Synthesis of some Phenylpyrazolo benzimidazolo quinoxaline derivatives as potent antihistaminic agents

Article abstract of DOI:10.1155/2010/524124

2,3-Diphenyl quinoxaline (NI) was fused with benzimidazole (NII) by a methylene bridge, which was then allowed for acetylation. The acetylated product (NIV) was made to react with different aromatic aldehydes to give chalcones (NV1-NV5). Chalcones refluxed with substituted acid hydrazides to afford different phenyl pyrazolo benzimidazole quinoxaline derivatives (NVI 1-NVI 15). The structure of chalcones and phenyl pyrazolo benzimidazole quinoxaline derivatives were confirmed by m.p, TLC and spectral data. All the synthesized compounds were screened for their antihistaminic activity. Compounds NVI-3, NVI-12, NVI-13, NVI-14 and NVI-15 were shown good % protection of antihistamic activity.

Full text of DOI:10.1155/2010/524124

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2010, 7(1), 234-238
http://www.e-journals.net
Synthesis of Some Phenylpyrazolo
Benzimidazolo Quinoxaline Derivatives as
Potent Antihistaminic Agents
C. H. SRIDEVI*, K. BALAJI, A. NAIDU and R. SUDHAKARAN
Dept. of Pharmaceutical Chemistry, Geethanjali College of Pharmacy,
Cheeryal(V),Keesara(M), Hyderabad-501301, India.
sridevi.phd@gmail.com
Received 22 May 2009; Accepted 15 July 2009
Abstract: 2,3-Diphenyl quinoxaline (NI) was fused with benzimidazole (NII) by
a methylene bridge, which was then allowed for acetylation. The acetylated product
(NIV) was made to react with different aromatic aldehydes to give chalcones
(NV1-NV5). Chalcones refluxed with substituted acid hydrazides to afford different
phenyl pyrazolo benzimidazole quinoxaline derivatives (NVI 1-NVI 15). The structure
of chalcones and phenyl pyrazolo benzimidazole quinoxaline derivatives were
confirmed by m.p, TLC and spectral data. All the synthesized compounds were
screened for their antihistaminic activity. Compounds NVI-3, NVI-12, NVI-13,
NVI-14 and NVI-15 were shown good % protection of antihistamic activity.
Keywords 2,3-Diphenyl quinoxaline, Benzimidazole, Phenyl pyrazolo benzimidazolo quinoxaline,
Antihistaminic activity.
Introduction
Benzimidazole moiety plays an important role in heterocyclic chemistry largely due to its
wide range of biological activities1-4 such as antimicrobial, antitubercular, anti-inflammatory,
anticancer etc. Quinoxaline derivatives have been reported to possess a wide variety of
biological activities5-7. Notable among these are antioxidant, anti-inflammatory
antimicrobial, anticancer and antihistamic activities. Drugs having pyrazoline ring system8-10
are well known for their anti-inflammatory, antioxidant, antihistamic, antimicrobial,
antidepressant, hypoglycemic, hypotensive, anticarcenogenic activities etc. In view of the
above facts, it was contemplated to design and synthesize some phenyl pyrazolo
benzimidazolo quinoxaline derivatives (Scheme 1) by condensing benzimidazole quinoxaline
chalcones with different aromatic acid hydrazides. All the synthesized compounds were
screened for their antihistaminic activity. The structure of chalcones and phenyl pyrazolo
benzimidazolo quinoxaline derivatives were confirmed by m.p, TLC, and spectral data.

Synthesis of Some Phenylpyrazolo Benzimidazolo Quinoxaline Derivatives
235
N
N
+
N
H
N
(N I)
( N II)
35%HCl
HCHO
N
N
N
N
H
Anhy.K2CO3
Acetone
(N III)
ClCH2COCH3
N
N
N
N
CH3
10% NaOH
(N IV)
OCH
X
O
N
N
N
N
(N V1-N V5)
O
( ArCONHNH2)
(Ar1-Ar3)
X
gla.acetic acid
N
N
N
N
CH2
X
N
N
(N VI1-N VI15)
COAr
X=H, OH,Cl, F,OCH3, Ar= -C6H5, -C6H4 OH, -C6H4 Cl
Scheme 1
Experimental
The melting point of the compounds were determined on a Thoshniwal electric melting point
apparatus and the values were uncorrected. IR spectra of the compounds were recorded on a
Thermo Nicolet Nexus670-FTIR, IICT, Hyderabad using KBr disc method. 1H NMR spectra were
recorded onAvance-300, IICT, Hyderabad using CDCl3 as solvent. Mass spectra were recorded on
HITACHI RMU GL, IICT, Hyderabad. All the solvents used were of analytical grade.

236
C H.SRIDEVI et al.
General procedure for synthesis of 6-((1H-benzo[d]imidazol-5-yl) methyl)-2, 3-
diphenylquinoxaline (NIII )8
2,3 Diphenyl quinoxaline (NI) and benzimidazole (NII) were prepared following the
literature method. NI and NII are linked with a methelyne bridge by treating equimolar
quantities of NI and NII in suitable solvent with 35 parts formaldehyde solution and 35%
o
HCl, stirring for 4 h. at 70 C using magnetic stirrer. Solution was made alkaline using
ammonia solution. Filtered the product and recrystallized with aqueous ethanol.
NIII: Yield 72%, m.p 108 oC, IR (KBr) in cm-1: 1665 (C=N str.), 1340 (C-N str.), 3085
(Ar-H str.) .1HNMR (CDCl3) δ: 5.0 (S, 1H, N-H of benzimidazole), 3.81 (S, 2H, methylene),
7.5-7.9 (m, 3H, quinoxaline), 7.2-7.4 (m, 10H, Ar-H), 7.0-8.1 (m, 3H, benzimidazole).
Mass: m/z: 428 (M+).
General procedure for Synthesis of 1-(5-((2,3-diphenylquinoxalin-6-yl)methyl)-1H-
benzo[d]imidazol-1-yl)propan-2-one (NIV)9
A solution of NIII (0.01 M) and chloroacetone (0.01 M) were taken into 250 mL round
bottom flask. Added to it 150 mL of dry acetone and 30 g of anhydride potassium carbonate
and the reaction mixture were refluxed for 6 h. below 75 oC. Filterate obtained was
concentrated under vacuum and recrystallized with aqueous ethanol.
o
N IV: Yield 68%, m.p 125 C, IR (KBr) cm-1: 1793 (C=O str.), 1668 (C=N str.), 1340
(C-N str.), 3085 (Ar-H str.), 3323 (C-H str).1HNMR (CDCl3) δ: 2.0 (S, 3H, methyl), 3.8,4.8
(S, 4H, methylene), 7.4-7.9 (m, 3H, quinoxaline), 7.2-7.4 (m, 10H,Ar-H), 7.0-8.0 (m, 4H,
benzimidazole). Mass: m/z: 468.2 (M+).
General procedure for synthesis of (Z)-4-phenyl-1-(5-((2,3-diphenylquinoxalin-6-
yl)methyl)-1H-benzo[d]imidazol-1-yl)but-3-en-2-one (NV1-NV5)10
Method of aldol condensation was followed. A solution of NaOH / KOH (8 mL, 10% in
water) was added drop wise to a well-stirred solution of NIV (0.01 M) and (0.01 M) of
appropriate aldehyde in 20 mL ethanol. The reaction mixture was stirred for 24 h. at cold
conditions. Then diluted with ice water and acidified with con. HCl. Filtered the product and
recrystallized with aqueous ethanol. The purity of the compound was checked by TLC and
melting point.
NV 1: Yield: 73%, m.p: 113 oC, IR (KBr) cm-1: 1773 (C=O str.), 1668(C=N str.), 1340
(C-N str.), 3085 (Ar-H str.), 3323 (C-H str.) cm-1.1HNMR (CDCl3) δ: 3.8, 5.3 (S, 4H,
methylene), 6.2,7.3(d, 2H,ethylene), 7.5-7.9(m, 3H, quinoxaline), 7.1-7.4 (m, 15H, Ar-H),
7.0-8.1 (m, 4H, benzimidazole). Mass: m/z: 556.2 (M+)
General procedure for Synthesis 6-((1-((1-benzyl-4, 5-dihydro-5-phenyl-1H-pyrazol-3-yl)
methyl)-1H Benzo [d]imidazol-5-yl) methyl)-2, 3-diphenylquinoxaline (NVI1– NVI15)11
Chalcone NIV (0.01 M) and aromatic acid hydrazide (0.02 M) were taken in 20 mL glacial
acetic acid and refluxed for 10 h. above 130 0C. The reaction mixture was concentrated and
poured in 300 mL of ice-cold water and recrystallized with aqueous ethanol. The purity of
the compound was checked by TLC and melting point.
NVI 1: Yield: 67%, m.p: 121 oC, IR (KBr) cm-1: 1790 (C=O str.), 1668 (C=N str.), 1339
1
(C-N str.), 3035 (Ar-H str.), 3320 (C-H str.) cm-1. HNMR (CDCl3): 1.79, 2.0 (m, 2H,
methylene), 3.8, 3.8 (S, 4H, methylene), 4.9 (m, 1H, methine), 7.5-7.9 (m, 3H, quinoxaline),
7.12-7.95 (m, 20H, Ar-H), 7.9-8.1 (m, 4H, benzimidazole). Mass: m/z: 674.2 (M+).

Synthesis of Some Phenylpyrazolo Benzimidazolo Quinoxaline Derivatives
237
Pharmacological evaluation
Antihistaminic activity15
Histamine chamber method
In this method, thirty two healthy adult guinea pigs of either sex divided into group of 2
animals each weighing around 400 g, fasted overnight, were kept in histamine chamber, and
exposed to histamine aerosol (0.5% aqueous solution of histamine acid phosphate in a
Nebulizer) until they collapse. Those that collapse within 2 minutes were revived with fresh
air and used for this test. Twelve hours later, the animals were given an oral dose of test
compound suspended in 1% acacia solution and after 1 h for absorption; the guinea pigs
were again exposed to the same concentration of histamine aerosol. Those that do not
collapse within 6 minutes are deemed protected. Percentage protection has been measured
by using the following formula:
[1-T1 / T2] x 100
Where T1 was the mean of control preconvultion time in vehicle treated group and T2
was the mean of control preconvultion time in drug treated group. The results are shown in
Table 2.
Table 2. Antihistaminic studies of phenyl pyrazolo benzimidazolo quinoxaline derivatives.
Onset of convulsions (s)
Mean SD
990 90
Compd.
X
Ar
Mol. formula
%Protection
H
OH
F
Cl
OCH3
H
C6H5
C6H5
C6H5
C6H5
C6H5
C45H34N6O
C45H34N6O2
C45H33FN6O
C45H33ClN6O
C46H36N6O2
89.3
89.5
90.8
89.4
89.4
89.5
90.4
90.5
89.7
89.7
90.5
90.9
91.0
90.8
91.1
NVI 1
NVI 2
NVI 3
NVI 4
NVI 5
NVI 6
NVI 7
NVI 8
NVI 9
NVI 10
NVI 11
NVI 12
NVI 13
NVI 14
NVI 15
Control
1000 98
1150 98
993 96
999 91
OHC6H4 C45H34N6O2
OHC6H4 C45H34N6O3
OHC6H4 C45H33FN6O2
OHC6H4 C45H33ClN6O2
1000 92
1100 91
1111 92
1020 92
1022 96
1113 92
1160 95
1170 96
1150 92
1180 92
105 16
OH
F
Cl
OCH3 OHC6H4 C45H36N6O3
H
OH
F
ClC6H4 C45H33ClN6O
ClC6H4 C45H33ClN6O2
ClC6H4 C45H32ClFN6O
ClC6H4 C45H32Cl2N6O
Cl
OCH3 ClC6H4 C46H35ClN6O2
CPM
1220 65
91.3
Conclusions
Synthesis of some phenyl pyrazolo benzimidazolo quinoxaline derivatives by condensing
benzothiazolo quinoxaline chalcones with different aromatic acid hydrazides have been done
successfully. The structure of chalcones and phenyl pyrazolo benzimidazole quinoxaline
derivatives were confirmed by M.P, TLC and Spectral data. Physical data are shown in
Table 1. All the synthesized compounds were screened for their Antihistaminic activity.
Compounds NVI 3, NVI 12, NVI 13, NVI 14 and NVI 15 were shown good % protection of
antihistamic activity i.e., 90.8%, 90.9%, 91.0%, 90.8% and 91.1% respectively.

238
C. H. SRIDEVI et al.
Table 1. Physical data of phenyl pyrazolo benzimidazolo quinoxaline derivatives.
Compd.
X
H
Ar
C6H5
Mol. Formula
C45H34N6O
C45H34N6O2
C45H33FN6O
C45H33ClN6O
C46H36N6O2
Melting point range, °C % Yield Rf value
122-124
114-115
112-115
112-114
116-118
120-124
120-124
108-110
102-105
110-112
120-122
120-122
131-133
130-134
123-126
70
67
66
78
67
66
80
45
45
67
56
78
76
56
54
0.8
0.82
0.8
NVI1
NVI2
NVI3
NVI4
NVI5
NVI6
NVI7
NVI8
NVI9
NVI10
NVI11
NVI12
NVI13
NVI14
NVI15
OH C6H5
C6H5
Cl C6H5
F
0.91
0.8
OCH3 C6H5
H
OHC6H4 C45H34N6O2
OH OHC6H4 C45H34N6O3
OHC6H4 C45H33FN6O2
0.81
0.9
0.9
0.8
F
Cl OHC6H4 C45H33ClN6O2
OCH3 OHC6H4 C45H36N6O3
0.83
0.8
H
ClC6H4
OH ClC6H4
ClC6H4
C45H33ClN6O
C45H33ClN6O2
C45H32ClFN6O
C45H32Cl2N6O
C46H35ClN6O2
0.82
0.80
0.98
0.81
F
Cl ClC6H4
OCH3 ClC6H4
Acknowledgements
The authors are thankful to IICT Hyderabad for spectral analysis and also thankful to
Geethanjali College of Pharmacy for providing facilities to carry out research work.
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