H16N6O3S, MW
420.44, calcd: C: 57.13, H: 3.84, N: 19.99. Found: C:
57.22, H: 3.70, N: 20.02. IR (KBr; cmˉ ): 3467, 3432,
3211 (2NH, NH2), 1681 (C═O), 1315 (SO2NH). H-
NMR (DMSO, δ ppm): 5.31, 9.80, 10.72 (3s, 2H, 2H,
NH2, 2NH), 7.10–8.0 (m, 12H, Ar–H). MS: (m/z) ~420
14b
15a
15b
Blank
Standard (Hemoclar 2 mg)
Standard (heparin 1.4 IU)
—
>30
(13.85%).
N-(2-Methyloxazol-4-yl)-4-(4-oxo-2-(pyridin-4-yl)quinazolin-
3(4H)-yl)benzene sulfonamide (2c).
Crystallized from
isopropanol, mp 246°C, yield 62%. Analysis: for
C23H17N5O4S, MW 459.48, calcd: C: 60.12, H: 3.73, N:
15.24. Found: C: 60.31, H: 3.70, N: 15.14. IR (KBr;
cmˉ ): 3320 (NH), 1692 (C═O), 1316 (SO2NH). H-NMR
(DMSO, δ ppm): 2.34 (s, 3H, CH3), 7.10–8.00 (m, 13H,
standard “Hemoclar” preparation (75% lysis). Similarly, the
“five compounds (2c, 11b, 2e, 14a, and 15b)” exhibited
anticoagulant activity higher than that of “other studied
compounds” despite it was still lower than that of standard
Journal of Heterocyclic Chemistry
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Month 2018
Biological Evaluation of Quinazoline Derivatives
Ar–H, 1H, isoxazole ring), 10.20 (s, 1H, NH exchangeable
with D2O). MS: (m/z) ~459 (13.02%).
4-(4-oxo-2-(Pyridin-4-yl)quinazolin-3(4H)-yl)benzene sulfonamide
(KBr; cmˉ ): 3423, 3280, (2NH), 1710 (C═O), 1311
(SO2NH), 1162 (C═S). H-NMR (DMSO, δ ppm): 2.00
(s, 10H, cyclohexane), 4.20 (m, 1H, CH–N), 7.02–7.92
(m, 12H, Ar–H), 9.20, 10.10 (2s, 2H, 2NH, exchangeable
(2d).
Crystallized from isopropanol, mp 263°C, yield
69%. Analysis: for C19H14N4O3S, MW 378.40, calcd: C:
60.31, H: 3.73, N: 14.81. Found: C: 60.21, H: 3.70, N:
14.86. IR (KBr; cmˉ ): 3207, 3153 (NH2), 1690 (C═O),
1391 (SO2NH). H-NMR (DMSO, δ ppm): 4.90 (s, 2H,
NH2 exchangeable with D2O), 7.20–8.00 (m, 12H,
with D2O). MS: (m/z) ~519 (17.32%).
4-(4-oxo-2-(Pyridin-4-yl)quinazolin-3(4H)-yl)-N-(phenylcarbamoyl)
benzene sulfonamide (3c). Crystallized from chloroform, mp
210°C, yield 69%. Analysis: for C26H19N5O4S, MW 497.53,
calcd: C: 62.77, H: 3.85, N: 14.08. Found: C: 62.75, H: 3.73,
N: 14.13. IR (KBr; cmˉ ): 3340, 3299 (2NH), 1689, 1665
(2C═O), 1312 (SO2NH). H-NMR (DMSO, δ ppm): 9.26,
10.35 (2s, 2H, 2NH exchangeable with D2O), 7.12–8.10
(m, 17H, Ar–H). MS: (m/z) ~497 (19.83%).
Ar–H). MS: (m/z) ~378 (19.01%).
4-(4-oxo-2-(Pyridin-4-yl)quinazolin-3(4H)-yl)-N-(pyridin-4-
yl)benzene
sulfonamide
(2e).
Crystallized from
isopropanol/petroleum ether, mp 207°C, yield 65%.
Analysis: for C24H17N5O3S, MW 455.49, calcd: C:
63.29, H: 3.76, N: 15.38. Found: C: 63.36, H: 3.59, N:
15.45. IR (KBr; cmˉ ): 3355 (NH), 1695 (C═O), 1327
(SO2NH). H-NMR (DMSO, δ ppm): 10.23 (s, 1H, NH,
exchangeable with D2O), 7.10–8.02 (m, 16H, Ar–H).
MS: (m/z) ~455 (11.51%).
4-(4-oxo-2-(Pyridin-4-yl)quinazolin-3(4H)-yl)-N-(pyrimidin-
3-(4-Aminophenyl)-2-(pyridin-4-yl)quinazolin-4(3H)-one
(4).
A mixture of compound 1 (0.01 mol) and
p-phenylenediamine (0.01 mol) was dissolved in (50 mL)
of anhydrous pyridine and heated on sand bath for 6 h.
The resulting solution was cooled in ice bath and treated
with 100 mL of dilute hydrochloric acid. The product was
filtered, washed with water, and crystallized from ethanol.
Crystallized from ethanol, mp >300°C, yield 75%.
Analysis: for C19H14N4O, MW 314.34, calcd: C: 72.60,
H: 4.49, N: 17.82. Found: C: 72.50, H: 4.51, N: 17.91.
IR (KBr; cmˉ ): 3410, 3390 (NH2), 1712 (C═O), 1614
(C═N). H-NMR (DMSO, δ ppm): 4.72 (s, 2H, NH2),
7.03–8.12 (m, 12H, Ar–H). MS: (m/z) ~314 (89%).
General procedure for preparation of compounds 5a,b.
A mixture of compound 4 (0.01 mol) and the appropriate
linear sugar, namely, D-mannose and/or D-arabinose
(0.01 mol), in absolute ethanol (30 mL) in the presence
of few drops of glacial acetic acid was heated at 80°C for
6 h. The reaction mixture was cooled, and the formed
precipitate was filtered off and recrystallized from
2-yl)benzene sulfonamide (2f).
Crystallized from
ethanol/petroleum ether, mp 267°C, yield 73%. Analysis:
for C23H16N6O3S, MW 456.48, calcd: C: 60.52, H: 3.53,
N: 18.41. Found: C: 60.47, H: 3.58, N: 18.81. IR (KBr;
cmˉ ): 3320 (NH), 1680 (C═O), 1620 (C═N), 1325
(SO2NH). H-NMR (DMSO, δ ppm): 10.23 (s, 1H, NH,
exchangeable with D2O), 7.21–8.13 (m, 15H, Ar–H).
MS: (m/z) ~456 (19.81%).
General procedure for preparation of compounds 3a–c.
A mixture of 2d (0.005 mol) and anhydrous potassium
carbonate (0.01 mol) in dry acetone (50 mL) was
refluxed with continuous stirring for 1.5 h. While hot, a
solution of the appropriate cyanate/isothiocyanate
derivatives, namely, ethyl isothiocyanate, cyclo
hexylisothioocyanate, and phenyl isocyanate (0.007 mol),
in dry acetone was added dropwisely, and the reflux was
continued for further 18 h. The excess acetone was
removed under reduced pressure, and the obtained solid
residue was washed with water, filtered, and
isopropanol to obtain the desired Schiff’s bases 5a,b.
2,3,4,5,6-Pentahydroxyhexylidene)amino)phenyl)-2-(pyridin-
4-yl)quinazolin-4(3H)-one
(5a).
Crystallized from
isopropanol, mp >300°C, yield 64%. Analysis: for
C25H24N4O6, MW 476.48, calcd: C: 63.02, H: 5.08, N:
11.76. Found: C: 63.10, H: 5.05, N: 11.79. IR (KBr;
cmˉ ): 3680–3480 (5OH), 1694 (C═O), 1609 (C═N). H-
NMR (DMSO, δ ppm): 2.43–2.92 (m, 5H, 5OH), 3.32–
3.83 (m, 6H, 4CH, CH2), 6.92–8.14 (m, 13H, Ar–H,
recrystallized from the proper solvent.
N-(Ethylcarbamothioyl)-4-(4-oxo-2-(pyridin-4-yl)quinazolin-
3(4H)-yl)benzene sulfonamide (3a).
Crystallized from
ethanol, mp >300°C, yield 59%. Analysis: for
C22H19N5O3S2, MW 465.55, calcd: C: 56.76, H: 4.11, N:
15.04. Found: C: 56.59, H: 4.08, N: 15.06. IR (KBr;
cmˉ ): 3340, 3333 (2NH), 1710 (C═O), 1320 (SO2NH),
1160 (C═S). H-NMR (DMSO, δ ppm): 1.20 (t, 3H,
CH3, ethyl group), 3.62 (q, 2H, CH2), 7.20–8.0 (m, 12H,
Ar–H), 9.80–10.20 (2s, 2H, 2NH exchangeable with
CH═N). MS: (m/z) ~476 (43.40%).
2-(Pyridin-4-yl)-2,3,4,5-tetrahydroxypentylidene)amino)phenyl)
quinazolin-4(3H)-one (5b). Crystallized from isopropanol,
mp >300°C, yield 71%. Analysis: for C24H22N4O5, MW
446.46, calcd: C: 64.53, H: 4.97. N: 12.55. Found: C: 64.53,
H: 4.95, N: 12.60. IR (KBr; cmˉ ): 3587–3481 (4OH), 1702
(C═O), 1613 (C═N). H-NMR (DMSO, δ ppm): 2.55–2.89
(m, 4H, 4OH), 3.38–3.87 (m, 5H, 3CH, CH2), 6.90–8.12
(m, 13H, Ar–H, CH═N). MS: (m/z) ~446 (86.73%).
General procedure for preparation of compounds 6a,b.
A mixture of compounds 5a,b (0.005 mol) and thiosalicylic
acid (0.005 mol) in dry benzene (20 mL) was refluxed for
16 h. The excess solvent was evaporated under reduced
D2O). MS: (m/z) ~465 (14.51%).
N-(Cyclohexylcarbamothioyl)-4-(4-oxo-2-(pyridin-4-yl)quinazolin-
3(4H)-yl)benzene sulfonamide (3b).
Crystallized from
ethanol/petroleum ether, mp 250°C, yield 63%. Analysis:
for C26H25N5O3S2, MW 519.64, calcd: C: 60.10, H:
4.85, N: 13.48. Found: C: 60.20, H: 4.90, N: 13.57. IR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

I. F. Zeid, E. M. Kassem, N. A. Mohamed, A. A. Salman, and AL. S. G. Shalaby
Vol 000
pressure, and the obtained residue was treated with
petroleum ether (60–80). The solid product was filtered
off, washed with petroleum ether (60–80), and crystallized
from isopropanol to obtain the desired products 6a,b,
3-Methyl-5-oxo-N-(4-(4-oxo-2-(pyridin-4-yl)quinazolin-3(4H)-
yl)phenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (9).
A
mixture of compound 7 (0.01 mol) and ethyl acetoacetate
(0.05 mol) was heated on a water bath for 8 h. The
reaction mixture was cooled, and the solid was filtered
off, air dried, and crystallized from methanol to give
compound 9.
Crystallized form methanol mp 160°C, yield 70%.
Analysis: for C24H18N6O2S, MW 454.50, calcd: C: 63.42,
H: 3.99, N: 18.49. Found: C: 63.30, H: 4.01, N: 18.51. IR
(KBr; cmˉ ): 3437 (NH), 1690, 1667 (2C═O), 1135
(C═S). H-NMR (DMSO, δ ppm): 1.97 (s, 3H, CH3), 2.15
(s, 2H, CH2), 7.11–7.95 (m, 12H, Ar–H), 10.15 (s, 1H,
NH exchangeable with D2O). MS: (m/z) ~454 (40%).
respectively.
3-(4-(4-oxo-2-(Pyridin-4-yl)quinazolin-3(4H)-yl)phenyl)-2-
1,2,3,4,5-pentahydroxypentyl)-2,3-dihydro-4H-benzo[e][1,3]
thiazin-4-one (6a).
Crystallized from isopropanol, mp
>300°C, yield 63%. Analysis: for C32H28N4O7S, MW
612.65, calcd: C: 62.73, H: 4.61, N: 9.14. Found: C:
62.70, H: 4.63, N: 9.15. IR (KBr; cmˉ ): 3565–3440
(OH), 1696, (C═O), 1610 (C═N). H-NMR (DMSO, δ
ppm): 3.34–3.51 (m, 6H, 4CH, CH2), 4.07–4.31 (m, 5H,
5OH), 6.51 (s, 1H, CH of benzothiazine ring), 7.01–7.96
(m, 16H, Ar–H). MS: (m/z) ~612 (18.41%).
General procedure for preparation of compounds 11a,b.
3-(4-(4-oxo-2-(Pyridin-4-yl)quinazolin-3(4H)-yl)phenyl)-1,2,3,4-
tetrahydroxybutyl)-2,3-dihydro-4H-benzo[e][1,3]thiazin-4-one
(6b). Crystallized from isopropanol, mp >300°C, yield
A
mixture of compound 10a (0.01 mol) and/or
acetyl/benzoyl chloride (0.01 mol) in pyridine (20 mL)
was refluxed for 6 h. The reaction mixture was cooled
and poured into ice-cold water, and then the formed
precipitate was filtered and crystallized from ethanol to
give the corresponding compounds 11a,b, respectively.
3-Cyclohexyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethanethioate
(11a). Crystallized from ethanol, mp 168°C, yield 77%.
Analysis:forC16H18N2O2S,MW302.39,calcd:C:63.55,H:
6.00, N: 9.26. Found: C: 63.57, H: 6.01, N: 9.19. IR (KBr;
cmˉ ): 1714, 1697 (C═O), 1615 (C═N). H-NMR (DMSO, δ
ppm): 1.98 (s, 11H, cyclohexane), 2.61 (s, 3H, COCH3),
71%. Analysis: for C31H26N4O6S, MW582.63, calcd: C:
63.91, H: 4.50, N: 9.62. Found: C: 63.80, H: 4.61, N:
9.55. IR (KBr; cmˉ ): 3545–3430 (OH), 1683 (C═O),
1609 (C═N). H-NMR (DMSO, δ ppm): 2.60–2.92 (m,
5H, 3CH, CH2), 4.11–4.30 (m, 4H, 4OH), 6.54 (s,
1H, CH of benzothiazine ring), 6.69–7.99 (m, 16H,
Ar–H). MS: (m/z) ~582 (22.13%).
N-(4-(4-oxo-2-(Pyridin-4-yl)quinazolin-3(4H)-yl)phenyl)
hydrazine carbothioamide (7). A solution of compound 4
(0.01 mol), sodium hydroxide (0.01 mol), and carbon
disulfide (0.01 mol) in dimethyl formamide (30 mL) was
stirred at 15–20°C and after 1 h was added with
hydrazine hydrate (0.01 mol), and the stirring continued
at 60°C for 1 h. The separated solid after adding water
was filtered off, washed with water, air dried, and then
crystallized from DMF/ethanol to give compound 7.
Crystallized from DMF/ethanol mp >300°C, yield 61%.
Analysis: for C20H16N6OS, MW 388.45, calcd: C: 61.84,
H: 4.15, N: 21.63. Found: C: 61.73, H: 4.20, N: 21.55.
IR (KBr; cmˉ ): 3455, 3391, 3287, 3189 (NH2, 2NH),
1672 (C═O), 1130 (C═S). H-NMR (DMSO, δ ppm):
5.41 (s, 2H, NH2 exchangeable with D2O), 6.72–7.41 (m,
12H, Ar–H), 11.01, 11.80 (2s, 2H, 2NH exchangeable
with D2O). MS: (m/z) ~388 (28.31%).
7.02–7.62(m,4H,Ar–H).MS:(m/z)~302(13.41%).
S-(3-Cyclohexyl-4-oxo-3,4-dihydroquinazolin-2-yl)benzothioate
(11b). Crystallized from ethanol, mp 104°C, yield 104%.
Analysis: for C21H20N2O2S, MW 364.46, calcd: C: 69.20,
H: 5.53, N: 7.69. Found: C: 69.10, H: 5.62, N: 7.67. IR
(KBr; cmˉ ): 1689 (C═O), 1533 (C═N). H-NMR
(DMSO, δ ppm): 2.16 (s, 11H, cyclohexane), 6.96–7.55
(m, 9H, Ar–H). MS: (m/z) ~364 (18.53%).
2-((3-Cyclohexyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio)
acetic acid (12).
Sodium hydroxide (22 mmol) was
dissolved in 50 mL of water, and 20 mmol of (10a) was
added. After stirring for 15 min, a solution of 20 mmol of
chloroacetic acid in 5 mL of methanol was added
dropwise over 20 min. After the addition was completed,
the solution was stirred at room temperature for about
2 h. The solid was filtered and recrystallized from ethanol
to give compound 12.
Crystallized from ethanol, mp 230°C, yield 80%.
Analysis: for C16H18N2O3S, MW 318.39, calcd: C:
60.36, H: 5.70, N: 8.80. Found: C: 60.37, H: 5.67, N:
8.83. IR (KBr; cmˉ ): 3433 (OH), 1714, 1685 (C═O),
1623 (C═N). H-NMR (DMSO, δ ppm): 2.01 (s, 11H,
cyclohexane), 4.52 (s, 2H, CH2), 7.11–7.90 (m, 4H, Ar–
H), 11.33 (s, 1H, OH exchangeable with D2O). MS: (m/z)
~318 (10.7%).
3,5-Dimethyl-N-(4-(4-oxo-2-(pyridin-4-yl)quinazolin-3(4H)-
yl)phenyl)-1H-pyrazole-1-carbothioamide (8).
A mixture
of 7 (0.01 mol) and acetyl acetone (0.05 mol) was heated
on a water bath for 9 h. The reaction mixture was cooled,
and the solid was filtered off, air dried, and crystallized
from methanol to give compound 8.
Crystallized from methanol mp 170°C, yield 65%.
Analysis: for C25H20N6OS, MW 452.53, calcd: C: 66.35,
H: 4.45, N: 18.57. Found: C: 66.21, H: 4.39, N: 18.62. IR
(KBr; cmˉ ): 3429 (NH), 1698 (C═O), 1614 (C═N), 1131
(C═S). H-NMR (DMSO, δ ppm): 2.37 (s, 6H, 2CH3),
6.82–8.12 (m, 13H, Ar–H, 1H of pyrazole), 10.82 (s, 1H,
NH exchangeable with D2O). MS: (m/z) ~452 (35%).
General procedure for preparation of compounds 13a,b.
Sodium hydroxide (0.022 mol) was dissolved in 50 mL of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Biological Evaluation of Quinazoline Derivatives
water, and 0.02 mol of compounds 10a,b was added. After
stirring for 15 min, a solution of 0.002 mol of ethyl
chloroacetate in 5 mL of methanol was added dropwise
over 20 min. After addition was completed, the solution
was stirred at room temperature for about 2 h. The solid
was filtered and recrystallized from ethanol to give
compounds 13a,b.
Ethyl 2-((3-cyclohexyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio)
acetate (13a). Crystallized from ethanol, mp 133°C, yield
69%. Analysis: for C18H22N2O3S, MW 346.44, calcd: C:
62.40, H: 6.40, N: 8.09. Found: C: 62.35, H: 6.17, N: 8.10.
IR (KBr; cmˉ ): 1710, 1683 (C═O), 1609 (C═N). H-
NMR (DMSO, δ ppm): 1.71 (t, 3H, CH3, ethyl group),
2.01 (s, 11H, cyclohexane), 3.62 (q, 2H, CH2, ethyl
group), 4.07 (s, 2H, S–CH2), 7.01–7.63 (m, 4H, Ar–H).
precipitate that formed was filtered off and crystallized
from ethanol.
2-(2-((3-Cyclohexyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio)
acetyl)hydrazine-1-carbothioamide (15a). Crystallized from
ethanol, mp 212°C, yield 70%. Analysis: for
C17H21N5O2S2, MW 391.51, calcd: C: 52.15, H: 5.41, N:
17.89. Found: C: 52.13, H: 5.42, N: 17.90. IR (KBr;
cmˉ ): 3401, 3240 (NH2, NH), 1695, 1678 (C═O), 1240
(C═S). H-NMR (DMSO, δ ppm): 2.31 (s, 11H,
cyclohexane), 4.41 (s, 2H, CH2), 5.48 (s, 2H, NH2
exchangeable with D2O), 6.83–7.52 (m, 4H, Ar–H), 9.87,
10.62 (2s, 2H, 2NH exchangeable with D2O). MS: (m/z)
~391 (19.81%).
2-(2-((4-oxo-3-(o-tolyl)-3,4-Dihydroquinazolin-2-yl)thio)
acetyl)hydrazine-1-carbothioamide (15b). Crystallized from
ethanol, mp 230°C, yield 78%. Analysis: for
C18H17N5O2S2, MW 399.49, calcd: C: 54.12, H: 4.29, N:
17.53. Found: C: 63.11, H: 4.29, N9.86. IR (KBr; cmˉ ):
3423, 3188 (NH2, NH), 1698, 1670 (C═O), 1251 (C═S).
H-NMR (DMSO, δ ppm): 2.29 (s, 3H, CH3), 4.52 (s,
2H, CH2), 5.40 (s, 2H, NH2 exchangeable with D2O),
7.51–8.22 (m, 8H, Ar–H), 9.84, 10.65 (2s, 2H, 2NH
exchangeable with D2O). MS: (m/z) ~399 (22.41%).
MS: (m/z) ~346 (8.25%).
Ethyl 2-((4-oxo-3-(o-tolyl)-3,4-dihydroquinazolin-2-yl)thio)
acetate (13b).
Crystallized from ethanol, mp 119°C,
yield 72%. Analysis: for C19H18N2O3S, MW 354.42,
calcd: C: 64.39, H: 5.12, N: 7.90. Found: C: 64.20, H:
5.23, N: 7.96. IR (KBr; cmˉ ): 1715, 1686 (C═O), 1611
(C═N). H-NMR (DMSO, δ ppm): 1.51 (t, 3H, CH3,
ethyl group), 2.40 (s, 3H, CH3), 3.60 (q, 2H, CH2, ethyl
group), 4.82 (s, 2H, S–CH2), 6.92–7.91 (m, 8H, Ar–H).
MS: (m/z) ~354 (13.51%).
General procedure for preparation of compounds 14a,b.
A mixture of compounds 13a,b (0.01 mol) and 4-
chloroaniline (0.01 mol) in ethanol (20 mL) was added in
flask. Then catalytic amount of concd sulfuric acid (five
drops) was added. The mixture was refluxed for 2 h. On
cooling, solid was separated out, filtered, and
recrystallized from ethanol.
N-(4-Chlorophenyl)-2-((3-cyclohexyl-4-oxo-3,4-dihydroquinazolin-
2-yl)thio)acetamide (14a). Crystallized from ethanol, mp
165°C, yield 68%. Analysis: for C22H22ClN3O2S, MW
427.95, calcd: C: 61.74, H: 5.18, N: 9.82. Found: C:
61.57, H: 5.20, N: 9.80. IR (KBr; cmˉ ): 3225 (NH),
1691, 1672 (C═O), 1603 (C═C). H-NMR (DMSO, δ
ppm): 2.10 (s, 11H, cyclohexane), 4.14 (s, 2H, CH2),
6.98–7.75 (m, 8H, Ar–H), 9.98 (s, 1H, NH exchangeable
Biological evaluation. Antimicrobial activity test.
The
different synthesized compounds were examined for its
antimicrobial activity against Gram-negative bacilli
bacteria, Gram-positive cocci bacteria, C. albicans, and
A. niger by well diffusion method [35,36]. The
experiment was performed using a culture at 37°C for
24 h on 20 mL of nutrient agar for bacteria or PDA for
yeast, which was poured into sterile Petri dishes and
allowed for solidification. Wells were made in agar
plates using sterile cork pore of 4 mm diameter. The
cultures were adjusted to approximately 106 CFU/mL
with sterile saline solution. One hundred and fifty
microliters of the suspensions were spread over the agar
plates using a sterile glass spreader. Each tested sample
was dissolved in 1 mL of DMSO and sterilized by
filtration through a 0.22-μm membrane filter (by using
Millipore membrane filter apparatus). To the appropriate
wells in the Petri dishes, 150 μg/mL of each sample was
with D2O). MS: (m/z) ~427 (15.21%).
N-(4-Chlorophenyl)-2-((4-oxo-3-(o-tolyl)-3,4-dihydroquinazolin-
2-yl)thio)acetamide (14b). Crystallized from ethanol, mp
added separately.
Minimum inhibitory concentration value of quinazoline
derivatives. Minimum inhibitory concentration value is
performed according to Andrews et al. [37] and
expressed as the lowest concentration of an antimicrobial
120°C, yield 71%. Analysis: for C23H18ClN3O2S, MW
435.93, calcd: C: 63.37, H: 4.16, N: 9.64. Found: C:
63.35, H: 4.19, N: 9.69. IR (KBr; cmˉ ): 3180 (NH),
1689, 1670 (C═O), 1614 (C═C). H-NMR (DMSO, δ
ppm): 2.45 (s, 3H, CH3), 4.95 (s, 2H, CH2), 6.65–7.40
(m, 12H, Ar–H), 11.20 (s, 1H, NH exchangeable with
D2O). MS: (m/z) ~435 (10.11%).
General procedure for preparation of compounds 15a,b.
To a solution of compounds 13a,b (0.01 mol) in DMF
(10 mL), thiosemicarbazide (0.01 mol) was added, and
the reaction mixture was refluxed for 6 h. The mixture
was then cooled and poured into crushed ice, and the
compound that inhibits the visible growth of
a
microorganism after incubation 24 h for bacteria at 37°C
and 48 h for fungi at 28°C. Well-cut diffusion technique
was used to determine the minimal inhibitory effect of
the final concentrations of antibacterial and antifungal
agents, which were 25, 50, 100, and 200 μg/mL DMSO
against all studied pathogens.
Antioxidant activity (DPPH assay).
This assay was
performed according to Brand-Williams et al. [38]. Stock
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

I. F. Zeid, E. M. Kassem, N. A. Mohamed, A. A. Salman, and AL. S. G. Shalaby
Vol 000
solutions from modified synthesized compounds samples
will be prepared by dissolving 10 mg of samples in 1 mL
DMSO is an organosulfur compound with the formula
(CH3)2SO and then diluted into several dilutions. A
triplicate of 10 μL from each concentration will be
prepared; after that, 90 μg/mL of DPPH was added on
ELISA plate, and then the plate will be stored in dark
cover with aluminum foil for 30 min then measured at
Acknowledgment. The authors thank the National Research
Centre for supporting this work.
CONFLICT OF INTERESTS
There are no conflicts of interest.
520 nm on ELISA apparatus /reader.
Anticoagulation activity. Adopting the method of the
REFERENCES AND NOTES
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Newly synthesized 3-phenyl-2-(pyridin-4-yl)quinazolin-
4(3H)-one and their modified derivatives were evaluated
with different biomedical activities as bactericidal and
fungicidal agents. Derivatives of quinazoline compounds
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