Synthesis, Characterization, and Biological Evaluation of 2-(p-Nitrophenyl)quinazolin-4(3H)-one Derivatives

Article abstract of DOI:10.1134/S1070428020080175

Abstract: A series of novel 2-(4-nitrophenyl)-3-(R-benzothiazol-2-yl)quinazolin-4(3H)-ones 4a–4g (R = Alk, AlkO, Hal, NO₂) were synthesized from the corresponding substituted 2-aminobenzothiazoles and 2-(4-nitrophenyl)-4H-3,1-benzoxazin-4-one v

Full text of DOI:10.1134/S1070428020080175

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 8, pp. 1455–1461. © Pleiades Publishing, Ltd., 2020.
Synthesis, Characterization, and Biological Evaluation
of 2-(p-Nitrophenyl)quinazolin-4(3H)-one Derivatives
a
a,b
a
a,
c
V. N. Giradkar , U. D. Kabra , R. S. Diwakar , R. T. Lohiya *, and M. J. Umekar
a
Department of Pharmaceutical Chemistry, Smt. Kishoritai Bhoyar College of Pharmacy, Nagpur, 441002 India
b
Department of Pharmaceutical Chemistry, Parul Institute of Pharmacy, Parul University, Vadodara, 391760 India
c
Principal of Smt. Kishoritai Bhoyar College of Pharmacy, Nagpur, 441002 India
*
e-mail: rtlohiya@gmail.com
Received February 24, 2020; revised February 29, 2020; accepted March 02, 2020
Abstract—A series of novel 2-(4-nitrophenyl)-3-(R-benzothiazol-2-yl)quinazolin-4(3H)-ones 4a–4g (R =
Alk, AlkO, Hal, NO ) were synthesized from the corresponding substituted 2-aminobenzothiazoles and
2
2
-(4-nitrophenyl)-4H-3,1-benzoxazin-4-one via a nucleophilic addition reaction. The structures of the novel com-
1
pounds were assigned on the basis of the elemental analyses and FTIR, H NMR, and mass spectra. The synthe-
sized compounds were tested for anticonvulsant, antimicrobial, and antioxidant activities. All the compounds
increased the seizure latency compared to control. Compound 4b (R = 6-NO ) exhibited significant anticonvulsant
2
activity, comparable to that of the standard drug Phenytoin. Antimicrobial activity testing revealed moderate
to good activity in all the test compounds, and 4a (R = H) and 4b compared in activity with the standard drug
Chloramphenicol. The antioxidant activity of compounds 4a, 4d (R = 5-Br), and 4f (R = 4,6-Me ) (IC 39.30,
2
50
1
4
5.55, and 42.95 μg/mL, respectively) was found to be higher compared to the standard drug ascorbic acid (IC50
8.30 μg/mL).
Keywords: quinazolinone, benzothiazole, anticonvulsant, antimicrobial, antioxidant
DOI: 10.1134/S1070428020080175
INTRODUCTION
nucleus improved the activity and potency of the
starting compounds. Benzothiazole and its derivatives
showed such interesting biological activities, including
anticonvulsant, antibacterial, anti-inflammatory, anti-
fungal, antioxidant, and anticancer [13–19]. In view
of the significant biological potential of both qui-
nazolinone and benzothiazole, we set ourselves the goal
to synthesize, characterize, and assess the biological
activity of a series of compounds comprising both the
quinazolinone and benzothiazole rings.
Quinazolinone belongs to the class of fused hete-
rocycles, which have diverse biological activities,
including antibacterial, antioxidant, antifungal, anti-
convulsant, anticancer, antidiabetic, and anti-
inflammatory [1–6]. Therefore, the quinazolinone
scaffold has been incorporated into variety of drugs:
Diproqualone (analgesic), Gefitinib (anticancer), and
Piriqualone (anticonvulsant) [7]. Inspection of the
2
literature showed that different substituents at the N or
3
N position of the quinazolinone nucleus modulate the
RESULTS AND DISCUSSION
biological activity [8]. Para substitution in the 2-phenyl
group of quinazolinone was found to induce a higher
biological activity than meta- or ortho-substitution;
furthermore, electron-acceptors substituents, like NO2,
F, or Cl, yielded more potent biologically active com-
pounds [9–11]. One of the most useful moieties,
2
-(4-Nitrophenyl)-3-(R-benzothiazol-2-yl)quinazo-
lin-4(3H)-ones 4a–4g were synthesized by the reaction
sequence shown in the scheme. The structures of the
intermediate and final products were confirmed by their
H NMR, IR, and mass spectra and elemental analyses
Scheme 1).
1
(
3
which can be introduced in the N position of the
quinazolinone ring to enhance the biological activity,
is benzothiazole [12]. Alkyl, alkoxy, or halogen
substituents at different positions of the benzothiazole
Compounds 4a–4g were screened for anticon-
vulsant, antibacterial, and antioxidant activity.
Among all the synthesized compounds, compound
1
455

1456
GIRADKAR et al.
Scheme 1.
1
a–1g
3
2
a–2g
4
a–4g
1
, 2, 4, R = H (a), 6-NO (b), 4-EtO (c), 5-Br (d), 4-Cl (e), 6-MeO (f), 4,6-Me (g).
2
2
4
b showed significant anticonvulsant activity in the
in activity with the standard drug Ciprofloxacin
(Table 2). The in vitro antioxidant activity of the
synthesized compounds was evaluated by the DPHH
assay. Compounds 4a, 4d, and 4f displayed antioxidant
activity better than the standard drug ascorbic acid
(Table 3).
pentylenetetrazole (PTZ)-induced seizure assay in
mice, comparable with the activity of the standard
drug Phenytoin. Compounds 4a, 4d, and 4e showed
medium activity, and compound 4c was the least active
(Table 1). Using the cup-plate assay, the synthesized
compounds were tested for antibacterial activity against
Gram-positive (S. aureus and B. subtilis) and Gram-
negative bacteria (E. coli and P. aeruginosa). Two of
the synthesized compounds, specifically, 4a and 4b,
were found to be potent antibacterial agents comparing
EXPERIMENTAL
All chemicals were purchased from Sigma-Aldrich
and used without further purification. The melting
points were determined in open capillary tubes using
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SYNTHESIS, CHARACTERIZATION, AND BIOLOGICAL EVALUATION
1457
Table 1. Anticonvulsant activity of compounds 4a–4g by the PTZ-induced seizure assay in micea
Entry no.
Compound no.
Seizure score
Latency time, s
1
2
3
4
5
6
7
8
9
4a
2.2
0
96.6
–
4b
4c
4.8
1.8
1
100.4
211.6
284.8
112.4
33
4d
4e
4f
4g
2.8
4.8
6
Saline (control)
Phenytoin (standard)
31.8
–
0
a
Values are expressed as mean (n = 5).
a Thermoink precision melting point apparatus and are
uncorrected. The purity and homogeneity of compounds
was controlled by TLC on silica gel G plates in
chloroform–toluene (3 : 1); compounds were applied
as methanol solutions with capillary tubes; spots were
visualized by exposure to iodine vapor or UV light.
The elemental analyses were obtained on a Heraus
Carlo Erba 1108 CHN analyzer. The IR spectra were
recorded for KBr pellets on a Shimadzu 8400s FTIR
in 30 mL of water) was slowly added to a warm
mixture of substituted aniline (0.2 mol) and conc. HCl
(20–25 mL). The resulting mixture was refluxed until
turbidity appeared and then poured into cold water. The
precipitate of substituted phenylthiourea that formed was
filtered off, washed with water, dried, and recrystallized
from dilute ethanol (70 vol %).
Synthesis of substituted 2-aminobenzothiazoles
2
a–2g [21]. In a beaker, the synthesized substituted
1
spectrophotometer. The H NMR spectra were recorded
phenylthiourea 1a–1g (0.1 mol) in CCl (150 mL) was
4
for DMSO-d on a Bruker Advance III 400 MHz
6
taken. The solution was brominated using a solution of
spectrometer, internal standard TMS. The mass spectra
were obtained on a Shimadzu LC-MS 8040 instrument.
bromine (5 vol % in CCl ) until the orange-yellow color
4
persists. The slurry was kept overnight; the dibromide
Synthesis of substituted phenylthiourea 1a–1g
precipitate that formed was filtered off and washed
[20]. A solution of ammonium thiocyanate (20 g
with CCl until the yellow color disappeared. The
4
Table 2. Antibacterial activity of compounds 4a–4g by the cup-plate assaya
Zone of inhibition, mm
Entry no.
Compound no.
B. subtilis
S. aureus
E. coli
P. aeruginosa
1
2
3
4
5
6
7
8
9
4a
19
18
–
14
14
–
13
15
–
16
15
–
4b
4c
4d
14
14
13
–
11
10
10
–
10
–
11
–
4e
4f
4g
12
–
13
–
DMSO (control)
Ciprofloxacin (standard)
–
–
–
–
20
16
16
18
a
(–) No inhibition.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 8 2020

1458
GIRADKAR et al.
Table 3. In vitro antioxidant activity of compounds 4a–4g by the DPPH assay
Inhibition, %
Entry no.
Compound no.
IC , μg/mL
50
2
0 μg/mL 40 μg/mL 60 μg/mL 80 μg/mL 100 μg/mL
1
2
3
4
5
6
7
8
4a
52.87
21.21
30.30
50
51.51
27.27
36.36
59.09
31.81
51.51
13.93
45.45
39.39
30.30
50
54.54
39.39
43.93
68.18
45.45
68.18
50.30
59.09
42.42
43.93
59.09
72.72
66.66
72.72
55.90
66.66
39.30
121.08
78.60
15.55
76.21
42.95
85.34
48.50
4b
4c
4d
60.60
43.93
62.12
38.33
54.54
4e
13.63
34.84
10
4f
4g
Ascorbic acid (standard)
42.42
–
1
precipitate was dissolved in a rectified spirit (200 mL),
and the solution was made basic with a concentrated
ammonia solution to precipitate the target substituted
λmax, nm: 205, 256.4, 292.4. IR spectrum, ν, cm : 3080
(C–H), 1697 (C=O), 1690 (C=N), 1456 (C=C), 1540
(N=O), 680 (C–S). H NMR spectrum (DMSO-d ),
1
6
2
-aminobenzothiazole. The precipitate was filtered off,
δ, ppm: 8.75–7.69 m (12Harom). Mass spectrum, m/z
+
washed with water, dried, and recrystallized from dilute
ethanol (70 vol %).
(I , %): 403.95 (1.5) [M] , 400.1 (100.0), 401.1 (25.2),
rel
402.1 (8.2). Found, %: C 63.97; H 3.06; N 13.96.
C H N O S. Calculated, %: C 63.99; H 3.02; N 13.99.
2
1
12
4
3
Synthesisof2-(4-nitrophenyl)-4H-3,1-benzoxazin-
4
-one (3) [22]. p-Nitrobenzoyl chloride (0.01 mol)
was added to a stirred solution of anthranilic acid
0.01 mol) in dry pyridine (15 mL). The reaction mixture
3-(6-Nitrobenzothiazol-2-yl)-2-(4-nitrophenyl)-
quinazolin-4(3H)-one (4b). Yield 2.61 g (95%),
(
yellow crystals, mp 152–154°C, R 0.47. UV spectrum
f
–1
was further stirred. Small samples of the reaction
mixture were taken periodically to check benzoxazin
formation: anthranilic acid, p-nitrobenzoyl chloride,
and pyridine are water-soluble, while benzoxazin not,
and it precipitates. Once benzoxazin had formed, the
entire reaction mixture was poured into 250 mL of
water containing 10% sodium bicarbonate. The product
was filtered off, dried, and recrystallized from ethanol
(CH OH), λ , nm: 256.4, 370. IR spectrum, ν, cm :
3 max
3050 (C–H), 1717 (C=O), 1636 (C=N), 1456 (C=C),
1
1506 (N=O), 680 (C–S). H NMR spectrum (DMSO-d ),
6
δ, ppm: 8.66–7.52 m (11Harom). Mass spectrum, m/z
+
(I , %): 446.1 (23.0) [M] , 445.0 (100.0), 447.0 (5.0),
rel
447.1 (3.7), 446.0 (2.6), 448.0 (1.1). Found, %: C 56.68;
H 2.43; N 15.77. C H N O S. Calculated, %: C 56.63;
2
1
11
5
5
H 2.49; N 15.72.
(70 vol %).
3
-(4-Ethoxybenzothiazol-2-yl)-2-(4-nitrophenyl)-
Synthesis of 2-(4-nitrophenyl)-3-(substituted ben-
quinazolin-4(3H)-one (4c). Yield 2.97 g (86%),
zothiazol-2-yl)quinazolin-4(3H)-ones 4a–4g [23].
-Aminobenzothiazole 2a–2g (0.005 mol) was added
in portions to a stirred solution of benzoxazinone 3
0.005 mol) in dry pyridine (15 mL). The reaction
white crystals, mp 124–126°C, R 0.30. UV spectrum
f
2
(CH OH), λmax, nm: 206.2, 256.4, 296. IR spectrum,
3
–
1
ν, cm : 3070 (C–H), 1684 (C=O), 1636 (C=N), 1456
1
(
(C=C), 1541 (N=O), 602 (C–S). H NMR spectrum
mixture was refluxed for about 9–12 h, and the hot
solution was poured into a beaker containing 100 g
of crushed ice and 5 mL of conc. HCl. The solid that
separated was filtered off, dried, and recrystallized from
glacial acetic acid.
(DMSO-d ), δ, ppm: 1.19 t (3H, OCH CH , J 2.3 Hz),
6
2
3
4.25 q (2H, OCH CH , J 2.0 Hz), 8.13– 6.39 m (11H ).
2
3
arom
+
Mass spectrum, m/z (I , %): 445.10 (27.3) [M] ,
rel
444.09 (100.0), 446.09 (5.9), 446.10 (3.0), 447.09 (1.2).
Found, %: C 62.19; H 3.68; N 12.64. C H N O S.
2
3
16
4
4
Calculated, %: C 62.15; H 3.63; N 12.61.
3
-(Benzothiazol-2-yl)-2-(4-nitrophenyl)quinazo-
lin-4(3H)-one (4a). Yield 2.76 g (86%), brown crystals,
mp 128–132°C, R 0.48. UV spectrum (CH OH),
3-(5-Bromobenzothiazol-2-yl)-2-(4-nitrophenyl)-
quinazolin-4(3H)-one (4d). Yield 1.21 g (48%), brown
f
3
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SYNTHESIS, CHARACTERIZATION, AND BIOLOGICAL EVALUATION
1459
crystals, mp 120–122°C, Rf 0.47. UV spectrum
CH OH), λmax, nm: 208.4, 250, 304. IR spectrum,
Animals. Swiss albino mice of either sex, 8–10 weeks
old and weighing between 25–30 g were used. Animals
were housed in perspex cages under standard conditions
of temperature (26 ± 2°C) and 12 : 12 h light : dark
cycles. Animals were allowed to acclimatize to laborato-
ry conditions with free access to food and water for a
period of 1 week before testing. All the experimental
protocols were approved by the Institutional Animal
Ethical Committee (IAEC) and experiments were
conducted in accordance with the guidelines provided by
the Committee for the Purpose of Control Supervision
of Experimental Animals (CPCSEA).
(
3
–1
ν, cm : 3080 (C–H), 1717 (C=O), 1670 (C=N), 1456
1
(
C=C), 1541 (N=O), 600 (C–S), 520 (C–Br). H NMR
spectrum (DMSO-d ), δ, ppm: 8.64–7.26 m (11Harom).
6
+
Mass spectrum, m/z (I , %): 478.98 (22.5) [M] , 479.97
rel
(100.0), 477.97 (97.9), 480.97 (24.9), 481.97 (4.9),
4
79.98 (3.2), 481.98 (3.1), 478.97 (2.2), 482.97 (1.0).
Found, %: C 52.66; H 2.35; N 11.62. C H BrN O S.
2
1
11
4
3
Calculated, %: C 52.62; H 2.31; N 11.69.
3
-(4-Chlorobenzothiazol-2-yl)-2-(4-nitrophenyl)-
quinazolin-4(3H)-one (4e). Yield 1.31 g (70%),
Biological screening. Anticonvulsant activity.
The anticonvulsant activity of compounds 4a–4g was
determined by the pentylenetetrazole (Metrazol or
PTZ)-induced seizure assay [24]. Mice were divided
randomly into different groups (control, standard, and
test) consisting of five animals each. The compounds
were administered intraperitoneally, 30 min prior to
subcutaneous injection of PTZ (60 mg/kg). Doses of the
test compounds were equimolar to the intraperitoneal
dose 30 mg/kg of the standard drug Phenytoin. The
animalswereobservedfor30minafterthePTZinjection.
The latency to the onset of first generalized tonic-clonic
seizures and behavioral changes were monitored. The
seizure scores were assigned as follows. An animal in
a group was assigned score 0, 1, 3, or 6 if it showed (a)
no behavioral signs, (b) any myoclonic jerks, (c) Straub
tail reaction (score 1 for jerk + score 2 for Straub tail),
or (d) clonus (score 1 for jerk + score 2 for Straub tail +
score 3 for clonus). The seizure scores were calculated
for each individual animal in a particular group after the
PTZ injection. Furthermore, a cumulative kindling score
was calculated by adding the score of all the animals in
a group divided by the total number of animals in this
group. The maximum score an animal could get after
PTZ injection was 6. The data were analyzed by One
Way ANOVA followed by Dunnett’s test using Graph
Pad Prism software. A value of P < 0.05 was considered
as statıstically significant. The results are listed in
Table 1.
brown crystals, mp 142–144°C, R 0.21. UV spectrum
f
(
CH OH), λmax, nm: 208.8, 256.2, 294. IR spectrum,
3
–1
ν, cm : 3060 (C–H), 1680 (C=O), 1640 (C=N), 1456
1
(C=C), 1540 (N=O), 680 (C–S), 760 (C–Cl). H NMR
spectrum (DMSO-d ), δ, ppm: 8.66–7.27 m (11Harom).
6
+
Mass spectrum, m/z (I , %): 435.03 (23.0) [M] , 434.02
rel
(
4
100.0), 436.02 (36.8), 437.02 (9.1), 436.03 (3.3),
35.02 (2.3), 438.02 (1.7), 438.03 (1.1). Found, %:
C 58.10; H 2.60; N 12.92. C H ClN O S. Calcula-
2
1
11
4
3
ted, %: C 58.00; H 2.55; N 12.88.
3
-(6-Methoxybenzothiazol-2-yl)-2-(4-nitrophe-
nyl)quinazolin-4(3H)-one (4f). Yield 2.36 g (66%),
gray crystals, mp 130–134°C, R 0.58. UV spectrum
f
(
CH OH), λmax, nm: 205.2, 256.2, 293.4. IR spectrum,
3
–1
ν, cm : 3070 (C–H), 2840 (OCH ), 1680 (C=O), 1660
3
1
(C=N), 1456 (C=C), 1520 (N=O), 710 (C–S). H NMR
spectrum (DMSO-d ), δ, ppm: 3.74 s (3H, OCH , J
6
3
3
.2 Hz), 7.95–7.01 m (11Harom). Mass spectrum,
+
m/z (I , %): 431.08 (24.1) [M] , 430.07 (100.0),
rel
4
32.07 (4.9), 432.08 (3.8), 431.07 (2.3), 433.07 (1.2).
Found, %: C 61.42; H 3.33; N 13.09. C H N O S.
2
2
14
4
4
Calculated, %: C 61.39; H 3.28; N 13.02.
3
-(4,6-Dimethylbenzothiazol-2-yl)-2-(4-nitrophe-
nyl)quinazolin-4(3H)-one (4g). Yield 0.55 g (19%),
black crystals, mp 124–126°C, R 0.30. UV spectrum
f
(
CH OH), λmax, nm: 210, 273.2, 331.2. IR spectrum,
3
–1
ν, cm : 2960 (C–H), 1716.65 (C=O), 1635.64 (C=N),
1
1
456.26 (C=C), 1541.12 (N=O), 669.30 (C–S). H
NMR spectrum (DMSO-d ), δ, ppm: 2.35 s (3H, 6-CH ,
Antibacterial activity. The antibacterial activity of
compounds 4a–4g was determined using the cup-plate
assay by measuring the zone of inhibition [25]. The test
organisms were Gram-positive (S. aureus and B. subtilis)
and Gram-negative bacteria (P. aeruginosa and E. coli)
at a concentration of 100 μg/mL, and Ciprofloxacin
(100 μg/mL) and DMSO were used as the standard
6
3
J 3.0 Hz), 2.51 s (3H, 4-CH , J 3.0 Hz), 8.19–7.52 m
3
(
10H ). Mass spectrum, m/z (I , %): 431.70 (1.2)
arom rel
+
[
M] , 428.09 (100.0), 429.10 (25.2), 430.09 (4.9),
30.10 (3.9), 429.09 (2.3). Found, %: C 64.51; H 3.80;
N 13.13. C H N O S. Calculated, %: C 64.47; H 3.76;
4
23
16
4
3
N 13.08.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 8 2020

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GIRADKAR et al.
drug and negative control, respectively. Nutrient agar
was used as a culture medium. The agar was poured
into a sterile Petri dish and inoculated with the test
microorganism with a glass spreader. After drying, cups
and providing the necessary facility to carry out the research
work. The author is also grateful to the Perfomics Analytical
Labs LLP, Hyderabad, Sophisticated Analytical Instruments
Facility STIC, Kochi and UDPS, Nagpur, for providing
spectral data.
6
mm in diameter were punched in the agar plates with a
sterile cork borer. The cups were then impregnated with
the standard drug and test compounds. The plates were
then incubated at 37°C for 24 h, after which the zones
of inhibition were measured and recorded. Control was
also maintained employing 0.1 mL of DMSO. The
results are presented in Table 2.
CONFLICT OF INTEREST
The authors is no conflict of interest.
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In the present study we synthesized a series of
novel 2-(4-nitrophenyl)-4(3H)-quinazolin-4(3H)-one
derivatives, which showed profound anticonvulsant,
antioxidant, and antibacterial activities. These results
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considered as useful templates for further development
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ACKNOWLEDGEMENT
The authors wish to express their deep gratitude to Dr.
Milind J. Umekar, Principle of Smt. Kishoritai Bhoyar
College of Pharmacy, New Kamptee, Nagpur for motivating
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