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

Article abstract of DOI:10.3109/14756366.2011.631184

A series of novel 2-(3-substituted propyl)-3-(2-methyl phenyl) quinazolin-4-(3H)-ones were synthesized by the reaction of 2-(3-bromopropyl thio)-3-(2-methyl phenyl) quinazolin-4-(3H)-one with various amines. The starting material, 2-(3-bromopropyl thio)-3

Full text of DOI:10.3109/14756366.2011.631184

Journal of Enzyme Inhibition and Medicinal Chemistry, 2013; 28(1): 65–71
© 2013 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2011.631184
RESEARCH ARTICLE
Design and synthesis of novel 2-(3-substituted propyl)-3-
(2-methyl phenyl) quinazolin-4-(3H)-ones as a new class of
H1-antihistaminic agents
V. Alagarsamy and P. Parthiban
Medicinal Chemistry Research Laboratory, MNR College of Pharmacy, Sangareddy, Gr. Hyderabad, Andhra Pradesh, India
Abstract
A series of novel 2-(3-substituted propyl)-3-(2-methyl phenyl) quinazolin-4-(3H)-ones were synthesized by the reaction
of 2-(3-bromopropyl thio)-3-(2-methyl phenyl) quinazolin-4-(3H)-one with various amines. The starting material, 2-(3-
bromopropyl thio)-3-(2-methyl phenyl) quinazolin-4-(3H)-one was synthesized from 2-methyl aniline. When tested
for their in vivo H -antihistaminic activity on conscious guinea pigs, all the test compounds protected the animals
from histamine i1nduced bronchospasm significantly. Compound 2-(3-(4-methylpiperazin-1-yl) propylthio)-3-(2-
methyl phenyl) quinazolin-4(3H)-one (OT5) emerged as the most active compound (71.70% protection) of the series
when compared to the reference standard chlorpheniramine maleate (70.09% protection). Compound OT5 shows
negligible sedation (7%) compared to chlorpheniramine maleate (33%). Therefore, compound OT5 can serve as the
leading molecule for further development into a new class of H1-antihistaminic agents.
Keywords: Quinazolin-4-ones, sedation, H1-antihistaminic agents
Introduction
compounds (Figure 1 terfenadine and cetirizine) also
Histamine is one of the most important chemical media-
tors and through its interaction with H1 receptors, pres-
ent in most tissues, is involved in the pathophysiology
of allergic rhinoconjuntivitis, urticaria and asthma1. e
first-generation antihistamines are effective and rela-
tively inexpensive against these symptoms; however,
they also cause sedation and dry mouth at therapeu-
tic doses, due to their blood-brain barrier penetration
and lack of receptor specificity2. A common feature of
the first-generation compounds includes two aryl or
heteroaryl rings linked to an aliphatic tertiary amine
via the side chain (Figure 1 diphenhydramine and
pheniramine3). In contrast, most of the second genera-
tion H1-antagonists such as terfenadine, cetirizine and
astemizole4, have a greatly improved benefit-to-risk
ratio compared to their predecessors. ese drugs are
lesser perspective to cross the blood-brain barrier and
possess the higher receptor specificity4 they are labeled
as “non sedative antihistamines”. e second-generation
containmanyofthestructuralfeaturesoffirst-generation
compounds. Condensed heterocycles containing new
generation of H1-antihistamines (loratadine, azelastine
and flazelastine) that do not possess the above men-
tioned pharmacophore for H1-antihistamines gave way
for the discovery of many novel H1-antihistaminic drugs
temelastine4 and mangostin5. Quinazolines and con-
densed quinazolines showed excellent antihistaminic
activity6–8. In this continuation, we demonstrated9–11 the
quinazoline derivatives (Figure 2) as potent antihista-
mines with least sedation. e present work is an exten-
sion of our ongoing efforts toward development and
identification of new molecules. erefore we under-
took to synthesize a series of 2-(3-substituted propyl)-
3-(2-methyl phenyl) quinazolin-4-(3H)-ones, in which
heterocyclic quinazoline ring linked to an aliphatic
tertiary amine via the side chain. e synthesized com-
pounds were tested for their in vivo H1-antihistaminic
activity on conscious guinea pigs. As sedation is one of
Address for Correspondence: V. Alagarsamy, Medicinal Chemistry Research Laboratory, MNR College of Pharmacy, Sangareddy, Gr.
Hyderabad, Andhra Pradesh, India. Tel: +91 8455-230690; Fax: +91 8455-230555. E-mail: drvalagarsamy@gmail.com
(Received 16 August 2011; revised 02 October 2011; accepted 07 October 2011)
65

66 V. Alagarsamy and P. Parthiban
IR, Infrared; mp, melting point;
NMR, nuclear magnetic resonance;
SAR, Structure-activity relationship;
CMC, carboxymethylcellulose;
Abbreviations
δ ppm, part per million;
DMSO, dimethyl sulfoxide;
GI50, 50% growth inhibition;
ANOVA, one-way analysis of variance
the major side effects associated with antihistamines,
the test compounds were also evaluated for their seda-
tive potentials by measuring the reduction in locomotor
activity using an actophotometer.
Spectrochem Pvt. Ltd. (India) and were used without
further purification.
Synthesis of 3-(2-methyl phenyl)-2-thioxo quinazolin-
4(3H)-one (4)
A solution of 2-methyl aniline (1.82 g; 0.02 mol) in dim-
ethyl sulfoxide (10 mL) was stirred vigorously. To this was
added carbon disulphide (1.6 mL) and aqueous sodium
hydroxide (1.2 mL; 20 molar) dropwise during 30 min
with stirring. Dimethyl sulphate (2.5 g; 0.02 mol) was then
added gradually keeping the reaction mixture in freezing
mixture with stirring and the stirring was continued for
further 2 h. e reaction mixture was then poured into ice
water. e solid obtained was filtered, washed with water,
dried and recrystallized from ethanol. Methyl anthra-
nilate (1.5 g; 0.01 mol) and the above prepared N-(2-
methyl phenyl) methyl dithiocarbamic acid (0.01 mol),
were dissolved in ethanol (20 mL). To this anhydrous
potassium carbonate (100 mg) was added and refluxed
for 18 h. e reaction mixture was cooled in ice and the
solid separated was filtered and purified by dissolving in
10% alcoholic sodium hydroxide solution and reprecipi-
tated by treating with dilute hydrocholoric acid. e solid
obtained was filtered, washed with water, and dried. It
was recrystallized from ethanol to afford (4). Yield = 85%;
mp 241–242°C; IR (KBr) cm−1: 3211 (NH), 1686 (C=O),
Experimental section
General
Melting points (mp) were taken in open capillaries on
omas Hoover melting point apparatus and are uncor-
rected. e IR spectra were recorded in film or in potas-
sium bromide disks on a Perkin-Elmer 398 spectrometer.
e 1H spectra were recorded on a DPX-500 MHz Bruker
FT-NMR spectrometer. e chemical shifts were reported
as parts per million (δ ppm) tetramethylsilane (TMS) as
an internal standard. Mass spectra were obtained on a
JEOL-SX-102 instrument using fast atom bombardment
(FAB positive). Elemental analysis was performed on
a Perkin-Elmer 2400 C, H, N analyzer and values were
within the acceptable limits of the calculated values. e
progress of the reaction was monitored on readymade
silica gel plates (Merck) using chloroform-methanol
(9:1) as a solvent system. Iodine was used as a develop-
ing 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 (C,H,N) analysis indicated
that the calculated and observed values were within the
acceptable limits ( 0.4%). All chemicals and reagents
were obtained from Aldrich (USA), Lancaster (UK) or
1
1213 (C=S); H NMR (CDCl3): δ 2.4 (s, 3H, CH3), 7.1–7.4
(m, 4H, Ar-H), 7.5–7.8 (m, 4H, Ar-H), 10.3 (br s, 1H, NH);
MS (m/z) 268 (M+); Anal. Calcd for C15H12N2OS: C, 67.14;
H, 4.51; N, 10.44; Found: C, 67.19; H, 4.57; N, 10.38.
Figure 1. Structure of some clinically available H1-antihistaminic agent.
Figure 2. Quinazolin-4-(3H)-one lead optimization from this laboratory.
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis of new class of H1-antihistaminic agents 67
3-(2-Methyl phenyl)-2-(3-(piperidin-1-yl)propylthio)
quinazolin-4(3H)-one (OT3)
Synthesis of 2-(3-bromopropyl thio)-3-(2-methyl
phenyl) quinazolin-4-(3H)-one (6)
Yield = 80%; mp 212–213°C; IR (KBr) cm−1: 1666 (C=O),
A solution of 3-(2-methyl phenyl)-2-thixo quinazolin-
4(3H) one (4) (2.53 g; 0.01 mol), 1,3-dibromopropane
(0.02 mol) and K2CO3 (4.14 g; 0.03 mol) in acetone (20 mL)
was heated to reflux temperature for 1h. e reaction
mixture was cooled to room temperature and filtered
off to remove the inorganic materials. e solvent was
removed under reduced pressure to afford 2-(3-bromo
propylthio)-3-(2-methyl phenyl) quinazolin-4-(3H)-one
(6), it was then recrystallized from ethanol. Yield = 85%;
mp 200–203°C; IR (KBr) cm−1: 1716 (C=O), 1610 (C=N),
1
1606 (C=N), 1250 (C-N); H NMR (CDCl3): δ 1.54–1.60
(m, 4H, CH2), 1.67–1.71 (m, 2H, CH2), 2.16–2.22 (m, 4H,
CH2), 2.36 (s, 3H, CH3), 2.80–2.83 (m, 4H, CH2), 3.29–3.31
(m, 2H, CH2), 7.18–7.19 (d, 1H, Ar-H), 7.30–7.43 (m, 4H,
Ar-H), 7.48–7.51 (d, 1H, Ar-H), 7.72–7.73 (d, 1H, Ar-H),
8.26–8.31 (dd, 1H, Ar-H); MS (m/z) 393 (M+); Anal. Calcd
for C23H27N3OS: C, 70.19; H, 6.92; N, 10.68; O, 4.07; S, 8.15
Found: C, 70.17; H, 6.90; N, 10.69.
1
3-(2-Methyl phenyl)-2-(3-(piperazin-1-yl) propylthio)
quinazolin-4(3H)-one (OT4)
1275 (C-N), 590 (C-Br); H NMR (CDCl3): δ 2.16–2.18
(m, 2H,CH2), 2.36–2.40 (m, 2H, CH2), 2.67 (s, 3H, CH3),
3.27–3.30 (m, 2H, CH2), 7.21–7.22 (d, 1H, Ar-H), 7.37–7.44
(m, 3H, Ar-H), 7.47–7.51 (m, 2H, Ar-H), 7.70–7.74 (d, 1H,
Ar-H), 8.25–8.27 (dd, 1H, Ar-H); MS (m/z) 389 (M+); Anal.
Calcd for C18H17BrN2OS: C, 55.53; H, 4.40; Br, 20.52; N,
7.20; O, 4.11; S, 8.24. Found: C, 55.58; H, 4.41; N, 07.18.
Yield = 81%; mp 171–173°C; IR (KBr) cm−1: 3292 (N-H),
1
1666 (C=O), 1606 (C=N), 1240 (C-N); H NMR (CDCl3):
δ 1.79–1.85 (m, 4H, CH2), 2.17–2.22 (m, 6H, CH2), 2.30
(s, 3H, CH3), 2.81–2.84 (m, 2H, CH2), 3.29–3.31 (m, 2H,
CH2), 7.18–7.19 (d, 1H, Ar-H), 7.30–7.43 (m, 4H, Ar-H),
7.48–7.51 (d, 1H, Ar-H), 7.72–7.73 (d, 1H, Ar-H), 8.26–8.31
(dd, 1H, Ar-H), 8.63 (br s, 1H, NH); MS (m/z) 394 (M+);
Anal. Calcd for C22H26N4OS: C, 66.97; H, 6.64; N, 14.20; O,
4.06; S, 8.13. Found: C, 66.99; H, 6.65; N, 14.23.
General procedure for synthesis of
2-(3-substitutedpropyl)-3-(2-methyl phenyl)
quinazolin-4-(3H)-one (OT1–OT10)
Amixtureof2-(3-bromopropylthio)-3-(2-methylphenyl)
quinazolin-4-(3H)-one (6) (3.75 g; 0.01 mol), alkyl/aryl
amine (0.015 mol), Potassium iodide (1.66 g; 0.015 mol)
and sodium carbonate (2.12 g; 0.02 mol) in 1-butanol
(25 mL) was heated at reflux temperature (for 3 h by con-
ventional refluxing or 15 min by microwave oven). e
reaction mixture was cooled, filtered and the filtrate was
then concentrated in vacuum and kept in refrigerator
overnight. e product obtained was filtered, dried and
recrystallized using chloroform-ethanol (50:50) mixture
to yield the title compounds.
2-(3-(4-Methylpiperazin-1-yl) propylthio)-3-(2-methyl phenyl)
quinazolin-4(3H)-one (OT5)
Yield = 78%; mp 214–215°C; IR (KBr) cm−1: 1666 (C=O),
1
1606 (C=N), 1300 (C-N); H NMR (CDCl3): δ 1.58 (s, 3H,
CH3), 2.16–2.17 (m, 8H, CH2), 2.43 (s, 3H, CH3), 2.81–2.84
(m, 2H, CH2), 2.90–2.97 (m, 2H, CH2), 3.28–3.29 (m, 2H,
CH2), 7.21–7.22 (d, 1H, Ar-H), 7.30–7.43 (m, 4H, Ar-H),
7.48–7.50 (d, 1H, Ar-H), 7.73–7.74 (d, 1H, Ar-H), 8.25–8.31
(dd, 1H, Ar-H); 13C NMR (CDCl3): 18.41, 29.37, 34.19,
44.24, 45.79, 54.25 (4C), 118.74, 120.19, 121.45, 125.64,
127.15, 128.15, 128.54, 129.14, 132.47, 133.47, 133.65,
145.64, 160.15, 162.18; MS (m/z) 409 (M+); Anal. Calcd
for C23H28N4OS: C, 67.61; H, 6.91; N, 13.71; O, 3.92; S, 7.85,
Found: C, 67.76; H, 6.90; N, 13.69.
2-(3-(Diethylamino)propylthio)-3-(2-methyl phenyl)
quinazolin-4(3H)-one (OT1)
Yield = 81%; mp 182–184°C; IR (KBr) cm−1: 1666 (C=O),
1606 (C=N), 1299 (C-N); 1H NMR (CDCl3): δ 0.97–1.15 (m,
J= 7.5 Hz, 6H, 2-CH3), 2.16–2.22 (m, 4H, CH2), 2.81–2.85
(m, 4H, CH2), 2.90 (s, 3H, CH3), 2.97–3.01 (m, 2H, CH2),
7.21–7.22 (d, 1H, Ar-H), 7.28–7.39 (m, 4H, Ar-H), 7.40–7.42
(d, 1H, Ar-H), 7.73–7.74 (d, 1H, Ar-H), 8.25–8.31 (dd, 1H,
Ar-H); MS (m/z) 381 (M+); Anal. Calcd for C22H27N3OS: C,
69.26; H, 7.13; N, 11.01; O, 4.19; S, 8.40. Found: C, 69.25;
H, 7.17; N, 11.03.
3-(2-Methyl phenyl)-2-(3-morpholinopropylthio)
quinazolin-4(3H)-one (OT6)
Yield = 82%; mp 175–176°C; IR (KBr) cm−1: 1666 (C=O),
1
1606 (C=N), 1299 (C-N); H NMR (CDCl3): δ 1.58–1.65
(m, 2H, CH2), 2.17–2.24 (m, 6H, CH2), 2.34 (s, 3H, CH3),
2.81–2.83 (m, 2H, CH2), 3.29–3.30 (m, 4H, CH2), 7.21–7.22
(d, 1H, Ar-H), 7.30–7.43 (m, 4H, Ar-H), 7.48–7.50 (d, 1H,
Ar-H), 7.73–7.74 (d, 1H, Ar-H), 8.25–8.28 (dd, 1H, Ar-H;
MS (m/z) 395 (M+); Anal. Calcd for C22H25N3O2S: C, 66.81;
H, 6.37; N, 10.62; O, 8.09; S, 8.11. Found: C, 66.80; H, 6.34;
N, 10.65.
3-(2-Methyl phenyl)-2-(3-(pyrrolidin-1-yl) propylthio)
quinazolin-4(3H)-one (OT2)
Yield = 78%; mp 186–187°C; IR (KBr) cm−1: 1668 (C=O),
1
1649 (C=N), 1258 (C-N); H NMR (CDCl3): δ 1.53–1.61
(m, 4H, CH2), 2.08–2.25 (m, 6H, CH2), 2.36 (s, 3H, CH3),
2.81–2.84 (m, 2H, CH2), 3.27–3.29 (m, 2H, CH2), 7.18–7.19
(d, 1H, Ar-H), 7.30–7.38 (m, 4H, Ar-H), 7.48–7.51 (d, 1H,
Ar-H), 7.72–7.73 (d, 1H, Ar-H), 8.26–8.31 (dd, 1H, Ar-H);
MS (m/z) 379 (M+); Anal. Calcd for C22H25N3OS: C, 69.62;
H, 6.64; N, 11.07; O, 4.22; S, 8.45. Found: C, 69.66; H, 6.66;
N, 11.05.
3-(2-Methyl phenyl)-2-(3-phenylpropylthio) quinazolin-4(3H)-
one (OT7)
Yield = 79%; mp 221–222°C; IR (KBr) cm−1: 3280 (N-H),
1
1666 (C=O), 1606 (C=N), 1300 (C-N); H NMR (CDCl3):
δ 1.76–1.79 (m, 2H, CH2), 2.33 (s, 3H, CH3), 2.81–2.84
(m, 2H, CH2), 3.29–3.30 (m, 2H, CH2), 7.17–7.95 (m, 11H,
Ar-H), 8.19–8.21 (m, 1H, Ar-H), 8.25–8.31 (m, 1H, Ar-H),
© 2013 Informa UK, Ltd.

68 V. Alagarsamy and P. Parthiban
8.74 (br s, 1H, NH); MS (m/z) 401 (M+); Anal. Calcd for
C24H23N3OS: C, 71.79; H, 5.77; N, 10.47; O, 3.98; S, 7.99.
Found: C, 71.78; H, 5.74; N, 10.44.
of 45–55%, under a 12 h light and dark cycle; they were
fed standard animal feed. All the animals were acclima-
tized for a week before the experiment. e Institutional
Animal Ethics committee approved the protocol adopted
for the experimentation of animals.
2-(3-(4-Chlorophenyl propylthio)-3-(2-methyl phenyl)
quinazolin-4(3H)-one (OT8)
Yield = 77%; mp 188–189°C; IR (KBr) cm−1: 3280 (N-H),
Antihistaminic activity
1
A modification of the technique of Van Arman was adopted
to determine the antihistaminic potential of the synthe-
sized compounds12. Male Dunkin Hartley Guinea pigs
(250–300g) were fasted for 12h. Six animals were taken in
each group. e test compounds and reference compound
chlorpheniraminemaleate(Avil;Hoechst,Mumbai,India),
was administered orally at a dose of 10mg/kg in 1% W/V
carboxymethylcellulose (CMC) and challenged with his-
tamine aerosol (0.2% aqueous solution of histamine acid
chloride 3mL) in a vaponephrin pocket nebulizer sprayed
into a closed transparent cage. e respiratory status
reflecting the increasing degree of bronchoconstriction
was recorded. e time for onset of convulsions (precon-
vulsion) was recorded. Animals remaining stable for more
than 6min were considered protected against histamine-
induced bronchospasm. An intraperitoneal injection of
Pheniramine maleate (Avil; Hoechst, Mumbai, India) at
a dose of 25mg/kg was given for the recovery of the test
animals. e mean preconvulsion time of animals treated
with the test compounds was compared to control and is
expressed in terms of percentage protection (Table 1).
1660 (C=O), 1609 (C=N), 1300 (C-N); H NMR (CDCl3):
δ 2.17–2.20 (m, 2H, CH2), 2.36 (s, 3H, CH3), 2.81–2.84
(m, 2H, CH2), 3.28–3.29 (m, 2H, CH2), 7.29–7.77 (m, 10H,
Ar-H), 7.94–7.95 (m, 1H, Ar-H), 8.11–8.14 (m, 1H, Ar-H),
8.64 (br s, 1H, NH); MS (m/z) 436 (M+); Anal. Calcd for
C24H22ClN3OS: C, 66.12; H, 5.09; Cl, 8.13; N, 9.64; O, 3.67;
S, 7.35. Found: C, 66.15; H, 5.07; N, 09.65.
2-(3-(4-Methylphenylpropylthio)-3-(2-methylphenyl)
quinazolin-4(3H)-one (OT9)
Yield = 81%; mp 179–181°C; IR (KBr) cm−1: 3278 (N-H),
1
1666 (C=O), 1606 (C=N), 1300 (C-N); H NMR (CDCl3):
δ 2.16–2.18 (m, 2H, CH2), 2.76–2.79 (m, 2H, CH2), 2.91 (s,
3H, CH3), 2.98 (s, 3H, CH3), 3.28–3.29 (m, 2H, CH2), 7.18–
7.85 (m, 11H, Ar-H), 8.05 (br s, 1H, NH), 8.25–8.32 (m, 1H,
Ar-H); MS (m/z) 415 (M+); Anal. Calcd for C25H25N3OS: C,
72.26; H, 6.06; N, 10.11; O, 3.85; S, 7.72, Found: C, 72.25;
H, 6.04; N, 10.14.
2-(3-(Benzylpropylthio)-3-(2-methylphenyl) quinazolin-4(3H)-
one (OT10)
Yield = 80%; mp 211–213°C; IR (KBr) cm−1: 3279 (N-H),
1666 (C=O), 1606 (C=N), 1300 (C-N); 1H NMR (CDCl3): δ
1.72 (ms, 2H, CH2), 2.19–2.23 (m, 2H,CH2), 2.82–2.84 (m,
2H, CH2), 2.97 (s, 3H, CH3), 3.28–3.29 (m, 2H, CH2), 7.17–
7.76 (m, 12H, Ar-H), 8.04 (brs 1H, NH), 8.25–8.31 (m, 1H,
Ar-H); MS (m/z) 415 (M+); Anal. Calcd for C25H25N3OS: C,
72.26; H, 6.06; N, 10.11; O, 3.85; S, 7.72, Found: C, 72.25;
H, 6.08; N, 10.13.
Percent protection = [1− (T /T )] × 100
1
2
T2—preconvulsive time of test compound; T1—
preconvulsive time of control.
e activity of the test compounds was compared with
the standard antihistamine chlorpheniramine maleate.
Sedative-hypnotic activity
Sedative-hypnotic activity was determined by mea-
suring the reduction in locomotor activity using
actophotometer13,14. Six albino Swiss mice were allotted
to each group. Basal activity score was taken and then
compounds OT1–OT10 and standard chlorpheniramine
Pharmacology
e synthesized compounds were evaluated for antihista-
minic and sedative-hypnotic activities. e animals were
maintained in colony cages at 25 2°C, relative humidity
Table 1. Antihistaminic and sedative-hypnotic activity of compounds OT1–OT10.
Percent CNS depression
Time of onset of
Compound Code
convulsion (in sec)
355 1.85*
370 3.06*
362 2.24*
396 1.53*
417 2.50*
390 2.27*
351 2.28*
352 2.41*
335 2.90*
346 1.64*
394 4.43*
% Protection
66.83 0.17*
67.61 0.37*
67.42 0.20*
70.21 0.11*
71.70 0.17*
69.75 0.17*
66.39 0.21*
66.54 0.22*
64.78 0.30*
65.90 0.16*
70.09 0.33*
0.5 h
1 h
2 h
3 h
OT1
13.77 1.06**
10.53 1.06**
11.68 1.56**
8.62 0.68**
8.19 0.73**
7.56 0.82**
8.97 1.00*
13.70 1.05**
11.03 0.92**
12.96 1.30**
8.79 0.64**
9.48 0.88**
9.20 1.06**
8.79 0.99**
9.20 0.65**
10.30 0.81**
9.37 1.35**
38.80 1.32**
14.95 0.99**
11.96 1.04**
13.29 0.77**
9.21 0.68**
9.25 0.73**
9.96 0.80**
10.34 0.84**
9.49 0.55**
11.54 0.73**
12.39 0.84**
34.80 0.72**
11.40 0.76**
8.14 0.80**
9.26 0.78**
6.31 0.67**
7.51 0.71**
7.44 0.83**
6.12 0.75**
6.13 0.97**
8.92 1.14**
7.56 0.69**
29.58 0.72**
OT2
OT3
OT4
OT5
OT6
OT7
OT8
8.33 0.61**
8.78 1.22**
9.23 1.35**
32.04 0.50**
OT9
OT10
Chlorpheniramine
Each value represents the mean SEM (n=6).
Significance levels *p<0.001, **p<0.05.
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis of new class of H1-antihistaminic agents 69
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. e percent reduction in loco
motor activity was calculated by the following formula
and shown in Table 1.
S-CH2CH2CH2 group; a singlet at δ 2.67 for−CH3 group
and multiplet for aromatic (8H) protons observed at δ
7.21–8.27. Data from the elemental analyses and molecu-
lar ion recorded in the mass spectrum further confirmed
the assigned structure.
e title compounds OT1–OT10were obtained in fair to
good yields through the nucleophilic displacement of−Br
group of 2-(3-bromo propyl thio)-3-(2-methyl phenyl)
quinazolin-4-(3H)-one (6) with a variety of amines, using
ethanol as solvent to afford 2-(3-substituted propyl)-3-(2-
methylphenyl) quinazolin-4-(3H)-one (OT1–OT10). e
formation of the title compounds is indicated by the dis-
appearance of peaks due to Br of the starting material and
the appearance of NH signal at 3320cm−1 in the IR spec-
tra of the compounds OT4, OT7, OT8, OT9 and OT10. It
also showed a peak for carbonyl (C=O) around 1680cm−1.
% Reduction in motor activity = [(A − B)/A] × 100
Where A-basal score, B-score after drug treatment.
Statistical analysis
Statistical analysis of the biological activity of the syn-
thesized compounds on animals was evaluated using
an one-way analysis of variance (ANOVA). 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 (standard deviations). For sta-
tistical analysis GraphPad Prism 3.0 version was used.
(GraphPad Software, Inc.San Diego, CA).
1
e H NMR spectra of the title compounds OT1–OT10
showed peaks for substituents at C-2 and singlet around
δ 8.04ppm due to NH, a multiplet at δ 7.10–8.31ppm
was observed for aromatic protons. In mass spectra of
compounds OT1–OT10 the common peak appeared due
quinazolin-4-one moiety cation at m/z 168. Elemental (C,
H, N) analysis satisfactorily confirmed elemental compo-
sition and purity of the synthesized compounds.
Results and discussion
Chemistry
e key intermediate 3-(2-methyl phenyl)-2-thioxo-2-
,3-dihydro-1H-quinazolin-4-one
4 was synthesized
by straightforward method. In this synthetic scheme,
3-methyl aniline (1) treated with carbon disulphide and
sodium hydroxide in dimethyl sulphoxide to give sodium
dithiocarbamate, which was methylated with dimethyl
sulphate to afford the dithiocarbamic acid methyl ester
(2). Compound 2 on reflux with methyl anthranilate
(3) in ethanol yielded the desired 3-(2-methyl phenyl)-
2-thioxo-2,3-dihydro-1H- quinazolin-4-one (4) via the
thiourea intermediate in good yield (85%). e use of
DMSO as the reaction solvent enhanced the rate of reac-
tion and the use of alkali in higher concentration helped
prevent the hydrolysis of the intermediate, probably due
to less solvation. e product obtained was cyclic and not
an open chain thiourea 3a. e IR spectrum of 4 show
intense peaks at 3211 cm−1 for cyclic thio urea (NH),
1686 cm−1 for carbonyl (C=O) and 1213 cm−1 for thioxo
Pharmacology
e compounds containing 2-(substituted propyl)-3-(2-
methyl phenyl) quinazolin-4-(3H)-ones, (OT1–OT10)
were evaluated for their in vivo antihistaminic activity.
Histamine causes bronchospasm and the guinea pigs
are most susceptible animals for histamine, hence pro-
tection against histamine-induced bronchospasm on
conscious guinea pigs method was adopted to determine
the antihistaminic potential of the test compounds12.
e advantage of this method is that it is one of the non-
invasive method and the animals are recovered after the
experiment.
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 64–71%. Biological
studies indicated that different substituents over the sec-
ond position of quinazoline ring exerted varied biologi-
cal activity. e presence of diethyl group (compound
OT1) showed significant activity, when the cyclic amines
with the similar lipophilicity are substituted (pyrrolidinyl
compound OT2 and piperidinyl Compound OT3) the
activity is retained. Placement of additional heteroatoms
like nitrogen (piperazinyl compound OT4 and N-methyl
piperazinyl compound OT5) and oxygen (morpholinyl
compound OT6) leads to increase in activity. Placement
of aryl substitutions (phenyl compound OT7; p-chloro-
phenyl compound OT8; p-methyl phenyl compound
OT9) results in decreased activity). Placement of arylalkyl
(benzyl compound OT10) further decreased the activity.
Compound 2-(3-(4-methylpiperazin-1-yl)propylthio)-3-
-(2-methyl phenyl) quinazolin-4(3H)-one (OT5) exhib-
ited the most potent activity of the series.
1
(C=S) stretching. H NMR spectrum of 4 showed singlet
at δ 2.42 due to methyl group; for aromatic (8H) protons
a multiplet at δ 7.14–7.45 and 7.53–7.81 ppm and a singlet
at δ 10.31 ppm indicating the presence of NH. Data from
the elemental analyses have been found to be in confor-
mity with the assigned structure. Further the molecular
ion recorded in the mass spectrum is also in agreement
with the molecular weight of the compound.
e 2-(3-bromo propyl thio)-3-(2-methyl phenyl) qui-
nazolin-4-(3H)-one (6) was prepared by heating at reflux
temperature, a solution of 2-thioxo-3-(2-methylphenyl)
quinazolin-4(3H)one (4), and 1,3-Dibromopropane in
acetone in the presence of K2CO3 for 1h. e 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 1716 cm−1. e 1H NMR spectrum
of compound 6 showed multiplet at δ 2.16–3.30 for
© 2013 Informa UK, Ltd.

70 V. Alagarsamy and P. Parthiban
Scheme 1. Synthesis of 2-(3-substituted propyl)-3-(2-methyl phenyl) quinazolin-4-(3H)-one (OT1–OT10).
Sedative-hypnotic activity was determined by
measuring the reduction in locomotor activity using
actophotometer13,14 on Albino Swiss mice. e results
of sedative-hypnotic activity indicate that all the test
compounds were found to exhibit only negligible seda-
tion (6–11%), whereas the reference standard chlorphe-
niramine maleate showed 33% sedation.
to obtain a clinically useful novel class of non-sedative
antihistamines.
Acknowledgement
e authors gratefully acknowledge the Central
Instrumentation Facility, IIT Chennai, India for the
spectral analysis of the compounds used in this study.
e authors are also wish to thank CSIR (Grant No: 01
(2163)/07/EMR-II), New Delhi and Management of MNR
College of Pharmacy for providing the financial and
infrastructure facilities to carry out this Research work.
Conclusion
In summary, synthesis of new series of 2-(3-
substitutedpropyl)-3-(2-methyl phenyl) quinazolin-4-
(3H)-one (OT1–OT10) have been described. e 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-(2-methyl
phenyl) quinazolin-4(3H)-one (OT5) was found to be
the most active compound (71.70%), which is more
potent when compared to reference standard chlorphe-
niramine maleate (70.09%). Interestingly compound
OT5 also showed negligible sedation (10%) compared
to chlorpheniramine maleate (33%) and could there-
fore serve as a lead molecule for further modification
Declaration of interest
e authors report no conflicts of interest.
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