Design and synthesis of novel 3-(phenyl)-2-(3-substituted propylthio) quinazolin-4-(3H)-ones as a new class of H1-antihistaminic agents

Article abstract of DOI:10.1002/jhet.1720

A series of novel 3-(phenyl)-2-(3-substituted propylthio) quinazolin-4-(3H)-ones were synthesized by the reaction of 2-(3-bromopropylthio)-3-(phenyl) quinazolin-4-(3H)-one with various amines. The starting material, 2-(3-bromopropylthio)-3-(phenyl) quinazolin-4-(3H)-one was synthesized from aniline. When tested for their in vivo H₁-antihistaminic activity on conscious guinea pigs, all the test compounds protected the animals from histamine-induced bronchospasm significantly. Compound 2-(3-(4-methylpiperazin-1-yl) propylthiothio)-3- (phenyl) quinazolin-4(3H)-one (Ph5) emerged as the most active compound (73.23% protection) of the series when compared with the reference standard chlorpheniraminemaleate (70.09% protection). Compound Ph5 shows negligible sedation (5.01 %) compared with chlorpheniramine maleate (29.58%). Therefore, compound Ph5 can serve as the leading molecule for further development into a new class of H1-antihistaminic agents.

Full text of DOI:10.1002/jhet.1720

November 2014
Design and Synthesis of Novel 3-(Phenyl)-2-(3-substituted
1615
propylthio) Quinazolin-4-(3H)-ones as a New Class
of H -Antihistaminic Agents
1
V. Alagarsamy* and P. Parthiban
Medicinal Chemistry Research Laboratory, MNR College of Pharmacy, Sangareddy, Gr. Hyderabad 502 294,
Andhra Pradesh State, India
*
E-mail: drvalagarsamy@gmail.com
Received February 27, 2012
DOI 10.1002/jhet.1720
Published online 17 April 2014 in Wiley Online Library (wileyonlinelibrary.com).
O
NH2
N
R
N
S
N
H
(
Ph1-Ph10)
A series of novel 3-(phenyl)-2-(3-substituted propylthio) quinazolin-4-(3H)-ones were synthesized by the
reaction of 2-(3-bromopropylthio)-3-(phenyl) quinazolin-4-(3H)-one with various amines. The starting material,
2-(3-bromopropylthio)-3-(phenyl) quinazolin-4-(3H)-one was synthesized from aniline. When tested for their
in vivo H -antihistaminic activity on conscious guinea pigs, all the test compounds protected the animals from
1
histamine-induced bronchospasm significantly. Compound 2-(3-(4-methylpiperazin-1-yl) propylthiothio)-3-
(phenyl) quinazolin-4(3H)-one (Ph5) emerged as the most active compound (73.23% protection) of the series
when compared with the reference standard chlorpheniramine maleate (70.09% protection). Compound Ph5 shows
negligible sedation (5.01 %) compared with chlorpheniramine maleate (29.58%). Therefore, compound Ph5 can
serve as the leading molecule for further development into a new class of H -antihistaminic agents.
1
J. Heterocyclic Chem., 51, 1615 (2014).
INTRODUCTION
derivatives (Fig. 2) as potent antihistamines with least
sedation. The present work is an extension of our ongoing
efforts towards development and identification of new
Histamine is one of the most important chemical
mediators and through its interaction with H receptors,
1
molecules. It has been proposed that for H -antihistaminic ac-
1
present in most tissues, is involved in the pathophysiology
of allergic rhinoconjuntivitis, urticaria, and asthma [1].
The first-generation antihistamines are effective and
relatively inexpensive against these symptoms; however,
they also cause sedation and dry mouth at therapeutic doses
because of their blood–brain barrier penetration and lack of
receptor specificity [2]. A common feature of the first-
generation compounds includes two aryl or heteroaryl rings
linked to an aliphatic tertiary amine via the side chain (Fig. 1
diphenhydramine and pheniramine) [3]. In contrast, most of
tivity, a compound should have the aforementioned
pharmacophore (heterocyclic quinazoline ring linked to
an aliphatic tertiary amine via the side chain). In view of these,
a series of 3-(phenyl)-2-(3-substituted propylthio) quinazolin-
4-(3H)-ones have been proposed to synthesize (Scheme 1)
and study their H -antihistaminc activity potential.
1
RESULTS AND DISCUSSION
the second-generation H -antagonists such as terfenadine,
Chemistry. The key intermediate 3-(4-phenyl)-2-thioxo-
2,3-dihydro-1H-quinazolin-4-one (4) was synthesized by
straightforward method. In this synthetic Scheme, Aniline
(1) treated with carbon disulphide and sodium hydroxide
in dimethyl sulfoxide to give sodium dithiocarbamate,
which was methylated with dimethyl sulfate to afford the
dithiocarbamic acid methyl ester (2). Compound 2 on
reflux with methyl anthranilate (3) in ethanol yielded the
desired 3-(phenyl)-2-thioxo-2,3-dihydro-1H-quinazolin-4-
one (4) via the thiourea intermediate in good yield (86%).
The use of DMSO as the reaction solvent enhanced the rate
of reaction, and the use of alkali in higher concentration
helped prevent the hydrolysis of the intermediate, probably
because of less solvation. The product obtained was cyclic
and not an open chain thiourea 3a. The IR spectrum of 4
1
cetirizine, and astemizole [4] have a greatly improved
benefit-to-risk ratio compared with their predecessors.
These drugs are reduced potential to cross the blood–brain
barrier and possess the higher receptor specificity [4]; they
are labeled as “nonsedative antihistamines.” The second-
generation compounds (Fig. 1 terfenadine and cetirizine)
also contain many of the structural features of first-
generation compounds. Condensed heterocycles containing
new generation of H -antihistamines (loratadine, azelastine,
1
and flazelastine) that do not possess the aforementioned
pharmacophore for H -antihistamines gave way for the
1
discovery of many novel antihistamines temelastine [4]
and mangostin [5]. Quinazolines and condensed quinazo-
lines show excellent antihistaminic activity [6–8]. In this
continuation, we demonstrated [9–11] the quinazoline
ꢀ
1
show intense peaks at 3220 cm for cyclic thiourea (NH),
©
2014 HeteroCorporation

1
616
V. Alagarsamy and P. Parthiban
Vol 51
Cl
N
O
N
N
HO
O
N
HO
O
N
N
HO
Diphenhydramine
Pheniramine
Terfenadine
Cetirizine
Figure 1. Structure of some clinically available H
1
-antihistaminic agent.
O
N
O
O
N
N
CH
3
N
R
1
N
N
S
N
N
N
N
R2
R
N
R
Figure 2. Quinazolin-4-(3H)-one lead optimization from this laboratory.
Scheme 1. Synthesis of 3-(phenyl)-2-(3-substituted propyl) quinazolin-4-(3H)-one (Ph1–Ph10).
S
S
(
CH ) SO
3 2 4
DMSO
NH
C
NH2
CS2
+
NaOH
NH
C
+
SCH3
-
+
S Na
(2)
(
1)
O
C
OCH3
EtOH
-
CH SH
NH2
3
(3)
O
C
O
N
O
OCH3
N
-CH3OH
N
NH
NH
SH
N
H
S
S
(4)
(4)
BrCH CH CH Br
2
2
2
-HBr
(5)
O
O
R
NH2
HBr
N
N
-
R
N
S
N
N
N
S
Br
H
(
Ph1-Ph10)
(6)
CH CH3
2
Ph5
N
NCH3
Ph1
Ph6
Ph2
N
N
Ph4
N
NH
Ph3
CH CH3
2
N
O
Ph7
HN
CH3
Ph10 HN H C
2
HN
Ph8
HN
Cl Ph9
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2014
New Class of H1-Antihistaminic Agents
1617
ꢀ
1
ꢀ1
1
(
660cm for carbonyl (C═O), and 1200 cm for thioxo
compounds Ph1–Ph10, the common peak appeared due
quinazolin-4-one moiety cation at m/z 168. Elemental
(C, H, and N) analysis satisfactorily confirmed elemental
composition and purity of the synthesized compounds.
1
C═S) stretching. H NMR spectrum of 4 showed a
multiplet at d 7.0–9.0 ppm for aromatic (9H) protons and a
singlet at d 10.5 ppm indicating the presence of NH. Data
from the elemental analyses have been found to be in
conformity with the assigned structure. Further, the
molecular ion recorded in the mass spectrum is also in
agreement with the molecular weight of the compound.
The 2-(3-bromopropyl)-3-(phenyl) quinazolin-4-(3H)-
one (6) was prepared by heating at reflux temperature, a
solution of 3-phenyl-2-thioxo quinazolin-4-one (4), and
,3-dibromopropane in acetone in the presence of K CO3
for 1 h. The IR spectrum of 6 showed disappearance of NH
and C═S stretching signals of cyclic thiourea. It showed a
peak for carbonyl (C═O) stretching at 1686 cm . The
H NMR spectrum of compound 6 showed multiplet
Pharmacology.
The compounds containing 2-(3-
substituted propylthio)-3-(phenyl) quinazolin-4-(3H)-ones,
(Ph1–Ph10) were evaluated for their in vivo antihistaminic
activity. Histamine causes bronchospasm, and the guinea
pigs are most susceptible animals for histamine; hence,
protection against histamine-induced bronchospasm on
conscious guinea pigs method was adopted to determine
the antihistaminic potential of the test compounds [12].
The advantage of this method is that it is one of the
noninvasive method, and the animals are recovered after
the experiment.
1
2
ꢀ
1
1
All the test compounds were found to exhibit good
antihistaminic activity (Table 1). Percentage protection data
showed that all test compounds of the series showed
significant protection in the range of 66–73%. Biological
studies indicated that different substituents over the second
position of quinazoline ring exerted varied biological
activity. The presence of diethyl group (compound Ph1)
showed significant activity; when the cyclic amines with
the similar lipophilicity are substituted (pyrrolidinyl
compound Ph2 and piperidinyl compound Ph3), the
activity is retained. Placement of additional heteroatoms
such as nitrogen (piperazinyl compound Ph4 and N-methyl
piperazinyl compound Ph5) and oxygen (morpholinyl
compound Ph6) leads to increase in activity. Placement of
aryl substitutions (phenyl compound Ph7; p-chlorophenyl
compound Ph8; and p-methyl phenyl compound Ph9)
results in decreased activity. Placement of arylalkyl
(benzyl compound Ph10) further decreased the activity. Com-
pound 2-(3-(4-methylpiperazin-1-yl) propylthio)-3-(phenyl)
quinazolin-4(3H)-one (Ph5) exhibited the most potent
activity of the series.
at d 2.03–3.25 for S-CH CH CH group; and multiplet
2
2
2
for aromatic (9H) protons observed at d 7.39–8.06.
Data from the elemental analyses and molecular ion
recorded in the mass spectrum further confirmed the
assigned structure.
The title compounds Ph1–Ph10 were obtained in fair to
good yields through the nucleophilic displacement of –Br
group of 2-(3-bromo propyl)-3-(phenyl) quinazolin-4-
(3H)-one (6) with a variety of amines, using ethanol as
solvent to afford 2-(3-substituted propylthio)-3-(phenyl)
quinazolin-4-(3H)-one (Ph1–Ph10). The formation of the
title compounds is indicated by the disappearance of peaks
due to Br of the starting material and the appearance of NH
ꢀ
1
signal at 3220 cm in the IR spectra of the compounds
Ph4, Ph7, Ph8, Ph9, and Ph10. It also showed a peak
ꢀ
1
1
for carbonyl (C═O) around 1680 cm . The H NMR
spectra of the title compounds Ph1 to Ph10 showed peaks
for substituents at C-2 and singlet around d 8.04 ppm
because of NH, and a multiplet at d 7.10–8.31 ppm was
observed for aromatic protons. In mass spectra of
Table 1
Antihistaminic and sedative-hypnotic activity of compounds Ph1–Ph10.
Percent CNS depression
Time of onset
Compound code
of convulsion (s)
% Protection
0.5 h
1 h
2 h
3 h
Ph1
Ph2
Ph3
Ph4
Ph5
Ph6
Ph7
Ph8
379 ꢁ 1.85*
388 ꢁ 2.46*
381 ꢁ 1.82*
410 ꢁ 2.40*
441 ꢁ 2.43*
408 ꢁ 2.86*
365 ꢁ 1.52*
370 ꢁ 4.29*
356 ꢁ 4.56*
351 ꢁ 2.46*
394 ꢁ 4.43*
68.88 ꢁ 0.15*
69.58 ꢁ 0.19*
69.02 ꢁ 0.14*
71.21 ꢁ 0.16*
73.23 ꢁ 0.14*
71.09 ꢁ 0.19*
67.66 ꢁ 0.13*
68.08 ꢁ 0.36*
66.82 ꢁ 0.42*
66.37 ꢁ 0.23*
70.09 ꢁ 0.33*
12.00 ꢁ 1.20**
8.16 ꢁ 0.73**
10.13 ꢁ 0.55**
7.10 ꢁ 0.88**
7.10 ꢁ 0.88**
6.07 ꢁ 0.59**
7.10 ꢁ 0.88**
6.07 ꢁ 0.59**
8.16 ꢁ 0.73**
9.81 ꢁ 1.52**
32.04 ꢁ 0.50**
13.02 ꢁ 1.22**
9.12 ꢁ 1.02**
10.14 ꢁ 0.56**
7.11 ꢁ 0.88**
8.16 ꢁ 0.73**
7.11 ꢁ 0.88**
7.11 ꢁ 0.88**
6.00 ꢁ 0.58**
8.18 ꢁ 0.74**
9.61 ꢁ 1.42**
38.80 ꢁ 1.32**
13.60 ꢁ 1.26**
9.15 ꢁ 1.02**
11.16 ꢁ 0.77**
8.16 ꢁ 0.73**
8.19 ꢁ 0.76**
7.17 ꢁ 0.87**
9.81 ꢁ 1.52**
7.17 ꢁ 0.87**
10.13 ꢁ 0.55**
10.14 ꢁ 0.56**
34.80 ꢁ 0.72**
9.81 ꢁ 1.52**
6.00 ꢁ 0.58**
8.03 ꢁ 0.91**
5.01 ꢁ 0.43**
6.00 ꢁ 0.58**
5.01 ꢁ 0.43**
6.00 ꢁ 0.58**
5.18 ꢁ 0.47**
6.07 ꢁ 0.59**
7.11 ꢁ 0.88**
29.58 ꢁ 0.72**
Ph9
Ph10
Chlorpheniramine
CNS, central nervous system.
Each value represents the mean ꢁ SEM (n = 6). Significance levels *p < 0.001, **p > 0.05
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
618
V. Alagarsamy and P. Parthiban
Vol 51
reaction mixture in freezing mixture with stirring, and the stirring
was continued for further 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 aforementioned prepared N-
Sedative-hypnotic activity was determined by measuring
the reduction in locomotor activity using actophotometer
Orchid Scientific Pvt Ltd, Nashik, India) [13,14] on
Albino Swiss mice. The results of sedative-hypnotic activity
indicate that all the test compounds were found to exhibit
only negligible sedation (6–11%), whereas the reference
standard chlorpheniramine maleate showed 33% sedation.
(
(
Phenyl) methyl dithiocarbamic acid (0.01 mol) were dissolved in
ethanol (20 mL). To this anhydrous potassium carbonate (100mg)
was added and refluxed for 18h. The reaction mixture was cooled
in ice, and the solid separated was filtered and purified by
dissolving in 10% alcoholic sodium hydroxide solution and
reprecipitated by treating with dilute hydrocholoric acid. The solid
obtained was filtered, washed with water, and dried. It was
recrystallized from ethanol to afford (4). Yield= 86%; mp 305–
CONCLUSION
In summary, synthesis of new series of 2-(3-substituted
propylthio)-3-(phenyl) quinazolin-4-(3H)-one (Ph1–Ph10)
have been described. The title compounds have exhibited
promising antihistaminic activity against histamine-
induced bronchospasm on conscious guinea pigs in vivo
model. Among the series, 2-(3-(4-methylpiperazin-1-yl)
propylthio)-3-(phenyl) quinazolin-4(3H)-one (Ph5) was
found to be the most active compound (73.23%), which is
more potent when compared with the reference standard
chlorpheniramine maleate (70.09%). Interestingly, compound
Ph5 also showed negligible sedation (5.01%) compared with
chlorpheniramine maleate (29.58%) and could therefore
serve as a lead molecule for further modification to obtain
a clinically useful novel class of nonsedative antihistamines.
ꢂ
ꢀ1
3
06 C; IR (KBr) cm : 3220 (NH), 1660 (C═O), 1200 (C═S);
1
H NMR (CDCl ): d 7.0–9.0 (m, 9H, Ar-H), 10.5 (br, s, 1H,
NH); MS (m/z) 254 (M ); Anal. Calcd for C H N OS: C,
3
+
14 10 2
6
6.12; H, 3.96; N, 11.02; Found: C, 66.15; H, 3.98; N, 11.07.
Synthesis of 2-(3-bromopropylthio)-3-(phenyl) quinazolin-4-
(
1
(
3H)-one (6). A solution of 3-(4-phenyl)-2-thioxo-2,3-dihydro-
H-quinazolin-4-one (4) (2.54g; 0.01mol), 1,3-dibromopropane
0.02 mol), and K CO (4.14 g; 0.03 mol) in acetone (20mL) was
2
3
heated to reflux temperature for 1 h. The reaction mixture was
cooled to room temperature and filtered off to remove the
inorganic materials. The solvent was removed under reduced
pressure to afford 2-(3-bromo propyl)-3-(phenyl) quinazolin-
4-(3H)-one (6), it was then recrystallized from ethanol.
ꢂ
ꢀ1
Yield = 83%, mp 195–198 C; IR (KBr) cm : 1686 (C═O),
1
1
603 (C═N), 592 (C-Br); H NMR (CDCl ): d 2.03–2.08 (m, 2H,
3
CH ), 3.22–3.25 (m, 4H, CH ), 7.39–7.46 (m, 4H, Ar-H),
2
2
EXPERIMENTAL
7.57–7.59 (m, 3H, Ar-H), 7.77–7.79 (d, 1H, Ar-H), 8.05–8.06
+
(
2
d, 1H, Ar-H); MS (m/z) 375 (M ). Anal. Calcd for C17H15BrN OS:
General. Melting points (mp) were taken in open capillaries
on Thomas Hoover melting point apparatus (Thomas Hoover,
Swedesboro, NJ) and are uncorrected. The IR spectra were
recorded in film or in potassium bromide disks on a Perkin-
C, 54.41; H, 4.03; N, 7.46. Found: C, 54.39; H, 4.00; N, 07.49.
General procedure for synthesis of 3-(phenyl)-2-(3-substituted
propylthio) quinazolin-4-(3H)-one (Ph1–Ph10). A mixture of
2
-(3-bromo propyl)-3-(phenyl) quinazolin-4-(3H)-one (6) (3.75 g;
1
0
.01mol), alkyl/aryl amine (0.015mol), potassium iodide
Elmer 398 spectrometer (Perkin-Elmer, San Jose, CA). The H
(
1
1.66 g; 0.015 mol), and sodium carbonate (2.12 g; 0.02 mol) in
-butanol (25 mL) was heated at reflux temperature (for 3 h by
NMR spectra were recorded on a DPX-500 MHz Bruker
FT-NMR spectrometer (Bruker, Santa Barbara, CA). The
chemical shifts were reported as parts per million (d ppm)
tetramethylsilane as an internal standard. Mass spectra were
obtained on a JEOL-SX-102 instrument (Jeol, Tokyo, Japan)
using fast atom bombardment (positive). Elemental analysis
was performed on a Perkin-Elmer 2400 C, H, N analyzer
conventional refluxing or 15 min by microwave oven). The
reaction mixture was cooled and filtered, and the filtrate was then
concentrated in vacuum and kept in refrigerator overnight. The
product obtained was filtered, dried, and recrystallized using
chloroform–ethanol (50:50) mixture to yield the title compounds.
2
-(3-(Diethylamino) propylthio)-3-(phenyl) quinazolin-4(3H)-
(
Perkin-Elmer, San Jose, CA), and values were within the
ꢂ
ꢀ1
one (Ph1).
Yield = 81%, mp 170–172 C; IR (KBr) cm
:
acceptable limits of the calculated values. The progress of the
reaction was monitored on readymade silica gel plates (Merck,
Spectrochem Ltd, Mumbai, India) using chloroform–methanol
1
1
(
684 (C═O), 1608 (C═N), 1288 (C-N);
CDCl ): d 0.89–0.95 (m, 6H, (CH
CH ), 2.38–2.42 (m, 6H, CH ), 3.22–3.25 (m, 2H, CH ),
H
NMR
3
3 2
) ), 2.05–2.07 (m, 2H,
(
9:1) as a solvent system. Iodine was used as a developing
2
2
2
7
.39–7.47 (m, 4H, Ar-H), 7.58–7.59 (m, 3H, Ar-H), 7.78–7.80
agent. Spectral data (IR, NMR, and mass spectra) confirmed
the structures of the synthesized compounds, and the purity of
these compounds was ascertained by microanalysis. Elemental
+
(d, 1H, Ar-H), 8.04–8.05 (d, 1H, Ar-H); MS (m/z) 367 (M ).
Anal. Calcd for C21 OS: C, 68.63; H, 6.86; N, 11.43.
H N
25 3
(
C, H, and N) analysis indicated that the calculated and
Found: C, 68.60; H, 6.89; N, 11.40.
observed values were within the acceptable limits (ꢁ0.4%). All
3-(Phenyl)-2-(3-(pyrrolidin-1-yl) propylthio) quinazolin-4(3H)-
ꢂ
ꢀ1
chemicals and reagents were obtained from Aldrich (St. Louis, MO),
one (Ph2).
Yield = 78%, mp 210–212 C; IR (KBr) cm
:
1
(Lancaster, London, UK), or Spectrochem Pvt. Ltd (Mumbai, India)
1685 (C═O), 1606 (C═N), 1262 (C-N); H NMR (CDCl
3
): d 1.60–
), 2.70–2.73 (m, 2H,
), 7.28–7.73 (m, 8H, Ar-H), 8.24–8.25
and were used without further purification.
Synthesis of 3-(4-phenyl)-2-thioxo-2,3-dihydro-1H-quinazolin-
1.62 (m, 4H, (CH
CH ), 3.28–3.31 (m, 2H, CH
23 3
(dd, 1H, Ar-H); MS (m/z) 365 (M ). Anal. Calcd for C21H N OS:
2
)), 2.17–2.20 (m, 6H, CH
2
2
2
+
4
-one (4). A solution of Aniline (1.86 g; 0.02 mol) in dimethyl
sulfoxide (10mL) was stirred vigorously. To this was added
carbon disulphide (1.6mL) and aqueous sodium hydroxide
C, 69.01; H, 6.34; N, 11.50. Found: C, 69.00; H, 6.37; N, 11.52.
3-(Phenyl)-2-(3-(piperidin-1-yl) propylthio) quinazolin-4(3H)-
ꢂ
ꢀ1
(1.2mL; 20 M) dropwise during 30min with stirring. Dimethyl
one (Ph3).
Yield = 82%, mp 186–188 C; IR (KBr) cm
:
1
sulfate (2.5 g; 0.02 mol) was then added gradually keeping the
1692 (C═O), 1606 (C═N), 1268 (C-N); H NMR (CDCl
3
): d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2014
New Class of H1-Antihistaminic Agents
1619
1
.23–1.34 (m, 6H, (CH -piperidinyl)), 2.05–2.08 (m, 2H,
Pharmacology. The synthesized compounds were evaluated
2
CH2), 2.18–2.22 (m, 4H, CH -piperidinyl), 3.23–3.26
for antihistaminic and sedative-hypnotic activities. The animals
2
ꢂ
(
m, 4H, CH
2
), 7.39–7.40 (d, 1H, Ar-H), 7.43–7.46 (m, 3H,
were maintained in colony cages at 25 ꢁ 2 C, relative humidity of
Ar-H), 7.58–7.61 (m, 3H, Ar-H), 7.78–7.80 (d, 1H, Ar-H),
45–55%, under a 12 h light and dark cycle; they were fed with
standard animal feed. All the animals were acclimatized for a week
before the experiment. The Institutional Animal Ethics committee
approved the protocol adopted for the experimentation of animals.
+
8
.05–8.06 (d, 1H, Ar-H); MS (m/z) 379 (M ). Anal. Calcd
for C H N OS: C, 69.62; H, 6.64; N, 11.07. Found: C,
2
2 25 3
6
9.65; H, 6.67; N, 11.05.
-(Phenyl)-2-(3-(piperazin-1-yl) propylthio) quinazolin-4(3H)-
3
Antihistaminic activity.
A modification of the technique of
ꢂ
ꢀ1
one (Ph4). Yield= 80%, mp 176–178 C; IR (KBr) cm : 3192
Van Arman was adopted to determine the antihistaminic potential
of the synthesized compounds [12]. Male Dunkin Hartley Guinea
pigs (250–300g) were fasted for 12h. Six animals were taken in
each group. The test compounds and reference compound,
chlorpheniramine maleate (Avil; Hoechst, Mumbai, India), were
administered orally at a dose of 10mg/kg in 1% CMC
(Carboxymethyl cellulose) and challenged 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 considered protected against
histamine-induced bronchospasm. An intraperitoneal injection of
chlorpheniramine maleate at a dose of 25mg/kg was given for the
recovery of the test animals. The mean preconvulsion time of
animals treated with the test compounds was compared to control
and is expressed in terms of percentage protection (Table 1).
1
(
(
NH), 1686 (C═O), 1614 (C═N), 1265 (C-N); H NMR
CDCl ): d 1.62–1.64 (m, 6H, (CH )), 2.17–2.22 (m, 4H, CH ),
3
2
2
2
2 2
.83–2.85 (m, 2H, CH ), 3.28–3.31 (m, 2H, CH ), 7.31–7.73
(
m, 8H, Ar-H), 8.24–8.25 (dd, 1H, Ar-H), 8.61 (br, s, 1H, NH);
+
MS (m/z) 380 (M ). Anal. Calcd for C21
24 4
H N OS: C, 66.29;
H, 6.36; N, 14.72. Found: C, 66.26; H, 6.34; N, 14.74.
2
-(3-(4-Methylpiperazin-1-yl) propylthio)-3-(phenyl) quinazolin-
ꢂ
4
(3H)-one (Ph5).
Yield= 79%, mp 180–182 C; IR (KBr)
ꢀ
1
1
cm : 1689 (C═O), 1606 (C═N), 1299 (C-N); H NMR
CDCl ): d 1.60–1.62 (m, 6H, (CH )), 2.18–2.22 (m, 4H, CH ),
.60 (s, 3H, CH ), 2.80–2.83 (m, 2H, CH ), 3.27–3.30 (m, 2H,
(
2
3
2
2
3
2
CH ), 7.29–7.70 (m, 8H, Ar-H), 8.20–8.21 (dd, 1H, Ar-H); MS
2
+
(
m/z) 394 (M ). Anal. Calcd for C22
26 4
H N OS: C, 66.97; H, 6.64;
N, 14.20. Found: C, 66.93; H, 6.67; N, 14.16.
2
-(3-Morpholinopropylthio)-3-(phenyl) quinazolin-4(3H)-one
ꢂ
ꢀ1
(
(
Ph6).
Yield = 81%, mp 166–170 C; IR (KBr) cm : 1690
1
C═O); 1606 (C═N); 1260 (C-N); H NMR (CDCl ): d 1.65–
3
1
.68 (m, 6H, (CH
2
)), 2.00–2.20 (m, 4H, CH
2
), 2.49–2.50
Percent protection ¼ ½1 ꢀ ðT1=T2Þꢃ ꢄ 100
(
m, 2H, CH ), 3.29–3.31 (m, 2H, CH
2
2
), 7.28–7.73 (m, 8H,
+
Ar-H), 8.24–8.25 (dd, 1H, Ar-H); MS (m/z) 381 (M ). Anal.
Calcd for C H N O S: C, 66.12; H, 6.08; N, 11.01. Found:
C, 66.16; H, 6.05; N, 11.04.
-(Phenyl)-2-(3-phenylpropylthio) quinazolin-4(3H)-one (Ph7).
Yield = 80%, mp 180–182 C; IR (KBr) cm : 3280 (NH),
where T is the preconvulsive time of test compound, T is the
2
1
21 23 3 2
preconvulsive time of control.
The activity of the test compounds was compared with the
standard antihistamine chlorpheniramine maleate.
3
ꢂ
ꢀ1
1
Sedative-hypnotic activity. Sedative-hypnotic activity was
determined by measuring the reduction in locomotor activity
using actophotometer [13,14]. Six Albino Swiss mice (National
Institute of Nutrition, Hyderabad, India) were allotted to each
group. Basal activity score was taken, and then compounds
Ph1–Ph10 and the standard chlorpheniramine maleate were
administered orally at the dose of 5 mg/kg in 1% cmc. Scores
were recorded at 0.5, 1, 2, and 3 h after the drug
administration. The percent reduction in locomotor activity
was calculated by the following formula and shown in Table 1.
1
2
686 (C═O), 1606 (C═N), 1299 (C-N); H NMR (CDCl ): d
.04–2.07 (m, 2H, CH ), 3.22–3.24 (m, 4H, CH ), 7.11–7.58
3
2
2
(
m, 11H, Ar-H), 7.75–7.79 (m, 2H, Ar-H), 8.04–8.05 (m, 1H,
+
Ar-H), 8.25 (br, s, 1H, NH); MS (m/z) 387 (M ). Anal. Calcd
for C23 OS: C, 71.29; H, 5.46; N, 10.84. Found: C,
1.33; H, 5.47; N, 10.82.
-(3-(4-Chlorophenyl) propylthio)-3-(phenyl) quinazolin-
21 3
H N
7
2
ꢂ
(3H)-one (Ph8). Yield= 78%, mp 188–190 C; IR (KBr) cm :
1
ꢀ1
4
3
(
286 (NH), 1685 (C═O), 1610 (C═N), 1271 (C-N); H NMR
): d 2.03–2.09 (m, 2H, (CH )), 3.24–3.27 (m, 4H, CH ),
.23–7.58 (m, 11H, Ar-H), 7.76–7.79 (m, 1H, Ar-H), 8.04–8.06
CDCl
7
3
2
2
%
Reduction in motor activity ¼ ½ðA ꢀ BÞ=Aꢃ ꢄ 100
where A is the basal score, B is the score after drug treatment.
Statistical analysis. Statistical analysis of the biological
activity of the synthesized compounds on animals was evaluated
using a one-way analysis of variance. In all cases, post hoc
comparisons of the means of individual groups were performed
using Tukey’s test. A significance level of p > 0.05 denoted
significance in all cases. All values are expressed as mean ꢁ SD.
For statistical analysis, GraphPad Prism 3.0 version was used.
(GraphPad Software, Inc., San Diego, CA, USA).
+
(
m, 1H, Ar-H), 8.26 (br, s, 1H, NH); MS (m/z) 421 (M ). Anal.
Calcd for C23 20ClN OS: C, 65.47; H, 4.78; N, 9.96. Found:
C, 65.45; H, 4.74; N, 9.98.
-(3-(4-Methylphenyl) propylthio)-3-(phenyl) quinazolin-
H
3
2
ꢂ
ꢀ1
4
(3H)-one (Ph9). Yield= 81%, mp 211–212 C; IR (KBr) cm :
1
3
274 (NH), 1689 (C═O); 1606 (C═N); 1298 (C-N); H NMR
): d 2.04–2.07 (m, 4H, (CH )), 2.49–2.51 (s, 3H, CH ),
.22–3.25 (m, 2H, CH ), 7.39–7.80 (m, 12H, Ar-H) 8.05–8.06
(
CDCl
3
2
3
3
2
+
(
dd, 1H, Ar-H), 8.51 (br, s, 1H, NH); MS (m/z) 401 (M ). Anal.
Calcd for C H N OS: C, 71.79; H, 5.77; N, 10.47. Found: C,
24 23 3
7
1.74; H, 5.79; N, 10.46.
-(3-(Benzyl) propylthio)-3-(phenyl) quinazolin-4(3H)-one
2
ꢂ
ꢀ1
(
Ph10).
Yield = 80%, mp 170–172 C; IR (KBr) cm : 3276
Acknowledgments. The authors gratefully acknowledge the
Central Instrumentation Facility, IIT Chennai, India for the spectral
analysis of the compounds used in this study. The authors are also
wish to thank CSIR, New Delhi and Management of MNR
College of Pharmacy for providing the financial and infrastructure
facilities to carry out this research work.
1
(
(
NH), 1689 (C═O); 1609 (C═N); 1289 (C-N); H NMR
CDCl ): d 2.18–2.20 (m, 4H, (CH )), 3.29–3.31 (m, 4H, CH ),
3
2
2
7
1
7
.31–7.73 (m, 13H, Ar-H), 8.24–8.25 (dd, 1H, Ar-H), 8.71 (br, s,
+
23 3
H, NH); MS (m/z) 401 (M ). Anal. Calcd for C24H N OS: C,
1.79; H, 5.77; N, 10.47. Found: C, 71.80; H, 5.74; N, 10.49.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
620
V. Alagarsamy and P. Parthiban
Vol 51
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