Design and Synthesis of 1-Substituted-4-(4-Nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones as a New Class of Antihistaminic Agents

Article abstract of DOI:10.1134/S1068162020030085

Abstract: Some new 1-substituted-4-(4-nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones were synthesized and screened for their H₁-antihistaminic activity. The structures of the newly synthesized compounds were confirmed by IR, ¹H NMR, and mass spectral data and purity of the compounds was determined by elemental analysis. Antihistaminic activity of synthesized compounds was determined by the protection against histamine-induced bronchospasm on conscious guinea pigs. Percentage protection data showed that all title compounds of the series show significant protection in the range of 68–71.56% when compared to reference drug chlorpheniramine maleate (70.17%). The sedative properties of the compounds were also evaluated and found to be negligible when compared to chlorpheniramine maleate.

Full text of DOI:10.1134/S1068162020030085

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2020, Vol. 46, No. 3, pp. 403–408. © Pleiades Publishing, Ltd., 2020.
Design and Synthesis of 1-Substituted-4-(4-Nitrophenyl)-
[
1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones as a New Class
of Antihistaminic Agents
M. Gobinath , N. Subramanian , V. Alagarsamy , S. Nivedhitha , and Viswas Raja Solomon
a
b
c, 1
a
c
a
Department of Pharmaceutical Chemistry, Ratnam Institute of Phamacy, Pidathapolur, Nellore, 524346 India
b
Department of Pharmaceutical Technology, Anna University of Technology Tiruchirappalli, Tiruchirappalli, 620024 India
c
Medicinal Chemistry Research Laboratory, MNR College of Pharmacy, Sangareddy, Gr. Hyderabad, 502294 India
Received February 28, 2019; revised June 14, 2019; accepted November 18, 2019
Abstract—Some new 1-substituted-4-(4-nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones
were synthesized and screened for their H -antihistaminic activity. The structures of the newly synthe-
1
1
sized compounds were confirmed by IR, H NMR, and mass spectral data and purity of the compounds
was determined by elemental analysis. Antihistaminic activity of synthesized compounds was deter-
mined by the protection against histamine-induced bronchospasm on conscious guinea pigs. Percentage
protection data showed that all title compounds of the series show significant protection in the range of
6
8–71.56% when compared to reference drug chlorpheniramine maleate (70.17%). The sedative proper-
ties of the compounds were also evaluated and found to be negligible when compared to chlorpheni-
ramine maleate.
Keywords: histamine, triazolo, quinazolin-5(4H)-ones, antihistaminic activity, sedative–hypnotic activity
DOI: 10.1134/S1068162020030085
INTRODUCTION
duced fatal arrhythmogenic events through impairing
cardiac muscle repolarization. As antihypertensive
agents, like prazocin, terazocin, and doxazocin (spe-
Heterocyclic synthesis is a powerful technique for
generating new chemical entities with clinically valu-
able pharmacophores. Quinazolines are classes of
fused heterocycles and the various structural modifi-
cations on quinazoline nucleus showed wide range of
biological activities like antihistaminic, antimicrobial,
antitubercular, antiviral, antihypertensive, analgesic,
anti-inflammatory, and anticancer activity. The hista-
cific α -blockers) derived from quinazoline have not
1
shown any arrhythmogenic effect, compounds
obtained with quinazoline are expected to have the
advantage of lack of cardiotoxic potential unlike some
of the second-generation antihistamines.
The present study was aimed to synthesize some
mine H -antagonists are used as the first-line treat-
1
novel
1,2,4-triazolo[4,3-a]quinazolin-5(4H)-ones
ment for patients with allergic rhinitis [1–3]. Cur-
rently used first generation antihistamines are effec-
tive and relatively inexpensive. But they cause sedation
and dry mouth at therapeutic doses, due to their
blood-brain barrier penetration and lack of receptor
specificity. Significant percentage (10 to 40%) of
containing aryl/hetero aryl substitution at position 4
and alkyl substitutions at position 1 [5, 7]. The syn-
thetic scheme for the synthesis of title compounds is
depicted in Scheme 1. The synthesized compounds
were determined from spectral and physicochemical
1
patients using these drugs experienced somnolence analysis. IR, H NMR, and mass spectrometry analy-
and also impairment in driving and other types of per- sis results confirmed the formation of desired prod-
formance [4–7]. Second-generation histamine H -
1
ucts. The synthesized compounds were evaluated for
their antihistaminic activity using protection against
histamine-induced bronchospasm on conscious
guinea pigs [8, 9]. Sedative potential was also evalu-
ated by measuring the reduction in locomotor activity
in actophotometer.
receptor antagonists showed improved antihistaminic
activity with less sedative potential. Unfortunately,
some of the second-generation antihistamines pro-
1
Corresponding author: phone: +91 8455-230690; fax: +91 8455
33888; e-mail: drvalagarsamy@gmail.com.
2
403

4
04
GOBINATH et al.
S
DMSO
O N
2
NH + CS2
+
NaOH
O2N
NH
C
2
Stirring
S−Na+
4-Nitroaniline
(CH3)2SO4
O
O
OCH3
NH2
S
OCH3
O N
2
NH C
EtOH
SCH3
NH
NH
NO2
−CH3SH
S
−CH3OH
NO2
NO2
O
O
N
N
NaOH/EtOH
(CH3)2SO4
N
H
(I)
N
S
SCH3
(II)
2,3-Dihydro-3-(4-nitrophenyl)-2-thioxoquinazolin-4(1H)-one 2-Methylthio-3-(4-nitrophenyl)quinazolin-4(3H)-one
−
CH3SH
EtOH
NH2NH2 · H2O
NO2
NO2
O
N
O
N
N
N
N
NHNH2
One carbon donors
N
R
Title compounds (IV−VIII)
(III)
-Hydrazinyl-3-(4-nitrophenyl)quinazolin-4(3H)-one
2
R = (IV) −H; (V) −CH ; (VI) −CH CH ; (VII) −(CH ) CH ; (VIII) −CH Cl
3
2
3
2 2
3
2
Scheme 1. Synthesis of 1-substituted-4-(4-nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones.
RESULTS AND DISCUSSION
product obtained was cyclic and not an open chain
thiourea. The 2-methylthio-3-(4-nitrophenyl)-
quinazolin-4(3H)-one (II) was obtained by dissolving
Chemistry
The key intermediate 2,3-dihydro-3-(4-nitrophe- compound (I) in 2% alcoholic sodium hydroxide
nyl)-2-thioxoquinazolin-4(1H)-one (I), was prepared solution and methylating with dimethyl sulfate with
by reacting 4-nitroaniline with carbon disulphide and stirring at room temperature. Nucleophilic displace-
sodium hydroxide in dimethyl sulfoxide to give ment of methylthio group of compound (II) with
sodium dithiocarbamate, which was methylated with hydrazine hydrate was carried out using ethanol as sol-
dimethyl sulfate to afford the dithiocarbamic acid vent to afford 2-hydrazinyl-3-(4-nitrophenyl)-
methyl ester, which upon reflux with methyl anthrani- quinazolin-4(3H)-one (III). The long duration of
late in ethanol yielded the desired 2,3-dihydro-3-(4- reaction (24 h) required might be due to the presence
nitrophenyl)-2-thioxoquinazolin-4(1H)-one (I) via of bulky aromatic ring at position 3, which might have
the thiourea intermediate in good yield (85%). The reduced the reactivity of quinazoline ring system at C-2
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
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DESIGN AND SYNTHESIS
405
Table 1. Antihistaminic and sedative–hypnotic activity of compounds (IV)–(VIII)
Percent CNS depression
2 h
Compound
code
Histamine-induced
bronchospasm, s
%
protection
1
h
3 h
(
(
(
(
(
IV)
V)
VI)
VII)
VIII)
396.00 ± 4.82**
415.00 ± 3.96**
408.00 ± 4.13**
374.33 ± 2.90**
369.50 ± 4.06**
394.00 ± 4.43*
70.20 ± 0.38**
71.56 ± 0.23**
71.07 ± 0.38**
68.47 ± 0.25**
68.06 ± 0.36**
70.09 ± 0.33*
8.94 ± 0.09**
10.80 ± 0.16**
11.73 ± 0.24**
11.90 ± 0.18**
07.66 ± 0.14**
38.80 ± 1.32**
8.12 ± 0.11**
09.62 ± 0.07**
10.38 ± 0.11**
10.10 ± 0.10**
08.71 ± 0.13**
34.80 ± 0.72**
7.23 ± 0.09**
8.35 ± 0.10**
9.04 ± 0.09**
9.40 ± 0.07**
6.76 ± 0.15**
29.58 ± 0.72**
Chlorpheniramine
Each value represents the mean ± SEM (n = 6). Statistical significance: **p < 0.05.
position. The title compounds (IV)–(VIII) were
Sedative–Hypnotic Activity
obtained in fair-to-good yields through the cyclization
As sedation is one of the major side effects associ-
ated with antihistamines, the test compounds were
also evaluated for their sedative potentials. Sedative–
hypnotic activity was determined by measuring the
of compound (III) with a variety of one-carbon
donors, such as formic acid, acetic acid, propionic
acid, butyric acid, and chloroacetyl chloride, at reflux.
1
The H NMR spectra of compounds (IV)–(VIII) reduction in motor activity. The results of this study
showed the absence of NH and NH signals. All the (Table 1) showed that almost all the test compounds
2
synthesized compounds were confirmed by spectral were found to exhibit mild activity (less than 10%).
Cetirizine and chlorpheniramine maleate were used as
references, chlorpheniramine showed nearly 35% of
sedation and cetirizine showed 10–13% of sedation
approximately. Compared to the reference standard
chlorpheniramine maleate (first-generation antihista-
mine), all the test compounds showed lower sedative
potential; compared to cetirizine (non-sedative anti-
histamine) the test compounds showed equipotent
sedative activity. Hence this series can be developed as
clinically useful non-sedative antihistamines.
data (IR, NMR, and mass spectra). Elemental (C, H,
N) analysis satisfactorily confirmed elemental compo-
sition and purity of the synthesized compounds.
Antihistaminic Activity
The series of compounds containing triazolo[4,3-
a]quinazolines ring system have been evaluated for
their in vivo antihistaminic activity. The protection
against histamine-induced bronchospasm on con-
scious guinea pigs method was adopted to determine
the antihistaminic potential of the test compounds. All
of them have been found to exhibit significant antihis-
taminic activity (Table 1). Percentage protection data
showed that all test compounds of the series show sig-
nificant protection in the range of 68–71.56%. Struc-
ture–activity relationship (SAR) studies indicated that
different substituents at the C-1 atom exerted varied
biological activity. It has been found that the presence
CONCLUSION
In summary, synthesis of a new series of 1-substi-
tuted-4-(4-nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-
5
(4H)-ones has been described. These derivatives
exhibited promising antihistaminic activity against
histamine-induced bronchospasm in the conscious
guinea pigs model. Among the series, 1-methyl-4-(4-
nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-
one (V) was found to be the most active antihistaminic
of methyl group showed better activity over the unsub- agent, which is more potent (71.56%) than the refer-
stituted compounds. When chain length increased ence standard chlorpheniramine maleate (71.00%).
from methyl to ethyl and propyl the activity decreased. Interestingly the sedative property of compound (V)
Replacement of a proton of the methyl group by was found to be negligible (9.59%) when compared to
chlorpheniramine maleate (34.6%), therefore it could
serve as a lead molecule for further modification to
obtain a clinically useful novel class of antihistaminic
agents.
chloro group showed further decrease in activity. The
order of activity was methyl > ethyl > unsubstituted >
propyl > chloromethyl. Among the series, 1-methyl-
4
-(4-nitrophenyl)-[1, 2, 4]triazolo[4,3-a]quinazolin-
(4H)-one (V) was the most potent with the percent-
5
age protection of 71.56 and it is comparable to that of
standard chlorpheniramine maleate (71.00%). As the
test compounds could not be converted to water-solu-
ble form, in vitro evaluation for antihistaminic activity
could not be performed.
EXPERIMENTAL
Chemistry
Starting material for the synthesis, reagents, and
solvents were of analytical grade and were purchased
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 46 No. 3 2020

4
06
GOBINATH et al.
from Aldrich Chemical Co., Merck Chemical Co., obtained was filtered, washed with water, dried, and
and dried when necessary. Histamine (Sigma Chemi- recrystallized from ethanol–chloroform (75 : 25) mix-
cals, USA), aminophylline (Unichem, Mumbai), ture [10]. Yield 86%, mp 160–161°C, IR: 1680
1
chlorpheniramine maleate (Hoechst, Mumbai), and (C=O), 1610 (C=N), 1510 (NO ). H NMR: 2.56 (s,
2
cetirizine (Sun Pharma, Mumbai) were procured for
the present biological study. All melting points
reported were taken on a Veego make Silicone oil
bath-type melting point apparatus and are uncor-
rected. NMR spectra (Bruker, USA, 500 MHz) were
3
H, SCH ), 4.45 (br s, 1H, NH), 6.77–6.79 (m, 1H,
3
Ar-H), 7.26–7.28 (m, 1H, Ar-H), 7.73 (d, J = 5.0 Hz,
H, Ar-H), 7.95 (d, J = 10.0 Hz, 2H, Ar-H), 8.16 (d,
1
13
J = 2.0 Hz, 2H, Ar-H); C NMR: 14.75, 116.75 (2C),
18.65 (2C), 122.27, 124.21, 125.65, 126.77, 131.18,
37.66, 141.76, 141.56, 157.44, 161.65; MS (m/z): 313
1
recorded in CDCl (unless specified) with TMS as
3
1
internal reference (chemical shift in δ, ppm). IR spec-
tra (Shimadzu FT-IR, 8300) were registered in KBr (ν
+
[
M ]; Anal. calculated for C H N O S: C, 57.56; H,
15 11 3 3
3.55; N, 13.43. Found: C, 57.56; H, 3.54; N, 13.41.
–1
max in cm ). Mass spectra were recorded at 70 eV on
a MASPEC msw 9629 instrument. Elemental analysis
was performed in Carlo Erba apparatus. Silica gel-G
2
-Hydrazinyl-3-(4-nitrophenyl)-quinazolin-4(3H)-
one (III). The 2-methylthio-3-(4-nitrophenyl)-
quinazolin-4(3H)-one (II) (0.01 mol, 3.14 g) was dis-
solved in ethanol (25 mL). To this hydrazine hydrate
(
Merck) was used for TLC and iodine vapors used for
exposure of TLC plates. Anhydrous sodium sulfate
(
99%) (5.0 g, 0.1 mol) and anhydrous potassium car-
(
S.D. fine chemicals) was used as drying agent.
,3-Dihydro-3-(4-nitrophenyl)-2-thioxoquinazolin-
(1H)-one (I). A solution of the 4-nitroaniline
bonate (100 mg) were added and refluxed for 23 h. The
reaction mixture was cooled and poured into ice-cold
water. The solid obtained was filtered, washed with
water, dried, and recrystallized from chloroform–
benzene (50 : 50) mixture [11]. Yield 78%, mp 211–
2
4
(
0.02 mol, 2.72 g) in dimethyl sulfoxide (10 mL) was
stirred vigorously. To this carbon disulfide (1.6 mL)
and aqueous sodium hydroxide (1.2 mL, 20 molar)
was added dropwise during 30 min with stirring.
Dimethyl sulfate (2.5 g, 0.02 mol) was added gradually
with stirring by keeping the reaction mixture in freez-
ing mixture and stirred for 2 h. The reaction mixture
was then poured into ice water. The solid obtained was
filtered, washed with water, dried, and recrystallized
from ethanol. Methyl anthranilate (1.5 g, 0.01 mol)
and the above prepared N-(4-nitrophenyl)-methyl
dithiocarbamic acid (0.01 mol) were dissolved in eth-
anol (20 mL). An anhydrous potassium carbonate
2
12°C, IR: 3332–3260 (NHNH ), 1680 (C=O), 1516
2
1
(
NO ). H NMR: 4.45 (br s, 2H, NH ), 4.65 (br s, 1H,
2
2
NH), 7.35 (d, J = 5.0 Hz, 1H, Ar-H), 7.37–7.39 (m,
H, Ar-H), 7.46–7.48 (m, 1H, Ar-H), 7.85 (d, J = 5.0
Hz, 1H, Ar-H), 7.97 (d, J = 10.0 Hz, 2H, Ar-H), 8.26
1
13
(
d, J = 2.0 Hz, 2H, Ar-H); C NMR: 116.75 (2C),
18.65 (2C), 122.27, 124.21, 125.65, 126.77, 131.18,
37.66, 141.56, 157.44, 161.45, 162.71; MS (m/z): 297
1
1
+
[
3
M ]; Anal. calculated for C H N O : C, 56.51; H,
14 11 5 3
.74; N, 23.53. Found: C, 56.56; H, 3.72; N, 23.55.
(
100 mg) was added to the above solution and refluxed
4-(4-Nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-
for 18 h. The reaction mixture was cooled in ice and 5(4H)-one (IV). The 2-hydrazinyl-3-(4-nitrophenyl)-
the solid separated was filtered and purified by dissolv- quinazolin-4(3H)-one (III) (0.01 mol, 2.92 g) and
ing in 10% alcoholic sodium hydroxide solution and formic acid (15 mL) were taken in a round bottom
re-precipitated in dilute hydrochloric acid. The solid flask and refluxed for 29 h, cooled, and poured into
ice-cold water. The solid obtained was filtered, washed
with water, dried, and recrystallized from chloro-
form–ethanol (75 : 25) mixture [12]. Yield 88%, mp
obtained was filtered, washed with water, dried, and
recrystallized from ethanol [4]. Yield 85%, mp 285–
2
86°C, IR: 3268 (NH), 1670 (C=O), 1226 (C=S),
1
239–240°C; IR: 1682 (C=O), 1610 (C=N), 1518
1
520 (NO ). H NMR: 4.47 (br s, 1H, NH), 6.64 (d,
2
1
(
NO ); H NMR: 7.25 (d, J = 5.0 Hz, 1H, Ar-H),
2
J = 5.0 Hz, 1H, Ar-H), 6.76–6.78 (m, 1H, Ar-H),
7
.35–7.37 (m, 1H, Ar-H), 7.44–7.46 (m, 1H, Ar-H),
7
.25–7.27 (m, 1H, Ar-H), 7.70 (d, J = 5.0 Hz, 1H),
7
.86 (d, J = 5.0 Hz, 1H, Ar-H), 7.95 (d, J = 10.0 Hz,
7
.91 (d, J = 10.0 Hz, 2H, Ar-H), 8.15 (d, J = 2.0 Hz,
2
1
H, Ar-H), 8.35 (d, J = 2.0 Hz, 2H, Ar-H), 8.75 (s,
13
2
H, Ar-H); C NMR: 116.87 (2C), 118.75 (2C),
13
H, Ar-H); C NMR: 116.81 (2C), 118.77 (2C),
1
22.34, 124.23, 125.62, 126.75, 131.14, 137.56, 141.87,
1
22.43, 124.56, 125.76, 126.58, 131.47, 137.85, 139.45,
41.89, 141.65, 148.76, 157.44; MS (m/z): 307 [M ];
+
1
41.32, 157.86, 177.91. MS (m/z): 299 [M ]; Anal. cal-
+
1
culated for C H N O S: C, 56.25; H, 3.05; N, 14.08.
14
9
3
3
Anal. cald. for C H N O : C, 58.56; H, 2.93; N,
15
9
5
3
Found: C, 56.18; H, 3.03; N, 14.04.
2
2.74. Found: C, 58.63; H, 2.95; N, 22.79.
2
-Methylthio-3-(4-nitrophenyl)-quinazolin-4(3H)-
1
-Methyl-4-(4-nitrophenyl)-[1,2,4]triazolo[4,3-
one (II). The 2,3-dihydro-3-(4-nitrophenyl)-2-thiox-
oquinazolin-4(1H)-one (I) (0.01 mol, 2.98 g) was dis-
solved in 20 mL of 2% alcoholic sodium hydroxide
a]quinazolin-5(4H)-one (V). The 2-hydrazinyl-3-(4-
nitrophenyl) quinazolin-4(3H)-one (IV) (0.01 mol,
2.92 g) and acetic acid (15 mL) were taken in a round-
solution. To this dimethyl sulfate (1.26 g, 0.01 mol) bottom flask and refluxed for 31 h, cooled, and poured
was added dropwise with stirring and stirring was con- into ice-cold water. The solid obtained was filtered,
tinued for 1 h after completion of addition. The reac- washed with water, dried, and recrystallized from eth-
tion mixture was then poured into ice water. The solid anol [5]. Yield 86%, mp 255–256°C. IR: 1670 (C=O),
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
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DESIGN AND SYNTHESIS
407
1
1
602 (C=N), 1526 (NO ). H NMR: 2.15 (s, 3H, J = 5.0 Hz, 1H, Ar-H), 7.41–7.48 (m, 1H, Ar-H),
2
7.51–7.53 (m, 1H, Ar-H), 7.95 (d, J = 5.0 Hz, 1H, Ar-
CH ), 7.24 (d, J = 5.0 Hz, 1H), 7.36–7.38 (m, 1H, Ar-
3
H), 8.02 (d, J = 10.0 Hz, 2H, Ar-H), 8.27 (d, J = 2.0 Hz,
H), 7.45–7.46 (m, 1H, Ar-H), 7.85 (d, J = 5.0 Hz, 1H,
13
2
H, Ar-H); C NMR: 10.18, 116.92 (2C), 118.89
(2C), 122.43, 124.56, 125.76, 126.58, 131.47, 137.85,
39.45, 141.89, 148.76, 148.81, 158.65; MS (m/z): 355
Ar-H), 7.97 (d, J = 10.0 Hz, 2H, Ar-H), 8.36 (d, J =
13
2
.0 Hz, 2H, Ar-H); C NMR: 10.18, 116.92 (2C),
1
1
18.89 (2C), 122.43, 124.56, 125.76, 126.58, 131.47,
+
[
M ] 357 [M + 2], Anal. calculated for C H N O Cl:
16 10 5 3
1
37.85, 139.45, 141.89, 148.76, 148.81, 158.65; MS
+
C, 54.11; H, 2.85; N, 19.65. Found: C, 54.02; H, 2.83;
N, 19.68.
(
m/z): 321 [M ]; Anal. calculated for C H N O : C,
16 11 5 3
5
9.74; H, 3.42; N, 21.80. Found: C, 59.81; H, 3.45; N,
2
1.79.
1
-Ethyl-4-(4-nitrophenyl)-[1,2,4]triazolo[4,3-
Pharmacology
a]quinazolin-5(4H)-one (VI). The 2-hydrazinyl-3-(4-
nitrophenyl) quinazolin-4(3H)-one (IV) (0.01 mol,
The synthesized compounds were evaluated for
antihistaminic and sedative–hypnotic activities. The
animals were maintained in colony cages at 25 ± 2°C,
relative humidity of 45–55%, under a 12-h light-and-
dark cycle; they were fed standard animal feed. All the
animals were acclimatized for a week before use.
2
.92 g) and propionic acid (15 mL) were taken in a
round-bottom flask and refluxed for 25 h, cooled, and
poured into ice-cold water. The solid obtained was fil-
tered, washed with water, dried, and recrystallized
from ethanol [13]. Yield 81%, mp 241–242°C, IR:
1
1
690 (C=O), 1610 (C=N), 1522 (NO ). H NMR:
Antihistaminic activity. A modification of the tech-
2
1
.21 (t, J = 10.0 Hz, J = 5.0 Hz, CH ), 2.84–2.88 (m, nique of Van Arman was adopted to determine the
1
1
3
2
H, CH ), 7.38 (d, J = 5.0 Hz, 1H, Ar-H), 7.40–7.41 antihistaminic potential of the synthesized com-
2
pounds [9]. Male Dunkin Hartley Guinea pigs (250–
(
m, 1H, Ar-H) 7.45–7.46 (m, 1H, Ar-H), 7.87 (d, J =
3
00 g) were fasted for 12 h. Six animals were taken in
5
.0 Hz, 1H, Ar-H), 7.97 (d, J = 10.0 Hz, 2H, Ar-H),
1
3
each group. The test compounds, was administered
orally at a dose of 10 mg/kg in 1% CMC and chal-
8
.17 (d, J = 2.0 Hz, 2H, Ar-H); C NMR: 10.08,
1
8.56, 116.78 (2C), 118.85 (2C), 121.93, 124.56,
1
25.87, 126.77, 131.81, 137.91, 139.67, 141.89, 148.56, lenged with histamine aerosol (0.2% aqueous solution
+
of histamine acid chloride 3 mL) in a vaponephrin
pocket nebulizer sprayed into a closed transparent
cage. The respiratory status reflecting the increasing
degree of bronchoconstriction was recorded. The time
for onset of convulsions (preconvulsion) was recorded.
Animals remaining stable for more than 6 min were con-
sidered protected against histamine-induced broncho-
spasm [15, 16]. An intraperitoneal injection of chlorphe-
niramine maleate (Hoechst, Mumbai, India) at a dose of
1
48.96, 158.87; Mass: (m/z) 335 [M ]; Anal. calcu-
lated for C H N O : C, 60.95; H, 3.91; N, 20.83.
17
13
5
3
Found: C, 60.89; H, 3.90; N, 20.88.
-(4-Nitrophenyl)-1-propyl-[1,2,4]triazolo[4,3-
4
a]quinazolin-5(4H)-one (VII). The 2-hydrazinyl-3-
(
(
4-nitrophenyl)
quinazolin-4(3H)-one
(IV)
0.01 mol, 2.92 g) and butyric acid (15 mL) were taken
in a round-bottom flask and refluxed for 23 h, cooled,
and poured into ice-cold water. The solid obtained was
filtered, washed with water, dried, and recrystallized
25 mg/kg was given for the recovery of the test animals.
from ethanol [14]. Yield 79%, mp 261–262°C, IR: The mean preconvulsion time of animals treated with the
1
test compounds was compared to control and is
expressed in terms of percentage protection (Table 1).
1
710 (C=O), 1612 (C=N), 1518 (NO ); H NMR: 0.92
2
(
t, J = 10.0 Hz, J = 5.0 Hz, CH ), 1.51–1.59 (m, 2H,
1
1
3
CH ), 2.52–2.59 (m, 2H, CH ), 7.36 (d, J = 5.0 Hz,
2
2
Percent protection =
[
1 –
(
T
T
)
]
×100%,
1
2
1
H), 7.39–7.40 (m, 1H), 7.44–7.45 (m, 1H), 7.89 (d,
where T is preconvulsive time of control; T precon-
J = 5.0 Hz, 1H), 7.97 (d, J = 10.0 Hz, 2H), 8.21 (d, J =
1
2,
13
vulsive time of test compound. The activity of the test
1
0.0 Hz, 2H); C NMR: 10.89, 18.75, 22.56, 116.78
compounds was compared with the standard antihis-
(
2C), 118.85 (2C), 121.93, 124.56, 125.87, 126.77,
1
31.81, 137.89, 139.87, 141.77, 148.56, 148.96, 159.11; tamine chlorpheniramine maleate.
+
MS (m/z): 349 [M ]; Anal. calculated for C H N O :
Sedative–hypnotic activity. Sedative–hypnotic
18
15
5
3
C, 61.95; H, 4.30; N, 20.01. Found: C, 61.88; H, 4.32; activity was determined by measuring the reduction in
N, 20.04.
locomotor activity using actophotometer [17, 18].
Swiss albino mice were chosen as test animals in a
1
-(Chloromethyl)-4-(4-nitrophenyl)-[1,2,4]tri-
azolo[4,3-a]quinazolin-5(4H)-one (VIII). The 2- group of six. Basal activity score was taken and then
hydrazinyl-3-(4-nitrophenyl) quinazolin-4(3H)-one compounds (IV)–(VIII) and standard chlorpheni-
(
(
IV) (0.01 mol, 2.92 g) and chloroacetyl chloride ramine maleate were administered orally at the dose of
0.01 mol) in glacial acetic acid (15 mL) were taken in 5 mg/kg in 1% CMC. Scores were recorded at 1, 2, and
a round-bottom flask and refluxed for 13 h, cooled, 3 h after the drug administration [19]. The percent
and poured into ice water. The solid obtained was fil- reduction in locomotor activity was calculated by the
tered, washed with water, dried, and recrystallized following formula and shown in Table 1.
from chloroform–ethanol (75 : 25) mixture [15]. Yield
%
Reduction in motor activity
A – B ×100%,
8
1
3%, mp 280–282°C, IR: 1680 (C=O), 1610 (C=N),
516 (NO ); H NMR: 4.15 (s, 2H, CH Cl), 7.28 (d,
1
=
[
(
)
A
]
2
2
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 46 No. 3 2020

4
08
GOBINATH et al.
where A is basal score, B, score after drug treatment.
6. Alagarsamy, V., Sharma, H.K., Parthiban, P., Singh, J.C.,
Murugan, S.T., and Solomon, V.R. Pharmazie, 2009,
vol. 64, pp. 5–12.
Statistical analysis. Statistical analysis of the bio-
logical activity of the test compounds on various ani-
mals was performed by one way ANOVA followed by
Dunnett’s test (manually). In all cases significance
level of the means of individual groups were performed
and compared with control. A significance level of p <
7
8
9
. Bousquet J., Van Cauwenberge, P., and Khaltaev, N.,
J. Allergy Clin. Immunol., 2001, vol. 108, pp. 147–152.
. Kuhn, W.L. and Van Maanen, E.F., J. Pharmacol. Exp.
Ther., 1961, vol. 134, pp. 60–68.
. Van Arman, C.G., Miller, L.M., and O’Malley, M.P.,
J. Pharmacol. Exp. Ther., 1961, vol. 133, pp. 90–97.
0
.5 denoted significance in all cases.
1
0. Alagarsamy, V., Narendhar, B., Sulthana, M.T., and
COMPLIANCE WITH ETHICAL STANDARDS
The Institutional Animal Ethics committee approved
the protocol adopted for the experimentation of animals.
All applicable international, national, and institutional
guidelines for the care and use of animals were followed.
Solomon, V.R., Med. Chem. Res., 2014, vol. 23,
pp. 4692–4299.
11. Nivedhitha, S., Solomon, V.R., Gobinath, M., Subra-
manian N., and Alagarsamy, V., Trop. J. Pharm. Res.,
2015, vol. 14, pp. 271–278.
12. Mallareddy, V., Ravinderreddy, P., and Jayamma, Y.,
Indian Drugs, 1987, vol. 25, pp. 182–186.
Conflict of Interests
13. Raghuram Rao, A., Chandrasekhar, V., and Mallared-
dy, V., Indian Drugs, 1986, vol. 24, pp. 40–48.
The authors report no conflicts of interest.
14. Hopp, R.J., Bewtra, A., Nair, N.M., and Townley, R.G., J.
Allergy Clin. Immunol., 1985, vol. 76, pp. 609–614.
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2020