Synthesis and in vitro microbiological evaluation of imidazo(4,5-b) pyridinylethoxypiperidones

Article abstract of DOI:10.1016/j.ejmech.2005.10.014

A series of imidazo(4,5-b)pyridinylethoxypiperidones was designed, synthesized and characterized for evaluation of potential antibacterial activity against Bacillus subtilis, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus and Pseudomonas a

Full text of DOI:10.1016/j.ejmech.2005.10.014

European Journal of Medicinal Chemistry 41 (2006) 268–275
http://france.elsevier.com/direct/ejmech
Short communication
Synthesis and in vitro microbiological evaluation
of imidazo(4,5-b)pyridinylethoxypiperidones
G. Aridoss, S. Balasubramanian 1, P. Parthiban, S. Kabilan *
Department of Chemistry, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India
Received 26 July 2005; received in revised form 24 October 2005; accepted 25 October 2005
Available online 27 December 2005
Abstract
A series of imidazo(4,5-b)pyridinylethoxypiperidones was designed, synthesized and characterized for evaluation of potential antibacterial
activity against Bacillus subtilis, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa and antifungal
activity against Candida albicans-6, Candida albicans, Aspergillus niger, Candida albicans-51 and Aspergillus flavus. Structure–activity rela-
tionship led to the conclusion that compound 39 exerted strong in vitro antibacterial activity against Bacillus subtilis and Staphylococcus aureus
whereas compounds 38 and 39 displayed promising antifungal activity against Aspergillus flavus. The interesting antimicrobial profile of com-
pound 39 led us to select this derivative for further development.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Piperidin-4-one; Cyanoethylation; Imidazo(4,5-b)pyridine; Antibacterial activity; Antifungal activity
1. Introduction
tuent at second and/or sixth positions with regard to is biologi-
cal activity have been well documented by many workers [5,6,
12,17]. Consequently, the establishment of general methods for
the synthesis of piperidine derivatives has been the topic of
considerable synthetic effort [18].
Heterocyclic ring systems having piperidin-4-one nucleus
have aroused great interest in the past and recent years due to
their wide variety of biological properties such as antiviral [1],
antitumor [1,2], anti inflammatory [3], central nervous system
[4–9], local anaesthetic [5,10], anticancer [11], and antimicro-
bial activity [12] and their derivative piperidines are also bio-
logically important and act as neurokinin receptor antagonists
[13], analgesic and antihypertensive agents [14]. The impor-
tance of piperidin-4-one as intermediates in the synthesis of a
variety of compounds of physiologically active has been re-
viewed by Prostakov and Gaivoronskaya [15]. The extensive
studies undertaken in the past on 4-piperidones have their rela-
tion to the synthesis of drug [16]. The utility of substituents at
second, third and sixth positions, particularly aromatic substi-
Compounds incorporating the imidazo(4,5-b)pyridine ring
system can be considered as structural analogues of purines
and have shown a diverse biological activity depending on
the substituents of the heterocyclic ring. Their activity includes
antibacterial [19], antimicrobial [20], mutagenic [21], antiphlo-
gistic [22], fungicidal [23], pesticidal [24], antiviral [25], antic-
ancer [26], antimitotic [27], antituberculostatic [28], antialler-
gic [29] and antihypertensive [30] actions. They have also been
evaluated as antagonists of various biological receptors includ-
ing angiotensin II [31], thromboxane A2 [32] and platelet acti-
vating factor [33] from human neutrophil membranes and car-
dio vascular agents [34]. In view of these findings, we have
attempted to incorporate both the biolabile components to-
gether to give a confined structure like title compound for eval-
uating its antimicrobial activity.
* Corresponding author.
E-mail address: skabilan@rediffmail.com (S. Kabilan).
Present address: Department of Chemistry, Bowman Oddy Laboratories,
1
In the recent years we have been involved in the synthesis
and chemistry of 2,6-diarylpiperidin-4-one derivatives with a
The University of Toledo, 2801, W. Bancroft Street, MS 602, Toledo, OH
43606, USA.
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.10.014

G. Aridoss et al. / European Journal of Medicinal Chemistry 41 (2006) 268–275
269
prospect to incorporate diverse bioactive heterocyclic nucleus
intact for evaluating their antibacterial and antifungal signifi-
cance and also as a reagent for effecting functional group inter
conversion [34–44].
Usually, cyanoethylation [47] is a base catalyzed reaction
and invariably requires an alkaline catalyst. But certain amines
are quite exceptional. Oxides, hydroxides, alkoxides, alkali me-
tal hydrides etc. are useful for this purpose. Solubility of the
bases in organic solvents should be taken into account. Mono
or multiple cyanoethylation depends upon the proper choice of
a catalyst with sufficient basicity to remove the labile proton
from the compound undergoing cyanoethylation. Triton B is
particularly employed here on account of its basicity and its
solubility in organic media. Cyanoethylation requires cooling
to avoid polymerization of acrylonitrile. Inert solvents like ben-
zene, dioxane, acetonitrile or pyridine can be used to dissolve
solid reactants or to moderate the reaction.
2. Chemistry
Cyclic ketones normally undergo Baeyer–Villiger oxidation
(oxygen insertion reaction) to yield lactones upon treatment
with peracids [45]. When 2,6-diarylpiperidin-4-ones were sub-
jected to Baeyer-Villiger type of reaction by using meta chlor-
operbenzoic acid (m-CPBA), 1-hydroxy-2,6-diarylpiperidin-4-
ones resulted instead of lactones. On treatment with acryloni-
trile, substituted tetrahydrothiopyran-4-ones containing active
hydrogen underwent cyanoethylation yielding 3-[2-cya-
noethoxy] derivatives [46]. In 1-hydroxy-2,6-diarylpiperidin-
4-ones, there are active methylenic hydrogens at C3 and C5
positions. Hence expectation of cyanoethylation to occur at
these positions besides at 1-hydroxyl group is quite normal.
However, in all the cases specifically the 1-hydroxy group
alone underwent cyanoethylation [36,38–40] to afford 1-[2-cy-
anoethoxy]-2,6-diarylpiperidin-4-ones in good yields (60–
74%) upon treatment with acrylonitrile in the presence of cat-
alyst Triton B.
1-(2-Cyanoethoxy)-2,6-diarylpiperdin-4-ones upon cyclo-
condensation with 2,3-diaminopyridine in acid medium af-
forded
1-[2-(imidazo(4,5-b)pyridin-2-yl)ethoxy-2,6-diaryl-
piperidin-4-ones in moderate yields. Formation of an iminoyl
chloride from the cyanoethylated compound in the presence of
HCl is presumed to be essential for the condensation. The im-
portance of the title compounds is due to their associated po-
tential broad-spectrum biological activity. The synthesis
of imidazo(4,5-b)pyridinylethoxy piperidones 34–42 was
achieved with a versatile and efficient synthetic route
outlined in Scheme 1 and the analytical data are reproduced
in Table 1.
Scheme 1.

270
G. Aridoss et al. / European Journal of Medicinal Chemistry 41 (2006) 268–275
Table 1
Analytical data for compounds 25–42a
Entry
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
a
R1
H
H
CH3
H
H
CH3
H
H
CH3
H
H
CH3
H
H
CH3
H
H
R2
H
R
H
H
H
Cl
Cl
Cl
OCH3
OCH3
OCH3
H
H
H
Cl
Cl
Cl
Yield (%) m.p. (°C)
70
74
69
65
64
67
69
70
63
24
26
30
23
27
28
24
27
25
87
76
92
71
60
68
80
73
62
148–149
105
123–124
100–101
87
114
109
130–131
90–91
CH3
CH3
H
CH3
CH3
H
CH3
CH3
H
CH3
CH3
H
CH3
CH3
H
CH3
CH3
Fig. 1.
102 cfu ml–1 for antifungal assay. Testing was performed at
pH 7.4 0.2. Exactly 0.2 ml of the solution of test compound
was added to 1.8 ml of seeded broth to form the first dilution.
One milliliter of this was diluted with a further 1 ml of the
seeded broth to give the second dilution and so on till six such
dilutions were obtained. A set of assay tubes containing only
seeded broth was kept as control and likewise solvent controls
were also run simultaneously. The tubes were incubated in
BOD incubators at 37 1 °C for bacteria and 28 1 °C for
fungi. The minimum inhibitory concentrations (MICs) were re-
corded by visual observations after 24 h (for bacteria) and 72–
96 h (for fungi) of incubation. Penicillin G, streptomycin and
amphotericin B were used as standards.
OCH3
OCH3
OCH3
CH3
The micro-analysis values for C, H and N were within 0.4% of the the-
oretical values.
To percept structure–activity relationship well, numberings
of the target compound are done and is shown below. Fig. 1.
3. Pharmacology
3.1. In vitro antibacterial and antifungal activity
The in vitro activities of the compounds were tested in Sa-
bourauds dextrose broth (SDB; Hi-media, Mumbai) for fungi
and Nutrient broth (NB; Hi-media, Mumbai) for bacteria by the
twofold serial dilution method [48]. The test compounds were
dissolved in dimethylsulfoxide (DMSO) to obtain 1 mg ml–1
stock solutions. Seeded broth (broth containing microbial
spores) was prepared in NB from 24-h-old bacterial cultures
on nutrient agar (Hi-media, Mumbai) at 37 1 °C while fungal
spores from 24-h- to 7-day-old Sabourauds agar slant cultures
were suspended in SDB. The colony forming units (cfu) of the
seeded broth were determined by plating technique and ad-
justed in the range of 104–105 cfu ml–1. The final inoculum
size was 105 cfu ml–1 for antibacterial assay and 1.1–1. 5 ×
4. Results and discussion
4.1. Structure–activity relationship results
4.1.1. Antibacterial activity
The synthesis of a series of these derivatives was carried out
and the obtained compounds 34–42 were tested for their in
vitro antibacterial activity against some Gram positive [Staphy-
lococcus aureus NCIM-2492 and Bacillus subtilis NCIM-
2439] and Gram negative [Escherichia coli NCIM-2345, Kleb-
siella pneumoniae (derived from Medical College, Annamalai
University) and Pseudomonas aeruginosa NCIM-2035] bacter-
Table 2
In vitro antibacterial activity of compounds 34–42
Entry
Minimum inhibitory concentration (MIC) in μg ml–1
Bacillus subtilis
Klebsiella
Escherichia coli
Staphylococcus
Pseudomonas
pneumoniae
–
–
100
25
aureus
100
200
100
50
aeruginosa
200
100
100
50
34
–
–
100
50
35
36
37
200
100
50
50
38
39
40
41
12.5
6.25
50
25
25
12.5
12.5
100
50
12.5
12.5
50
50
12.5
50
100
100
50
50
6.25
50
100
25
12.5
50
12.5
12.5
100
100
50
42
Penicillin G
Streptomycin
25
12.5
50
25
12.5

G. Aridoss et al. / European Journal of Medicinal Chemistry 41 (2006) 268–275
271
ia. Penicillin G and streptomycin were used as standard drugs
whose minimum inhibitory concentration values are summar-
ized in Table 2.
P. aeruginosa whereas against E. coli, 50% decrease in activity
was observed. Substitution of methyl group at C3 position of
the six-member heterocyclic ring showed 50% improved activ-
ity against B. subtilis and K. pneumoniae while against E. coli
and S. aureus 50% decrease in activity was observed when
compared to compound 40. Introduction of another methyl
group at C5 of 40 (compound 42) along with C3 methyl group
exerted 50% enhancement in activity against K. pneumoniae
and P. aeruginosa whereas against S. aureus, 100% increase
in activity was noted. Against B. subtilis and E. coli, the activ-
ity did not change by the introduction of another methyl group
at C5 in 41 (compound 42).
The antibacterial screening put in evidence that all the
synthesized novel imidazo(4,5-b)pyridinylethoxypiperidones
34–42 exhibited a wide spectrum of antibacterial profile in vi-
tro against the tested organisms except 34 against B. subtilis,
K. pneumoniae only. Compounds 34–36 without any substitu-
ent at para position of aryl groups present at C2 and C6 of
piperidone ring exerted moderate antibacterial activity in vitro
at 50–200 μg ml–1 against B. subtilis, E. coli, S. aureus and
P. aeruginosa with an exception of compound 34 against
B. subtilis and E. coli. Among 34–36, introduction of methyl
group at C3 position in 34 (compound 35) improved the activ-
ity against B. subtilis and E. coli while against S. aureus, one-
fold decrease in activity was observed. From Table 2, it is ob-
vious that introduction of another methyl group at C5 in
addition to C3 in 34 (compound 36) has appreciably enhanced
the activity not only against K. pneumoniae but also against
rest of the bacterial strains.
4.1.2. Antifungal activity
The in vitro antifungal activity of compounds 34–42 were
examined against the fungal strains viz., Candida albicans-6
(NCIM-C27), Candida albicans (NCIM-C27), Aspergillus ni-
ger (NCIM-590), Candida albicans-51 (NCIM-C27) and As-
pergillus flavus (NCIM-539). Amphotericin B was used as
standard drug whose minimum inhibitory concentration values
are reproduced in Table 3.
Introduction of chloro function at the para position of the
aryl groups at C2 and C6 of 34 (compound 37) produced anti-
bacterial activity in the range of 6.25–50 μg ml–1 against all the
tested bacterial strains. This introduction causes further in-
crease (i.e. 50%) in activity against B. subtilis, S. aureus and
P. aeruginosa except against E. coli whereas against
K. pneumonia the activity was increased by 100%. Replace-
ment of hydrogens at C3 of heterocyclic ring in 37 by methyl
group showed onefold increase in activity against B. subtilis,
K. pneumoniae and P. aeruginosa except E. coli and S. aureus
against which the activity did not change.
The antibacterial profile of compounds 34–36 without any
substituents at the para position of the aryl groups at C2 and C6
of the six-member heterocyclic moiety falls in the region of
50–200 μg ml–1 except 34 against C. albicans-6, C. albicans
and A. flavus and 35 against A. flavus even at the high concen-
tration of 200 μg ml–1. Of these, the activity was rich in 35
compared to 34 due to the introduction of methyl group at C3
position in 34 against C. albicans-6 and C. albicans while
against A. flavus, the activity was not improved. Introduction
of another methyl group at C5 position of the six-member het-
erocyclic moiety (compound 36) enhanced the activity against
C. albicans and A. flavus whereas against rest of the fungal
strains, the activity did not change appreciably.
Introduction of one more methyl group at C5 along with the
C3 methyl group in 37 (compound 39) was in turn improved
the activity by onefold against B. subtilis and E. coli while
against S. aureus twofold increased activity was noted. But
against K. pneumoniae and P. aeruginosa, the activity was re-
tained as such without any further improvement.
Due to the introduction of chloro functions at the para posi-
tion of aryl groups which the nitrogen is flanked by in piper-
idone ring of 34 (compound 37) significantly improved the
antifungal activity against C. albicans-6 while against
A. niger, C. albicans-51 and A. flavus only 50% increase in
activity was observed. Replacement of hydrogen at C3 in 37
(compound 38) by methyl group improved the activity further
by about 100% against C. albicans, A. flavus whereas against
C. albicans-51 activity was enhanced by 50%. Against C. al-
Replacement of chloro moieties present at the para position
of aryl groups which the nitrogen is flanked by in piperidone
heterocyclic ring system through methoxy functionalities in 37
(compound 40), the activity was suppressed against all the
tested organisms. This decrease in activity was significant
against B. subtilis, K. pneumoniae, S. aureus and
Table 3
In vitro antifungal activity of compounds 34–42
Entry
Minimum inhibitory concentration (MIC) in μg ml–1
Candida albicans-6
Candida albicans
Aspergillus niger
Candida albicans-51
Aspergillus flavus
34
35
36
37
38
39
40
41
–
–
200
100
100
50
100
50
50
–
–
50
25
6.25
6.25
50
12.5
12.5
50
200
200
12.5
50
50
25
50
12.5
25
100
50
50
12.5
25
50
25
25
25
25
50
12.5
12.5
100
25
50
25
12.5
100
50
50
50
42
Amphotericin B

272
G. Aridoss et al. / European Journal of Medicinal Chemistry 41 (2006) 268–275
bicans-6, onefold decreased activity was noted. Similarly, in-
troduction of another methyl group at C5 position of the six-
member heterocyclic moiety (i.e. in 39), onefold increase in
activity was observed against A. niger while against C. albi-
cans-6, C. albicans-51 and A. flavaus, the activity remained
unchanged compared to compound 38. Moreover, against
C. albicans, the activity was suppressed by 50% due to this
methyl group modification.
Replacement of chloro moieties at the para positions of the
aryl groups at C2 and C6 in 37 by methoxy functions caused a
significant reduction in activity against all the tested fungal
strains except C. albicans-6 towards which activity was en-
hanced by 50% compared to compound 40.
Compound 41 having methyl group at C3 of heterocyclic
ring instead of hydrogen exerted modest activity against
C. albicans, A. niger, C. albicans -51, and A. flavaus while
against C. albicans-6 activity was suppressed. Besides, further
methyl group modification at C5 of compound 40 along with a
methyl group at C5 position, the activity did not alter against
C. albicans, A. niger and A. flavus whereas against C. albi-
cans-6, onefold increase in activity was noted. But towards
C. albicans-51, activity was decreased by about 50% due to
the second methyl group introduction.
plates to generate better drugs to fight bacterial and fungal in-
fections.
6. Experimental
The course of reaction and the purity were ascertained by
performing TLC. Melting points were determined in open ca-
pillaries and are uncorrected. IR spectra were recorded in Per-
kin-Elmer 297 spectrophotometer with KBr pellets and only
noteworthy absorption levels (reciprocal centimeter) are listed.
1H-NMR spectra were recorded at 400 MHz on Bruker amx
400 MHz spectrophotometer in CDCl3 using tetramethyl silane
(TMS) as internal standard and 13C-NMR spectra were re-
corded at 100 MHz on Bruker amx 400 MHz spectrophot-
ometer in CDCl3. Mass spectra were recorded on a VG analy-
tical 7070E instrument equipped with VG 11-250 data
acquisition system. Elemental analyses (C, H and N) were car-
ried out on a Carlo Erba Model 1106 and Perkin Elmer models
240 CHN analyzer. The results are within 0.4% of the theo-
retical values.
Unless otherwise stated, all the starting materials and re-
agents were of high grade, purchased from Aldrich, Fluka
and Merck. All the solvents were distilled prior to use.
5. Conclusion
From the literature precedent [49] 2,6-diarylpiperidin-4-ones
7–15 were prepared by the condensation of appropriate ke-
tones, aldehydes and ammonium acetate in 1:2:1 ratio.
A close examination of in vitro antibacterial and antifungal
profile of variously substituted novel imidazo(4,5-b)pyridiny-
lethoxypiperidones against the tested bacterial and fungal
strains provide a better structure–activity correlate which is
summarized below. Chloro and methoxy functions at the para
position of the aryl moieties present at C2 and C6 of piperidone
moiety along with or without methyl substituent at C3 and
C3/C5 positions play an important role in eliciting inhibition
of all the bacteria and fungi assayed.
Of the novel nine compounds tested, those with C3 and C5
dimethyl groups along with a chloro functions at the para po-
sitions of the aryl moieties at C2 and C6 exerted the highest
level of antibacterial activity against B. subtilis and S. aureus
while against the fungal strain A. flavus, the compound with C3
methyl and C3, C5 dimethyl groups showed striking influence
in inhibiting the fungal growth. The MIC values of the target
compounds indicated that the compound 39 is showing promis-
ing activity against B. subtilis and S. aureus when compared to
both the standard drugs namely penicillin G and streptomycin.
Similarly, the compounds 38 and 39 exhibited comparatively
good activity than amphotericin B against A. flavus.
The high efficacy exhibited by the compounds 38 and 39
clearly reveals that the methyl group modification is essential
at C3 and C5 in addition to chloro substitution at the para posi-
tion of aryl moieties at C2 and C6 of heterocyclic ring moiety.
The effect of methyl group substitution on structure–activity
relationship may perhaps be due to an effect on stereochemical
preferences on the piperidone ring which could influence their
antimicrobial properties. Thus, in future, this class of novel
imidazo(4,5-b)pyridinylethoxypiperidones may be used as tem-
6.1. 1-Hydroxy-2,6-diphenylpiperidin-4-one (16)
A solution of 2,6-diphenylpiperidin-4-one 1 (0.005 mol)
and m-CPBA (0.005 mol) in 40 ml of dry chloroform was stir-
red for 15 min at 0 °C and kept aside overnight at 20 °C. Then
the mixture was extracted with chloroform and washed well
with 10% sodium bicarbonate solution. The chloroform layer
was dried over anhydrous sodium sulfate and distilled off un-
der reduced pressure. Purifications with silicagel column chro-
matography with 4:1 benzene/pet. ether (b.p. 40–60 °C) mix-
ture yielded the product 16. The compounds 17–24 were
prepared similarly.
6.2. 1-(2-Cyanoethoxy)-2,6-diphenylpiperidin-4-one (25)
A mixture of 1-hydroxy-2,6-diphenylpiperidin-4-one 16
(0.005 mol) and acrylonitrile (0.005 mol) in 50 ml of 1,4-diox-
ane was taken in a 100 ml round-bottom flask and cooled in an
ice-bath. A few crystals of resorcinol were added followed by
drop-wise addition of Triton B with shaking. Then, the con-
tents were stirred for 9 h at 65–75 °C and concentrated. After
cooling, the resulting solution was poured over 1:3 benzene/
pet. ether mixture. The solid obtained was recrystallized from
methanol to afford the product 25. The compounds 26–33 were
prepared similarly.

G. Aridoss et al. / European Journal of Medicinal Chemistry 41 (2006) 268–275
273
6.3. 1-[2-(Imidazo(4,5-b)pyridin-2-yl)ethoxy]-2,6-
diphenylpiperidin-4-one (34)
(M+), 322,295, 190, 177, 146, 132, 118, 103 (100%), 100, 77,
56, 51; 1H-NMR (δ ppm): 3.61 (d, 3J = 11.62 Hz; 2H, H2a, H6a),
2.82–2.91 (m, 2H, H3a, H5a), 2.69 (t, J = 6.50 Hz, 2H,
–OCH2CH2–), 3.91 (t, J = 6.50 Hz, 2H, –OCH2CH2–), 7.28–
7.55 (m, 13H, aryl protons), 0.82 (d, J=6.60 Hz, 6H, CH3 at
C3 and C5); 13C-NMR (δ ppm): 76.025 (C2 and C6); 49.477
(C3 and C5); 209.192 (C=O), 141.120 (C2′ and C6′), 114.257,
118.940, 119.097, 127.854, 129.794, 130.676, 133.112,
143.163 (aryl carbons), 67.608 (–OCH2CH2–), 27.712
(–OCH2CH2–), 10.976 (–CH3 at C3 and C5).
To a mixture of 1-(2-cyanoethoxy)-2,6-diphenylpiperidin-4-
one 25 (0.005 mol) and 2,3-diaminopyridine (0.005 mol), di-
lute hydrochloric acid (10%) was added with constant shaking.
The contents of the flask were refluxed on an oil bath. After
the completion of reaction, 50 ml of water was added to the
reaction mass. Later this was filtered to remove impurities. To
isolate the product as a base, the acid solution was treated with
aqueous ammonia (15 ml) and then poured into water. The
precipitated compound 34 was recrystallized twice from etha-
nol.
6.6. 1-[2-(Imidazo(4,5-b)pyridin-2-yl)ethoxy]-2,6-bis(p-
chlorophenyl)piperidin-4-one (37)
IR (KBr) (cm–1): 3259 (N–H), 3025, 3010, 2947, 2934,
2858, 2766 (C–H), 1708 (C=O), 1591, 1561, 1499, 1352,
1318, 1298, 1246, 1155, 1128, 1038, 908, 862, 820, 784,
IR (KBr) (cm–1): 3226 (N–H); 3026, 3008, 2928, 2842,
2798 (C–H), 1705 (C=O), 1632, 1584, 1492, 1431, 1419,
1366, 1335, 1311, 1326, 1293, 1171, 1135, 1055, 1017, 958,
888, 853, 756, 740, 698. 680, 679, 528, 499; Mass (m/z): 480
(M+), 348, 335, 318, 290, 276, 166, 146, 137, 132, 118, 111,
75, 53 (100%), 50; 1H-NMR (δ ppm): 4.08 (dd, 3J = 12.60 Hz;
+
758, 730, 697, 669, 603, 519, 490; Mass (m/z): 412 (M ),
280, 250, 222, 208, 194, 145, 132, 118, 103(100%), 91, 77,
1
3
65, 55, 51; H-NMR (δ ppm): 4.05 (dd, J = 12.65 Hz; 3.81
Hz, 2H, H2a, H6a), 2.61–2.84 (m, 6H, H3a,3e; H5a,5e,
–OCH2CH2–), 3.93 (t, J = 6.51 Hz; 2H, –OCH2CH2–), 7.28–
7.49 (m, 13H, aryl protons), 13C-NMR (δ ppm): 69.262 (C2,
C6), 49.341 (C3, C5); 206.060 (C=O), 141.739 (C2′ and C6′),
114.289, 118.943, 119.058, 127.791, 129.773, 130.710,
133.105, 143.120 (aryl carbons), 162.614 (CB), 67.533
(–OCH2CH2–), 27.630 (–OCH2CH2–).
3.80 Hz, 2H, H2a, H6a), 2.60–2.89 (m, 6H, H3a,
H5a,
5e,
3e,
–OCH2CH2–), 3.92 (t, J = 6.51 Hz, 2H, –OCH2CH2–), 7.34–
7.62 (m, 11H, aryl protons); 13C-NMR (δ ppm) : 68.470 (C2
and C6), 48.992 (C3 and C5), 205.007 (C=O), 139.892 (C2′ and
C6′), 134.932 (C2′′′′ and C6′′′′), 114.290, 118.984, 119.080,
129.124, 129.963, 133.139, 143.347 (aryl carbons), 162.633
(CB), 67.541 (–OCH2CH2–), 27.634 (–OCH2CH2–).
The compounds 35–42 were also synthesized similarly.
6.4. 1-[2-(Imidazo(4,5-b)pyridin-2-yl)ethoxy]-2,6-dipheny-3-
6.7. 1-[2-(Imidazo(4,5-b)pyridin-2-yl)ethoxy]-2,6-bis(p-
methylpiperidin-4-one (35)
chlorophenyl)-3-methylpiperidin-4-one (38)
IR (KBr) (cm–1): 3252 (N–H), 3027, 3014, 2965, 2944,
2927, 2866, 2803 (C–H), 1696 (C=O), 2359, 2190, 1940,
1899, 1585, 1576, 1494, 1437, 1331, 1310, 1288, 1228,
1139, 1099, 1060, 943, 938, 912, 898, 856, 835, 824, 792,
734, 688, 628, 582, 541 Mass (m/z): 426 (M+), 294, 281,
IR (KBr) (cm–1): 3222 (N–H), 3028, 3013, 2966, 2934,
2853, 2728 (C–H), 1695 (C=O), 2973, 1952, 1826, 1641,
1591, 1580, 1496, 1377, 1382, 1324, 1316, 1279, 1228,
1142, 1118, 1053, 1021, 961, 942, 923, 888, 860, 760, 752,
700, 684, 661, 544, 487; Mass (m/z): 494(M+), 362, 349,
332, 307, 262, 196, 180, 155, 146, 137, 133, 118, 111, 75,
69, 53 (100%), 50; H-NMR (δ ppm): 4.07 (dd, J = 13.00
Hz; 3.30 Hz, 1H, H6a), 3.68 (d, 3J = 11.60 Hz; 1H, H2a),
2.63–2.93 (m, 5H, H3a, H5a,5e, –OCH2CH2–), 3.92 (t,
J = 6.5 Hz, 2H, –OCH2CH2–), 7.12–7.46 (m, 11H, aryl pro-
tons), 0.80 (d, J = 6.54 Hz, 3H, CH3 at C3), 13C-NMR (δ
ppm): 74.970 (C2), 68.858 (C6), 48.856 (C3), 48.490 (C5),
206.226 (C=O), 139.953 (C6′), 139.094 (C2′), 134.948 (C6′′′′),
134.753 (C2′′′′), 114.202, 118.976, 119.162, 129.361, 129.373,
129.883, 133.004, 133.120, 143.333 (aryl carbons), 162.633
(CB), 67.614 (–OCH2CH2–), 27.739 (–OCH2CH2–), 10.676
(–CH3 at C3).
1
239, 162, 145, 133, 118, 103 (100%), 91, 77, 69, 65, 51; H-
3
1
3
NMR (δ ppm): 4.05 (dd, J = 13.01 Hz; 3.30 Hz, 1H, H6a),
3.61 (d, 3J = 11.60 Hz, 1H, H2a), 2.61–2.9 (m, 5H, H3a,
H
and –OCH2 CH2–), 3.91 (t, J = 6.50 Hz, 2H, –O
5a, 5e
CH2CH2–), 7.30–7.50 (m, 13H, aryl protons), 0.82 (d, J = 6.6
Hz, 3H, –CH3 at C3); 13C-NMR (δ ppm): 75.767 (C2), 69.570
(C6), 49.152 (C3), 48.787 (C5), 207.488 (C=O), 140.979 (C2′),
141.820 (C6′), 114.204, 118.938, 119.101, 127.743, 129.712,
129.820, 130.601, 130.714, 133.110, 143.140 (aryl carbons),
162.638 (CB), 67.600 (–OCH2CH2–), 27.730 (–OCH2CH2–),
10.629 (–CH3 at C3).
6.5. 1-[2-(Imidazo(4,5-b)pyridin-2-yl)ethoxy]-2,6-diphenyl-
3,5-dimethylpiperidin-4-one (36)
6.8. 1-[2-(Imidazo(4,5-b)pyridin-2-yl)ethoxy]-2,6-bis(p-
chlorophenyl)-3,5-dimethyl piperidin-4-one (39)
IR (KBr) (cm–1): 3259 (N–H), 3028, 3016, 2966, 2925, 2848,
2815 (C–H), 1699 (C=O), 2361, 1607, 1582, 1480, 1461, 1441,
1381, 1338, 1324, 1272, 1191, 1142, 1099, 1011, 990, 926, 870,
823, 799, 769, 736, 679, 627, 559, 477, 451; Mass (m/z): 440
IR (KBr) (cm–1): 3219 (N–H), 3024, 3014, 2958, 2930, 2845,
2798 (C–H), 1697 (C=O), 2347, 1618, 1600, 1583, 1475, 1440,
1363, 1331, 1186, 1150, 1089, 1021, 982, 931, 889, 815, 761,

274
G. Aridoss et al. / European Journal of Medicinal Chemistry 41 (2006) 268–275
740, 701, 650, 540, 523, 489; Mass (m/z): 508 (M+), 390, 363,
1319, 1290, 1244, 1081, 1042, 841, 790, 735, 655, 540, 480,
334, 211, 193, 180, 152, 146, 132, 118, 111, 100, 91, 75, 53
450; Mass (m/z): 500 (M+), 382, 355, 220, 207, 189, 176, 161,
1
3
1
(100%), 50; H-NMR (δ ppm): 3.64 (d, J = 11.62 Hz; 2H, H2a,
H6a), 2.80–2.89 (m, 2H, H3a and H5a), 2.70 (t, J = 6.51 Hz, 2H,
–OCH2CH2–), 3.91 (t, J = 6.50 Hz, 2H, –OCH2CH2–), 7.31–7.54
(m, 11H, aryl protons), 0.80 (d, J = 6.52 Hz, 6H, CH3 at C3 and
C5); 13C-NMR (δ ppm): 75.283 (C2 and C6), 49.210 (C3 and C5),
208.162 (C=O), 139.143 (C2′ and C6′), 134.841 (C2′′′′ and C6′′′′),
114.239, 118.943, 119.162, 129.290, 129.819, 133.029, 143.359
(aryl carbons), 162.635 (CB), 67.633 (–OCH2CH2–), 27.709
(–OCH2CH2–), 10.876 (–CH3 at C3 and C5).
146, 132, 118, 107, 100, 75, 53(100%), 50; H-NMR(δ ppm):
3
3.63 (d, J = 11.65 Hz; 2H, H2a, H6a), 2.79–2.86 (m, 2H, H3a
and H5a), 2.69 (t, J = 6.49 Hz, 2H, –OCH2CH2–), 3.93 (t, 6.52
Hz, 2H, –OCH2CH2–), 6.88 (4H) and 7.35–7.49 (m, 7H, aryl
protons), 3.80 (s, 6H, –OCH3), 0.81 (d, J = 6.55 Hz, 6H, CH3
at C3 and C5), 13C-NMR (δ ppm): 75.476 (C2 and C6); 49.538
(C3 and C5), 209.419 (C=O), 158.882 (C2′′′′ and C6′′′′),
135.127 (C2′ and C6′), 114.235, 114.528, 118.864, 119.014,
133.002, 133.226, 143.343 (aryl carbons), 162.611 (CB),
67.704 (–OCH2CH2–), 27.677 (–OCH2CH2–), 55.
213(–OCH3), 10.957 (–CH3 at C3 and C5).
6.9. 1-[2-(Imidazo(4,5-b)pyridin-2-yl)ethoxy]-2,6-bis(p-
methoxyphenyl)piperidin-4-one (40)
Acknowledgements
IR (KBr) (cm–1): 3237 (N–H), 3028, 3013, 2928, 2855,
2788 (C–H), 1707 (C=O), 1645, 1579, 1472, 1445, 1371,
1355, 1322, 1258, 1185, 1143, 1038, 931, 790, 738, 700,
650, 644, 535, 509, 450; Mass (m/z): 472 (M+), 354, 327,
310, 282, 254, 162, 147, 145, 132, 118, 107, 75, 65, 55, 53
Authors are thankful to Professor K. Pandiarajan, Head, De-
partment of Chemistry, Annamalai University for the facilities
provided. One of the authors (S.K.) is grateful to University
Grants Commission, New Delhi, India for financial support in
the form of Major Research Project. S.B. wishes to thank
Council of Scientific and Industrial Research, New Delhi, India
for the award of Senior Research Fellowship. The authors
place sincere thanks to Professor M. Vasudevan, JSS College
of Pharmacy, Ooty, India for his kind help in conducting
screening studies.
1
3
(100%), 50, 43; H-NMR (δ ppm) : 4.06 (dd, J = 12.60 Hz;
3.8 Hz, 2H, H2a, H6a), 2.57–2.85 (m, 6H, H3a,3e; H5a,5e
;
–OCH2CH2–), 3.93 (t, J = 6.54 Hz 2H, –OCH2CH2–), 6.88
(d,4H) and 7.34–7.59 (m, 7H, aryl protons), 3.81 (s, 6H,
–OCH3), 13C-NMR (δ ppm): 68.612 (C2 and C6), 49.395 (C3
and C5); 206.177 (C=O), 158.806 (C2′′′′ and C6′′′′), 135.571
(C2′ and C6′), 114.342, 114.490; 118.974, 119.011, 133.019,
133.148, 143.362 (aryl carbons), 162.598 (CB), 67.620 (–O
CH2CH2–), 27.688 (–OCH2CH2–), 55.113 (–OCH3).
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