Synthesis of novel 2-phenyl-3-[2-(substituted amino) ethylamino] quinazolin-4(3H)-ones as a new class of H1-antihistaminic agents

Article abstract of DOI:10.1007/s00044-012-0243-3

A series of novel 2-phenyl-3-[2-(substituted amino) ethylamino] quinazolin-4(3H)-ones was synthesized by the nucleophilic substitution of 3-(2-bromo ethylamino)-2-phenyl quinazolin-4(3H)-one with various amines. The starting material, 3-(2-bromo ethylamin

Full text of DOI:10.1007/s00044-012-0243-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:2486–2492
DOI 10.1007/s00044-012-0243-3
ORIGINAL RESEARCH
Synthesis of novel 2-phenyl-3-[2-(substituted amino) ethylamino]
quinazolin-4(3H)-ones as a new class of H1-antihistaminic agents
•
V. Alagarsamy P. Shyam Sundar M. Gobinath S. Nivedhitha
•
•
•
•
P. Parthiban D. Shankar M. T. Sulthana V. Raja Solomon
•
•
Received: 21 March 2012 / Accepted: 14 September 2012 / Published online: 26 September 2012
Ó Springer Science+Business Media New York 2012
Abstract A series of novel 2-phenyl-3-[2-(substituted
amino) ethylamino] quinazolin-4(3H)-ones was synthesized
by the nucleophilic substitution of 3-(2-bromo ethylamino)-
2-phenyl quinazolin-4(3H)-one with various amines. The
starting material, 3-(2-bromo ethylamino)-2-phenyl qui-
nazolin-4(3H)-one, was synthesized from anthranilic acid by
a multistep synthesis. All the title compounds were tested for
their in vivo H1-antihistaminic activity on conscious guinea
pigs at the dose level of 10 mg/kg using chlorpheniramine as
the standard drug. The results of the biologic activity
revealed that all the test compounds protected the animals
from histamine-induced bronchospasm significantly. Com-
pound 2-phenyl-3-[2-(piperazinyl) ethylamino] quinazolin-
4(3H)-one (S3) emerged as the most active compound of the
series (73.67 % protection) when compared to the standard
chlorpheniramine (70.09 % protection). Interestingly,
compound S3 shows negligible sedation (8.21 %) compared
to chlorpheniramine maleate (29.58 %). Therefore, com-
pound S3 can serve as the lead molecule for further devel-
opment into a new class of H1-antihistaminic agents.
Introduction
Histamine is one of the most important chemical media-
tors, and through its interaction with H1 receptors, present
in most tissues, is involved in the pathophysiology of
allergic rhinoconjuntivitis, urticaria, and asthma (Simons
and Simons, 1994). The first-generation antihistamines are
effective and relatively inexpensive against these symp-
toms; however, they also cause sedation and dry mouth at
therapeutic doses due to their blood–brain barrier pene-
tration and lack of receptor specificity (Ellis et al. 1985). 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] (Carr and Meyer, 1982). In contrast, most of
the second generation H1-antagonists, such as terfenadine,
cetirizine and astemizole, have a greatly improved benefit-
to-risk ratio compared to their predecessors. These drugs
have lesser perspective to cross the blood–brain barrier and
possess the higher receptor specificity (Hopp et al.,
1985; Chairungsrilerd et al., 1996); they are labeled as
‘‘non-sedative antihistamines.’’ The second-generation
compounds [Fig. 1, terfenadine and cetirizine] also contain
many of the structural features of the first-generation
compounds. Condensed heterocycles containing new gen-
eration of H1-antihistamines (loratadine, azelastine, and
flazelastine) that do not possess the above mentioned
pharmacophore for H1-antihistamines gave way for the
discovery of many novel H1-antihistaminic drugs tem-
elastine and mangostin (Hopp et al., 1985; Chairungsrilerd
et al., 1996). Quinazolines and condensed quinazolines
showed excellent antihistaminic activity (Raghuramrao
et al., 1986; Devsingh et al., 2001; Raju et al., 1999). In
this continuation, we demonstrated (Alagarsamy et al., 2002;
Alagarsamy, 2004; Alagarsamy et al., 2002 Alagarsamy
Keywords Quinazolin-4-ones ꢀ
H1-Antihistaminic agents ꢀ Sedation
V. Alagarsamy (&) ꢀ P. Shyam Sundar ꢀ P. Parthiban ꢀ
D. Shankar ꢀ M. T. Sulthana
Medicinal Chemistry Research Laboratory, MNR College
of Pharmacy, Sangareddy, Gr., Hyderabad 502 294, India
e-mail: drvalagarsamy@gmail.com
M. Gobinath ꢀ S. Nivedhitha
Department of Pharmaceutical Chemistry, Ratnam Institute
of Pharmacy, Nellore 524 346, India
V. Raja Solomon
Medicinal & Process Chemistry Division, Central Drug Research
Institute, Lucknow 226 001, India
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Med Chem Res (2013) 22:2486–2492
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Cl
N
O
N
HO
N
O
N
HO
O
N
N
HO
Terfenadine
Cetirizine
Diphenhydramine
Pheniramine
Fig. 1 Structure of some clinically available H1 antihistaminic agent
et al., 2007) the quinazoline derivatives as potent antihista-
mines with least sedation. The present work is an extension of
our ongoing efforts toward the development and identifica-
tion of new molecules. Therefore, we undertook to synthesize
a series of 2-phenyl-3-[2-(substituted amino) ethylamino]
quinazolin-4(3H)-ones, in which heterocyclic quinazoline
ring is linked to an aliphatic tertiary amine via the side chain.
The synthesized compounds were tested for their in vivo H1-
antihistaminic activity on conscious guinea pigs. As sedation
is one of the major side effects associated with antihista-
mines, the test compounds were also evaluated for their
sedative potentials by measuring the reduction in locomotor
activity using an actophotometer.
Synthesis of 2-phenyl-3,1-benzoxazin-4-one (3)
To a solution of anthranilic acid (13.7 g, 0.1 mol) dis-
solved in pyridine (60 mL), benzoyl chloride (0.1 mol) was
added. The mixture was stirred for 0.5 h followed by
treatment with 5 % sodium bicarbonate (50 mL). The
separated solid was recrystallized from ethanol. Yield:
80 %, m.p. 122–124 °C, IR (KBr) cm-1: 1675 (C=O); H
1
NMR (CDCl3) d ppm: 7.22 (d, J = 7.5 Hz, 2H, Ar–H),
7.29–7.31 (m, 1H, Ar–H), 7.48–7.50 (m, 2H, Ar–H), 7.56
(s, 1H, Ar–H), 7.58 (d, J = 8.0 Hz, 2H, Ar–H), 8.08 (s, 1H,
Ar–H); MS (m/z, %): 223 (M?, 100), 153 (45).
Synthesis of 3-amino-2-phenyl quinazolin-
4(3H)-one (5)
Experimental section
A mixture of 2-phenyl-3,1-benzoxazin-4-one(0.05 mol) and
hydrazine hydrate (4) (0.5 mol) in ethanol was refluxed for
5 h and cooled. The separated solid was recrystallized from
ethanol. Yield : 81 %, m.p. 196 °C, IR (KBr) cm-1: 3300,
3252 (NH2), 1680 (C=O), 1620 (C=N); 1H NMR (CDCl3) d
ppm : 4.51 (s, 2H, NH2), 7.24 (d, J = 7.5 Hz, 2H, Ar–H),
7.31–7.33 (m, 1H, Ar–H), 7.49–7.51 (m, 2H, Ar–H), 7.58 (s,
1H, Ar–H), 7.60 (d, J = 8.0 Hz, 2H, Ar–H), 8.09 (s, 1H, Ar–
H); MS (m/z, %): 237 (M?, 100), 222 (65), 146 (45).
General
Melting points (mp) were taken in open capillaries on
Thomas Hoover melting point apparatus and are uncor-
rected. The IR spectra were recorded in film or in potas-
sium bromide disks on a Perkin-Elmer 398 spectrometer.
1
The H NMR spectra were recorded on a DPX-500 MHz
Bruker FT-NMR spectrometer. The chemical shifts were
reported as parts per million (d ppm) tetramethylsilane
(TMS) as an internal standard. Mass spectra were obtained
on a JEOL-SX-102 instrument by 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. The
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 developing 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. Ele-
mental (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 Spectrochem Pvt. Ltd
(India) and were used without further purification.
Synthesis of 3-(2-bromo ethylamino)-2-phenyl
quinazolin-4(3H)-one (7)
A solution of 3-amino-2-phenyl quinazolin-4(3H)-one (5)
(0.1 mol) in dry ethanol (25 mL), potassium carbonate
(0.1 mol), and 1,2-dibromoethane (0.1 mol) was added, and
the reaction mixture was heated with stirring for 6 h. The
reaction mixture was then poured into ice water and
extracted with ether and dried over anhydrous sodium sul-
fate, which upon evaporation afford compound 7. Yield:
86 %, m.p. 240–242 °C, IR (KBr) cm-1 : 3249 (NH), 1669
(C=O), 1610 (C=N), 595 (C–Br); 1H NMR (CDCl3) d ppm :
2.55–2.58 (m, 2H, CH2), 3.22–3.25 (m, 2H, CH2), 7.39–7.46
(m, 4H, Ar–H), 7.52–7.59 (m, 3H, Ar–H), 7.77–7.79 (d,
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Med Chem Res (2013) 22:2486–2492
J = 8.0 Hz, 1H, Ar–H), 8.05–8.06 (d, J = 7.5 Hz, 1H, Ar–
H), 8.49 (s, 1H, NH). MS (m/z, %): 346 (M?2, 55), 344 (M?,
100), 265 (46), 236 (43), 146 (35).
2.44–2.48 (m, 4H, CH2), 2.60–2.66 (m, 6H, CH2), 3.81–3.83
(m, 2H, CH2), 7.22 (d, J = 7.5 Hz, 2H, Ar–H), 7.29-7.31 (m,
1H, Ar–H), 7.52–7.54 (m, 2H, Ar–H), 7.58 (s, 1H, Ar–H),
7.62 (d, J = 8.0 Hz, 2H, Ar–H), 8.12 (s, 1H, Ar–H), 8.29 (br
s, 1H, NH); MS (m/z, %): 349 (M?, 100), 265 (62), 236 (52),
146 (42). Anal. Calcd for C20H23N5O: C, 68.74; H, 6.63; N,
20.04. Found: C, 55.58; H, 4.41; N, 07.18.
General procedure for synthesis of 2-phenyl-3-[2-
(substituted amino) ethylamino] quinazolin-4(3H)-
ones (S1-S10)
A mixture of 3-(2-bromo ethylamino)-2-phenyl quinazolin-
4(3H)-one (7) (0.005 mol), anhydrous potassium carbonate
(100 mg), and the desired amine (0.005 mol) in 1, 4-dioxan
(25 mL) was refluxed for 14–15 h. The reaction mixture was
then poured into crushed ice. The solid obtained was filtered,
washed with water, dried, and recrystallized from ethanol.
3-[2-(Benzyl amino) ethylamino]-2-phenyl-
quinazolin-4(3H)-one (S4)
Yield : 85 %, m.p. 260–261 °C, IR (KBr) cm-1: 3251 (NH),
1664 (C=O), 1605 (C=N); 1H NMR (CDCl3) d ppm :
2.73–2.78 (m, 2H, CH2), 2.88–2.92 (m, 2H, CH2), 3.78 (s,
2H, CH2), 6.38 (d, J = 7.5 Hz, 2H, Ar–H), 6.48 (d,
J = 8.0 Hz, 2H, Ar–H), 6.98–7.01 (m, 1H, Ar–H), 7.18 (d,
J = 7.5 Hz, 2H, Ar–H), 7.20–7.22 (m, 1H, Ar–H),
7.38–7.40 (m, 2H, Ar–H), 7.46 (s, 1H, Ar–H), 7.62 (d,
J = 8.0 Hz, 2H, Ar–H), 8.21 (s, 1H, Ar–H), 8.45 (br s, 1H,
NH), 8.55 (br s, 1H, NH); MS (m/z, %): 370 (M?, 100), 265
(66), 236 (53), 146 (36). Anal. Calcd for C23H22N4O: C,
74.57; H, 5.98; N, 15.12. Found: C, 55.58; H, 4.41; N, 07.18.
2-Phenyl-3-[2-(phenylamino) ethylamino] quinazolin-
4(3H)-one (S1)
Yield : 81 %, m.p. 196–198 °C, IR (KBr) cm-1: 3428 (NH),
1680 (C=O), 1630 (C=N); 1H NMR (CDCl3) d ppm :
2.49–2.50 (m, 2H, CH2), 3.22–3.24 (m, 2H, CH2), 6.43 (d,
J = 7.5 Hz, 2H, Ar–H), 6.58 (d, J = 8.0 Hz, 2H, Ar–H),
7.04 (m, 1H, Ar–H), 7.22 (d, J = 7.5 Hz, 2H, Ar–H),
7.29–7.31 (m, 1H, Ar–H), 7.48–7.50 (m, 2H, Ar–H), 7.56 (s,
1H, Ar–H), 7.58 (d, J = 8.0 Hz, 2H, Ar–H), 8.08 (s, 1H, Ar–
H), 8.50 (br s, 1H, NH), 8.75 (br s, 1H, NH); MS (m/z, %):
371 (M?, 88), 265 (66), 236 (53), 146 (36). Anal. Calcd for
C22H20N4O: C, 74.13; H, 5.65; N, 15.71. Found: C, 55.58; H,
4.41; N, 07.18.
3-(2-Morpholinoethylamino)-2-phenylquinazolin-
4(3H)-one (S5)
Yield: 82 %, m.p. 245–247 °C, IR (KBr) cm-1: 3364 (NH),
1733 (C=O), 1603 (C=N); 1H NMR (CDCl3) d ppm:
2.35–2.39 (m, 4H, CH2), 2.74–2.78 (m, 6H, CH2), 3.74–3.82
(m, 2H, CH2), 7.12 (d, J = 8.0 Hz, 2H, Ar–H), 7.25–7.28
(m, 1H, Ar–H), 7.42–7.48 (m, 2H, Ar–H), 7.58 (s, 1H, Ar–
H), 7.72 (d, J = 7.5 Hz, 2H, Ar–H), 8.09 (s, 1H, Ar–H), 8.25
(br s, 1H, NH); MS (m/z, %): 350 (M?, 100), 265 (66), 236
(53), 146 (36). Anal. Calcd for C20H22N4O: C, 68.55; H,
6.32; N, 15.98. Found: C, 55.58; H, 4.41; N, 07.18.
3-[2-(4-Chloro phenyl amino) ethylamino]-2-phenyl-
quinazolin-4(3H)-one (S2)
Yield : 79 %, m.p. 220–221 °C, IR (KBr) cm-1: 3317 (NH),
1669 (C=O), 1630 (C = N); 1H NMR (CDCl3) d ppm :
2.03–2.09 (m, 2H, CH2), 3.22–3.25 (m, 2H, CH2), 6.35 (d,
J = 7.5 Hz, 2H, Ar–H), 7.03 (d, J = 8.0 Hz, 2H, Ar–H), 7.22
(d, J = 7.5 Hz, 2H, Ar–H), 7.31–7.33 (m, 1H, Ar–H), 7.46–7.48
(m, 2H, Ar–H), 7.54 (s, 1H, Ar–H), 7.60 (d, J = 8.0 Hz, 2H, Ar–
H), 8.25 (s, 1H, Ar–H), 8.53 (br s, 1H, NH), 9.49 (br s, 1H, NH);
MS (m/z, %): 392 (M?2, 66) 390 (M?, 100), 265 (76), 236 (43),
146 (32). Anal. Calcd for C22H19ClN4O: C, 67.60; H, 4.89; N,
14.33. Found: C, 55.58; H, 4.41; N, 07.18.
3-[2-(4-Methoxy phenylamino) ethylamino]-2-
phenyl-quinazolin-4(3H)-one (S6)
Yield: 86 %, m.p. 185–186 °C, IR (KBr) cm-1: 3260
(NH), 1661 (C=O), 1609 (C=N); 1H NMR (CDCl3) d ppm:
2.49–2.54 (m, 2H, CH2), 3.28–3.32 (m, 2H, CH2), 3.75 (s,
3H, OCH3), 6.32 (d, J = 8.0 Hz, 2H, Ar–H), 6.54 (d,
J = 7.5 Hz, 2H, Ar–H), 7.28 (d, J = 7.5 Hz, 2H, Ar–H),
7.27–7.29 (m, 1H, Ar–H), 7.38–7.42 (m, 2H, Ar–H), 7.58
(s, 1H, Ar–H), 7.61 (d, J = 8.0 Hz, 2H, Ar–H), 8.18 (s, 1H,
Ar–H), 8.25 (br s, 1H, NH), 8.55 (br s, 1H, NH); MS (m/z,
%): 386 (M?, 100) 265 (62), 236 (48), 146 (34). Anal.
Calcd for C23H22N4O2: C, 71.48; H, 5.73; N, 14.49. Found:
C, 55.58; H, 4.41; N, 07.18.
2-Phenyl-3-[2-(piperazinyl) ethylamino] quinazolin-
4(3H)-one (S3)
Yield : 88 %, m.p. 225–227 °C, IR (KBr) cm-1: 3387 (NH),
1736 (C=O), 1615 (C=N); 1H NMR (CDCl3) d ppm:
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2489
2-Phenyl-3-(2-(thiazol-2-ylamino)
ethylamino)quinazolin-4(3H)-one (S7)
7.20 (d, J = 7.5 Hz, 2H, Ar–H), 7.33–7.35 (m, 1H, Ar–H),
7.47–7.49 (m, 2H, Ar–H), 7.57 (s, 1H, Ar–H), 7.62 (d,
J = 8.0 Hz, 2H, Ar–H), 8.27 (s, 1H, Ar–H), 8.33 (br s, 1H,
NH), 8.49 (br s, 1H, NH); MS (m/z, %): 401 (M?, 100), 265
(72), 236 (65), 146 (42). Anal. Calcd for C22H19N5O3: C,
65.82; H, 4.77; N, 17.44. Found: C, 55.58; H, 4.41; N, 07.18.
Yield: 91 %, m.p. 235–236 °C, IR (KBr) cm-1: 3261
(NH), 1668 (C=O), 1608 (C=N); 1H NMR (CDCl3) d ppm :
2.34–2.38 (m, 2H, CH2), 3.22–3.29 (m, 2H, CH2), 6.56 (s,
1H, Ar–H), 7.04 (m, 1H, Ar–H), 7.22 (d, J = 7.5 Hz, 2H,
Ar–H), 7.29–7.31 (m, 1H, Ar–H), 7.48–7.50 (m, 2H, Ar–
H), 7.53 (s, 1H, Ar–H), 7.58 (d, J = 8.0 Hz, 2H, Ar–H),
8.18 (s, 1H, Ar–H), 8.25 (br s, 1H, NH), 8.55 (br s, 1H,
NH); MS (m/z, %): 363 (M?, 100) 265 (56), 236 (48), 146
(24). Anal. Calcd for C19H17N5OS: C, 62.79; H, 4.71; N,
19.26. Found: C, 55.58; H, 4.41; N, 07.18.
Pharmacology
The synthesized compounds were evaluated for antihista-
minic and sedative-hypnotic activities. The animals were
maintained in colony cages at a temperature of 25 2 °C,
relative humidity of 45–55 %, and under a 12 h light and
dark cycle; they were fed standard animal feed. All the
animals were acclimatized for a week before the experi-
ment. The Institutional Animal Ethics committee approved
the protocol adopted for the experimentation of animals.
3-(2-(o-Toluidino)ethylamino)-2-phenylquinazolin-
4(3H)-one (S8)
Yield: 88 %, m.p. 223–225 °C, IR (KBr) cm-1: 3261
(NH), 1668 (C=O), 1609 (C=N); 1H NMR (CDCl3) d ppm :
2.30 (s, 3H, CH3), 2.52–2.56 (m, 2H, CH2), 3.38–3.42 (m,
2H, CH2), 6.32 (d, J = 8.0 Hz, 2H, Ar–H), 6.54 (d,
J = 7.5 Hz, 2H, Ar–H), 7.28 (d, J = 7.5 Hz, 2H, Ar–H),
7.27–7.29 (m, 1H, Ar–H), 7.38–7.42 (m, 2H, Ar–H), 7.58
(s, 1H, Ar–H), 7.61 (d, J = 8.0 Hz, 2H, Ar–H), 8.08 (s, 1H,
Ar–H), 8.15 (br s, 1H, NH), 8.35 (br s, 1H, NH); MS (m/z,
%): 370 [M?]. Anal. Calcd for C23H22N4O: C, 74.57; H,
5.98; N, 15.12. Found: C, 55.58; H, 4.41; N, 07.18.
Antihistaminic activity
A modification of the technique of Van Arman was
adopted to determine the antihistaminic potential of the
synthesized compounds (Van Arman et al., 1961). Male
Dunkin Hartley Guinea pigs (250–300 g) were fasted for
12 h. 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 10 mg/kg in 1 % W/V carboxymethyl-
cellulose (CMC) 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 chlorphe-
niramine maleate at a dose of 25 mg/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 protec-
tion (Table 1).
3-[2-(3-Methoxy phenylamino) ethylamino]-2-
phenyl- quinazolin-4(3H)-one (S9)
Yield: 87 %, m.p. 255–256 °C, IR (KBr) cm-1: 3258
(NH), 1670 (C=O), 1605 (C=N); 1H NMR (CDCl3) d ppm:
2.42–2.47 (m, 2H, CH2), 3.32–3.36 (m, 2H, CH2), 3.76 (s,
3H, OCH3), 6.34 (d, J = 7.5 Hz, 2H, Ar–H), 6.57 (d,
J = 8.0 Hz, 2H, Ar–H), 7.26 (d, J = 8.0 Hz, 2H, Ar–H),
7.29–7.31 (m, 1H, Ar–H), 7.42–7.44 (m, 2H, Ar–H), 7.56
(s, 1H, Ar–H), 7.63 (d, J = 8.0 Hz, 2H, Ar–H), 8.20 (s, 1H,
Ar–H), 8.23 (br s, 1H, NH), 8.35 (br s, 1H, NH); MS (m/z,
%): 386 (M?, 100), 265 (75), 236 (62), 146 (42). Anal.
Calcd for C23H22N4O2: C, 71.48; H, 5.73; N, 14.49. Found:
C, 55.58; H, 4.41; N, 07.18.
Percent protection ¼ ½1 ꢁ ðT1=T2Þꢂ ꢃ 100
T2 is the preconvulsive time of test compound and T1 is the
preconvulsive time of control.
The activity of the test compounds was compared with
the standard antihistamine chlorpheniramine maleate.
3-[2-(4-Nitrophenylamino) ethylamino]-2-phenyl
quinazolin-4(3H)-one (S10)
Yield: 87 %, m.p. 266–268 °C, IR (KBr) cm-1: 3261 (NH),
1632 (C=O), 1607 (C=N); 1H NMR (CDCl3) d ppm :
2.61–2.66 (m, 2H, CH2), 2.91–2.95 (m, 2H, CH2), 6.45 (d,
J = 7.5 Hz, 2H, Ar–H), 6.99 (d, J = 8.0 Hz, 2H, Ar–H),
Sedative-hypnotic activity
Sedative-hypnotic activity was determined by measuring
the reduction in locomotor activity using actophotometer
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Med Chem Res (2013) 22:2486–2492
(Dews, 1953; Kuhn and Van Maanen, 1961). Six albino
Swiss mice were allotted to each group. Basal activity
score was taken and then compounds S1–S10 and 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 fol-
lowing formula and shown in Table 1
% reduction in motor activity ¼ ½ðA ꢁ BÞ=Aꢂ ꢃ 100
where A is the basal score and B is the score after drug
treatment.
Statistical analysis
Statistical analysis of the biologic activity of the synthe-
sized compounds on animals was evaluated using a one-
way analysis of variance (ANOVA). In all cases, post hoc
comparisons of the means of individual groups were per-
formed by 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 statistical anal-
ysis, GraphPad Prism 3.0 version was used. (GraphPad
Software, Inc.11452 El Camino Real, #215, San Diego, CA
92130 USA).
Results and discussion
Chemistry
The key intermediate 3-(2-bromo ethylamino)-2-phenyl
quinazolin-4(3H)-one (7) was prepared by stirring at hot
condition a solution of 3-amino-2-phenyl quinazolin-
4(3H)-one and 1,2-dibromoethane in potassium carbonate
for 6 h. The formation of compound 5 is confirmed by the
disappearance of peak due to –NH2 of the starting material
in the IR and NMR spectrum. The IR spectrum of 3-(2-
bromo ethylamino)-2-phenyl quinazolin-4(3H)-one (7)
showed a peak for NH group at 3,249 cm-1 and peak for
1
carbonyl (C=O) stretching at 1,669 cm-1. The H NMR
spectrum of compound (7) showed multiplet at d
2.55–3.25 ppm for –CH2CH2- group and multiplet for
aromatic (9H) protons observed at d 7.39–8.06 ppm.
Compound 5, in turn, was prepared from anthranilic acid
via 2-phenyl-3,1-benzoxazin-4-one (3) as shown in
Scheme 1. 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 title compounds were obtained in fair- to good yield
through the nucleophilic displacement of –Br group of 3-(2-
123

Med Chem Res (2013) 22:2486–2492
2491
bromo ethylamino)-2-phenyl quinazolin-4(3H)-one (7) with
a variety of amines using 1,4-dioxan as solvent to afford
2-phenyl-3-[2-(substituted amino) ethylamino] quinazolin-
4(3H)-ones (S1–S10). The formation of title compounds is
indicated by the disappearance of peaks due to –Br of the
starting material and the appearance of –NH signal at
3,350–3,200 cm-1 in the IR spectra of the compounds S1–
S10. It also showed a peak for carbonyl (C=O) around
1,720–1,650 cm-1. The 1H NMR spectra of title compounds
S1–S10 showed peaks for substituent around N-3 of qui-
nazolinones and singlet around d 8.25–9.45 ppm; due to NH,
a multiplet around d 7.00–8.15 ppm was observed for
aromatic protons. Data from the elemental analyses and
molecular ion recorded in the mass spectrum further con-
firmed the assigned structure. In mass spectra of compounds
S1–S10, the common peak appeared due quinazolin-4-one
moiety cation at m/z 168. Elemental (C, H, N) analysis sat-
isfactorily confirmed elemental composition and purity of
the synthesized compounds.
Pharmacology
The compounds containing 2-phenyl-3-[2-(substituted
amino) ethylamino] quinazolin-4(3H)-one (S1–S10) were
Scheme 1 Synthesis of
2-phenyl-3-[2-(substituted
amino) ethylamino]
quinazolin-4(3H)-ones
(S1–S10)
O
COCl
COOH
O
pyridine
-HCl
+
N
NH2
(3)
(2)
(1)
(4)
NH2NH2.H2O
Ethanol
-H2O
O
O
N
NHCH2CH2Br
NH2
N
N
(6)
BrCH2CH2Br
-HBr
N
(5)
(7)
RNH2
-HBr
O
N
N
NHCH2CH2
NH
R
(S1-S10)
HN
HN
S-1
S-6
S-2
S-3
HN
Cl
HN
N
NH
S-4
S-5
N
O
N
S-8
HN
S-9
S-10
OCH3
OCH3 S-7
HN
HN
NO2
HN
S
H3C
123

2492
Med Chem Res (2013) 22:2486–2492
evaluated for their in vivo antihistaminic activity. Hista-
mine causes bronchospasm and the guinea pigs are the
most susceptible animals for histamine; hence, the pro-
tection against histamine-induced bronchospasm on con-
scious 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 non-inva-
sive method and the animals are recovered after the
experiment.
[2-(piperazinyl) ethylamino] quinazolin-4(3H)-one (S3)
emerged as the most potent compound of the series com-
pound (73.67 %), which is more potent when compared to
reference standard chlorpheniramine maleate (70.09 %).
Interestingly, compound S3 also showed negligible seda-
tion (8.21 %) compared to chlorpheniramine maleate
(29.58 %) and could therefore serve as a lead molecule for
further modification to obtain a clinically useful novel class
of non-sedative antihistamines.
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 68–73 %. Biologic
studies indicated that different substituents over the third
position of quinazoline ring exerted varied biologic activ-
ity. The presence of piperazinyl group (compound S3)
showed significant activity. When the additional heteroat-
oms like oxygen is introduced (morpholinyl substitution
compound S5), the activity is retained. Placement of aryl
group (phenyl substitution (compound S1)) and aryl ring
with electron-donating substituents (2-methyl phenyl sub-
stitution (compound S8)) showed decrease in activity;
whereas, placement of aryl ring with electron-withdrawing
group (p-chloro aniline substitution (compound S2)) and
heteroaryl group (2-amino thiazole substitution compound
(S7)) results in retaining of activity. Placement of aralkyl
group (benzyl substitution compound (S4)) further decreased
the activity. Compound 2-phenyl-3-[2-(piperazinyl) ethyl-
amino] quinazolin-4(3H)-one (S3) emerged as the most
potent compound of the series.
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In summary, the synthesis of new series of 2-phenyl-3-[2-
(substituted amino) ethylamino] quinazolin-4(3H)-one
(S1–S10) have been described. The title compounds have
exhibited promising antihistaminic activity against hista-
mine-induced bronchospasm on conscious guinea pigs in
vivo model. Among the series, compound 2-phenyl-3-
123