Design, synthesis and biological evaluation of benzimidazole-pyridine-piperidine hybrids as a new class of potent antimicrobial agents

Article abstract of DOI:10.2174/1570180811666140725185713

A series of novel benzimidazole-pyridine-piperidine hybrids was synthesized in good yields and characterized by spectral and elemental analyses. The compounds 4a-h and 5a-c were evaluated for their in vitro antibacterial activity against gram-positive org

Full text of DOI:10.2174/1570180811666140725185713

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38
Letters in Drug Design & Discovery, 2015, 12, 38-45
Design, Synthesis and Biological Evaluation of Benzimidazole-pyridine-
Piperidine Hybrids as a New Class of Potent Antimicrobial Agents
Kothapally. Beulahb, Akula Ravi Kumara, Boddupally Peda Venkat Lingaiaha, Pamulaparthy
Shanthan Raoa,*, Banda Narsaiaha, Aaramadaka Sunil Kumar Reddyb and Upadhyayula Surya
Narayana Murtyc
aFluoroorganic Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad- 500007, India
bDepartment of Pharmaceutical Chemistry, Bharat Institute of Technology (Pharmacy), Mangalpally, Hyderabad-
501510, India
cBiology Division (Bioinformatics), CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad- 500007, India
Abstract: A series of novel benzimidazole-pyridine-piperidine hybrids was synthesized in good yields and characterized
by spectral and elemental analyses. The compounds 4a-h and 5a-c were evaluated for their in vitro antibacterial activity
against gram-positive organisms viz., Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis, gram-
negative organisms viz., Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia and also against fungal strains
like Candida albicans, Saccharomyces cervisiae of yeasts, Aspergillus flavus, Aspergillus niger according to the CLSI
Standard Protocol. Compound 5a showed promising activity against all tested organism excluding Bacillus subtilis when
compared to standard drugs.
Keywords: 2-substituted benzimidazole, antibacterial activity, antifungal activity, ethyl-piperidine-4-carboxylic acid, hybrid
molecules, pyridine.
1. INTRODUCTION
considered privileged scaffolds in drug discovery with a
wide array of biological activities. The pyridine nucleus is
prevalent in numerous natural products and is extremely im-
portant in the chemistry of biological systems. Pyridine de-
rivatives have been used as bactericides [32], fungicides
[33], and anticancer agents [34-37]. Moreover, Piperidine
and its analogues, an important pharmacophore of many
drug molecules, are reported to act as antibacterials [38],
antitubercular agents [39] and AChE inhibitors [40].
The treatment of infectious diseases remains an important
issue because of the combination of factors including emerg-
ing newer infectious diseases and increasing number of
multi-drug resist antimicrobial pathogens. This problem is
particularly pronounced for the Gram-positive bacteria [1-4].
Despite a large number of antibiotics and chemotherapeutics
available for medical use, the emerging resistance to old and
new antibiotics has created a substantial need for new class
of antimicrobial agents. A potential approach to overcome
the problem of antibiotic resistance is to design innovative
agents with different modes of action so that no cross resis-
tance with present drugs can occur [5].
In view of the above mentioned findings, and as a con-
tinuation of our effort to identify new candidates that may be
of value in designing new, potent, selective, and less toxic
biologically active molecules [41-45], we report herein the
synthesis and antimicrobial evaluation of some novel struc-
tural hybrids incorporating the benzimidazole, pyridine and
piperidine ring systems. This combination was suggested to
investigate the influence of such hybridization and structure
variation on the anticipated biological activities, hoping to
add some synergistic biological significance to the target
molecules. The target compounds were rationalized so as to
comprise some pharmacophores that are believed to be re-
sponsible for the biological activity of some relevant che-
motherapeutic agents. The substitution pattern of the ben-
zimidazole and pyridine rings was carefully selected in order
to confer different electronic environment to the molecules.
Benzimidazoles are a familiar group of heterocyclic
compounds possessing a wide variety of biological activity.
Benzimidazole and its derivatives are reported to be physio-
logically and pharmacologically active and find applications
in the treatment of several diseases like epilepsy, diabetes,
antifertility [6, 7]. It is an important pharmacophore and
privileged structure in medicinal chemistry [8, 9] encom-
passing a diverse range of biological activities including an-
tibacterial [10], anti-inflammatory, analgesic [11, 12], anti-
histamine [13], antiulcerative [14], antioxidant [15], antipro-
liferative [16, 17], antiallergic [18, 19], antitumor [20, 21],
antikinase [22, 23], anticancer [24-28], cytotoxic [29], and
anti-HIV activities [30, 31]. On the other hand, Pyridines are
2. RESULTS AND DISCUSSION
2.1. Chemistry
*Address correspondence to this author at the Fluoroorganic Division,
CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-
500007, India. Tel: +91-40-27193171; Fax: +91-40-2719 3185;
E-mail: shanthanpp1954@gmail.com
The general route for the synthesis of the target benzimi-
dazole-pyridine-piperidine hybrids is depicted in Scheme (1).
1875-628X/15 $58.00+.00
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Design, Synthesis and Biological Evaluation
Letters in Drug Design & Discovery, 2015, Vol. 12, No. 1 39
CF3
F3C
CN
O
CF3
CN
O
piperidine
50% H2SO4 (aq)
+
H2N
O
EtOH
reflux
150-155 oC
O
R
N
H
R
N
H
O
R
1a R = Ph
1b R = CH3
2a R = Ph
2b R = CH3
R = Ph, CH3
POCl3/PCl5
110-115oC
CF3
HN
N
CF3
N
HN
R1
R
N
N
N
R
Cl
HN
NaHCO3/DMF
reflux
R1
3a R = Ph
3b R = CH3
4a-h
4a R = C6H5 & R1 = H
4e R = C6H5 & R1 = CO-C6H5
4b R = C6H5 & R1 = Cl
4c R = C6H5 & R1 = F
4d R = C6H5 & R1 = CH3
4f R=CH3 & R1 = H
4g R=CH3 & R1 = CO-C6H5
4h R=CH3 & R1 = Cl
Scheme (1). Synthesis of benzimidazole-pyridine-piperidine hybrid molecules 4a- h.
CF3
CF3
R2 - X
N
N
K2CO3/acetone
N
N
N
N
reflux
N
HN
R2
5a-c
4a
5a R2 = CH3
5b R2 = C2H5
5c R2 = CN
Scheme (2). Synthesis of hybrid molecules 5a-c from 4a.
The synthetic methodology was designed to start with the re-
action of cyano acetamide and 4,4,4-trifluoro-1-meth-
yl/phenylbutane-1,3-dione in presence of base at 75-80 °C that
afforded 2-oxo-6-methyl/phenyl-4-(trifluoromethyl)-1,2-dihy-
dropyridine-3-carbonitrile 1a-b [46]. The pyridone was fur-
ther hydrolyzed and decarboxylated to give 6-methyl/phenyl-
4-(trifluoromethyl) pyridin-2(1H)-one 2a-b [47] in excellent
yields. The pyridones 2a-b when reacted with freshly dis-
tilled POCl3 in the presence of PCl5 furnished 2-chloro-6-
methyl/phenyl-4-(trifluoromethyl) pyridine 3a-b. The conden-
sation of 2-chloro-6-methyl/phenyl-4-(trifluoro-methyl) pyri-
dine with various 2-(piperidin-4-yl)-1H-benzo[d] imidazoles
[48] in presence of NaHCO3/DMF furnished 2-(1-(6-
methyl/phenyl-4-(trifluoromethyl) pyridin-2-yl) piperidin-4-
yl)-1H-benzo[d] imidazoles 4a-h in excellent yields and the
schematic diagram is depicted in (Scheme 1).
The compound 4a was reacted with aklylhalide in
K2CO3/acetone under refluxing conditions furnished 1-
substituted-2-(1-(6-phenyl-4-(trifluoromethyl) pyridin-2-yl)
piperidin-4-yl)-1H-benzo[d] imidazole 5a-c (Scheme 2). The
reaction was initially conducted in dry DMF solvent at re-
fluxing temperature that furnished the products 5a-c in 40 %
yield. The product yield was improved to 72-83 % by chang-
ing the solvent to acetone.
The structure of compound 5b was established by syn-
thesizing an independent route starting from 1-chloro-2-
o
nitrobenzene reacting with n-propyl amine at 110-115 C

40 Letters in Drug Design & Discovery, 2015, Vol. 12, No. 1
Beulah et al.
H
N
H
N
Cl
n-propyl amine
Pd/C / EtOH
110-115 oC
NH2-NH2 / reflux
NO2
NO2
NH2
6
7
ethyl
CF3
N
piperidine-4
-carboxylate
N
N
NH
3a
4N HCl, 72 h
N
N
NaHCO3/DMF
reflux
N
5b
8
Scheme (3). Synthesis of 2-(1-(6-Phenyl-4-(trifluoromethyl) pyridin-2-yl) piperidin-4-yl)-1-propyl-1H-benzo[d] imidazole 5b.
Table 1. In vitro antibacterial activity of hybrid molecules 4a-h, 5a-c.
MIC (ꢀg/mL)
Compound
B.subtilis
S.aureus
S.epidermidis
E.coli
P.aeroginosa
K.pneumoniae
4a
>150
>150
>150
>150
>150
>150
>150
150
>150
>150
>150
>150
>150
>150
>150
>150
9.375
>150
>150
1.562
1.17
>150
>150
>150
>150
>150
75
>150
>150
>150
>150
>150
>150
>150
75
>150
>150
>150
>150
>150
>150
>150
75
>150
>150
>150
>150
>150
>150
>150
>150
37.5
4b
4c
4d
4e
4f
4g
75
4h
5a
75
150
4.68
>150
>150
3.125
1.17
9.375
>150
>150
12.5
4.68
>150
>150
12.5
1.17
5b
>150
>150
1.562
9.375
>150
>150
6.25
5c
Penicillin
Norfloxacin
18.75
9.375
DMSO-negative control showed no activity.
condition affording 2-nitro-N-propylaniline 6. The later was
treated with metal catalyzed reduction using Pd/C in the
presence of hydrazine hydrate resulting in N1-propyl-
benzene-1, 2-diamine 7. Compound 7 was reacted with
ethyl-piperidine-4-carboxylic acid [48] furnishing 2-(piperi-
din-4-yl)-1-propyl-1H-benzo[d]imidazole 8. Compound 8
was further reacted with 2-chloro-6-phenyl-4-(trifluoro-
methyl) pyridine affording 2-(1-(6-phenyl-4-(trifluoro-
methyl) pyridin-2-yl) piperidin-4-yl)-1-propyl-1H-benzo[d]
imidazole 5b (Scheme 3). The structure of alkylated com-
pound 5b was found to be identical with the compound ob-
tained by unambiguous route (Scheme 3) in all respects
which was further confirmed by super imposable IR spectra.
All the final compounds were well characterized with spec-
tral and elemental analysis.
2.2. Evaluation of Biological Activity
2.2.1. In Vitro Antibacterial Activity
The title hybrid molecules 4a-h and 5a-c were tested
against bacterial organism such as Gram-positive organisms
Bacillus subtilis (MTCC 441), Staphylococcus aureus
(MTCC 96), Staphylococcus epidermidis, Gram-negative
organisms viz Escherichia coli (MTCC 443), Pseudomonas
aeruginosa (MTCC 741), Klebsiella pneumonia (MTCC

Design, Synthesis and Biological Evaluation
Letters in Drug Design & Discovery, 2015, Vol. 12, No. 1 41
Table-2. In viro antifungal activity of 1-Ethyl-2- (1- (6-phenyl-4- (trifluoromethyl) pyridine-2- yl) piperidin-4-yl) -1H-benzo[d]
imidazole 5a.
Zone of Inhibition in mm
Compound
C. albicans
S. cervisiae
A. niger
A. flavus
100ꢁg
150ꢁg
10
100ꢁg
150ꢁg
10
100ꢁg
-
150ꢁg
-
100ꢁg
-
150ꢁg
-
7
7
5a
Amphotericin(50 ꢁg)
23.5
22
24
25
Negative control; DMSO showed no activity; well or cup method; the concentrations are expressed in mg/mL and inhibitory zone diameters are expressed in mm.
618) and also against fungal strains like Candida albicans
(MTCC 227), Saccharomyces cervisiae (MTCC36) of yeasts,
Aspergillus flavus (MTCC 277), Aspergillus niger (MTCC
282) was done according to CLSI Standard Protocol [49] and
the results were tabulated in Table 1, 2. Compound 5a
showed excellent activity against all tested organism exclud-
ing Bacillus subtilis (MTCC 441). In gram-negative organ-
isms, it is more active against Escherichia coli (MTCC 443)
strain MIC value 9.375 with comparison to norfloxacin
which is a broad range microbial agent and also penicillin. It
is also active against gram-positive organisms with
comparison to penicillin especially Staphylococcus
epidermidis with MIC value 4.68. Compounds 4f-h showed
moderate activity against bacterial organisms. The optimum
alkyl group on benzimidazole NH is found to be as ethyl
moiety and did not show any interesting activity either by
increasing the number of carbons or by replacement of nitrile
groups. The standard samples are considered as resistant to
Escherichia coli (MTCC 443), however compound 5a
showed enhanced activity than standard samples.
t (triplet), quart (quartet), m (multiplet) and br (broad), re-
spectively. All the reactions were monitored by thin layer
chromatography (TLC) on pre-coated silica gel 60 F254
(mesh); spots were visualized with UV light. Merck silica
gel (60-120 mesh) was used for column chromatography
CHN analysis was recorded on a vario EL analyzer.
3.2. Chemistry
Synthesis of 2-(1-(6-methyl/phenyl-4-(trifluoromethyl)
Pyridin-2-yl) Piperidin-4-yl)-1H-benzo[d] imidazoles (4a-
h).
General Procedure
A
mixture of 2-chloro-6-phenyl/methyl-4-(trifluoro-
methyl) pyridine 3 (1 mmol) and 6-substituted-2-(piperidin-
4-yl)-1H-benzo[d] imidazole (1.2 mmol) was charged and
added NaHCO3 (3.8 mmol), and DMF (5 mL) were added.
o
The reaction mixture was heated for 18 h at 120-125 C in
N2 atmosphere. Progress of the reaction was monitored by
TLC. The reaction mixture was cooled and poured onto
crushed ice. That obtained solid was filtered, washed with
water, hot 4N HCl and followed by water. The obtained
crude product was purified at the column chromatography
over silica gel using the solvent system 4:6 ethyl acetate:
hexane as eluent to give the title compounds (4a-h).
2.2.2. In Vitro Antifungal Activity
The in vitro antifungal activities of hybrid molecules 4a-
h and 5a-c were evaluated against four fungi includ-
ing Candida albicans Y0109, Candida
albicans SC5314,
Saccharomyces cervisiae, Aspergillus niger, Aspergillus
flavus. The positive control, Amphotericin, was obtained
from their respective manufacturers. Compound 5a showed
moderate activity against fungal organism like Candida
albicans (MTCC 227), Saccharomyces cervisiae (MTCC36).
Remaining compounds showed poor activity against all
fungal organisms. Compound 5a is identified as a new class
of antimicrobial agent against broad range microbial
organisms and further biological studies and modification
are under progress.
2-(1-(6-Phenyl-4-(trifluoromethyl) Pyridin-2-yl) Piperidin-
4-yl)-1H-benzo[d] imidazole (4a)
Yield: 76 %. M.P: 202-204 oC, I.R: 3447.15 (-NH),
1
1608.96 (-C=N-), 1392.56 (CF3). H NMR (DMSO-d6): ꢀ
2.03-2.11 (m, 2H), 2.24 (d, 2H, J = 11.71 Hz), 3.16-3.22 (m,
3H), 4.60-4.65 (d, 2H, J = 12.84 Hz), 6.84 (s, 1H), 7.17-7.21
(m, 2H, Ar-H), 7.44-7.49 (m, 5H, Ar-H), 7.65 (s, 1H, Ar-H),
8.02 (d, 2H, Ar-H, J = 6.61Hz), 11.69 (br., NH). ESI-MS
m/z: 423 (M++H). Anal. Calcd. for C24H21F3N4: C, 68.24; H,
5.01; N, 13.26. Found: C, 68.19; H, 4.96; N, 13.25.
3. EXPERIMENTAL SECTION
3.1. Materials & Methods
6-Chloro-2-(1-(6-phenyl-4-(trifluoromethyl) Pyridin-2-yl)
piperidin-4-yl)-1H-benzo[d] Imidazole (4b)
Melting points of all the compounds were recorded on
Casia-Siamia (VMP-AM) melting point apparatus and were
uncorrected. IR spectra were recorded on a Perkin-Elmer FT-
Yield: 73.4 %. M.P: >250 oC, I.R: 3436.87 (-NH),
1
1614.16 (-C=N-), 1416.48 (CF3). H NMR (DMSO-d6): ꢀ
1
IR 240-C spectrophotometer using KBr optics. H NMR
2.03-2.19 (m, 2H), 2.33-2.44 (m, 2H), 3.69-3.82 (m, 3H),
4.68-4.73 (d, 2H, J = 13.59 Hz), 6.88 (s, 1H, Ar-H), 7.26 (s,
1H, Ar-H), 7.43-7.50 (m, 3H, Ar-H), 7.57 (m, 2H), 7.72 (d,
1H, Ar-H, J = 8.87 Hz), 8.03 (d, 2H, Ar-H, J = 7.55 Hz),
spectra were recorded on Bruker AV 300 MHz and INOVA
400 & 500 MHz in DMSO-d6 using TMS as internal stan-
dard. Multiplicity is reported as s (singlet), d (doublet),

42 Letters in Drug Design & Discovery, 2015, Vol. 12, No. 1
Beulah et al.
11.25 (br., NH). ESI-MS m/z: 457 (M++H). Anal. Calcd. for
C24H20ClF3N4: C, 63.09; H, 4.41; N, 12.26. Found: C, 63.05;
H, 4.39; N, 12.24.
J = 13.97 Hz), 6.64 (s, 1H), 6.73 (s, 1H), 7.47-7.52 (m, 2H,
Ar-H), 7.58-7.63 (m, 2H, Ar-H), 7.73-7.80 (m, 3H, Ar-H),
8.03 (s, 1H, Ar-H), 11.46 (br., NH). ESI-MS m/z: 465
(M++H). Anal. Calcd. for C26H23F3N4O: C, 67.23; H, 4.99;
12.27; N, 12.06. Found: C, 67.19; H, 4.96; N, 12.04.
6-Fluoro-2-(1-(6-phenyl-4-(trifluoromethyl) Pyridin-2-yl)
piperidin-4-yl)-1H-benzo[d] Imidazole (4c)
6-Chloro-2-(1-(6-methyl-4-) pyridin-2-yl) Piperidin-4-yl)-
1H-benzo[d] Imidazole (4h)
Yield: 76 %. M.P: >250 oC, I.R: 3443.67 (-NH), 1612.70
1
(-C=N-), 1397.37 (C-F). H NMR (DMSO-d6): ꢀ 2.07-2.09
(m, 2H), 2.36-2.39 (d, 2H, J = 11.09 Hz), 3.19-3.25 (m, 2H),
3.73-3.79 (m, 1H), 4.70-4.73 (d, 2H, J = 13.16 Hz), 6.88 (s,
1H), 6.99 (d, 1H, J = 8.09 Hz), 7.22-7.28 (m, 3H, Ar-H),
7.31-7.35 (t, 1H, Ar-H, J = 8.09 Hz), 7.75 (t, 1H, Ar-H, J =
8.09 Hz), 8.02-8.04 (m, 3H, Ar-H), 11.61 (br., NH). ESI-MS
m/z: 441 (M++H). Anal. Calcd. for C24H20F4N4: C, 65.45; H,
4.58; N, 12.72. Found: C, 65.43; H, 4.56; N, 12.68.
Yield: 62 %. M.P:197-198 oC, I.R: 3441.75 (-NH),
1
1612.99 (-C=N-), 1401.31 (CF3). H NMR (DMSO-d6): ꢀ
1.96-2.04 (m, 2H), 2.19-2.24 (m, 2H), 2.45 (s, 3H, Ar-CH3),
3.05-3.11 (m, 2H), 3.22-3.28 (m, 1H), 4.49-4.53 (d, 2H, J =
13.55 Hz), 6.64 (s, 1H), 6.67 (s, 1H), 7.16-7.19 (m, 1H, Ar-
H), 7.47-7.49 (m, 1H, Ar-H), 7.53-7.55 (m, 1H, Ar-H), 11.23
(br., NH). ESI-MS m/z: 395 (M++H, 100%). Anal. Calcd. for
C19H18ClF3N4: C, 57.80; H, 4.60; N, 14.18. Found: C, 57.7;
H, 4.55; N, 14.15.
6-Methyl-2-(1-(6-phenyl-4-(trifluoromethyl
piperidin-4-yl)-1H-benzo[d] Imidazole (4d)
pyridin-2-yl)
Synthesis of N-alkylated 2-(1-(6-phenyl-4-(trifluoromethyl)
pyridin-2-yl) piperidin-4-yl)-1H-benzo[d] Imidazoles (5a-c)
Yield: 65 %. M.P: >250 oC, I.R: 3438.53 (-NH), 1612.43
1
(-C=N-), 1396.46 (CF3). H NMR (DMSO-d6): ꢀ 2.00-2.11
(m, 2H), 2.27-2.31 (m, 2H), 2.47 (m, 3H, Ar-CH3), 3.15-3.24
(m, 2H), 3.48-3.56 (m, 1H), 4.64-4.68 (d, 2H, J = 12.84 Hz),
6.85 (s, 1H, Ar-H), 7.12-7.15 (d, 1H, Ar-H, J = 8.50 Hz),
7.23 (s, 1H, Ar-H), 7.42-7.50 (m, 5H, Ar-H), 8.02-8.04 (d,
2H, Ar-H, J = 6.80 Hz), 11.32 (br., NH). ESI-MS m/z: 437
(M++H). Anal. Calcd. for C25H23F3N4: C, 68.79; H, 5.31; N,
12.84. Found: C, 68.74; H, 5.29; N, 12.81.
General Procedure:
A mixture of 2-(1- (6-Phenyl-4-(trifluoromethyl) pyridin-
2-yl) piperidin-4-yl)-1H-benzo[d] imidazole (4a) (0.355
mmol), activated K2CO3 (1.78 mmol), alkyl bromide (3
equiv.) and acetone (3 mL) was refluxed in N2 atmosphere
for 18-24 h. Reaction progress was monitored by TLC.
Acetone was evaporated from the reaction mixture and DM
water was added to the residue. The solid obtained was
filtered, washed with water and dried at a temperature of 60
°C. Crude product obtained was purified at the column
chromatography over silica gel at 4:6 ethyl acetate: hexane
as eluent.
Phenyl (2-(1-(6-phenyl-4-(trifluoromethyl) Pyridin-2-yl)
piperidin-4-yl)-3H-benzo[d] Imidazol-5-yl) Methanone (4e)
Yield: 70 %. M.P: >250 oC, I.R: 3359.15 (-NH), 1612.81
1
(-C=N-), 1396.45 (CF3). H NMR (DMSO-d6): ꢀ 2.11-2.16
(m, 2H), 2.39-2.43 (m, 3H), 3.74-3.86 (m, 2H), 4.71-4.75 (d,
2H, J = 13.40 Hz), 6.89 (s, 1H, Ar-H), 7.27 (s, 1H, Ar-H),
7.46-7.55 (m, 5H, Ar-H), 7.76-7.78 (d, 3H, Ar-H, J = 7.17
Hz), 7.89-7.90 (m, 2H, Ar-H), 8.03-8.05 (m, 2H, Ar-H), 8.17
(s, 1H, Ar-H), 11.12 (br., NH). ESI-MS m/z: 527(M++H).
Anal. Calcd. for C31H25F3N4O: C, 70.71; H, 4.79; N, 10.64.
Found: C, 70.67; H, 4.75; N, 10.61.
1-Ethyl-2- (1- (6-phenyl-4- (trifluoromethyl) Pyridine-2-yl)
piperidin-4-yl) -1H-benzo[d] Imidazole (5a)
o
Yield: 77 %. M.P: 136-138 C, I.R: 1611.35 (-C=N-),
1
1393.35 (CF3). H NMR (DMSO-d6): ꢀ 1.50-1.55 (t, 3H, N-
CH2-CH3, J = 6.99 Hz), 2.09-2.30 (m, 4H), 3.14-3.27 (m,
3H), 4.30-4.38 (q, 2H, N-CH2-CH3, J = 6.99 Hz), 4.69-4.73
(d, 2H, J = 13.60 Hz), 6.84 (s, 1H, Ar-H), 7.24 (s, 1H, Ar-
H), 7.30-7.33 (m, 2H, Ar-H), 7.40-7.48 (m, 5H, Ar-H), 8.02
(d, 2H, Ar-H, J = 6.98 Hz). ESI-MS m/z: 451 (M++H). Anal.
Calcd. for C26H25F3N4: C, 69.32; H, 5.59; N, 12.44. Found:
C, 69.28; H, 5.54; N, 12.39.
2-(1-(6-Methyl-4-(trifluoromethyl) Pyridin-2-yl) Piperidin-
4-yl)-1H-benzo[d] Imidazole (4f)
Yield: 62 %. M.P: 185-187 oC, I.R: 3446.59 (-NH),
1
1612.70 (-C=N-), 1397.37 (CF3). H NMR (DMSO-d6): ꢀ
1.25-1.31 (m, 2H), 1.97-2.07 (m, 3H), 2.17-2.22 (m, 2H),
2.41 (s, 3H, Ar-CH3), 4.45-4.48 (d, 2H, J = 13.22 Hz), 6.65-
6.72 (m, 2H, Ar-H), 7.40-7.44 (m, 2H, Ar-H), 7.56-7.64 (m,
2H), 11.54 (br., NH). ESI-MS m/z: 361(M++H). Anal. Calcd.
for C19H19F3N4: C, 63.32; H, 5.31; N, 15.55. Found: C,
63.29; H, 5.28; N, 15.50.
2-(1-(6-Phenyl-4-(trifluoromethyl) Pyridin-2-yl) piperidin-
4-yl)-1-propyl-1H-benzo[d] Imidazole (5b)
o
Yield: 75 %. M.P: 150-152 C, I.R: 1612.61 (-C=N-),
1
1396.91 (CF3). H NMR (DMSO-d6): ꢀ 1.01-1.06 (t, 3H, N-
CH2-CH2-CH3, J = 7.55 Hz, 7.18 Hz), 1.87-1.94 (m, 2H, N-
CH2-CH2-CH3, J = 7.55 Hz, 7.18 Hz ), 2.05-2.23 (m, 5H),
3.18-3.25 (m, 2H), 4.17-4.22 (m, 2H, N-CH2-CH2-CH3, J =
7.55 Hz, 7.18 Hz), 4.67-4.72 (d, 2H, J = 13.21 Hz), 6.85 (s,
1H, Ar-H), 7.18-7.24 (m, 1H, Ar-H), 7.36-7.48 (m, 5H, Ar-
H), 7.57 (s, 1H, Ar-H), 7.69 (d, 1H, Ar-H, J = 7.74 Hz), 8.02
(d, 2H, Ar-H, J = 6.61 Hz). ESI-MS m/z: 465 (M++H). Anal.
(2-(1-(6-Methyl-4-(trifluoromethyl) Pyridin-2-yl) Piperidin-
4-yl)-3H-benzo[d] Imidazol-5-yl), phenyl-methanone (4g)
Yield: 59 %. M.P: 192-194 oC, I.R: 3372.12 (-NH),
1
1612.79 (-C=N-), 1402.27 (CF3). H NMR (DMSO-d6): ꢀ
1.97-2.10 (m, 2H), 2.20-2.23 (m, 2H), 2.44 (s, 3H, CH3),
3.07-3.18 (m, 2H), 3.33-3.40 (m, 1H), 4.51-4.59 (d, 2H,

Design, Synthesis and Biological Evaluation
Letters in Drug Design & Discovery, 2015, Vol. 12, No. 1 43
Calcd. for C27H27F3N4: C, 69.81; H, 5.86; N, 12.06. Found:
C, 69.78; H, 5.82; N, 12.02.
plates were incubated at 27 °C for 48 h. Inhibition zones
were measured, the diameter was calculated in millimeter
and the corresponding results were in Table 2.
2-(2-(1-(6-Phenyl-4-(trifluoromethyl) Pyridin-2-yl) Piperi-
din-4-yl)-1H-benzo[d] imidazol-1-yl) Acetonitrile (5c)
4. CONCLUSION
o
Yield: 83 %. M.P: 174-176 C, I.R: 1610.87 (-C=N-),
In conclusion, we have discovered that a number of ben-
zimidazole-pyridine-piperidine hybrids displayed moderate
activity against various fungal organisms as well as bacterial
organisms. One promising compound 5a exhibited broad
spectrum antifungal activity including antibacterial activity
in vitro and was more potent than the standard drugs.
1
1396.06 (CF3). H NMR (DMSO-d6): ꢀ 2.18-2.27 (m, 4H),
3.23-3.37 (m, 2H), 3.49-3.62 (m, 1H), 4.71-4.80 (d, 2H, J =
11.51 Hz), 5.59 (s, 2H, N-CH2-CN), 6.97 (s, 1H, Ar-H),
7.27-7.30 (m, 2H, Ar-H), 7.41-7.49 (m, 3H, Ar-H), 7.57-7.61
(m, 1H, Ar-H), 7.65-7.69 (m, 1H, Ar-H), 8.08-8.10 (m, 2H,
Ar-H). ESI-MS m/z: 462 (M++H). Anal. Calcd. for
C26H22F3N5: C, 67.67; H, 4.81; F, 12.35; N, 15.18. Found: C,
67.63; H, 4.77; N, 15.14.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
2-(Piperidin-4-yl)-1-propyl-1H-benzo[d]imidazole (8)
Yield: 72%. Gummy, I.R: 1608.96 (-C=N-), 1392.56. 1H
NMR (DMSO-d6): ꢀ 0.94-1.05 (m, 4H), 1.65-1.75 (m, 1H),
1.83-2.10 (m, 4H), 3.01-3.09 (m, 2H), 3.28-3.32 (d, 2H, J =
12.84 Hz), 4.04-4.12 (m, 2H), 6.69 (d, 1H, Ar-H, J = 9.01
Hz), 7.20-7.35 (m, 2H, Ar-H), 7.67-76 (d, 1H, Ar-H, J =
8.56 Hz). ESI-MS m/z: 244 (M++H). Anal. Calcd. for
C15H21N3: C, 74.03; H, 8.70; N, 17.27; Found: C, 74.69; H,
8.67; N, 17.24.
ACKNOWLEDGEMENTS
We are thankful to the CSIR for financial assistance
through XII five year plan project: DISTF (code: CSC-
0204). One of the authors (A. RAVI KUMAR) also thankful
to Council of Scientific and Industrial Research (CSIR), In-
dia for the financial assistance in the form of senior research
fellowship and contingency grant.
3.3. In vitro Antimicrobial Assay
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