Synthesis, spectral, crystal structure and in vitro antimicrobial evaluation of imidazole/benzotriazole substituted piperidin-4-one derivatives

Article abstract of DOI:10.1016/j.ejmech.2011.02.036

Imidazole/benzotriazole analogues substituted piperidin-4-one derivatives (17-26) have been synthesized. Their chemical structures were characterized by IR, ¹H NMR, ¹³C NMR and mass spectral analysis. In addition, single crystal X-ra

Full text of DOI:10.1016/j.ejmech.2011.02.036

European Journal of Medicinal Chemistry 46 (2011) 1926e1934
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis, spectral, crystal structure and in vitro antimicrobial evaluation of
imidazole/benzotriazole substituted piperidin-4-one derivatives
,
,
a,
R. Ramachandran a b, M. Rani a, S. Senthan a, Yeon Tae Jeong b , S. Kabilan
*
*
a Department of Chemistry, Annamalai University, Annamalainagar e 608 002, Tamil Nadu, India
b Department of Image Science and Engineering, Pukyong National University, Busan 608-737, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Imidazole/benzotriazole analogues substituted piperidin-4-one derivatives (17e26) have been synthe-
sized. Their chemical structures were characterized by IR, 1H NMR, 13C NMR and mass spectral analysis. In
addition, single crystal X-ray diffraction has also been recorded for compounds 21 and 23. The synthe-
sized compounds were subjected to their in vitro antibacterial and antifungal activities against patho-
genic microbial strains. The results pointed out that compounds 19 & 24 against B. subtilis and 20 & 24
against E. coli were explored superior inhibition activity.
Received 22 October 2010
Received in revised form
13 February 2011
Accepted 15 February 2011
Available online 23 February 2011
Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords:
2,6-Diarylpiperidin-4-ones
Imidazoles
Benzotriazole
Antimicrobial activity
1. Introduction
2,4-[diaryl-3-azabicyclo[3.3.1]nonan-9-yl]-5-spiro-4-acetyl-2-(ace-
tylamino)-
D
2-1,3,4-thiadiazoline [13], 2,6-diarylpiperidin-4-one
Imidazole and benzotriazole derivatives are of synthetically
important analogues and are associated with several biological and
pharmacological properties [1,2]. It is known that clinically useful
drugs such as miconazole, econazole and oxiconazole (Fig. 1) con-
taining imidazole moiety exhibit strong antifungal activity. Simi-
larly, benzotriazole derivatives are of wide interest because of their
diverse biological activity and potential clinical applications [3,4].
The 1H-benzotriazol compounds regulate important pharmaco-
logical activities such as anti-inflammatory, antiviral, antifungal,
antineoplastic and antidepressant activities [5,6]. 1- and 2-[3-(1-
piperazinyl)propyl]-benzotriazoles exhibit remarkable antiseroto-
nergic, antiadrenergic and antihistaminic activities, as well as in
vivo analgesic action [5]. Besides, recent studies have shown that
several benzotriazole compounds act antiinflammation, antivirus,
antifungal, and antitumor agents, and as selective inhibitors of
PTP1B and antidepressants, resulting from the potent bioactivity of
benzotriazole [7e11].
O-benzyloxime ethers [14], 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-
ones and their oxime ethers/ [15]. In connection to these, we report
some imidazole and benzotriazole analogues substituted piperidin-
4-one derivatives and their in vitro antibacterial and antifungal
activities.
2. Chemistry
The synthetic pathway that leads to the formation of title
compounds (17e26) are sketched in Scheme 1. A well numbered
target compound structure was given in Fig. 2 for structural and
biological analysis. By adopting the literature precedent [16], 2,6-
diarylpiperidin-4-ones were prepared using one pot multi-
component Mannich reaction by condensing suitable aromatic
aldehydes, ketones and ammonium acetate in 1:2:1 ratio. This upon
nucleophilic substitution reaction with chloroacetyl chloride in the
presence of base catalyst (triethylamine) afforded N-chloroacetyl-
2,6-diarylpiperidin-4-ones (9e16) [17]. Further, the imidazole/
benzotriazole undergoes nucleophilic substitution with N-chlor-
oacetyl-2,6-diarylpiperidin-4-ones under reflux condition afforded
the title compounds (17e26). All the newly synthesized compounds
were fully characterized on the basis of spectroscopic techniques
(IR, 1H NMR, 13C NMR and mass). In addition, for compounds 21 and
23, single crystal X-ray diffraction was also recorded.
Recently our team have reported some heterocyclic com-
pounds with significant biological activity viz. 2-[(2,4-diaryl-3-azabi-
cyclo[3.3.1]nonan-9-ylidene)hydrazono]-1,3-thiazolidin-4-ones [12],
* Corresponding authors.
E-mail addresses: ytjeong@pknu.ac.kr (Y.T. Jeong), chemkabilan@rediffmail.com
(S. Kabilan).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.02.036

R. Ramachandran et al. / European Journal of Medicinal Chemistry 46 (2011) 1926e1934
1927
due to H-3 and H-5 protons. For compound 19, H-3 and H-5 protons
observed as multiplet and double doublet at 2.82e2.92 and
2.65 ppm, respectively.
13C NMR spectra of compounds 19 and 20 show a pair of less
intense signals in the higher frequency region at 208.22/169.03 and
210.384/169.32 ppm. These two set of signals in each compound
represent carbonyl and amide carbonyl carbons of 19 and 20,
respectively. Benzylic carbon signals of both compounds are
observed at 57.26 ppm (C-2)/56.93 ppm(C-6) (19) and 61.44 ppm
(C-2 and C-6) (20). The C-3/C-5 carbon signals are observed at
54.68/45.39 and 45.46 ppm respectively for 19 and 20. The acetyl
methylene carbon signal for 19 and 20 are observed at 48.93 and
49.03 ppm, respectively. Two methyl carbon signals at C-3 and C-5
of 20 are observed at 14.20 ppm whereas the signal of methyl group
in isopropyl analogue of 19 is observed at 20.89 and 20.43 ppm. The
other compounds signal assignments were made based on the
assignment of compounds 19 and 20.
3.2. Crystal structure analysis of 21 and 23
Good quality crystals were grown by the slow evaporation
technique using absolute ethanol as solvent. Table 1 gives crystal
data, data collection, and refinement parameters of 21 and 23
whereas Tables 2 and 3 showthe selected bond lengths and angles of
non hydrogen atoms and Figs. 3 and 4 shows the ORTEP diagram of
the compounds 21 and 23 respectively with 30% probability. All the
hydrogen atoms are placed at chemically acceptable positions. The
bond distances and bond angles of compounds 21 and 23 are in good
agreement with the standard values. The observed bond length
N1eC6 (1.376 (3) Å) (21) and (N1eC18/N5eC45 1.353(5) Å/1.359(5)
Å) (23) are shorter than reported values. This indicates the effective
conjugation between lone pair of nitrogen in piperidine ring and
amide carbonyl group. The NeCOCH2 groupis coplanaras confirmed
by the torsion angles C5eN1eC6eO2 & C1eN1eC6eC7 of ꢀ8.44ꢁ
and 2.83ꢁ (21) and C1eN1eC18eO2 and C5eN1eC18eC19 of 6.3ꢁ
and ꢀ11.1ꢁ (23).
Fig. 1. Structures of the active antifungal agents.
3. Results and discussion
3.1. Spectral characterization
For both imidazole and benzotriazole substituted compounds,
an intense band was observed around 1715 cmꢀ1 corresponds to
ring carbonyl stretching frequency (C]O at C-4). Similarly, a sharp
band appeared around 1650 cmꢀ1 which is due to amide carbonyl
stretching frequency. A bunch of medium intense bands observed
in the region 3079e2809 cmꢀ1 is due to aromatic and aliphatic
CeH stretching vibrations. The obtained molecular mass (m/z) of
21 and 23 are in good agreement with the proposed molecular
formula.
3.3. Antimicrobial studies
All the newly synthesized compounds 17e26 were screened for
their in vitro antibacterial activity against Staphylococcus aureus
(ATCC-25930), Bacillus subtilis (ATCC-530), Salmonella typhi (ATCC-
25021), Escherichia coli (ATCC-26032) and Klebsiella pneumoniae
(ATCC-16425) and antifungal activity against Candida albicans
(ATCC-3430), Cryptococcus neoformans (ATCC-3235), Rhizopus
species (ATCC-2842), Aspergillus niger (ATCC-635) and Aspergillus
flavus (ATCC-525) and their MIC values were determined by serial
dilution method. DMSO is used as a control while Streptomycin and
Amphotericin B are used as standard drugs respectively for bacte-
rial and fungal strains.
The antibacterial activity of MIC values are given in Table 4.
Among the compounds reported in this series, 18 and 21 against
B. subtilis, 20 against S. aureus, 19 and 24 against K. pneumonia and
26 against E. coli did not show any inhibitory activity even at
maximum concentration (200 mg/mL). However, bulkier isopropyl
group at C-3 position in the piperidine ring (19) against B. subtilis
and methyl group at C-3 and C-5 in piperidine ring (20) against
In order to assign the 1H and 13C NMR signals, we have chosen
19 and 20 as the representative compounds. The aryl proton signals
for compounds 19 and 20 are observed as multiplet in the region
6.70e7.40 ppm. The acetyl methylene protons of compound 20
appeared as a singlet at 4.55 ppm whereas the same protons in
compound 19 appeared as two double doublet at 4.60 ppm
(J ¼ 16.38 Hz) and 4.39 ppm (J ¼ 18.01 Hz). It is mainly due to the
loss of symmetry in the molecule (19) [18e20]. For compound 20,
there is a broad singlet observed at 5.41 ppm. As the singlet
corresponds to two protons integral, it is ascribed to benzylic
protons (H-2 and H-6) whereas for 19, the same protons signal
appeared as two broad singlets at 6.43 and 5.23 ppm. Here, the
each signal represents one proton integral value. By considering the
substituent effect at C-3 position, the deshielded signal is assigned
to H-2 proton whereas shielded one is assigned to H-6 proton. For
compound 20, the two methyl groups at C-3/C-5 is observed as
doublet at 1.07 ppm (J ¼ 6.90 Hz) with six proton integration
whereas for 19, the isopropyl methyl group signal observed as two
separate doublet at 1.08 ppm (J ¼ 1.14 Hz) and 1.10 ppm
(J ¼ 1.32 Hz). In addition, one more signal observed for the same
compound (19) at 2.07 is due to methine proton in isopropyl
analogue. There is a well resolved multiplet centered at 3.18 ppm
for compound 20, which corresponds to two protons and may be
E. coli explored good inhibitory activity (12.5 and 6.25 mg/mL
respectively). Compounds containing para fluorophenyl substit-
uent at C-2 & C-6 in the piperidine ring (24) increase the growth
inhibition activity against E. coli (12.5 mg/mL). Surprisingly,
replacement of methyl group by ethyl at C-3 and hydrogen at C-5 in
compound 24 (Compound 26) shows superior inhibition activity

1928
R. Ramachandran et al. / European Journal of Medicinal Chemistry 46 (2011) 1926e1934
O
O
R
R
2
3
R
R
2
3
O
O
+
R
R
R
R
R
R
R
R
1
1
1
1
A
N
H
H
H
NH4OAC
1-8
B
O
N
O
N
R
R
R
R
2
3
2
3
R
R
R
R
R
R
R
R
1
1
1
1
C
O
O
Cl
N
9-16
N
D
17-22
O
N
R
R
2
3
R
R
R
R
1
1
O
N
N
N
23-26
Scheme 1. Schematic diagram showing the synthesis of compounds (17e26).
against B. subtilis (6.25
mg/mL). The other compounds exhibit
4. Conclusion
minimum to moderate activity (25e200
mg/mL).
The antifungal activity results (Table 5) show that alkyl group
substitution at the C-3/C-5 of piperidine ring exhibit moderate
In summary, a close examination of in vitro antibacterial and
antifungal activities of variously substituted 1-[2-(1H-imidazol/
benzotriazole-1-yl)acetyl]-2,6-diarylpiperidin-4-ones against the
tested bacterial and fungal strains provide a better structureeactivity
correlation. Of thetested compounds, thosewith methyl group at C-3
and C-5 along with m-fluorophenyl and p-methoxyphenyl at C-2 and
C-6 exerted highest level of antibacterial and antifungal activity.
Thus, in future, this class of imidazole and benzotriazole derivatives
may be used as templates to generate better drugs to fight bacterial
and fungal infections.
activity (25e200
mg/ml). But compound 19 against A. niger shows
better activity at 12.5
mg/mL. It is due to the replacement of ethyl
group by bulkier isopropyl function at C-3 in piperidine ring.
Compound 20 (having methyl group at C-3 & C-5 and unsubstituted
phenyl group at C-2 & C-6) shows minimum to poor activity
(100e200
tion of the two phenyl groups (21) exhibit maximum inhibition at
6.25 g/mL against C. neoformans and moderate activity (25 g/mL)
mg/mL). But, introduction of fluoro function at meta posi-
m
m
against Rhizopus sp. Similarly, compound 20 against C. albicans was
inactive but introduction of electron donating group (OCH3) (22)
shows superior activity but modification of imidazole group by ben-
zotriazole analogue shows poor inhibition activity. Modification of
fluorosubstitutionand imidazoleanaloguein22bymethoxyfunction
and benzotriazole analogue respectively, shows significant activity
against Rhizopus sp and A. niger. Rest of the compounds exhibit
minimum to poor activity (25e200 mg/ml). However, compounds 18
and 22 against A. niger, 20 and 23 against C. albicans, 21 and 24 against
A. flavus and 25 against Rhizopus sp. did not show any growth inhi-
5. Experimental
All the reagents and solvents used were of high grade and
purchased from Alfa Aesar and were distilled prior to use unless
otherwise stated. The melting points were recorded in open
capillaries and are uncorrected. IR spectra were recorded using
AVATAR-330 FT-IR spectrophotometer (Thermo Nicolet) 1H-NMR
spectra were recorded at 400 and 500 MHz on BRUKER AMX 400
and 500 MHz spectrophotometer using CDCl3 and DMSO-d6 as
solvent and TMS as an internal standard. 13C-NMR spectra were
bition activity even at the maximum concentration (200 mg/mL).

R. Ramachandran et al. / European Journal of Medicinal Chemistry 46 (2011) 1926e1934
1929
O
O
R
R
2
2
4
R
R
3
2
5
6
2
2
4
3
2
5
6
6''
2''
R
R
1
N
2'
6'
6''
2''
2'''
R
6'''
R
1
N
6'''
2'
6'
2'''
2''''
6''''
R
2''''
R
1
O
R
1
1
6''''
1
R
O
N
a
N
N
a
b
b
N
b
N
b
c
Compound
R
R1
H
R2
CH3
R3
H
17
18
19
20
21
22
23
24
25
26
H
H
H
H
F
H
CH2CH3
CH(CH3)2
CH3
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
H
H
CH3
H
F
OCH3
H
CH3
CH3
H
H
H
F
CH3
OCH3
F
CH3
CH2CH3
Fig. 2. A well numbered target molecules (17e26).
recorded at 100 MHz on BRUKER AMX 400 MHz spectrometer in
CDCl3 and DMSO-d6 and tetramethylsilane (TMS) as internal stan-
dard. Results are presented in the following format; chemical shift
proton’s position. Multiplicities are shown as the following abbre-
viations: s (singlet), bs (broad singlet), d (doublet), dd (doublet of
doublet), t (triplet), q (quartet) and m (multiplet). Mass spectra
were recorded on JEOL JMS-700 spectrophotometer.
d
in ppm, multiplicity, J values in Hertz (Hz), number of protons,
Table 1
Crystal data and structure refinement parameters of compounds 21 and 23.
Empirical formula
Formula weight
C24 H22 F2 N3 O2
422.45
C54 H48 F4 N8 O4.50
478
Wavelength
0.71073 Å
0.71073 Å
Crystal system, space group
Cell dimensions
Orthorhombic , P2(1)2(1)2(1)
Monoclinic, P21/n
a ¼ 18.6505(7) Å, b ¼ 13.9451(5) Å,
a ¼ 8.8467(5) Å; b ¼ 9.1233(5) Å;
c ¼ 26.3523(12) Å ;
4, 1.319 mg mꢀ3
0.097 mmꢀ1
2126.92(19) Å3
1.55e28.28ꢁ
884
a
¼
b
¼
g
¼ 90ꢁ
c ¼ 19.0945(6) Å;
4, 1.327
b
¼ 105.343(2)
Z, Density (calculated)
Absorption coefficient
Volume
0.097 mmꢀ1
4789.2(3) Å3
1.36e22.71ꢁ
2000
q
range for data collection
F(000)
Crystal size
Index range
0.40 ꢂ 0.35 ꢂ 0.32 mm
0.30 ꢂ 0.20 ꢂ 0.20 mm
ꢀ20 ꢃ h ꢃ 20, ꢀ15 ꢃ k ꢃ 12, ꢀ20 ꢃ l ꢃ 20
39136/6421 [R(int) ¼ 0.0368]
686
ꢀ11 ꢃ h ꢃ 11, ꢀ5 ꢃ k ꢃ 12, ꢀ31 ꢃ l ꢃ 23
Reflections collected/unique
No. of parameters:
Goodness-of-fit
Largest diff. peak and hole
Data/restraints/parameters
Refinement method
CCDC
9324/4944 [R(int) ¼ 0.0222]
305
0.838
1.099
00.242 and ꢀ0.226 e Åꢀ3
4944/1/305
0.837 and ꢀ0.407 e Åꢀ3
6421/4/686
Full-matrix least-squares on F2
704386
Full-matrix least-squares on F2
705115

1930
R. Ramachandran et al. / European Journal of Medicinal Chemistry 46 (2011) 1926e1934
Table 2
ring); 129.625, 129.318, 129.191, 128.829, 128.368, 128.296, 127.494,
126.761, 125.412 (other aryl carbons); 13.378 (CH3 at C-3).
Geometric parameters of compound 21.
Atom
Bond length (Å) Atom
Bond length (Å)
5.1.2. 1-[2-(1H-imidazol-1-yl)acetyl]-3-ethyl-2,6-diphenylpiperidin-
4-one (18)
C(1)eN(1)
C(1)eC(11)
C(3)eO(1)
C(4)eC(5)
C(5)eN(1)
1.482(3)
1.525(3)
1.211(3)
1.547(3)
1.488(3)
C(6)eN(1)
C(10)eN(2)
C(13)eF(1)
C(15)eF(1A)
C(23)eF(2)
1.376(3)
1.356(4)
1.308(4)
1.112(6)
1.352(4)
A white solid; yield (68%); mp 147 ꢁC; IR (cmꢀ1): 3065, 2964,
2930, 2869 (CeH stretching); 1714 (C]O stretching); 1663 (NeC]
O stretching); 1505, 1453, 1386, 1291, 1234, 1080, 1031, 769, 743,
Atom
Bond angle (ꢁ)
Atom
Bond angle (ꢁ)
702, 664, 465 (other stretching frequency). 1H NMR (
d ppm): 6.08
N(1)eC(1)eC(11) 111.82(18)
F(1)eC(13)eC(12)
C(24)eC(19)eC(5)
F(2)eC(23)eC(24)
F(2)eC(23)eC(22)
C(6)eN(1)eC(1)
C(6)eN(1)eC(5)
C(10)eN(2)eC(7)
C(8)eN(3)eC(9)
121.3(3)
120.6(2)
118.0(3)
119.2(3)
117.26(19)
122.03(18)
128.2(2)
104.3(3)
(bs, 1H, H-2a); 5.41 (bs, 1H, H-6a); 4.59, 4.45 (2d, 2H, J ¼ 16.36 and
C(3)eC(2)eC(17)
C(3)eC(2)eC(1)
C(2)eC(3)eC(4)
N(1)eC(5)eC(4)
108.8(3)
112.4(2)
117.2(2)
14.87, NCOCH2); 2.94e3.08 (m, 2H, H-5a and H-3a); 2.67 (dd, 1H,
3
2J5a,5e ¼ 17.75 Hz and J5a,6a ¼ 4 Hz, H-5e); 1.52e1.72 (m, 2H,
CH2eCH3); 1.05 (t, 3H, J ¼ 7.45 Hz, CH3 at C-3); 7.05 (s, 1H, H-a
proton of Imidazole); 6.77e7.35 (m, 12H, aryl and H-b-Imidazole
111.36(18)
C(19)eC(5)eC(4) 108.14(17)
protons). 13C NMR (
d ppm): 56.72 (C-2 & C-6); 51.92 (C-3); 45.03
N(1)eC(6)eC(7)
N(2)eC(7)eC(6)
C(10)eC(9)eN(3)
C(9)eC(10)eN(2)
117.07(19)
112.0(2)
110.5(3)
106.8(3)
(C-5); 208.23 (C]O at C-4); 169.22 (N-C]O); 140.63 (C-20 ipso);
141.33 (C-60 ipso); 137.93 (C-a Carbon of imidazole ring); 120.0 (C-b
Carbon of imidazole ring); 129.58, 129.07, 128.82, 128.40, 128.20,
127.47, 126.10, 125.35 (other aryl carbons); 48.92 (N-COCH2); 23.01
(CH2 at CH2 CH3); 11.76 (CH3 at CH2 CH3).
C(5)eN(1)eC(6)eO(2) ꢀ8.44 (5)
C(1)eN(1)eC(6)eC(7) 2.83 (5)
5.1. General procedure for the preparation of 1-[2-(1H-imidazo-1-
yl)acetyl]-2,6-diarylpiperidin-4-ones and 1-[2-(1H-benzotriazol-1-
yl)acetyl]-2,6-diarylpiperidin-4-ones (17e26)
5.1.3. 1-[2-(1H-imidazol-1-yl)acetyl]-3-isopropyl-2,6-diphenyl-
piperidin-4-one (19)
A
mixture
of
N-chloroacetyl-2,6-diarylpiperidin-4-one
A white solid; yield (72%); mp 63 ꢁC; IR (cmꢀ1): 3061, 2963,
2929, 2874 (CeH stretching); 1714 (C]O stretching); 1658 (NeC]
O stretching); 1507, 1450, 1400, 1274, 1226, 1080, 1032, 917, 812,
(1 mmol), triethylamine (3 mmol) and imidazole/1,2,3-benzo-
triazole (1.2 mmol) in toluene or benzene was refluxed for about
5e6 h. The reaction was monitored by TLC. After the completion of
reaction, excess of solvent was removed under reduced pressure.
The final mass was poured into 3% sodium bicarbonate solution to
remove the formed quaternary ammonium salt. This was then
extracted with ether and dried over anhydrous sodium sulphate.
The residue thus obtained was purified by column chromatography.
The above general method was adopted for the synthesis of
following compounds.
762, 700, 664, 623, 519, 468 (other stretching frequency). 1H NMR (
d
ppm): 6.43 (bs, 1H, H-2a); 5.23 (bs, 1H, H-6a); 4.64 (d, 1H, J ¼ 16.38,
NCOCHH); 4.39 (d, 1H, J¼18.01, NCOCHH); 2.82e2.92 (m, 2H, H-3a
and H-5a protons are merged together); 2.65 (dd, 1H,
2J5a,5e ¼ 19.38 Hz and 3J5a,6a ¼ 4 Hz, H5e); 2.07 [m, 1H, (CH (CH3)2) at
0
C-3]; 1.10 (d, 3H, J ¼ 1.32 Hz, [CH(CH3 ) (CH300)]); 1.08 (d, 3H,
J ¼ 1.14 Hz, [CH(CH3 ) (CH300)]); 6.78e7.38 (m, 13H, aryl and H-a &
0
H-b-Imidazole protons). 13C NMR (
d
ppm): 57.261 (C-2); 56.934 (C-
6); 54.685 (C-3); 45.399 (C-5); 208.229 (C]O at C-4); 169.039
(NeC]O); 140.921 (C-20 ipso); 141.214 (C-60 ipso) 128.532, 127.404,
126.626 (other aryl carbons); 48.936 (NeCOCH2); 137.966 (C-
a Carbon of imidazole ring); 120.278 (C-b Carbon of imidazole
ring); 129.414, 128.819, 128.630, 128.164, 127.903, 127.421, 125.910,
5.1.1. 1-[2-(1H-imidazol-1-yl)acetyl]-3-methyl-2,6-
diphenylpiperidin-4-one (17)
A white solid; yield (71%); mp 123 ꢁC; IR (cmꢀ1): 3049, 2972,
2927, 2852, (CeH stretching); 1717 (C]O stretching); 1654 (NeC]
O stretching); 1509, 1454, 1395, 1274, 1233, 1080, 1031, 918, 777,
0
125.599, (0other aryl carbons); 28.872 0[CHe(CH3 ) (CH300)]; 20.890
743, 702, 667, 616, 465. 13C NMR (
d ppm): 62.467 (C-2); 54.259 (C-
[CHe(CH3 ) (CH300)]; 20.436 [CHe(CH3 ) (CH300)].
6); 46.263 (C-3); 43.042 (C-5); 207.888 (C]O at C-4); 169.035
(NeC]O); 140.779 (C-20 ipso); 141.056 (C-60 ipso) 128.532, 127.404,
126.626 (other aryl carbons); 49.144 (NeCOCH2); 137.998 (C-
a Carbon of imidazole ring); 120. 204 (C-b Carbon of imidazole
5.1.4. 1-[2-(1H-imidazol-1-yl)acetyl]-3,5-dimethyl-2,6-diphenyl-
piperidin-4-one (20)
A pale yellow solid; yield (75%); mp 163 ꢁC; IR (cmꢀ1): 3061,
2978, 2936, 2876 (CeH stretching); 1716 (C]O stretching); 1644
(NeC]O stretching); 1502,1453,1385,1285,1233,1203,1080,1031,
Table 3
Geometric parameters of compound 23.
916, 817, 762, 703, 665, 628, 530, 421. 1H NMR (
d ppm): 5.41 (bs, 2H,
Atom
Bond length (Å) Atom
Bond length (Å)
H-2a and H-6a); 4.55 (s, 2H, NCOCH2); 3.18 (m, 2H, H-3a and H-5a);
7.05 (s, 1H, H-a proton of imidazole); 6.73e7.36 (12H, aryl and H-
b proton of imidazole); 1.07 (d, 6H, J ¼ 6.90 Hz, CH3 at C-3 and C-5).
C(1)eN(1)
C(1)eC(2)
C(2)eC(3)
C(1)eC(12)
C(2)eC(26)
C(3)eO(1)
C(3)eC(4)
C(4)eC(27)
C(4)eC(5)
1.488(5)
1.522(6)
1.495(6)
1.511(6)
1.526(6)
1.206(5)
1.506(6)
1.519(5)
1.542(5)
C(5)eN(1)
C(5)eC(6)
1.487(5)
1.514(5)
1.211(4)
1.353(5)
1.510(5)
1.211(4)
1.353(5)
1.510(5)
1.447(5)
C(18)eO(2)
C(18)eN(1)
C(18)eC(19)
C(18)eO(2)
C(18)eN(1)
C(18)eC(19)
C(19)eN(2)
13C NMR (
d ppm): 61.447 (C-2 and C-6); 45.466 (C-3 and C-5);
210.384 (C]O at C-4); 169.327 (NeC]O); 140.776 (C-20 and C-60
ipso); 137.952 (C-a Carbon of imidazole ring); 120.291 (C-b Carbon of
imidazolering); 129.223,128.562,128.412,128.128,127.613,127.084,
(other aryl carbons); 49.038 (N-COCH2); 14.205 (CH3 at C-3 and C-5).
Atom
Bond angle (ꢁ)
Atom
Bond angle (ꢁ)
5.1.5. 1-[2-(1H-imidazol-1-yl)acetyl]-3,5-dimethyl-2,6-bis(m-fluoro-
phenyl)piperidin-4-one (21)
N(1)eC(1)eC(12) 112.1(3)
N(1)eC(1)eC(2) 109.6(3)
N(1)eC(5)eC(6) 114.0(3)
N(1)eC(5)eC(4) 110.3(3)
O(2)eC(18)eN(1) 122.9(4)
C(12)eC(1)eC(2) 117.6(3)
C(2)eC(3)eC(4)
C(3)eC(4)eC(5)
115.8(4)
108.6(3)
112.9(3)
109.7(3)
118.0(4)
124.2(4)
6.3(2)
A pale yellow solid; yield (67%); mp 127 ꢁC; IR (cmꢀ1): 3073,
2969, 2931, 2871, 2853, 2809 (CeH stretching); 1710 (C]O
stretching); 1666 (NeC]O stretching); 1591, 1513, 1488, 1450,
1386, 1354, 1277, 1240, 1192, 1079, 1038, 950, 884, 789, 747 (other
C(4)eC(5)eC(27)
C(6)eC(5)eC(4)
C(13)eC(12)eC(1)
C(17)eC(12)eC(1)
C(1)eN(1)eC(18)eO(2)
C(1)eC(2)eC(3)
C(1)eC(2)eC(26) 111.6(4)
112.4(3)
stretching frequency). 1H NMR (
d
ppm): 5.49 (bs, 2H, H-2a and H-
C(5)eN(1)eC(18)eC(19) ꢀ11.1(2)
6a); 3.10 (m, 2H, H-3a and H-5a); 4.71 (s, 2H, NCOCH2); 7.76 (s, 1H,

R. Ramachandran et al. / European Journal of Medicinal Chemistry 46 (2011) 1926e1934
1931
Fig. 3. ORTEP diagram of compound 21 with 30% probability.
Fig. 4. ORTEP diagram of compound 23 with 30% probability.

1932
R. Ramachandran et al. / European Journal of Medicinal Chemistry 46 (2011) 1926e1934
Table 4
In vitro antibacterial activity of compounds 17e26 against selected bacterial strains.
Compounds
Minimum inhibitory concentration (MIC) in mg/ml
S. aureus (ATCC-25930)
B. subtils (ATCC-530)
S. tyhpi (ATCC-25021)
E. coli (ATCC-26032)
K. pneumonia (ATCC-16425)
17
18
19
20
21
22
23
100
200
100
e
25
e
200
200
25
100
50
100
50
100
6.25
200
25
50
100
e
12.5
100
e
100
200
200
25
50
100
50
50
25
100
25
50
24
25
26
100
25
50
50
50
100
50
12.5
50
e
200
6.25
12.5
100
100
25
e
Streptomycin
50
50
12.5
e, No inhibition even at maximum concentration.
H-a imidazole proton); 6.89e7.39 (m, 10H, aryl and H-b imidazole
1098, 955, 878, 792, 746, 704 and 523 (other stretching frequency). 1H
NMR ( ppm): 5.46 (bs, 2H, H-2a and H-6a); 5.27 (s, 2H, NCOCH2); 3.09
protons); 1.10 (d, 6H, J ¼ 6.92 Hz, CH3 at C-3 and C-5). 13C NMR (
d
d
ppm): 60.878 (C-2 and C-6); 45.368 (C-3 and C-5); 209.348 (C]O at
C-4); 169.160 (NeC]O); 143.151 (C-20 and C-60 ipso); 137.702 (C-
a Carbon of imidazole ring); 120.706 (C-b Carbon of imidazole
ring); 143.165 and 143.102 (C-20 and C-60); 164.341 and 161.869 (C-
2000 and C-6000); 130.966, 130.883, 127.408, 123.336, 123.308, 115.717,
115.509, 114.695, 114.472 (other aryl carbons); 49.223 (NeCOCH2);
14.181 (CH3 at C-3 and C-5). HR-MS, (m/z) 423.10 (Mþ).
(m, 2H, H-3a and H-5a); 7.05e7.52 (m, 11H, aryl protons); 8.06 (d, 1H,
H-c proton of benzotriazole).1.00 (d, 6H, J ¼ 6.96 Hz, CH3 at C-3 and C-
5). 13C NMR (
d ppm): 50.892 (C-2 and C-6); 45.306 (C-3 and C-5);
209.179 (C]O at C-4); 167.938 (NeC]O); 164.325 and 161.851 (C-2000
and C-6000 ipso); 142.983,142.923 (C-20 and C-60 ipso carbons); 133.603,
130.931, 128.320, 125.057, 123.357, 119.623, 115.691, 115.479, 114.720,
114.492,109.984 (other aryl carbons); 60.971 (NeCOCH2); 14.037 (CH3
at C-3 and C-5). HR-MS (m/z): 473.86 (M þ 1).
5.1.6. 1-[2-(1H-imidazol-1-yl)acetyl]-3,5-dimethyl-2,6-bis(p-
methoxyphenyl)piperidin-4-one (22)
5.1.8. 1-[2-(1H-benzotriazol-1-yl)acetyl]-3,5-dimethyl-2,6-bis(p-
methoxyphenyl)piperidine-4-one (24)
Awhite solid; yield (77%); mp 139 ꢁC; IR (cmꢀ1): 2997, 2935, 2839
(CeH stretching); 1715 (C]O stretching); 1645, 1610 (NeC]O and
C]N stretching); 1513, 1548,1396,1286, 1180, 1112, 1108, 1080, 835,
A white solid; yield (70%); mp 183 ꢁC; IR (cmꢀ1): 3079, 2969,
2922, 2851 (CeH stretching); 1715 (C]O stretching); 1643 and
1611 (NeC]O and C]N stretching); 1512, 1458, 1429, 1395, 1285,
1252, 1177, 1093, 1034, 840, 746, 666, 594, 541 (other stretching
663, 591 and 539 (otherstretching frequency).1H NMR (
d ppm): 5.32
(bs, 2H, H-2a and H-6a); 4.51 (s, 2H, NCOCH2); 3.15 (m, 2H, H-3a and
H-5a); 6.87 (d, 4H, aryl protons ortho to methoxy group); 7.08 (d, 4H,
aryl protons meta to methoxy group); 7.22 (s, 1H H-a imidazole
protons); 7.03 (2H, H-b proton of imidazole); 3.81 (s, 6H, OCH3 at C-
frequency). 1H NMR (
d ppm): 5.38 (bs, 2H, H-2a and H-6a); 5.18 (s,
2H, NCOCH2); 3.08 (m, 2H, H-3a and H-5a); 3.75 (s, 6H, OCH3 at C-
20000 and C-60000); 0.96 (d, 6H, J ¼ 6.80 Hz, CH3 at C-3 and C-5); 6.82
(d, 4H, aryl protons ortho to the substituent); 7.08 (d, 4H, aryl
protons meta to the substituent) 7.96 (d, 1H, H-c proton of benzo-
triazole); 7.24e7.40 (m, 3H, H-b proton in benzotriazole). 13C NMR
2
(
0000 and C-60000); 1.06 (d, 6H, J ¼ 6.90 Hz, CH3 at C-3 and C-5).13C NMR
d ppm): 61.020 (C-2 and C-6); 45.696 (C-3 and C-5); 210.704 (C]O
at C-4); 169.267 (NeC]O); 132.797 (C-20 and C-60 ipso); 159.469 (C-
2
0000 and C-60000 ipso); 137.986 (C-a Carbon of imidazole ring); 120.100
(d ppm): 50.907 (C-2 and C-6); 45.610 (C-3 and C-5); 210.697 (C]O
(C-b Carbon of imidazole ring); 130.284, 129.343, 128.816 (C-200 and
C-600) 114.219,114.519 (C-2000 and C-6000); 48.970 (NeCOCH2); 55.386
(OCH3 at C-20000 and C-60000), 14.241 (CH3 at C-3 and C-5).
at C-4); 167.907 (NeC]O); 132.601 (C-20 and C-60 ipso carbon);
159.346 (C-20000 and C-40000); 128.836, 128.002 124.480, 119.683,
114.432,109.954 (other aryl carbons); 55.340 (OCH3 at C-20000 and C-
6
0000); 14.083 (CH3 at C-3 and C-5).
5.1.7. 1-[2-(1H-benzotriazol-1-yl)acetyl]-3,5-dimethyl-2,6-bis(m-
fluorophenyl)piperidin-4-one (23)
5.1.9. 1-[2-(1H-benzotriazol-1-yl)acetyl]-3-ethyl-2,6-bis(p-fluoro-
phenyl)piperidin-4-one (25)
Awhiteyellowsolid;yield(69%);mp 161 ꢁC; IR (cmꢀ1):3064, 2921,
2851 (CeH stretching); 1717 (C]O stretching); 1663 and 1613 (NeC]
O and C]N stretching); 1588, 1490, 1454, 1386,1319, 1274, 1240, 1133,
A pale yellow solid; yield (64%); mp 154 ꢁC; IR (cmꢀ1): 3072,
2969, 2934, 2871 (CeH stretching); 1719 (C]O stretching); 1653
Table 5
In vitro antifungal activity of compounds 17e26 against selected fungal strains.
Compounds
Minimum inhibitory concentration (MIC) in mg/ml
C. neoformans (ATCC-3235)
C. albicans (ATCC-3430)
Rhizopus sp. (ATCC-2842)
A. niger (ATCC-635)
A. flavus(ATCC-525)
17
18
19
20
21
22
23
24
100
50
25
100
6.25
50
100
200
100
50
100
200
100
e
100
100
50
200
25
100
100
6.25
e
200
e
100
200
100
100
e
12.5
100
100
e
50
6.25
e
100
200
e
200
12.5
50
100
50
50
25
26
200
100
25
50
50
50
25
25
Amphotericin-B
25
d, no inhibition even at maximum concentration.

R. Ramachandran et al. / European Journal of Medicinal Chemistry 46 (2011) 1926e1934
1933
and 1605 (NeC]O and C]N stretching); 1509, 1456, 1392, 1228,
minimum inhibitory concentrations (MICs) were recorded by visual
observations after 24 h (for bacteria) and 72e96 h (for fungi except
C. albicans) of incubation. Streptomycin and Amphotericin B were
used as standards for bacterial and fungal study, respectively.
1266, 1163, 1093, 1011, 955, 834, 749, 668, 597 and 520 (other
stretching frequency). 1H NMR (
d ppm): 6.02 (bs,1H, H-2a); 5.14 (bs,
1H, H-6a); 5.50e5.68 (m, 2H, NCOCH2); 3.03 (dd, 2J5a5e ¼ 17.00 Hz),
3J5a6a ¼ 8.00 Hz, 1H, H-5a; 2.85e2.97 (m, 1H, H-3a); 2.68 (m, 1H, H-
5e); 1.50e1.58 (m, 2H, CH2 CH3); 0.88, t, 2H (J ¼ 7.25 Hz, CH2 CH3);
6.89e7.53 (m, 11H, aryl protons); 8.08 (d, 1H, J ¼ 8.3 Hz, H-c proton
Acknowledgements
of benzotriazole). 13C NMR (
d
ppm): 55.763 (C-2); 54.759 (C-6);
We thank NMR Research Centre, Indian Institute of Science
Bangalore, for providing NMR facilities to record NMR spectra and
Department of Chemistry & SAIF, Indian Institute of Technology e
Madras for recording X-ray Data collection.
52.553 (C-3); 44.032 (C-5); 207.516 (C]O at C-4); 167.742 (NeC]
O); 163.510 & 161.061 (C-20000 and C-60000); (146.185 (C-20 and C-60
ipso)); 136.185, 133.546, 130.733, 129.328, 128.289, 128.070,
127.572, 124.281, 120.282, 116.409, 116.200, 115.952, 115.737,
115.422, 109.805 (other aryl carbons); 56.736 (NeCOCH2); 23.222
(CH2 at CH2 CH3); 11.476 (CH3 at CH2 CH3).
References
[1] (a) A.R. Katritzky, A.K. Verma, H. He, R. Chandra, Novel synthesis of 1,2,3,4-
tetrahydropyrazino[1,2-a]indoles, J. Org. Chem. 68 (2003) 4938e4940;
(b) R.K. Tiwari, J. Singh, D. Singh, A.K. Verma, R. Chandra, Highly efficient one-pot
synthesis of 1-substituted-1,2,3,4-tetrahydropyrazino[1,2-a]indoles, Tetrahe-
dron 61 (2005) 9513e9518;
(c) A.R. Katritzky, X. Lan, J.Z. Yang, O.V. Denisko, Properties andsynthetic utility of
N-substituted benzotriazoles, Chem. Rev. 98 (1998) 409e548.
[2] R.K. Tiwari, D. Singh, J. Singh, V. Yadav, A.K. Phatak, R. Dabur, A. Chhillar,
R. Singh, G.L. Sharma, R. Chandra, A.K. Verma, Synthesis and antibacterial
activity of substituted 1,2,3,4-tetrahydropyrazino [1,2-a] indoles, Bioorg. Med.
Chem. Lett. 16 (2006) 413e416.
5.1.10. 1-[2-(1H-benzotriazol-1-yl)acetyl]-3,5-dimethyl-2,6-bis(p-
fluorophenyl)piperidin-4-one (26)
A pale yellow solid; yield (68%); mp 208 ꢁC; IR (cmꢀ1): 3090,
2969, 2923, 2853 (CeH stretching); 1716 (C]O stretching); 1647,
1604 (N-C]O and C]N stretching); 1510, 1457, 1396, 1321, 1285,
1231, 1162, 1095, 1019, 839, 750, 671, 588, 534 (other stretching
frequency). 1H NMR (
d ppm): 5.40 (bs, 2H, H-2a and H-6a); 3.02 (m,
2H, H-3a and H-5a); 5.22 (s, 2H, NCOCH2); 0.94 (d, 6H, J ¼ 6.80 Hz,
[3] K.Z. Katarzyna, N. Andzelika, Z. Justyna, C. Lidia, P. Janusz, M. Przemys1aw,
B. Maria, Synthesis and activity of 1H-benzimidazole and 1H-benzotriazole
derivatives as inhibitors of Acanthamoeba castellanii, Bioorg. Med. Chem. 12
(2004) 2617e2624.
CH3 at C-3 and C-5); 7.98 (d, 2H, H-a proton of benzotriazole);
6.81e7.42 (aryl protons). 13C NMR (
d ppm): 50.40 (C-2 and C-6);
45.53 (C-3 and C-5); 60.713, NCOCH2; 209.63 (C]O at C-4); 167.99
(NeC]O); 145.62 (C-20 and C-60 ipso carbon); 161.58 & 161.10 (C-20000
and C-40000); 136.33, 136.30, 133.542, 130.74, 129.39, 124.38, 116.31,
116.10, 109.75 (other aryl carbons); 14.053 (CH3 at C-3 and C-5).
[4] M.D. Kamal, A.G. Hassan, E. Mohey, A.M. Hanan, H. Bahira, Synthesis,
anticonvulsant, and anti-inflammatory evaluation of some new benzo-
triazole and benzofuran-based heterocycles, Bioorg. Med. Chem. 14 (2006)
3672e3680.
[5] Y.A. Al-Soud, N.A. Al-Masoudi, A.S. Ferwanah, Synthesis and properties of new
substituted 1,2,4-triazoles: potential antitumor agents, Bioorg. Med. Chem. 11
(2003) 1701e1708.
[6] C.Y. Wu, K.Y. King, C.J. Kuo, J.M. Fang, Y.T. Wu, M.Y. Ho, C. L Liao, J.J. Shie,
P.H. Liang, C.H. Wong, Stable benzotriazole esters as mechanism-based inac-
tivators of the severe acute respiratory syndrome 3CL protease, Chem. Biol. 13
(2006) 261e268.
[7] (a) Shinohara, Ken-Ichi, Anticancer activities of alkylating pyrrole-imidazole
polyamides with specific sequence recognition, Anti-Cancer Drugs 21 (2010)
228e242;
5.2. Recording of single crystal XRD
Suitable crystals of the thiadiazoles 4a and 5c were grown
from ethanol at room temperature. The data collection was carri-
ed out on Bruker APEXII CCD area detector diffractometer [21].
Graphite monochromatic Mo K
a
radiation (
l
¼ 0.71073 Ǻ) was
(b) Yaseen A. Al-Soud, Najim A. Al-Masoudi, Abd El-Rahman S. Ferwanah,
Synthesis and properties of new substituted 1,2,4-triazoles: potential anti-
tumor agents, Bioorg. Med. Chem. 11 (2003) 1701e1708;
(c) J. Fatimi, J.F. Lagorce, J.L. Duroux, M.L. Chabernaud, J. Buxeraud, C. Raby,
1,4,5-Trialkyl imidazole system anti-inflammatory properties of new
substituted derivatives, Chem. Pharm. Bull. 42 (1994) 698e701;
(d) Lee R. Roberts, Justin Bryans, Kelly Conlon, Gordon McMurray,
Alan Stobie, Gavin A. Whitlock, Novel 2-imidazoles as potent, selective and
CNS penetrant a1A adrenoceptor partial agonists, Bioorg. Med. Chem. Lett. 18
(2008) 6437.
used throughout. The structures were solved by direct methods
(SHELXS97) [22], which revealed the position of all non-hydrogen
atoms and refined by full-matrix least-squares method (SHELXL97).
Hydrogen atoms were geometrically fixed and were given riding
model refinement. Molecular graphics and geometric calculations
were obtained from ORTEP-3 [23].
5.3. Pharmacology
[8] S. Emami, M. Falahati, A. Banifatemi, A. Shafiee, Stereoselective synthesis and
antifungal activity of (Z)-trans-3-azolyl-2-methylchromanone oxime ethers,
Bioorg. Med. Chem. 12 (2004) 5881e5889.
The bacterial strains viz., S. aureus (ATCC-25930), B. subtilis
(ATCC-530), S. typhi (ATCC-25021), E. coli (ATCC-26032) and
K. pneumonia (ATCC-16425) and fungal strains viz., C. albicans
(ATCC-3430), Crytococcus neoformans (ATCC-3235), R. species
(ATCC-2842), A. niger (ATCC-635) and A. flavus (ATCC-525) are
procured from National Chemical Laboratory, Pune, India.
[9] G. Biagi, I. Giorgi, O. Livi, V. Scartoni, P.L. Barili, V. Calderone, Synthesis and
antiproliferative activity of 3-aryl-2-[1H(2H)-benzotriazol-1(2)-yl]acryloni-
triles variously substituted: part 4, Il Farmaco 56 (2001) 827e834.
[10] G. Scapin, S.B. Patel, J.W. Becker, Q. Wang, C. Desponts, D. Waddleton,
K. Skorey, W. Cromlish, C. Bayly, M. Therien, J.Y. Gauthier, C.S. Li, C.K. Lau,
C. Ramachandran, B.P. Kennedy, Asante-Appiah E 42 (2003) 11,451e11,459.
[11] C. Antonio, P. Michele, B. Gianpiero, B. Bernardetta, M. Marta, L. Roberta,
Synthesis and antiproliferative activity of 3-aryl-2-[1H(2H)-benzotriazol-1(2)-
yl]acrylonitriles variously substituted: part 4, Il Farmaco 59 (2004) 637e644.
[12] R. Ramachandran, M. Rani, S. Kabilan, Design, synthesis and biological eval-
uation of novel 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydra-
zono]-1,3-thiazolidin-4-ones as a new class of antimicrobial agents, Bioorg.
Med. Chem. Lett. 19 (2009) 2819e2823.
[13] M. Rani, R. Ramachandran, S. Kabilan, Efficient synthesis, spectral analysis and
antimicrobial studies of nitrogen and sulfur containing spiro heterocycles
from 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones, Bioorg. Med. Chem. Lett. 20
(2010) 6637e6643.
[14] P. Parthiban, G. Aridoss, P. Rathika, V. Ramkumar, S. Kabilan, Synthesis, spectral,
crystal and antimicrobial studies of biologically potent oxime ethers of nitrogen,
oxygen and sulfur heterocycles, Bioorg. Med. Chem. Lett. 19 (2009) 2981e2985.
[15] P. Parthiban, G. Aridoss, P. Rathika, V. Ramkumar, S. Kabilan, Synthesis,
stereochemistry and antimicrobial studies of novel oxime ethers of aza/dia-
zabicycles, Bioorg. Med. Chem. Lett. 19 (2009) 6981e6985.
5.3.1. In vitro antibacterial and antifungal activity
In vitro activities of the compounds were tested in Sabourauds
dextrose broth (SDB) for fungi and in Nutrient broth (NB) for
bacteria by the two-fold serial dilution method [24]. Seeded broth
(broth containing microbial spores) was prepared in NB from 24 h
old bacterial cultures on nutrient agar (Hi-media, India) at 37 ꢄ 1 ꢁC
while fungal spores from 24 h to 7 days old Sabourauds agar slant
cultures were suspended in SDB. The bacterial suspension was
adjusted with sterile saline to a concentration of 1 ꢂ104e105 CFU.
The tested compounds and reference drugs were prepared by two-
fold serial dilution to obtain the required concentrations of 200,
100, 50 25, 12.5 and 6.25 mg/mL. The tubes were incubated in BOD
[16] C.R. Noller, V. Baliah, The preparation of some piperidine derivatives by the
mannich reaction, J. Am. Chem. Soc. 970 (1948) 3853e3855.
incubators at 37 ꢄ 1 ꢁC for bacteria and 28 ꢄ 1 ꢁC for fungi. The

1934
R. Ramachandran et al. / European Journal of Medicinal Chemistry 46 (2011) 1926e1934
[17] (a) G. Aridoss, S. Balasubramanian, P. Parthiban, S. Kabilan, Synthesis,
stereochemistry and antimicrobial evaluation of some N-morpholinoacetyl-
2,6-diarylpiperidin-4-ones, Eur. J. Med. Chem. 41 (2007) 851e860;
[20] A. Greenberg, T.D. Thomas, C.R. Berilacqua, M. Coville, D. Ji, J.C. Tsai, G.J. Wu,
Determination of the nitrogen N1s and oxygen O1s core energies in planar
and distorted lactams and amides: relationships with the concept of reso-
nance, J. Org. Chem. 57 (1992) 7093e7099.
[21] Bruker, APEXII and SAINT-Plus, Area Detector Control and Integration Soft-
ware. Bruker AXS Inc., Madison, WI, USA, 2004.
[22] G.M. Sheldrick, SHELXS97 and SHELXL97, Program for the refinement of
crystal structures, University of Gottingen: Germany, 2003; G.M. Sheldrick,
Acta Cryst A64 (2008) 112e122.
(b) G. Aridoss, P. Parthiban, R. Ramachandran, M. Prakash, S. Kabilan,
Y.T. Jeong, Synthesis and spectral characterization of a new class of N-(N-
methylpiperazinoacetyl)e2,6ediarylpiperidin-4-ones: antimicrobial, anal-
gesic and antipyretic studies, Eur. J. Med. Chem. 44 (2009) 577e592.
[18] R. Krishnakumar, M. Krishnapillai, A. Nagarajan, G. Jeyaraman, Conforma-
tional analysis of some heterocyclic systems: part II
e conformational
analysis of substituted N-benzoylpiperidin-4-ones, Ind. J. Chem. 39B (2000)
419e425.
[19] R. Krishnakumar, M. Krishnapillai, Conformational analysis of some hetero-
cyclic systems: part 1 e conformational analysis of substituted N-phenyl
carbamoylpiperidin-4-ones, Ind. J. Chem. 35B (1996) 418e425.
[23] L.J. Farrugia, ORTEP-3 for Windows, J. Appl. Cryst 30 (1997) 565.
[24] National Committee for Clinical Laboratory Standards, in: Methods for Dilu-
tion Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, fifth
ed. National Committee for Clinical Laboratory Standards, Villanova, PA, 2000
Approved Standard. NCCLS Document M7-A5.