Synthesis and pharmacological evaluation of novel 1-(piperidin-4-yl)-1H- benzo[d]imidazol-2(3H)-one derivatives as potential antimicrobial agents

Article abstract of DOI:10.1007/s00044-013-0799-6

Novel compounds of biological interest were synthesized by in situ reduction of Schiff's base of 5,6-dimethoxy indanone and 1-(piperidin-4-yl)-1H- benzo[d] imidazol-2(3H)-one in the presence of Ti(OiPr)₄ and NaBH₃CN. Further alkylation using different alkyl/aryl halides in the presence of NaH in DMF gave a series of novel compounds. A formation of newly synthesized compounds was confirmed on the basis of their spectral and elemental analysis. Further these compounds were screened for their antimicrobial activity and found to have promising antibacterial and antifungal activity. Springer Science+Business Media 2013.

Full text of DOI:10.1007/s00044-013-0799-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:2133–2139
DOI 10.1007/s00044-013-0799-6
ORIGINAL RESEARCH
Synthesis and pharmacological evaluation of novel 1-(piperidin-
4-yl)-1H-benzo[d]imidazol-2(3H)-one derivatives as potential
antimicrobial agents
•
•
•
Vimal Patel Nilay Bhatt Pralav Bhatt
H. D. Joshi
Received: 23 February 2013 / Accepted: 17 September 2013 / Published online: 9 October 2013
Ó Springer Science+Business Media New York 2013
Abstract Novel compounds of biological interest were
synthesized by in situ reduction of Schiff’s base of 5,6-
dimethoxy indanone and 1-(piperidin-4-yl)-1H-benzo[d]
imidazol-2(3H)-one in the presence of Ti(OiPr)4 and
NaBH3CN. Further alkylation using different alkyl/aryl
halides in the presence of NaH in DMF gave a series of
novel compounds. A formation of newly synthesized
compounds was confirmed on the basis of their spectral and
elemental analysis. Further these compounds were
screened for their antimicrobial activity and found to have
promising antibacterial and antifungal activity.
Introduction
Benzimidazoles are extremely prevalent in pharmaceuti-
cals (Kleemann et al., 1999). Two of the top 25 selling
drugs, esomeprazole and lansoprazole, contain the benz-
imidazole core structure. Benzimidazolone derivatives
have been found to exhibit anti-HIV (Barreca et al.,
2007), antitrichinellosis (Mavrova et al., 2005), antinoci-
ceptive (Nacak et al., 1999), antitumor activities (Kho-
darahmi et al., 2005), and other pharmacological
activities. For instance, it has been reported in recent
literature that benzimidazolone bearing a sugar or piper-
idine residue on the aromatic nitrogen effectively inhibits
the growth of bacteria (Vora et al., 2010 and Messaoudi
et al., 2004).
Keywords 1-(Piperidin-4-yl)-1H-benzo[d]
imidazol-2(3H)-one Á 5,6-Dimethoxy indanone Á
In situ reduction of Schiff’s base Á Antimicrobial agents
Benzimidazolone containing Piperidine nucleus is a
constituent of many bioactive heterocyclic compounds
that are of wide interest because of their diverse bio-
logical and clinical applications (Kleemann et al.,
1999). They exhibit a wide variety of interesting bio-
chemical and pharmacological properties including CNS-
inhibitors and anti-inflammatory agents (Yoshinao et al.,
1978), for inhibiting emesis or mental disorders
(Raymond et al., 1996), ORL1-receptor agonists,
antimuscarinic agents (Ito et al., 2000), treatment of
glaucoma (Wayne et al., 1998), selective NOP antago-
nist (Kawamoto et al., 1999), treatment of obesity
(Lynch et al., 2005), and treatment of type 2 diabetes
(Liang et al., 2006). In hope to synthesize novel
potential antimicrobial derivatives using backbone of
Domperidone which itself is an active API (anti-emetic
drug), 1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one,
a series of 5-chloro-3-(1-(5,6-dimethoxy-2,3-dihydro-1H-
inden-1-yl)piperidin-4-yl)-1-alkyl-1H-benzo[d]imidazol-
2(3H)-ones are prepared.
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-013-0799-6) contains supplementary
material, which is available to authorized users.
V. Patel (&) Á H. D. Joshi
Department of Chemistry, Saurashtra University, Rajkot,
Gujarat, India
e-mail: drvimalpatel@rediffmail.com
N. Bhatt
JJT University, Jhunjhunu, Rajasthan, India
P. Bhatt
School of Chemistry, University of KwaZulu-Natal, Westville
Campus, Durban, South Africa
123

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Med Chem Res (2014) 23:2133–2139
Benzimidazolone containing piperidine-based drug
O
O
N
N
N
N
F
F
N
N
N
O
O
O
N
H
N
H
N
H
Droperidol
Oxatomide
Benperidol
(neuroleptanesthesia)
(antiallergic)
(neuroleptic)
F
O
NH
N
N
N
F
N
N
O
O
N
H
N
H
l
C
Pimozide
(neuroleptic)
Domperidone
(anti-emetic)
Antimicrobial study
Experimental
The in vitro antimicrobial activity of the compounds 4a–
4m were studied by disk agar diffusion technique at a
different concentration 50 mg/mL using Dimethylform-
amide as solvent. The specific bacterial culture was
spread uniformly over nutrient agar in Petri plates. Then
the test solution, standard, and control of known similar
concentrations were spotted in sample wells at specific
distance. The zones of inhibition were measured after
24 h. The in vitro antibacterial activity was performed
against Gram-positive bacteria including Staphylococcus
aureus (MTCC 96), Streptococcus pyogenes (MTCC 442)
and Gram negative bacteria including Escherichia coli
(MTCC 443) and Pseudomonas aeruginosa (MTCC 424).
Yeast including Candida albicans (MTCC 227) and fungi
Aspergillus clavatus (MTCC 1323) were used to test
antifungal activity. Known antibiotics like Ampicillin and
Chloramphenicol (the reference antibacterial drugs) and
Fluconazole (the reference antifungal drug) were used for
comparison. The antimicrobial activities are summarized
in Table 1.
Reagents, instrumentation and measurements
Melting points were determined in open capillary tubes and
are uncorrected. NMR was recorded either in CDCl3 or
DMSO-d6 on a Bruker Avance 400 MHz and signal is
given in ppm (d) relative to TMS. Elementary analyses
were taken on Euro EA 3000 elementary analysis instru-
ment. LCMS were measured on Agilent 1100 Series MS
spectrometer. MS were measured on a Waters ZQ 2000
spectrometer. All the solvent and materials are reagent
grades and purified before use. Log P were calculated by
Chembiodraw. Purity of all reagents and products were
checked by TLC (hexane: ethylacetate; 70:30).
5,6-Dimethoxy-1-indanone1 was prepared according to
the literature procedure (Haadsma-Svensson et al., 2001) in
60.0 % overall yield based on 3,4-dimethoxybenzaldehyde
purity was confirmed by TLC and mp. 5-Chloro-1-(piper-
idin-4-yl)-1H-benzo[d]imidazol-2(3H)-one2 was obtained
from Galaxy PharmaChem (Vadodara,Gujarat,India). Its
purity was confirmed by TLC and mp.
123

Med Chem Res (2014) 23:2133–2139
2135
Reaction scheme
3
O
O
O
O
H
N
O
N
N
i
r
(
)
,
NaBH
Ti P 4
O
3CN
O
RX, NaH
DMF, RT
N
O
THF, Reflux 36 Hrs
O
N
N
N
N
l
C
H
O
O
N
H
l
C
l
C
R
2
1
3
4a-4m
Synthesis of 5-chloro-1-(1-(5,6-dimethoxy-2,3-dihydro-
1H-inden-1-yl)piperidin-4-yl)-1H-benzo[d]imidazol-
2(3H)-one (3)
ethanol, the filtrate was evaporated, and the residue was
purified by chromatography on silica gel (hexane/ethyl-
acetate 3–8 %) to yield a beige solid; (10.7 g, 48 %): mp
1
229–231 °C; H NMR (CDCl3, 400 MHz): d = 10.1 (s, 1
A solution of 10.0 g (0.052 mol) 5,6-dimethoxy-1-inda-
none, 13.1 g (0.052 mol) 5-chloro-1-(piperidin-4-yl)-1H-
benzo[d]imidazol-2(3H)-one, and 26.0 g (0.067 mol)
titanium(IV) isopropoxide in 400 mL THF was stirred for
18 h at reflux temperature. Sodium cyanoborohydride
3.27 g (0.052 mol) was added at room temperature with
stirring, again reflux was continued for 20 h. Water
(200 mL) was added, and the mixture was filtered through
Celite. The filter cake was washed thoroughly with
H, NH), 7.34 (s, 1 H, ArH), 7.2 (d, 1 H, ArH), 7.15–6.9
(d, 1 H, ArH), 6.7 (dd 1 H, ArH), 4.4 (m, 1 H, CH), 4.25
(t, 1 H, indane CH), 3.85 (s, 6 H, 2OCH3),2.9–2.85 (t, 2
H, indane CH2), 2.6–2.5 (t, 2 H, CH2), 2.4 (m, 2 H,
indane CH2), 2.3 (m, 2 H, CH2), 2.1–2.0 (m, 2 H, indane
CH2), 1.9–1.8 (m, 2 H, CH2) ppm;ESI MS: m/z 427.8
(M?); Anal. Calcd. for C23H26ClN3O3: C, 64.55; H,6.12;
Cl,8.28; N,9.82; O,11.22; Found: C, 64.86; H, 6.78; N,
9.35.
Table 1 Antibacterial and antifungal activity of novel compounds at concentration 50 mg/mL in DMF (4a–m)
Compound no.
Zone diameter of growth inhibition in mm
Antibacterial activity
Antifungal activity
Gram ?ve
Gram -ve
C. albicans
A clavatus
S. aureus
S. pyrogenes
E. coli
P. aeruginosa
4a
19
13
15
12
10
11
17
13
14
11
20
18
13
18
21
–
16
11
14
12
13
10
09
11
16
14
11
16
18
19
20
–
13
19
11
13
14
11
19
17
12
15
13
10
14
20
23
–
10
09
11
12
15
13
09
10
11
13
08
11
16
20
21
–
19
18
19
17
24
25
16
17
15
07
10
17
18
–
18
25
24
14
15
17
19
22
14
21
11
13
10
–
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
Ampicillin
Chloramphenicol
Fluconazole
–
–
24
24
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Med Chem Res (2014) 23:2133–2139
General procedure for 5-chloro-1-(1-(5,6-dimethoxy-2,3-
dihydro-1H-inden-1-yl)piperidin-4-yl)-3-alkyl-1H-
benzo[d]imidazol-2(3H)-one (4a–4m)
40 MHz): 152.9 (C-17), 148.7 (C-13), 147.8 (C-14), 135.2
(C-10,11), 130.3 (C-19), 126.9 (C-23), 125.0 (C-20), 120.2
(C-22), 109.8 (C-21), 108.2 (C-12), 108.0 (C-15), 107.9
(C-24), 69.2 (C-7), 55.7(C-28), 55.4 (C-26), 51.3 (C-4), 45.
2 (C-2,6), 41.8 (C-30), 30.4 (C-8), 29.1 (C-3,5), 21.0 (C-
31), 10.9 (C-32) ppm; TOF MS: m/z 470.003(M?); Anal.
Calcd. For C26H32ClN3O3: C,66.44;H,6.86;Cl,7.54;N,8.
94;O,10.21; Found: 66.50;H,6.90;N,8.90.
To the suspension of 1000 mg (2.34 mol) of 5-chloro-1-(1-
(5,6-dimethoxy-2,3-dihydro-1H-inden-1-yl)piperidin-4-
yl)-1H-benzo[d]imidazol-2(3H)-one 3, 1.2 equivalent
(2.34 mol) of the corresponding alkyl halide and 5.0 mL
DMF, 125 mg (2.57 mol) NaH (50 % suspension in min-
eral oil) was charged at room temperature, reaction was
stirred at room temperature for 15 h, and the mixture was
cooled to 10 °C. The mixture was quenched with 10 mL
water and extracted with 15 mL ethylacetate. Organic
phases were pooled, and dried with MgSO4, and the sol-
vents were removed in vacuo. The residue was purified by
chromatography on silica gel (ethyl acetate/hexane, 2–8 %)
to yield 4a–4m.
3-Butyl-5-chloro-1-(1-(5,6-dimethoxy-2,3-dihydro-1H-inden-
1-yl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (4c) White
powder, yield: 430 mg (38.02 %); mp 139–140 °C; 1H
NMR (400 MHz, CDCl3):d = 7.32 (s, 1 H, ArH), 7.30–7.
28 (d, 1 H, ArH), 7.06–7.04 (d, 1 H, ArH), 6.85–6.81 (dd, 1
H, ArH), 4.30–4.27 (m, 1 H, CH), 4.12 (t, 1 H, indane CH),
3.81–3.72 (s, 6 H, 2OCH3), 3.58–3.54 (t, 2 H, CH2), 2.
95–2.84 (t, 2 H, indane CH2), 2.79–2.56 (t, 2 H, CH2), 2.
40–2.22 (m, 2 H, indane CH2), 2.04–2.02 (m, 2 H, CH2), 2.
01–1.99 (m, 2 H, CH2), 1.68–1.66 (m, 2 H, CH2), 0.89–0.
85 (t, 3 H, CH3) ppm; 13C NMR (CDCl3, 40 MHz):152.8
(C-17), 148.7 (C-13), 147.8 (C-14), 135.1 (C-10), 134.1
(C-11), 130.2 (C-19), 126.9 (C-23), 125.0 (C-20), 120.2
(C-22), 109.8 (C-21), 108.2 (C-12), 108.0 (C-15), 107.9
(C-24), 69.2 (C-7), 55.7 (C-28), 55.4 (C-26), 51.3 (C-4),
50.1 (C-2,6), 45.2 (C-30), 40.1 (C-8), 39.8 (C-9), 30.4 (C-
3,5), 29.7 (C-31), 19.3 (C-32), 13.5 (C-33) ppm;TOF MS:
m/z 484.030(M?); Anal. Calcd. For C27H34ClN3O3: C,67.
00;H,7.08;Cl,7.32;N,8.68;O,9.92; Found: C,67.03;H,7.
09;N,7.70.
Analytical data
5-Chloro-1-(1-(5,6-dimethoxy-2,3-dihydro-1H-inden-1-
yl)piperidin-4-yl)-3-ethyl-1H-benzo[d]imidazol-2(3H)-one
(4a) Off-white powder; yield: 200 mg (18.77 %); mp
149–151 °C; 1H NMR (CDCl3, 400 MHz): d = 7.63 (s,
J = 2.1 Hz, 1 H, ArH), 7.60–7.58 (d, 1 H, ArH), 6.95–6.93
(d, J = 2.0, 8.3 Hz, 1 H, ArH), 6.67–6.65 (d, 1 H, ArH), 4.
20–4.14 (m, 1 H, CH), 4.03–3.97 (t, 1 H, indane CH), 3.84
(s, 6 H, 2OCH3), 3.75 (m, 2 H, CH2), 2.92 (t, 2 H, CH2), 2.
83–2.70 (m, 3 H, indane CH2), 2.61–2.54 (m, 2 H, CH2), 2.
35–2.25 (m, 1 H, CH), 2.19–2.13 (m, 2 H, CH2), 2.00 (ddd,
J = 3.5, 7.1, 8.0 Hz, 1 H, CH), 1.90–1.81 (m, 2 H, CH2),
1.20 (t, J = 6.9 Hz, 3 H, CH3) ppm; 13C NMR (CDCl3,
40 MHz): d = 154.3 (C-17), 148.0 (C-13,14), 137.4 (C-
10), 136.6 (C-11), 131.4 (C-19), 129.3 (C-20), 128.0 (C-
23), 122.3 (C-22), 111.2 (C-21), 109.0 (C-12), 108.1 (C-
24), 108.0 (C-15), 68.9 (C-7), 56.2 (C-28), 56.0 (C-26), 53.
8 (C-4), 49.8 (C-2,6), 38.0 (C-30), 32.1 (C-8), 31.6 (C-9),
29.7 (C-3,5), 13.5 (C-31) ppm; TOF MS: m/z 456.97 (M?);
Anal. Calcd. for C25H30ClN3O3: C,65.85; H,6.63; Cl,7.78;
N,9.22; O,10.53; Found: C, 65.86; H, 6.78; N, 9.25.
5-Chloro-1-(1-(5,6-dimethoxy-2,3-dihydro-1H-inden-1-yl)
piperidin-4-yl)-3-isobutyl-1H-benzo[d]imidazol-2(3H)-one
(4d) Off-white powder, yield: 290 mg (25.59 %); mp
137–139 °C, 1H NMR (400 MHz CDCl3):d = 7.67 (s, 1
H, ArH), 7.60–7.58 (d, 1 H, ArH), 6.91–6.90 (d, 1 H, ArH),
6.67–6.66 (dd, 1 H, ArH), 4.19–4.13 (m, 1 H, CH), 4.03–3.
98 (t, 1 H, indane CH), 3.84–3.78 (s, 6 H, 2OCH3), 3.57–3.
58 (d, 2 H, CH2), 2.96–2.88 (t, 2 H, indane CH2),2.76–2.55
(t, 2 H, CH2), 2.36 – 2.25 (m, 2 H, indane CH2), 2.20–2.14
(m, 2 H, CH2), 2.10–2.03 (m, 1 H, CH), 2.0–1.93 (m, 2 H,
CH2), 1.88–1.80 (m, 2 H, CH2), 0.94–0 0.92 (d, 3 H,
2CH3) ppm; 13C NMR (CDCl3, 40 MHz): 152.8 (C-17),
148.7 (C-13), 147.8 (C-14), 135.1 (C-10), 134.1 (C-11),
130.2 (C-19), 126.9 (C-23), 125.0 (C-20), 120.2 (C-22),
109.8 (C-21), 108.2 (C-12), 108.0 (C-15), 107.9 (C-24), 69.
2 (C-7), 55.7 (C-28), 53.8 (C-4), 49.8(C-2,6),32.0 (C-8),
31.6 (C-9), 29.7 (C-3,5), 27.5 (C-31), 20.10 (C-32,34) ppm;
TOF MS: m/z 484.11(M?); Anal. Calcd. For C27H34
ClN3O3: C,67.00;H,7.08;Cl,7.32;N,8.68;O,9.92; Found:
C,67.03;H,7.09;N,8.70.
5-Chloro-1-(1-(5,6-dimethoxy-2,3-dihydro-1H-inden-1-yl)
piperidin-4-yl)-3-propyl-1H-benzo[d]imidazol-2(3H)-one
(4b) White Powder; yield: 240 mg (24.13 %); mp 108–
110 °C; 1H NMR (400 MHz, CDCl3):d = 7.35 (s, 1 H,
ArH), 7.34–7.29 (d, 1 H, ArH), 7.07 (d, 1 H, ArH), 6.85– 6.
82 (dd, 1 H, ArH), 4.3–4.27 (m, 1 H, CH), 4.13 (t, 1 H,
indane CH), 3.76–3.72 (s, 6 H, 2-OCH3), 3.71 (t, 2 H,
CH2), 2.96–2.8 (t, 2 H, indane CH2), 2.78–2.56 (t, 4 H,
2CH2), 2.40–2.22 (m, 2H, indane CH2), 2.05 (m, 4 H,
CH2), 2.00 (ddd, 2 H, indane CH2), 1.69–1.66 (m, 2 H,
CH2), 0.86–0.82 (t, 3 H, CH3) ppm; 13C NMR (CDCl3,
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2137
5-Chloro-1-(1-(5,6-dimethoxy-2,3-dihydro-1H-inden-1-yl)
piperidin-4-yl)-3-(methoxymethyl)-1H-benzo[d]imidazol-
2(3H)-one (4e) Cream powder, yield: 240 mg (22.64 %);
mp 125–126 °C, 1H NMR (400 MHz, CDCl3):d = 7.85
(s, 1 H, ArH), 7.79–7.77 (d, 1 H, ArH), 6.93–6.90 (d, 1 H,
ArH), 6.67–6.66 (dd, 1H, ArH), 5.07 (s, 2 H, CH2), 4.17–4.
13 (m, 1 H, indane CH), 4.03–3.97 (t, 1 H, indane CH), 3.
84–3.78 (s, 6 H, 2OCH3), 3.52 (s, 3 H, CH3), 2.94–2.77 (t,
2 H, indane CH2), 2.76–2.55 (t, 2 H, CH2), 2.36–2.25 (m, 2
H, indane CH2), 2.19–2.13(m,2H,CH2), 2.02–1.93
(m,2H,indane CH2), 1.89–1.81 (m, 2 H, CH2) ppm; 13C
NMR (CDCl3, 40 MHz):152.9 (C-17), 148.7 (C-13), 147.8
(C-14), 135.7 (C-10), 135.2 (C-11), 134.1 (C-19), 132.1
(C-23), 129.8 (C-20), 129.2, 128.6, 127.0, 125.1(C-22),
120.7(C-21), 110.1 (C-12), 108.2 (C-24), 107.9 (C-15), 69.
2 (C-7), 55.7 (C-32), 55.4 (C-26), 51.5 (C-4), 50.1 (2,6),
38.8 (C-8), 30.4 (C-9), 29.1 (C-3,5) ppm, TOF MS: m/
z 472.2(M?); Anal. Calcd. For C25H30ClN3O4: C,63.
62;H,6.41;Cl,7.51;N,8.90;O, 13.56; Found: C,6368;H,6.
52;N,8.88.
00 (m, 2 H, indane CH2), 1.98–1.65 (m, 2 H, CH2) ppm;
13C NMR (CDCl3, 40 MHz):152.9 (C-17), 148.7 (C-13),
147.8 (C-14), 135.7 (C-10), 135.2 (C-11), 134.1 (C-31),
132.1 (C-34), 129.8 (C-19), 129.2 (C-32,36), 128.6 (C-23),
127.0 (C-20), 125.1 (C-33,35), 120.7 (C-22), 110.1 (C-21),
108.2 (C-12), 107.9 (C-24,15), 69.2 (C-7), 55.7 (C-28), 55.
4 (C-26), 51.5 (C-4), 50.1 (C-2,6), 45.2 (C-30), 30.4 (C-
8,9), 29.1 (C-3,5) ppm; TOF MS: m/z 552.16(M?); Anal.
Calcd. For C30H31Cl2N3O3: C, 65.22; H, 5.66; Cl, 12.83;
N, 7.61; O, 8.69; Found: C, 65.15; H, 5.82; N, 7.5.
5-Chloro-1-(1-(5,6-dimethoxy-2,3-dihydro-1H-inden-1-yl)
piperidin-4-yl)-3-(4-nitrobenzyl)-1H-benzo[d]imidazol-2(3H)-
one (4h) Cream powder, yield: 220 mg (16.72 %); mp
106–108 °C, 1H NMR (CDCl3, 400 MHz):d = 8.28–8.26
(d, 1 H, ArH), 7.61 (s, 1 H, ArH), 7.44–7.42 (d, 1 H, ArH),
7.38 (d, 1 H, ArH), 7.17–7.15 (d, 1 H, ArH), 6.93–6.89 (dd,
1H, ArH), 5.27 (s, 2 H, CH2), 4.38–4.35 (m, 1 H, CH), 4.25
(t, 1 H, indane CH), 3.82–3.79 (s, 6H, 2OCH3), 2.91–2.87
(t, 2 H, indane CH2), 2.85–2.79 (t, 2 H, indane CH), 2.
77–2.65 (t, 2 H, CH2), 2.50–2.48 (m, 2 H, indane CH2), 2.
34–2.15 (m, 2 H, CH2), 2.12–2.09 (m, 2 H, indane CH2), 2.
06–1.74 (m, 2 H, CH2) ppm; 13C NMR (CDCl3, 40 MHz):
152.9 (C-17), 148.7 (C-13), 147.8 (C-14), 146.9 (C-34),
144.4 (C-31), 135.2 (C-10), 129.8 (C-11), 128.3 (C-19),
127.1 (C-23), 125.2 (C-20), 123.8 (C-32,36), 120.8 (C-
33,35), 110.2 (C-22),111.01 (C-21), 108.2 (C-12),108.8 (C-
24), 107.9 (C-15), 69.2 (C-7), 55.7 (C-28), 55.4 (C-26), 51.
6 (C-4), 50.1 (C-2,6), 43.1 (C-30), 30.6 (C-8), 30.4 (C-9),
29.0 (C-3,5) ppm; TOF MS: m/z 563.0(M?); Anal. Calcd.
For C30H31ClN4O5:C, 64.00; H, 5.55; Cl, 6.30; N, 9.95; O,
14.21; Found: C, 64.80; H, 5.68; N, 9.96.
3-Benzyl-5-chloro-1-(1-(5,6-dimethoxy-2,3-dihydro-1H-inden-
1-yl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (4f) Off
white, yield: 300 mg (24.78 %); mp 172–174 °C, 1H NMR
(400 MHz,CDCl3):d = 7.34 (s, 1 H, ArH), 7.31–7.30 (d, 1
H, ArH), 7.28 (d, 1 H, ArH), 7.27(d, 1 H, ArH), 7.25 (t, 1
H, ArH), 7.22(t, 1 H, ArH), 7.07–7.05 (d, 1 H, ArH), 6.
86–6.82 (dd, 1 H, ArH), 5.03 (s, 2 H, CH2), 4.31–4.28 (m,
1 H, CH), 4.17 (t, 1 H, indane CH), 3.75–3.72 (s, 6 H,
2OCH3), 2.94–2.88 (t, 2 H, CH2), 2.75–2.58(t, 2 H, CH2),
2.43–2.27 (m, 2 H, indane CH2), 2.25–2.05 (m, 2 H, CH2),
2.03–2.00 (m, 2 H, indane CH2), 1.98–1.73 (m, 2 H, CH2),
1.64 (m, 2 H, CH2) ppm; 13C NMR (CDCl3, 40 MHz):
153.0 (C-17), 148.7 (C-13), 147.8 (C-14), 136.6 (C-10),
135.2 (C-11), 134.1 (C-31), 129.9 (C-19), 128.6 (C-23),
127.4 (C-20), 127.2 (C-33,35), 127.0 (C-34), 125.0 (C-22),
120.5 (C-21), 110.0 (C-12), 108.2 (C-24), 107.9 (C-15), 69.
2 (C-7), 55.7 (C-28), 55.4 (C-26), 51.5 (C-4), 50.1 (C-2,6),
45.2 (C-30), 30.4 (C-8), 29.1 (C-9), 29.0 (C-3,5) ppm, TOF
MS: m/z 518.10(M?); Anal. Calcd. For C30H32ClN3O3: C,
69.55; H, 6.23; Cl, 6.84; N, 8.11; O, 9.27; Found: C, 69.45;
H, 6.14; N, 8.23.
Ethyl 2-(6-chloro-3-(1-(5,6-dimethoxy-2,3-dihydro-1H-inden-
1-yl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-
1-yl)acetate (4i) Off white, yield: 220 mg (18.32 %); mp
208–210 °C, 1H NMR (400 MHz CDCl3):d = 7.38 (d, 1
H, ArH), 7.35–7.33 (s, 1 H, ArH), 7.11–7.09 (d, 1 H, ArH),
6.87–6.83 (dd, 1 H, ArH), 4.70 (s, 2 H, CH2), 4.20–4.60
(m, 1 H, CH), 4.12–4.06 (m, 2 H, CH2), 4.02–3.98 (t, 1 H,
indane CH), 3.84 (s, 6H, 2OCH3), 2.94–2.88 (t, 2 H, in-
dane CH2), 2.82–2.77 (t, 2 H, CH2), 2.76–2.71 (t, 2 H,
CH2), 2.33–2.26 (m, 2 H, indane CH2), 2.22–2.14 (m, 2 H,
CH2), 2.02–1.92 (m, 2 H, CH2), 1.9–1.82 (m, 2 H, CH2),
1.32–1.28 (t, 3 H, CH3) ppm; 13C NMR (CDCl3,
40 MHz):167.9 (C-31), 152.8 (C-17), 147.8 (C-13,14),
137.3 (C-10,11) 131.54 (C-19),131.06 (C-23),130.2 (C-20),
122.2 (C-22), 111.7 (C-21), 110.0 (C-12), 108.6 (C-15),
107.9 (C-24), 69.3 (C-7), 61.1 (C-33), 55.6 (C-28), 55.5 (C-
26), 53.7 (C-4), 49.75 (C-2,6),47.1 (C-30), 32.2 (C-8,9),
30.4 (C-3,5), 13.9 (C-34) ppm; TOF MS: m/z 514.22(M?);
Anal. Calcd. For C27H32ClN3O5:C,63.09;H,6.27;Cl,6.
90;N,8.17;O, 15.56; Found: C,63.18;H,6.36;N,8.25.
5-Chloro-3-(4-chlorobenzyl)-1-(1-(5,6-dimethoxy-2,3-dihydro-
1H-inden-1-yl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-
one (4g) Off-white powder, yield: 610 mg (47.27 %); mp
176–176.5 °C, 1H NMR (400 MHz,CDCl3):d = 7.40 (s, 1
H, ArH), 7.38–7.32 (d, 1 H, ArH), 7.08 (d, 1 H, ArH), 6.
98–6.85 (dd, 1 H, ArH), 6.82 (s, 1 H, ArH), 5.03 (s, 2 H,
CH2), 4.31–4.27 (m, 1 H, CH), 4.16 (t, 1 H, indane CH), 3.
75–3.72 (s, 6 H, 2OCH3), 2.94–2.80 (t, 3 H, indane CH2),
2.78–2.74 (t, 2 H, CH2), 2.72–2.57 (t, 2 H, CH2), 2.42–2.
37 (m, 2 H, indane CH2), 2.26–2.21 (m, 2H, CH2), 2.06–2.
123

2138
Med Chem Res (2014) 23:2133–2139
Ethyl 6-chloro-3-(1-(5,6-dimethoxy-2,3-dihydro-1H-inden-
1-yl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-
1-carboxylate (4j) Cream powder, yield: 300 mg (25.68 %
); mp 185–190 °C, 1H NMR (400 MHz CDCl3):d = 7.38
(d, 1 H, ArH), 7.35–7.33 (s, 1 H, ArH), 7.11–7.09 (d, 1 H,
ArH), 6.87–6.83 (dd, 1 H, ArH), 4.20–4.60 (m, 1 H, CH), 4.
12–4.06 (m, 2 H, CH2), 4.02–3.98 (t, 1 H, indane CH), 3.84
(s, 6H, 2OCH3), 2.94–2.88 (t, 2 H, indane CH2), 2.82–2.77
(t, 2 H, CH2), 2.76–2.71 (t, 2 H, CH2), 2.33–2.26 (m, 2 H,
indane CH2), 2.22–2.14 (m, 2 H, CH2), 2.02–1.92 (m, 2 H,
CH2), 1.9–1.82 (m, 2 H, CH2), 1.32–1.28 (t, 3 H, CH3)
ppm; 13C NMR (CDCl3, 40 MHz): 167.8 (C-30), 152.8 (C-
17), 147.75 (C-13,14), 137.3 (C-10,11) 131.46 (C-19),131.
01 (C-23),130.2 (C-20), 122.2 (C-22), 111.7 (C-21), 110.06
(C-12), 108.61 (C-15), 107.89 (C-24), 69.29 (C-7), 61.1 (C-
32), 55.6 (C-28), 55.5 (C-26), 53.7 (C-4), 49.75 (C-2,6), 32.2
(C-8,9), 30.4 (C-3,5), 13.96 (C-33) ppm;TOF MS: m/z 499.
98(M?); Anal. Calcd. For C26H30ClN3O5: C,62.46;H,6.
05;Cl,7.09;N,8.40;O, 16.00; found: C,62.55;H,6.15;N,8.45.
(C-22), 109.8 (C-21), 108.2 (C-12), 108.0 (C-24), 107.9
(C-15), 69.2 (C-7), 55.7 (C-28), 55.4 (C-26), 51.3 (C-4),
49.2 (C-2,6), 39.0 (C-31), 38.8 (C-30), 32.3 (C-8), 31.4 (C-
9), 29.1 (C-3,5) ppm; TOF MS: m/z 490.78 (M?); Anal.
Calcd. For C25H29Cl2N3O3:C,61.23;H,5.96;Cl,14.46;N,8.
57;O, 9.79; Found: C,61.50;H,5.72;N,8.67.
5-Chloro-1-(1-(5,6-dimethoxy-2,3-dihydro-1H-inden-1-yl)
piperidin-4-yl)-3-(3-(dimethylamino)propyl)-1H-benzo
[d]imidazol-2(3H)-one (4m) Off-white powder, yield:
300 mg (25.5 %); mp 185–190 °C, 1H NMR (400 MHz
CDCl3):d = 7.7 (s, 1 H, ArH), 7.61–7.57 (d, 1 H, ArH), 6.
93–6.91 (d, 1 H, ArH), 6.69–6.65 (dd, 1 H, ArH), 4.30–4.23 (m,
1 H, CH), 4.1–4.03 (t, 1 H, indane CH), 3.88–3.84 (s, 6 H,
2OCH3), 3.60–3.59 (d, 2 H, CH2), 3.55–3.53 (s, 1 H, 2NCH3),
3.00–2.96 (t, 2 H, indane CH2), 2.85–2.80 (t, 2 H, CH2), 2.
36–2.25 (m, 2 H, indane CH2), 2.11–2.00 (m, 2 H, CH2), 1.
96–1.93 (m, 2 H, CH2), 1.88–1.80 (m, 2 H, CH2) ppm; 13C
NMR (CDCl3, 40 MHz):152.8 (C-17), 148.7 (C-13), 147.8 (C-
14), 135.1 (C-10), 134.1 (C-11), 130.2 (C-19), 126.9 (C-23),
125.0 (C-20), 120.2 (C-22), 109.8 (C-21), 108.2 (C-12), 108.0
(C-15), 107.9 (C-24), 69.2 (C-7), 55.7 (C-28), 55.4 (C-26), 51.3
(C-4), 49.8 (C-2,6), 49.4 (C-30), 32.0 (C-8), 31.6 (C-3,5), 29.7
(C-31), 27.5 (C-32), 20.10 (C-34,36) ppm; TOF MS: m/z 513.
80 (M?); Anal. Calcd. ForC28H37ClN4O3:C,65.55;H,7.
27;Cl,6.91;N,10.92;O, 9.36; Found:C,65.67;H,7.10;N,10.95.
6-Chloro-3-(1-(5,6-dimethoxy-2,3-dihydro-1H-inden-1-yl)
piperidin-4-yl)-N,N-diethyl-2-oxo-2,3-dihydro-1H-
benzo[d]imidazole-1-carboxamide (4k) Off-white powder,
yield: 300 mg (26.12 %); mp 195–198 °C, 1H NMR
(400 MHz CDCl3):d = 7.35 (s, 1 H, ArH), 7.34–7.29 (d, 1
H, ArH), 7.07 (d, 1 H, ArH), 6.85–6.82 (dd, 1 H, ArH), 4.3–4.
27 (m, 1 H, CH), 4.13 (t, 1 H, indane CH), 3.76–3.72 (s, 6 H,
2OCH3), 3.71 (t, 2 H, CH2), 2.96–2.8 (t, 2 H, indane CH2),
2.78–2.56 (t, 4 H, 2CH2), 2.40–2.22 (m, 2H, indane CH2), 2.
05 (d, 2 H, CH2), 2.00 (ddd, 2 H, indane CH2), 1.69-1.66 (m,
2 H, CH2), 0.86–0.82 (t,3 H, CH3) ppm;13C NMR (CDCl3,
40 MHz): 168.01 (C-30),152.9 (C-17), 148.7 (C-13), 147.8
(C-14), 135.2 (C-10,11), 130.3 (C-19), 126.9 (C-23),125.0
(C-20), 120.2 (C-22), 109.8 (C-21), 108.2 (C-12), 108.0 (C-
15), 107.9 (C-24), 69.2 (C-7), 55.7 (C-28), 55.4 (C-26), 53.01
(C-4),51.3 (C-2,6), 35.5 (C-8,9), 30.4 (C-3,5), 20.0 (C-
34,36), 15.9 (C-35,37) ppm; TOF MS: m/z 527.2(M?); Anal.
Calcd. For C28H35ClN4O4: C,63.81;H,6.69;Cl,6.73;N,10.
63;O,12.14; Found: C,63.85;H,6.72;N,10.55.
Result and discussion
A series of different alkyl/ary substituents on 5-chloro-1-
(1-(5,6-dimethoxy-2,3-dihydro-1H-inden-1-yl)piperidin-4-
yl)-1H-benzo[d]imidazol-2(3H)-one was synthesized in
order to get novel bioactive compounds. The purity of
compounds was analyzed by TLC. The structures of all
compounds were confirmed by 1H –NMR,13C-NMR, Mass
analysis, and Elemental analyses. The supporting infor-
mations can be seen from the spectral data.
From the result of antifungal data shows that compounds
4e, 4f were active against C. albicans. While compounds
4b, 4c, 4h, 4j were active against A. clavatus. Further
Antibacterial study shows that compounds 4a, 4k, 4l, 4g
were active against Staphylococcus aureus. In case of
E. coli compounds 4b, 4g, 4h show good activity.
5-Chloro-3-(2-chloroethyl)-1-(1-(5,6-dimethoxy-2,3-dihydro-
1H-inden-1-yl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-
one (4l) Cream powder, yield: 340 mg (29.56 %); mp
179–182 °C, 1H NMR (400 MHz CDCl3):d = 7.33 (s, 1
H, ArH), 7.34–7.30(d, 1 H, ArH), 7.06 (d, 1 H, ArH), 6.
87–6.8 (dd, 1 H, ArH), 4.35–4.3 (m, 1 H, CH), 4.2 (t, 1 H,
indane CH), 3.78–3.75 (s, 6 H, 2OCH3), 3.71 (t, 2 H,
CH2), 2.96–2.8(t, 2 H, indane CH2), 2.78–2.56 (t, 4 H,
2CH2), 2.40–2.22 (m, 2 H, indane CH2), 2.05 (m, 4 H,
CH2), 2.00 (ddd, 2 H, indane CH2), 1.69–1.66 (t, 2 H,
CH2), 0.86–0.82 (t, 2 H, CH2) ppm; 13C NMR (CDCl3,
40 MHz): 152.9 (C-17), 148.7 (C-13), 147.8 (C-14), 135.2
(C-10,11), 131.36 (C-19),130.3 (C-20),126.9 (C-23), 125.0
Conclusion
In conclusion, the synthesized compounds 4a–m have
remarkable antifungal and antibacterial activity. The
activity of compounds with different alkyl/aryl substituents
indicates the importance of functional groups in enhancing
123

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