Microwave-assisted, solvent-free and parallel synthesis of some novel substituted imidazoles of biological interest

Article abstract of DOI:10.1248/cpb.58.375

Solvent free microwave assisted synthesis of some novel substituted imidazoles of biological interest is reported. First, primary aromatic or heteryl amine was condensed with aryl or heteryl aldehydes to afford corresponding Schiff's base. The Schiff's base further on treatment with ammonium acetate (NH₄OAC) and isatin using silica gel as the solid support, yielded the corresponding aryl imidazoles. In this paper a comparative study between the developed microwave method and conventional method is described. The synthesized compounds were analyzed by physical and analytical data. The synthesized compounds were evaluated for their antibacterial, anthelmintic, short-term anticancer and antitubercular activity. All the synthesized substituted imidazoles have shown good antibacterial activity against gram negative bacterial strains Klebsiella pneumoniae and Escherichia coli and moderate to good anthelmintic activity. The synthesized imidazole derivative possessed signifi-cant cytotoxic activity against Ehrlich's ascites carcinoma (EAC) cell lines. None of the compounds exhibited prominent antitubercular activity.

Full text of DOI:10.1248/cpb.58.375

March 2010
Chem. Pharm. Bull. 58(3) 375—380 (2010)
375
Microwave-Assisted, Solvent-Free and Parallel Synthesis of Some Novel
Substituted Imidazoles of Biological Interest
Gyanendra Kumar SHARMA* and Devender PATHAK
Department of Pharmaceutical Chemistry, Rajiv Academy for Pharmacy; Mathura–281001, Uttar Pradesh, India.
Received November 4, 2009; accepted December 22, 2009
Solvent free microwave assisted synthesis of some novel substituted imidazoles of biological interest is re-
ported. First, primary aromatic or heteryl amine was condensed with aryl or heteryl aldehydes to afford corre-
sponding Schiff’s base. The Schiff’s base further on treatment with ammonium acetate (NH4OAC) and isatin
using silica gel as the solid support, yielded the corresponding aryl imidazoles. In this paper a comparative study
between the developed microwave method and conventional method is described. The synthesized compounds
were analyzed by physical and analytical data. The synthesized compounds were evaluated for their antibacter-
ial, anthelmintic, short-term anticancer and antitubercular activity. All the synthesized substituted imidazoles
have shown good antibacterial activity against gram negative bacterial strains Klebsiella pneumoniae and Es-
cherichia coli and moderate to good anthelmintic activity. The synthesized imidazole derivative possessed signifi-
cant cytotoxic activity against Ehrlich’s ascites carcinoma (EAC) cell lines. None of the compounds exhibited
prominent antitubercular activity.
Key words aryl imidazole; anticancer activity; anthelmintic activity
A survey of the pertinent literature reveals that aryl imida- Results and Discussion
zoles have been found to possess a wide spectrum of biologi-
The results and discussion pertaining to the synthesis of
cal activity such as antibacterial,1) antirheumatoid arthritis,2) Schiff’s bases and finally substituted imidazoles are as fol-
antitubercular,3) antiviral,4) antiepileptic,5) anti-inflamma- lows:
tory6) and anticancer activities.7—9) Since, we have made an
First, the primary aromatic or heteroarylamine was con-
attempt to synthesize and screen aryl imidazoles which are densed with aryl or heteryl aldehydes afforded the corre-
incorporated with some antibacterial pharmacophores such sponding Schiff’s base.25) To prepare aryl imidazoles, the
as sulphanilamide, its bioisoester PABA (p-aminobenzoic Schiff’s base was further treated with ammonium acetate and
acid), INH (isoniazid) and p-amino phenol by using both mi- isatin (cyclization steps involving diketone) in the presence
crowave assisted synthesis as well as conventional synthetic of glacial acetic acid as a solvent, gave a corresponding aryl
method and screened them as potential antibacterial, anti- imidazoles 1b—20b (Chart 1). On the basis of above facts
cancer, anthelmintic and antitubercular agents.
(as depicted in the introduction) that the novel series of syn-
It has been revealed from the literature that imidazoles thesized derivative of aryl imidazoles containing indole moi-
fused with indole nucleus possess various biological activi- ety may yield compounds with high therapeutic potential. All
ties10—12) including anticancer activity especially against the synthesized compounds were analyzed by TLC, mp, FT-
1
breast cancer.
IR, H-NMR, 13C-NMR, MASS and elemental analysis. Mi-
In 1858, Debus reported the reaction between glyoxal and crowave irradiation was done using microwave oven supplied
ammonia, ever since this reaction became a novel route to the by catalyst microwave synthesis system, model: CATA-2R.
synthesis of imidazoles.13) Later, a number of articles have The microwave assisted parallel synthesis was performed
described the synthesis of imidazoles and their medicinal under solvent free conditions using activated silica gel
significance.14—22)
In the last decade, microwave assisted organic synthesis
(MAOS) have become a new and quickly growing area in the
synthetic organic chemistry.23,24) This synthetic technique is
based on the empirical observation that some organic reac-
tions proceed much faster and with higher yields under mi-
crowave irradiation as compared to conventional heating. In
many cases reactions that normally require many hours at re-
flux temperature under classical conditions can be completed
within several minutes or even seconds in a microwave oven.
Recent simplifications of MORE (microwave organic reac-
tion enhancement) technique have increased safety and prac-
tical utility of the microwave oven for their use in organic
laboratories without any modification. An eco-friendly
method is an important salient feature of MORE chemistry,
since it requires no solvent (dry media synthesis) or very lit-
tle solvent as energy transfer medium.
Chart 1
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: gyane007@indiatimes.com

376
Vol. 58, No. 3
1
1000 W. Schiff’s base formation was completed after 8 min
The H-NMR showed a characteristic peak for NH2 be-
of microwave irradiation, whereas aryl imidazoles formed tween 6.22—6.39 d ppm for compounds containing sul-
between 14—22 min of microwave irradiation. We are of the phanilamide 1b—6b and characteristic peak for COOH was
opinion that the acidic nature of silica gel would have en- observed between 11.13—11.96 d ppm for compounds con-
hanced this process particularly during dehydration steps. taining PABA (p-aminobenzoic acid) 7b—10b. A character-
The list of synthesized compounds and the comparative yield istic peak for NH was observed between 8.31—9.28 d ppm
statement between microwave and conventional method is as for compounds containing INH (isoniazid) 11b—15b. A
shown in Table 1.
characteristic peak for OH was observed between 8.58—
The microwave method was found to be better than con- 8.76 d ppm for compounds containing p-amino phenol 16b—
ventional method in terms of reaction time, yield and rela- 20b.
tively simple method to perform parallel synthesis. Thus, this
methodology becomes an efficient strategy for the rapid syn- chemotherapeutic pharmacophores were evaluated for their
thesis of aryl imidazoles, selectively. in vitro antibacterial activity against two-gram positive bacte-
All the synthesized imidazoles incorporated with
Table 1. Data of All Synthesized Aryl Imidazoles Compounds Screened against EAC Cell Line
Reaction time
MWb) (min) Conventional (h)
Yield (%)a)
Conventional
c)
mp
(°C)
CTC50
Comp. no.
R
Rꢀ
(mg/ml)
MW
1b
2b
14
16
13
13
89
83
61
58
130
180
262.50
275.50
3b
15
14
86
67
185
400.00
4b
5b
20
22
15
15
90
91
62
63
205
180
380.00
31.25
6b
7b
21
19
15
15
88
93
61
72
220
212
420.00
91.61
8b
9b
17
14
14
13
81
90
77
50
183
240
360.00
143.67
10b
11b
12b
16
19
21
12
14
13
89
78
78
45
55
67
251
191
149
114.00
322.47
50.32
13b
14b
15
18
15
13
67
76
56
49
188
201
380.00
198.50
15b
16b
19
21
13
14
81
82
56
60
205
221
50.00
94.63
17b
18b
13
12
15
14
75
77
58
45
223
263
ꢁ500
360.34
19b
20b
14
13
12
11
84
83
50
52
256
262
350.00
31.25
a) Isolated yield. b) Microwave irradiation. c) The cytotoxic concentration (which inhibited 50 % of total cells).

March 2010
377
Table 2. Antibacterial Data of All Synthesized Aryl Imidazoles Com- Table 3. Anthelmintic Activity of All Synthesized Aryl Imidazoles Com-
pounds Screened against Various Bacterial Strains
pounds Screened against Various Earthworm Species
Earthworm species
Diameter of zone of inhibition (mm)
Bacterial strains
M. konkanensis
P. corethruses
Compound
Compound
Gram (ꢃve)
S. aureus B. subtilis
Gram (ꢂve)
Mean
paralyzing
Mean
death
Mean
Mean
death
E. coli
K. pneumoniae
paralyzing
time (min)a) time (min)a) time (min)a) time (min)a)
1b
2b
3b
4b
5b
6b
7b
8b
9b
5.9 (50)
5.1 (25)
8.6 (25)
13.1 (50)
9.1 (25)
5.7 (100)
12.5 (50)
11.9 (50)
12.1 (25)
13.1 (25)
11.2 (50)
6.2 (100)
7.2 (100)
10.3 (25)
12.3 (50)
9.1 (100)
6.1 (100)
7.3 (100)
13.2 (25)
12.4 (25)
—
6.9 (50)
5.5 (25)
8.4 (25)
12.5 (25)
8.8 (50)
5.9 (100)
12.1 (25)
11.3 (25)
13.8 (50)
12.3 (25)
12.4 (25)
7.2 (100)
8.7 (50)
12.4 (12.5)
13.6 (25)
8.3 (100)
7.4 (100)
7.4 (100)
14.5 (12.5)
12.7 (25)
—
7.2 (50)
8.1 (50)
9.2 (12.5)
11.9 (25)
7.6 (100)
6.6 (50)
11.9 (25)
10.9 (100)
14.3 (25)
15.4 (12.5)
13.5 (12.5)
9.2 (50)
10.2 (50)
14.5 (6.2)
14.6 (25)
9.1 (50)
8.1 (50)
8.9 (50)
9.5 (12.5)
12.5 (6.2)
7.8 (100)
6.9 (50)
11.6 (25)
10.7 (50)
12.5 (50)
11.8 (25)
9.1 (50)
7.5 (50)
10.3 (25)
13.3 (12.5)
14.6 (25)
10.2 (25)
6.9 (50)
9.7 (50)
11.5 (25)
11.1 (50)
—
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
20b
Control
28.38ꢄ0.52 40.58ꢄ0.59 35.57ꢄ1.26 50.26ꢄ1.02
13.54ꢄ0.83 22.18ꢄ1.28 17.47ꢄ1.47 29.02ꢄ1.18
13.73ꢄ1.90 22.73ꢄ0.49 17.52ꢄ2.23 29.58ꢄ1.63
36.10ꢄ0.23 65.13ꢄ0.92 57.62ꢄ1.90 82.30ꢄ0.49
16.22ꢄ0.37 25.56ꢄ0.72 20.65ꢄ1.25 32.22ꢄ1.29
26.66ꢄ1.46 35.22ꢄ0.94 31.98ꢄ1.17 43.76ꢄ0.41
11.28ꢄ0.62 20.03ꢄ1.34 13.76ꢄ0.51 21.72ꢄ0.45
26.22ꢄ0.67 35.54ꢄ0.90 30.34ꢄ1.12 42.56ꢄ1.40
25.50ꢄ0.34 34.12ꢄ0.87 29.83ꢄ1.45 41.53ꢄ1.67
09.44ꢄ0.56 17.49ꢄ0.72 14.34ꢄ0.69 26.21ꢄ0.54
36.78ꢄ0.21 62.48ꢄ0.91 49.35ꢄ1.65 72.24ꢄ1.02
27.67ꢄ0.17 36.48ꢄ1.95 31.38ꢄ0.74 42.45ꢄ1.55
12.22ꢄ0.32 18.12ꢄ0.34 13.56ꢄ0.67 19.57ꢄ0.53
22.12ꢄ0.84 30.12ꢄ0.31 26.12ꢄ1.12 35.43ꢄ0.52
10.12ꢄ0.13 15.56ꢄ0.81 17.12ꢄ0.32 21.17ꢄ0.13
35.12ꢄ0.72 40.15ꢄ0.12 42.13ꢄ0.19 52.19ꢄ0.16
10.56ꢄ0.19 18.16ꢄ0.29 13.56ꢄ0.81 20.22ꢄ0.89
16.34ꢄ0.65 24.75ꢄ0.67 21.87ꢄ1.56 28.23ꢄ0.45
12.34ꢄ1.12 20.45ꢄ2.23 15.34ꢄ0.12 24.12ꢄ0.23
23.12ꢄ0.23 27.83ꢄ1.23 12.32ꢄ0.49 17.23ꢄ0.34
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
20b
Control
Ciprofloxacin
8.3 (50)
9.5 (50)
14.6 (12.5)
13.1 (50)
—
18 (12.5)
19 (6)
19 (12.5)
17 (6)
—
—
—
—
Mebendazole 12.22ꢄ0.54 20.12ꢄ0.76 17.45ꢄ1.23 28.76ꢄ1.06
Values in bracket are MIC values (mg mlꢂ1).
a) Data are given as meanꢄS.D. (nꢅ3).
ria such as Bacillus subtilis and Staphylococcus aureus and
two gram negative bacteria such as Escherichia coli and them devoid of side effects. Hydroxyl and carboxyl group are
Klebsiella pneumoniae. Almost all the newly synthesized responsible for inhibition of respiration and blocking glucose
substituted imidazoles showed good antibacterial activity absorption by the intestinal adult worms. The results of an-
against gram negative bacterial strains Escherichia coli and thelmintic studies are tabulated in Table 3.
Klebsiella pneumonia. The results of antibacterial studies are
All the synthesized compounds were evaluated for their
presented in Table 2.
possible antimycobacterial activity toward strain of M. tuber-
Anticancer activity of the synthesized compounds was culosis H37Rv strain sensitive to isoniazid. Middlebrook
evaluated by determining the percentage growth inhibition of (MB) 7H10 agar medium was used for testing antitubercular
Erlich’s ascites carcinoma (EAC) cells by tryphan blue dye activity. The minimum inhibitory concentration (MIC) deter-
exclusion technique. Compounds 5b, 7b, 12b, 15b, 16b and mination was performed from 1 to 25 mg/ml concentrations.
20b showed good anticancer activity with CTC50 (cytotoxic But, no compound exhibited MIC below 25 mg/ml concentra-
concentration). The CTC50 values of the newly synthesized tion including the aryl imidazoles containing isoniazid moi-
imidazoles are shown in Table 1. Presence of phenolic group ety.
in compound 16b and 20b significantly affect activity due to
Experimental
the binding capability to the cytoplasmic hormone recep-
Materials and Methods The laboratory grade chemicals and reagents
were used to synthesize all the reported compounds. The melting points
tors.26) Compound 5b containing sulfur in its structure de-
were determined in open capillaries and are uncorrected. The temperatures
are expressed in °C and are uncorrected. The IR spectra of newly synthe-
sized compounds were recorded on Perkin-Elmer Infrared-283 FTIR spec-
creases the melting temperature of DNA in EAC cells and
thereby showing significant activity. Presence of carboxylic
acid and its amide also increases the potential of compound
7b and 12b.
1
trometer by KBr pellet technique and are expressed in cmꢂ1. H- and 13C-
NMR spectra were recorded on Bruker DRX-300 (300 MHz, FT-NMR)
spectrophotometer using tetramethylsilane (TMS) as an internal standard,
CDCl3 and DMSO as a solvents. Mass spectrum was obtained using LC-MS
(Shimadzu-2010AT) under electro spray ionization (ESI) technique and ele-
mental analysis was performed using Elemental Vario EL III, Carlo-Erba
1108. TLC was performed to monitor the reactions and to determine the pu-
rity of products on a precoated aluminum plates using 10% methanol in
chloroform or 20% ethyl acetate in chloroform as a mobile phase.
General Procedure for the Preparation of Schiff’s Bases (1a—20a).
Conventional Method Equimolar amounts (0.01 M) of primary aromatic
amine and aromatic aldehyde were transferred to a 250 ml flat bottom flask
containing 15 ml glacial acetic acid and refluxed for 6 h. The reaction mix-
ture was allowed to cool to give product. The reactions were monitored
All the newly synthesized imidazole derivatives showed
moderate to good anthelmintic activity at 2 mg mlꢂ1 in Tween
80 (0.5%) and distilled water. Compounds 7b, 10b, 13b, 15b
and 17b were found to be most active possessing more activ-
ity against M. konkanensis and P. corethruses in comparison
to standard drug (mebendazole). Presence of amide group
(–CONH) in compounds 13b and 15b make them more po-
tent with low toxicity and several times more potent than
Mebendazole. Substituents at Rꢀ (2nd) position was intro-
duced to prevent metabolic inactivation. Presence of car-
boxylic and hydroxyl group in compound 10b and 17b make through thin layer chromatography (TLC). The completed reactions were

378
Vol. 58, No. 3
amide (4b) White crystals. 1H-NMR (CDCl3-d6, ppm) d: 6.39 (2H, bs,
NH2, D2O exchangeable), 7.11—8.13 (12H, m, Ar-H), 8.66 (1H, s, OH);
8.99 (1H, bs, NH, D2O exchangeable). 13C-NMR d: 110.7, 115.8 (2C),
118.8, 120.5 (2C), 121.9, 122.5 (2C), 123.1, 124.5, 127.7 (2C), 128.1 (2C),
134.8, 135.9, 139.5, 140.1, 144.2, 158.9. IR (KBr) cmꢂ1: 3405 (O–H), 3312
(N–H), 1622 (CꢅC), 1563 (CꢅN), 1278 (C–N), 1123 (SO), 1061 (C–S).
MS (m/z): 403.75, 404 (MꢃH)ꢃ, 325.37, 312.35, 249.27, 157.76. Anal.
Calcd for C21H16N4O3S: C, 62.36; H, 3.99; N, 13.85; S, 7.93. Found: C,
62.49; H, 3.80; N, 13.75; S, 7.85.
taken directly for the preparation of aryl imidazoles.
Microwave Method Equimolar amounts (0.01 M) of primary aromatic
amine and aromatic aldehyde were transferred to a clean and dry mortar,
triturated to form uniform mixture. The reaction mixture was then trans-
ferred to a 100 ml beaker containing 2 g of activated silica gel. All the
beakers containing different reaction mixtures were also kept inside the mi-
crowave oven and then microwave irradiation was carried out at 1000 W
power for about 8 min. Intermittent cooling was done after every 60 s of mi-
crowave irradiation. During intermittent cooling, the reaction mixtures were
thoroughly mixed. The reactions were monitored through TLC. The prod-
ucts so obtained were taken directly for the preparation of aryl imidazoles.
General Procedure for the Preparation of Aryl Imidazoles by Solid
Phase, Solvent Free, Multicomponent Reaction (1b—20b). Conventional
Method Isatin (0.01 M) was transferred along with excess of ammonium
acetate (0.1 M) into a flask containing the Schiff’s base (ca. 0.01 M) obtained
by conventional procedure. The reaction mixture was stirred and refluxed on
heating plate with magnetic stirrer for about 12—15 h. The reaction was
monitored through TLC.
The reaction mixture was poured into 250 ml of water to remove ammo-
nium acetate and acetic acid then it was filtered and dried in hot air oven.
The crude product was washed with 2ꢆ10 ml of benzene to remove traces of
any unreacted isatin and products were recrystallized by ethyl acetate.
Microwave Method This reaction was carried out in a parallel synthetic
way as shown in Chart 1. Isatin (0.01 M) was transferred along with excess
of ammonium acetate (0.1 M) in to a dry mortar containing the Schiff’s base
(ca. 0.01 M) obtained in the previous microwave procedure. Triturate to be-
come a uniform mixture. The reaction mixture was then transferred to
100 ml beaker. Like this all other beakers containing different reaction mix-
tures were kept inside the microwave oven in a circle and then microwave
irradiation was carried out at 1000 W power for about 14—22 min. Inter-
mittent cooling was done after every 60 s of microwave irradiation. During
intermittent cooling, the reaction mixtures were thoroughly mixed. The reac-
tions were monitored through TLC. The reaction mixtures were withdrawn
from microwave oven soon after the reaction is completed based on TLC
data at regular intervals.
4-[2-(4-Nitrophenyl)imidazo[4,5-b]indol-3(4H)-yl]benzenesulfon-
1
amide (5b) Pale yellow crystals. H-NMR (CDCl3-d6, ppm) d: 6.22 (2H,
bs, NH2, D2O exchangeable), 7.11—8.22 (12H, m, Ar-H), 8.69 (1H, bs, NH,
D2O exchangeable). 13C-NMR d: 110.4, 118.9, 120.6 (2C), 121.9 (2C),
122.1, 123.1 (2C), 124.6, 128.7 (2C), 129.2 (2C), 134.9, 135.9, 136.2, 138.8,
140.1, 144.2, 147.8. IR (KBr) cmꢂ1: 3339 (N–H), 1619 (CꢅC), 1567
(CꢅN), 1462 (NO2) 1279 (C–N), 1134 (SO), 1065 (C–S). MS (m/z): 432.95,
433 (MꢃH)ꢃ, 354.37, 312.35, 278.27, 157.12, 78.11. Anal. Calcd for
C21H15N5O4S: C, 58.19; H, 3.49; N, 16.16; S, 7.40. Found: C, 58.30; H,
3.52; N, 16.25; S, 7.52.
4-[2-(4-Dimethylaminophenyl)imidazo[4,5-b]indol-3(4H)-yl]benzene-
1
sulfonamide (6b) Yellow amorphous solid. H-NMR (CDCl3-d6, ppm) d:
6.26 (2H, bs, NH2, D2O exchangeable ), 2.32 [(6H, s, (CH3)2], 7.12—8.32
(12H, m, Ar-H), 8.71 (1H, bs, NH, D2O exchangeable). 13C-NMR d: 39.5
(2C), 111.4, 113.8 (2C), 118.6, 119.7 (2C), 120.3, 121.9, 123.8 (2C), 124.6,
127.9 (2C), 128.1 (2C), 134.8, 136.2, 138.9, 140.1, 144.1, 149.3. IR (KBr)
cmꢂ1: 3382 (N–H), 2965 (C–H), 1619 (CꢅC), 1576 (CꢅN), 1283 (C–N),
1135 (SO), 1065 (C–S). MS (m/z): 430.45, 431 (MꢃH)ꢃ, 352.44, 312.35,
276.34, 157.19. Anal. Calcd for C23H21N5O2S: C, 64.02; H, 4.91; N, 16.23;
S, 7.43. Found: C, 64.15; H, 4.80; N, 16.12; S, 7.50.
4-[2-(4-Methoxyphenyl)imidazo[4,5-b]indol-3(4H)-yl]benzoic
Acid
(7b) White crystals. 1H-NMR (CDCl3-d6, ppm) d: 2.91 (3H, bs, OCH3),
7.15—8.34 (12H, m, Ar-H), 8.82 (1H, bs, NH, D2O exchangeable), 11.34
(1H, s, COOH). 13C-NMR d: 55.6, 111.2, 114.1 (2C), 118.5, 119.6 (2C),
121.8, 122.1 (2C), 122.9, 124.6, 127.9 (2C), 129.1, 130.8 (2C), 134.9, 136.1,
141.9, 144.1, 159.9, 168.1. IR (KBr) cmꢂ1: 3350 (N–H), 3032 (C–H), 1665
(CꢅO), 1621 (CꢅC), 1575 (CꢅN), 1271 (C–N). MS (m/z): 382.76, 383
(MꢃH)ꢃ, 339.40, 263.30, 227.28, 157.18, 108.14. Anal. Calcd for
C23H17N3O3: C, 72.05; H, 4.47; N, 10.96. Found: C, 71.95; H, 4.48; N,
10.91.
The completed and cooled reaction mixture was poured in to 250 ml of
water to remove ammonium acetate and acetic acid, filtered and dried it in
hot air oven. The crude product was washed with 2ꢆ10 ml of benzene to re-
move traces of any unreacted isatin, further extracted with ethyl acetate. The
ethyl acetate was heated, filtered in hot condition and allowed to cool. The
solid crystals formed were collected by filtration and dried under vacuum.
The analytical and spectral data of final compounds are given in the fol-
lowing text.
4-[2-(4-Chlorophenyl)imidazo[4,5-b]indol-3(4H)-yl]benzoic Acid (8b)
White redish amorphous solid. 1H-NMR (CDCl3-d6, ppm) d: 6.52—7.70
(12H, m, Ar-H), 8.82 (1H, s, NH, D2O exchangeable), 11.25 (1H, s,
COOH). 13C-NMR d: 110.5, 119.6, 119.8 (2C), 121.7, 122.7 (2C), 124.8,
127.1, 127.7 (2C), 129.2, 129.6 (2C), 131.9 (2C), 134.9, 135.3, 136.9, 141.9,
144.5, 170.1. IR (KBr) cmꢂ1: 3309 (N–H), 3054 (C–H), 1685.48 (CꢅO),
1540 (NꢅC), 1519 (CꢅC), 1257 (C–N), 698 (C–Cl). MS (m/z): 386.78, 387
(MꢃH)ꢃ, 343.82, 277.28, 267.72, 157.18, 112.56. Anal. Calcd for
C22H14ClN3O2: C, 68.13; H, 3.64; Cl, 9.14; N, 10.83. Found: C, 68.11; H,
3.62; Cl, 9.11; N, 10.82.
4-[2-(4-Nitrophenyl)imidazo[4,5-b]indol-3(4H)-yl]benzoic Acid (9b)
Cream color crystals. 1H-NMR (CDCl3-d6, ppm) d: 6.52—7.61 (12H, m,
Ar-H), 8.82 (1H, s, NH, D2O exchangeable), 11.13 (1H, s, COOH). 13C-
NMR d: 110.9, 118.8, 120.4 (2C), 122.0 (2C), 122.7, 122.9 (2C), 123.6,
127.7 (2C), 129.1, 131.9 (2C), 135.8, 136.0, 136.8, 141.8, 144.1, 147.9,
168.7. IR (KBr) cmꢂ1: 3381 (N–H), 3020 (C–H), 1640 (CꢅN), 1619.91
(CꢅO), 1463.71 (NO2). MS (m/z): 397.80, 398 (MꢃH)ꢃ, 354.37, 278.27,
277.28, 157.18, 123.11. Anal. Calcd for C22H14N4O4: C, 66.33; H, 3.54; N,
14.06. Found: C, 66.30; H, 3.52; N, 14.02.
4-(2-Phenylimidazo[4,5-b]indol-3(4H)-yl)benzenesulfonamide
(1b)
White crystals. 1H-NMR (CDCl3-d6, ppm) d: 6.25 (2H, bs, NH2, D2O ex-
changeable), 7.12—8.35 (13H, m, Ar-H), 8.75 (1H, bs, NH, D2O exchange-
able). 13C-NMR d: 110.5, 118.5, 119.4 (2C), 120.5, 123.3 (2C), 123.8, 126.4
(2C), 127.8 (2C), 128.2, 129.9 (2C), 130.1, 134.9, 136.1, 139.7, 140.8,
145.5. IR (KBr) cmꢂ1: 3322 (N–H), 3120 (C–H), 1625 (CꢅC), 1570
(CꢅN), 1280 (C–N), 1148 (SO), 1075 (C–S). MS (m/z): 387.80, 388
(MꢃH)ꢃ, 312.35, 309.37, 233.28, 157.19. Anal. Calcd for C21H16N4O2S: C,
64.93; H, 4.15; N, 14.42; S, 8.25. Found: C, 64.90; H, 4.30; N, 14.26; S,
8.35.
4-[2-(4-Methoxyphenyl)imidazo[4,5-b]indol-3(4H)-yl]benzenesulfon-
amide (2b) White amorphous solid. 1H-NMR (CDCl3-d6, ppm) d: 3.11
(3H, s, OCH3), 6.22 (2H, bs, NH2, D2O exchangeable), 7.05—8.32 (12H, m,
Ar-H), 8.82 (1H, bs, NH, D2O exchangeable). 13C-NMR d: 55.3, 111.3,
116.1 (2C), 119.8, 120.5 (2C), 121.4, 121.8 (2C), 122.9, 123.3, 126.1 (2C),
126.5 (2C), 135.5, 135.6, 138.1, 140.9, 143.7, 161.3. IR (KBr) cmꢂ1: 3350
(N–H), 3032 (C–H), 1621 (CꢅC), 1575 (CꢅN), 1271 (C–N), 1143 (SO),
1070 (C–S). MS (m/z): 417.50, 418 (MꢃH)ꢃ, 339.40, 312.35, 263.30,
156.92. Anal. Calcd for C22H18N4O3S: C, 63.14; H, 4.34; N, 13.39; S, 7.66.
Found: C, 63.20; H, 4.20; N, 13.20; S, 7.60.
4-[2-(2,6-Dichlorophenyl)imidazo[4,5-b]indol-3(4H)-yl]benzoic Acid
1
(10b) Yellow crystals. H-NMR (CDCl3-d6, ppm) d: 6.52—7.70 (12H, m,
Ar-H), 8.98 (1H, s, NH, D2O exchangeable), 11.96 (1H, s, COOH). 13C-
NMR d: 111.8, 119.7, 120.5 (2C), 121.8, 122.1 (2C), 123.8, 126.8 (2C),
129.6, 130.8 (2C), 132.3, 135.1 (2C), 136.1, 136.9, 137.8, 142.1, 144.7,
168.1. IR (KBr) cmꢂ1: 3325 (N–H), 3050 (C–H), 1686 (CꢅO), 1570
(CꢅN), 1520 (CꢅC), 1250 (C–N), 670 (C–Cl). MS (m/z): 421.90, 422
(MꢃH)ꢃ. 378.20, 302.17, 277.28, 157.18, 146.89. Anal. Calcd for
C22H13Cl2N3O2: C, 62.58; H, 3.10; Cl, 16.79; N, 9.95. Found: C, 62.49; H,
3.22; Cl, 16.61; N, 9.62.
4-[2-(4-Chlorophenyl)imidazo[4,5-b]indol-3(4H)-yl]benzenesulfon-
1
amide (3b) Pale yellow crystals. H-NMR (CDCl3-d6, ppm) d: 6.31 (2H,
bs, NH2, D2O exchangeable), 7.07—8.13 (12H, m, Ar-H), 8.63 (1H, bs, NH,
D2O exchangeable). 13C-NMR d: 110.5, 118.5, 119.4 (2C), 120.5, 123.3
(2C), 123.8, 126.4 (2C), 127.8 (2C), 128.2, 129.9 (2C), 130.1, 134.9, 136.1,
139.7, 140.8, 145.5. IR (KBr) cmꢂ1: 3352 (N–H), 1625 (CꢅC), 1568
(CꢅN), 1285 (C–N), 1131 (SO), 691 (C–Cl), 1065 (C–S). MS (m/z):
422.90, 422 (MꢂH)ꢂ, 343.82, 312.35, 267.72, 157.19. Anal. Calcd for
C21H15ClN4O2S: C, 59.64; H, 3.58; Cl, 8.38; N, 13.25; S, 7.58. Found: C,
59.60; H, 3.50; Cl, 8.30; N, 13.36; S, 7.66.
N-[2-(4-Methoxyphenyl)imidazo[4,5-b]indol-3(4H)-yl]isonicotinamide
(11b) White crystals. 1H-NMR (CDCl3-d6, ppm) d: 2.39 (3H, s, OCH3),
7.05—8.12 (12H, m, Ar-H), 8.31 (1H, bs, NH, D2O exchangeable), 10.24
(1H, bs, NH, D2O exchangeable). 13C-NMR d: 54.1, 110.9, 113.9 (2C),
118.3, 120.7 (2C), 122.1, 122.9 (2C), 123.4, 123.9, 128.1 (2C), 134.9, 135.6,
136.8, 141.0, 150.0 (2C), 159.9, 165.8. IR (KBr) cmꢂ1: 3395 (N–H), 3029
4-[2-(4-Hydroxyphenyl)imidazo[4,5-b]indol-3(4H)-yl]benzenesulfon-

March 2010
379
118.8, 120.5 (2C), 121.0, 122.5, 123.3 (2C), 124.8, 128.0 (2C), 129.5, 134.8,
136.7, 144.1, 150.3, 157.3. IR (KBr) cmꢂ1: 3411 (O–H), 3397 (N–H), 3046
(C–H), 1549 (CꢅN), 1534 (CꢅC), 1221 (C–N). MS (m/z): 368.50, 368
(MꢂH)ꢂ, 325.37, 276.34, 249.27, 157.18. Anal. Calcd for C23H20N4O: C,
74.98; H, 5.47; Cl, 15.21; N, 16.59. Found: C, 74.91; H, 5.41; Cl, 15.12; N,
16.55.
4-[2-(2,6-Dichlorophenyl)imidazo[4,5-b]indol-3(4H)-yl]phenol (20b)
White crystals. 1H-NMR (CDCl3-d6, ppm) d: 7.01—8.12 (11H, m, Ar-H),
8.76 (1H, s, OH), 9.76 (1H, bs, NH, D2O exchangeable). 13C-NMR d: 111.6,
116.1 (2C), 118.8, 120.6 (2C), 122.2, 123.2 (2C), 124.0, 126.9 (2C), 129.7,
130.9, 133.9 (2C), 134.8, 135.7, 137.1, 144.2, 156.9. IR (KBr) cmꢂ1: 3434
(O–H), 3321 (N–H), 3056 (C–H), 1578 (CꢅN), 1525 (CꢅC), 1234 (C–N),
1167 (C–Cl). MS (m/z): 393.50, 394 (MꢃH)ꢃ, 325.37, 302.17, 157.18,
146.92. Anal. Calcd for C21H13Cl2N3O: C, 63.98; H, 3.32; Cl, 17.98; N,
10.66. Found: C, 63.90; H, 3.23; Cl, 17.81; N, 10.55.
(C–H), 1695 (CꢅO), 1545 (CꢅN), 1503 (CꢅC), 1234 (C–N). MS (m/z):
383.60, 383 (MꢂH)ꢂ, 353.39, 277.29, 263.30, 157.18, 122.13. Anal. Calcd
for C22H17N5O2: C, 68.92; H, 4.47; N, 18.27. Found: C, 68.78; H, 4.53; N,
18.20.
N-[2-(4-Chlorophenyl)imidazo[4,5-b]indol-3(4H)-yl]isonicotinamide
(12b) Redish white crystals. 1H-NMR (CDCl3-d6, ppm) d: 7.11—8.19
(12H, m, Ar-H), 9.01 (1H, bs, NH, D2O exchangeable), 10.34 (1H, bs, NH,
D2O exchangeable). 13C-NMR d: 111.3, 118.7, 120.3 (2C), 122.5, 122.9
(2C), 124.5, 128.9, 129.1, 129.5 (2C), 134.6, 135.1, 136.4, 136.8, 140.7
(2C), 149.5 (2C), 166.4. IR (KBr) cmꢂ1: 3390 (N–H), 3032 (C–H), 1701
(CꢅO), 1565 (CꢅN), 1515 (CꢅC), 1223 (C–N); 705 (C–Cl). MS (m/z):
386.70, 387 (MꢃH)ꢃ, 353.39, 277.29, 267.72, 157.18, 122.13. Anal. Calcd
for C21H14ClN5O: C, 65.04; H, 3.64; Cl, 9.14; N, 18.06. Found: C, 65.14; H,
3.66; Cl, 9.21; N, 18.11.
N-[2-(4-Nitrophenyl)imidazo[4,5-b]indol-3(4H)-yl]isonicotinamide
1
Antibacterial Studies The synthesized imidazole derivatives were
screened for their antibacterial activity against two gram positive bacterial
strains B. subtilis (NCIM 2063), S. aureus (NCIM 2079) and two gram neg-
ative bacterial strains K. pneumonia (NCIM 2087), E. coli (NCIM 2065) by
using modified Kirby–Bauer disc diffusion method.27,28) Minimum in-
hibitory concentration (MIC) values of test compounds were determined by
tube dilution technique.29) All the synthesized compounds were dissolved
separately to prepare a stock solution of 1 mg mlꢂ1 using N,N-dimethylfor-
mamide (DMF). Stock solution was aseptically transferred and suitably di-
luted with sterile broth medium to have seven different concentrations of
each test compound ranging from 200 to 3.1 mg mlꢂ1 in different test tubes.
All the tubes were inoculated with one loopful of one of the test bacteria.
The process was repeated with different test bacteria and different samples.
Tubes inoculated with bacterial cultures were incubated at 37 °C for 18 h and
the presence/absence of growth of the bacteria was observed. From these re-
sults, MIC of each test compound was determined against each test bac-
terium. A spore suspension in sterile distilled water was prepared from 5-d-
old culture of the test bacteria growing on nutrient broth media. About 20 ml
of the growth medium was transferred into sterilized petri plates and inocu-
lated with 1.5 ml of the spore suspension (spore concentration 6ꢆ104 spores
mlꢂ1). Filter paper disks of 6 mm diameter and 2 mm thickness were steril-
ized by autoclaving at 121 °C (15 psi) for 15 min. Each petri plate was di-
vided into five equal portions along the diameter to place one disc. Three
discs of test sample were placed on three portions together with one disc
with reference drug ciprofloxacin and a disk impregnated with the solvent
(DMF) as negative control. Test sample and reference drugs were tested at
the concentration of 10 mg mlꢂ1. The petri plates inoculated with bacterial
cultures were incubated at 37 °C for 18 h. Diameters of the zones of inhibi-
tion (mm) were measured and the average diameters for test sample were
calculated in triplicate sets. The diameters obtained for the test sample were
compared with that produced by the standard drug ciprofloxacin.
Anticancer Activity Anticancer activities of the synthesized com-
pounds were assessed by determining the percentage inhibition of EAC cells
by tryphan blue dye exclusion technique according to the standard proce-
dure.30—32) We checked anticancer activity of all the synthesized compounds
at the concentration of 500, 250, 125, 62.5, 31.25 mg/ml. The percentage
growth inhibition was calculated by using the following formula: % growth
inhibitionꢅ[(total cellsꢂlive cells)ꢆ100]/total cells.
The CTC50 values were calculated by plotting the graph between concen-
tration versus percentage growth inhibition and by bisecting concentration at
the 50% growth inhibition. The synthesized aryl imidazoles and their CTC50
values are as shown in Table 1. Cyclophosphamide was used as standard
drug (CTC50, 12 mg/ml).
Anthelmintic Studies Anthelmintic activity studies were carried out
against two different species of earthworms M. konkanensis (ICARBC 211)
and P. corethruses (ICARBC 408) by Garg and Atal method33) at 2 mg mlꢂ1
concentration. Suspensions of samples were prepared by triturating synthe-
sized compounds (100 mg) with Tween 80 (0.5%) and distilled water and the
resulting mixtures were stirred using a mechanical stirrer for 30 min. The
suspensions were diluted to contain 0.2% w/v of the test samples. Suspen-
sion of reference drug, mebendazole, was prepared with the same concentra-
tion in a similar way. Three sets of five earthworms of almost similar sizes (2
inch in length) were placed in Petri plates of 4 inch diameter containing
50 ml of suspension of test sample and reference drug at RT. Another set of
five earthworms was kept as control in 50 ml suspension of distilled water
and Tween 80 (0.5%). The paralyzing and death times were noted and their
mean was calculated for triplicate sets. The death time was ascertained by
placing the earthworms in warm water (50 °C) which stimulated the move-
ment, if the worm was alive.
(13b) Off white crystals. H-NMR (CDCl3-d6, ppm) d: 7.21—8.35 (12H,
m, Ar-H), 9.06 (1H, bs, NH, D2O exchangeable), 10.29 (1H, bs, NH, D2O
exchangeable). 13C-NMR d: 110.7, 118.5, 119.7 (2C), 120.9 (2C), 121.9,
123.0 (2C), 124.5, 128.9 (2C), 134.7, 135.5, 136.1, 136.9, 140.5, 147.9,
149.0 (2C), 164.4. IR (KBr) cmꢂ1: 3323 (N–H), 3031 (C–H), 1705 (CꢅO),
1556 (CꢅN), 1498 (CꢅC), 1230 (C–N). MS (m/z): 397.90, 398 (MꢃH)ꢃ,
353.39, 278.27, 277.29, 122.13. Anal. Calcd for C21H14N6O3: C, 63.31; H,
3.54; N, 21.10. Found: C, 63.19; H, 3.53; N, 21.20.
N-[2-[4-(Dimethylamino)phenyl]imidazo[4,5-b]indol-3(4H)-yl]isoni-
1
cotinamide (14b) Brown amorphous solid. H-NMR (CDCl3-d6, ppm) d:
2.32 [(6H, s, (CH3)2], 7.02—8.32 (12H, m, Ar-H), 8.95 (1H, bs, NH, D2O
exchangeable), 10.65 (1H, bs, NH, D2O exchangeable). 13C-NMR d: 38.6
(2C), 110.7, 114.9 (2C), 119.4, 119.9 (2C), 120.6, 121.9, 122.1 (2C), 123.6,
129.1 (2C), 135.7, 136.4, 136.9, 141.2, 148.6, 149.2 (2C), 165.3. IR (KBr)
cmꢂ1: 3353 (N–H), 3056 (C–H), 1701 (CꢅO), 1578 (CꢅN), 1520 (CꢅC),
1230 (C–N). MS (m/z): 395.86, 396 (MꢃH)ꢃ, 387.95, 339.40, 312, 309.05,
263, 156.92. Anal. Calcd for C23H20N6O: C, 69.68; H, 5.08; N, 21.20.
Found: C, 69.58; H, 5.03; N, 21.27.
N-[2-(2,6-Dichlorophenyl)imidazo[4,5-b]indol-3(4H)-yl]isonicotin-
amide (15b) Pale white crystals. 1H-NMR (CDCl3-d6, ppm) d: 7.16—8.33
(11H, m, Ar-H), 9.28 (1H, bs, NH, D2O exchangeable), 10.56 (1H, bs, NH,
D2O exchangeable). 13C-NMR d: 110.7, 118.6, 119.6 (2C), 121.8, 122.1
(2C), 124.0, 126.6 (2C), 130.8, 133.1 (2C), 135.1, 136.1, 136.9, 137.2,
139.5, 149.1 (2C), 167.1. IR (KBr) cmꢂ1: 3235 (N–H), 3050 (C–H), 1699
(CꢅO), 1563 (CꢅN), 1534 (CꢅC), 1227 (C–N), 671 (C–Cl). MS (m/z):
421.90, 422 (MꢃH)ꢃ, 353.39, 302.17, 277.29, 157.18, 122.13. Anal. Calcd
for C21H13Cl2N5O: C, 59.73; H, 3.10; Cl, 16.79; N, 16.59. Found: C, 59.68;
H, 3.13; Cl, 16.61; N, 16.55.
4-[2-(4-Methoxyphenyl)imidazo[4,5-b]indol-3(4H)-yl]phenol (16b)
White crystals. 1H-NMR (CDCl3-d6, ppm) d: 2.34 (3H, s, OCH3), 7.09—
8.18 (12H, m, Ar-H), 8.66 (1H, s, OH), 9.34 (1H, bs, NH, D2O exchange-
able). 13C-NMR d: 56.1, 110.9, 114.2 (2C), 117.1 (2C), 119.2, 120.4 (2C),
121.9, 122.8, 123.3 (2C), 124.5, 128.6 (2C), 129.5, 135.1, 135.9, 145.1,
158.5, 160.3. IR (KBr) cmꢂ1: 3435 (O–H), 3311 (N–H), 3034 (C–H), 1589
(CꢅN), 1551 (CꢅC), 1231 (C–N). MS (m/z): 354.60, 355 (MꢃH)ꢃ, 325.37,
263.30, 249.27, 157.18. Anal. Calcd for C22H17N3O2: C, 74.35; H, 4.82; N,
11.82. Found: C, 74.45; H, 4.77; N, 11.76.
4-[2-(4-Chlorophenyl)imidazo[4,5-b]indol-3(4H)-yl]phenol (17b)
Bright yellow amorphous solid. 1H-NMR (CDCl3-d6, ppm) d: 7.01—8.05
(12H, m, Ar-H), 8.74 (1H, s, OH), 9.43 (1H, bs, NH, D2O exchangeable).
13C-NMR d: 110.7, 117.1 (2C), 118.5, 120.6 (2C), 122.0, 123.1 (2C), 124.8,
127.9, 128.3 (2C), 129.0 (2C), 130.4, 134.6, 135.9, 136.7, 144.3, 160.0. IR
(KBr) cmꢂ1: 3454 (O–H), 3391 (N–H), 3095 (C–H), 1556 (CꢅN), 1501
(CꢅC), 1252 (C–N); 697 (C–Cl). MS (m/z): 358.75, 359 (MꢃH)ꢃ, 325.37,
267.72, 249.27, 112.56. Anal. Calcd for C21H14ClN3O: C, 70.10; H, 3.92; Cl,
9.85; N, 11.68. Found: C, 69.98; H, 3.83; Cl, 9.79; N, 11.55.
4-[2-(4-Nitrophenyl)imidazo[4,5-b]indol-3(4H)-yl]phenol (18b)
White crystals. 1H-NMR (CDCl3-d6, ppm) d: 7.13—8.24 (12H, m, Ar-H),
8.58 (1H, s, OH), 9.65 (1H, bs, NH, D2O exchangeable). 13C-NMR d: 111.3,
115.6 (2C), 118.7, 120.0 (2C), 120.9 (2C), 122.6, 123.2 (2C), 124.6, 129.1
(2C), 130.6, 134.9, 136.1, 136.9, 145.0, 148.4, 156.7. IR (KBr) cmꢂ1: 3419
(O–H), 3364 (N–H), 3042 (C–H), 1590 (CꢅN), 1531 (CꢅC), 1245 (C–N).
MS (m/z): 369.68, 370 (MꢃH)ꢃ, 325.37, 278.27, 249.27, 157.12. Anal.
Calcd for C21H14N4O3: C, 68.10; H, 3.81; N, 15.13. Found: C, 68.20; H,
3.83; N, 15.24.
4-[2-[4-(Dimethylamino)phenyl]imidazo[4,5-b]indol-3(4H)-yl]phenol
(19b) White amorphous solid. 1H-NMR (DMSO-d6, ppm) d: 2.65 [(6H, s,
(CH3)2], 7.19—8.45 (12H, m, Ar-H), 8.67 (1H, s, OH), 9.89 (1H, bs, NH,
D2O exchangeable). 13C-NMR d: 38.5 (2C), 110.7, 113.9 (2C), 116.1 (2C),

380
Antitubercular Activity Middlebrook (MB) 7H10 agar medium was
Vol. 58, No. 3
(1996).
used for testing of antitubercular activity of the compounds. Culture of M.
tuberculosis H37Rv grown on Lowenstein–Jensen (L–J) was harvested in
16) Weinmann H., Harre M., Koeing K., Merten E., Tilstam U., Tetrahe-
dron Lett., 43, 593—595 (2002).
saline containing 0.05% Tween-80 and used according to the standard proce- 17) Balalaie S., Arabanian A., Green Chem., 2, 274—276 (2000).
dure.34,35) The minimum concentration of the drug or compounds that com-
pletely inhibited the growth of different mycobacterium was recorded as
minimum inhibitory concentration (MIC) with respect to the used inoculum.
The MIC for test compounds was performed up to 25 mg/ml concentrations.
Isoniazid (INH) was used as a standard drug (MIC, 21 mg/ml).
18) Wolkenberg S. E., Wisnoski D. D., Leister W. H., Wang Y., Zhao Z.,
Lindsley C. W., Org. Lett., 6, 1453—1456 (2004).
19) Usyatinsky A. Y., Khemelnitsky Y. L., Tetrahedron Lett., 41, 5031—
5034 (2000).
20) Kawase M., Saito S., Kurihara T., Chem. Pharm. Bull., 49, 461—464
(2001).
Acknowledgements The authors are thankful to the Head, University 21) Raghavendra N. M., Thampi P., Gurubasavarajaswamy P. M., Sriram
Science Instrumentation Centre, Delhi University, Delhi for providing 1H-
D., Chem. Pharm. Bull., 55, 1615—1619 (2007).
NMR and mass spectrum studies. We are also thankful to Head, C.P.C.R.I., 22) Bhaskar V. H., Puli K., Sangameswaran B., Jayakar B., Ind. J. Hetro-
Kasaragod, Kerala for providing earthworms for testing anthelmintic activ-
ity.
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23) Balalaie S., Hashemi M. M., Akhbari M., Tetrahedron Lett., 44,
1709—1711 (2003).
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