Synthesis, stereochemical, structural and biological studies of some 2,6-diarylpiperidin-4-one N(40)-cyclohexyl thiosemicarbazones

Article abstract of DOI:10.1016/j.molstruc.2013.05.008

A new series of 2,6-diarylpiperidin-4-one N(40)-cyclohexyl thiosemicarbazones (13-23) were synthesized by corresponding 2,6-diarylpiperidin-4-ones (1-11) reaction with cyclohexyl thiosemicarbazide (12). The chemical structures were confirmed by means of IR, one and two dimensional NMR, Mass spectra and single crystal X-ray diffraction analysis. Compounds 13-23, exist in chair conformation with equatorial orientation of all the substituents at piperidine ring except the methyl group at C-5 of compounds 21-23 oriented at axial disposition to stabilize the chair conformation. Single crystal X-ray structural analysis of compound 18, evidences that the configuration about C@N double bond is syn to C-5 carbon (E-form). All the synthesized compounds were screened their biological activity.

Full text of DOI:10.1016/j.molstruc.2013.05.008

Journal of Molecular Structure 1047 (2013) 237–248
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, stereochemical, structural and biological studies of some
2,6-diarylpiperidin-4-one N(40)-cyclohexyl thiosemicarbazones
⇑
A. Sethukumar, C. Udhaya Kumar, R. Agilandeshwari, B. Arul Prakasam
Department of Chemistry, Annamalai University, Annamalainagar, 608 002 Chidambaram, India
h i g h l i g h t s
ꢀ
ꢀ
ꢀ
Synthesis of 2,6-diarylpiperidin-4-one N(40)-cyclohexyl thiosemicarbazones.
Spectral and stereochemical analysis by means of 1D NMR, 2D NMR, and single crystal X-ray diffraction analysis.
Screening of compounds for antibacterial and antifungal activities.
a r t i c l e i n f o
a b s t r a c t
A new series of 2,6-diarylpiperidin-4-one N(40)-cyclohexyl thiosemicarbazones (13–23) were synthesized
by corresponding 2,6-diarylpiperidin-4-ones (1–11) reaction with cyclohexyl thiosemicarbazide (12). The
chemical structures were confirmed by means of IR, one and two dimensional NMR, Mass spectra and
single crystal X-ray diffraction analysis. Compounds 13–23, exist in chair conformation with equatorial
orientation of all the substituents at piperidine ring except the methyl group at C-5 of compounds 21–
23 oriented at axial disposition to stabilize the chair conformation. Single crystal X-ray structural analysis
of compound 18, evidences that the configuration about C@N double bond is syn to C-5 carbon (E-form).
All the synthesized compounds were screened their biological activity.
Article history:
Received 8 March 2013
Received in revised form 7 May 2013
Accepted 7 May 2013
Available online 16 May 2013
Keywords:
Piperidone
Cyclohexyl thiosemicarbazone
Antibacterial activity
Antifungal activity
Single crystal XRD
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
the thiosemicarbazone contained aliphatic amine moieties at 4th
position, the effect was more obvious [27]. The in vitro cytotoxici-
Heterocyclic ring systems having the piperidin-4-one nucleus
have aroused great interest in the past and recent years due to
their wide variety of biological properties, such as analgesic [1,2],
anti-inflammatory [1], central nervous system (CNS) depressants
[3–7], local anaesthetic [3,8], anticancer [9] and antimicrobial
activity [10].
Thiosemicarbazones were reported to be associated with anti-
microbial activity [11–13]. Several semicarbazones, as well as their
sulfur analogues and its derivatives, have proved their efficiency
and efficacy in combating various diseases [14]. It is of great inter-
est because of their chemistry and potentially beneficial biological
activities such as antitumour, antibacterial, antiviral, antimalarial
and antiprotozoal activities [15–18]. Semicarbazones have docu-
mented consistent advances in the design of novel anticonvulsant
agents, through the work of Dimmock and others [19–26]. When
ties of the liquiritigenin thiosemicarbazone derivatives against
K562 (human leukemia cell line), DU-145 (human prostate carci-
noma cell line), SGC-7901 (human gastric cancer cell line), HCT-
116 (human colon cancer cell line) and Hela (human cervical car-
cinoma cell line) cells were evaluated. The cytotoxicities of the
resulting liquiritigenin thiosemicarbazone derivatives appeared
to be related to the nature of the substituent group at thiocarbonyl.
From the structure activity relationship results the introduction of
thiosemicarbazone at 4th position in liquiritigenin is associated
with enhanced cytotoxic activity. By considering the synthetic
and biological significance of piperidin-4-one thiosemicarbazones,
it was thought worthwhile to synthesize and screen their biologi-
cal activity. A new series of 2,6-diarylpiperidin-4-one N(40)-cyclo-
hexyl thiosemicarbazones (13–23) were synthesized and
characterized by IR, Mass, NMR (1H, 13C, 1H–1H COSY, 1H–13C COSY,
HMBC and NOESY) spectra and single crystal X-ray diffraction
techniques. The synthesized compounds were screened for their
antibacterial and antifungal activity.
⇑
Corresponding author. Tel.: +91 9443583619.
E-mail address: arul7777@yahoo.com (B. Arul Prakasam).
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.05.008

238
A. Sethukumar et al. / Journal of Molecular Structure 1047 (2013) 237–248
2.3. In vitro antibacterial and antifungal activity
2. Experimental
2.1. Materials and methods
The in vitro activities of the compounds were tested in sabou-
rauds dextrose broth (SDB) (Hi-media, Mumbai) for fungi and
nutrient broth (NB) (Hi-media, Mumbai) for bacteria by the two-
fold serial dilution method [31]. The test compounds were dis-
solved in dimethylsulfoxide (DMSO) to obtain 1 mg mlꢁ1 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 1 to
7 days old sabourauds agar (Hi-media, Mumbai) slant cultures
were suspended in SDB. The colony forming units (cfu) of the
seeded broth were determined by plating technique and adjusted
in the range of 102–105 cfu mlꢁ1. The final inoculum size was 105 -
cfu mlꢁ1 for antibacterial assay and 1.1–1.5 ꢂ 102 cfu mlꢁ1 for anti-
fungal assay. Testing was performed at pH 7.4 0.2. 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 con-
taining only inoculated broth was kept as control and likewise sol-
vent controls were also seen simultaneously. The tubes were
incubated in BOD incubators at 37 1 °C for bacteria and
28 1 °C for fungi. The MICs were recorded by visual observations
after 24 h (for bacteria) and 72–96 h (for fungi) of incubation.
Ampicillin and amphotericin-B were used as standards.
All the chemicals were commercial and were obtained from Sig-
ma–Aldrich and were used as received. The melting points were re-
corded in open capillaries and are uncorrected. IR spectra were
recorded in AVATAR 330 FT-IR Thermo Nicholet spectrophotome-
ter (range 4000–400 cmꢁ1) as KBr pellets. 1H NMR spectra were re-
corded on Bruker AMX-400 spectrometer operating at 400.23 MHz
and Bruker AVIII 500 MHz spectrometer operating at 500.3 MHz
using TMS as internal reference. 13C NMR spectra were recorded
on Bruker AMX-400 spectrometer operating at 100.63 MHz and
Bruker AVIII 500 MHz spectrometer operating at 125.75 MHz.
1H–1H COSY, HSQC, HMBC and phase-sensitive NOESY spectra of
18 were recorded on a Bruker DRX-500 NMR spectrometer using
standard parameters. Mass spectra were measured on a JEOL GC
MATE II spectrometer.
2.1.1. X-ray crystallography
Crystal was grown by slow evaporation technique using ethanol
as solvent. Diffraction data were collected on a Bruker, 2004 APEX
2 diffractometer using graphite-monochromated Mo K
(K = 0.71073 Å) at 293 K with crystal
a
radiation
size of
0.30 ꢂ 0.20 ꢂ 0.20 mm. The structure was solved by direct meth-
ods and successive Fourier difference syntheses (SHELXS-97) [28]
and refined by full matrix least square procedure on F2 with aniso-
tropic thermal parameters. All non-hydrogen atoms were refined
(SHELXL-97) [29] and placed at chemically acceptable positions.
A total of 696 parameters were refined with 8113 unique reflec-
tions which covered the residuals to R1 = 0.0435. Crystallographic
data have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 893461
for 18. Copies of the data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336 033: or e-mail:
deposit@ccdc.cam.ac.uk.
3. Results and discussion
3.1. IR Spectral characterization of compounds 13–23
IR spectra of the synthesized compounds (13–23) showed the
absence of C@O stretching frequency around 1720–1700 cmꢁ1
and the presence of C@N and C@S stretching frequencies around
1533–1516 cmꢁ1 and 1247–1205 cmꢁ1 confirms the condensation
of 2,6-diarylpiperidin-4-one with cyclohexyl thiosemicarbazide.
Besides, the target compounds were confirmed by the presence
of cyclohexyl thiosemicarbazone NAH stretching frequency
around 3357–3171 cmꢁ1 and also the intense aliphatic stretching
frequency around 2854–2848 cmꢁ1 due to the presence of cyclo-
hexyl ring. IR spectral data were presented in Table 2.
2.2. Synthesis of 2,6-diarylpiperidin-4-one N(40)-
cyclohexylthiosemicarbazones
2.2.1. 2,6-Diarylpiperidin-4-ones (1–11)
3.2. 1H NMR spectral analysis of compound 18
Piperidin-4-ones 1–11, were prepared following the procedure
of Noller and Baliah [30]. Dry ammonium acetate (100 mmol)
was dissolved in ethanol and the solution was mixed with appro-
priated ketones (2-butanone, 3-methyl-2-butanone, 4-methyl-2-
pentanone, 3-pentanone) (100 mmol) and appropriate substituted
benzaldehyde (200 mmol). The mixture was just heated to boil and
allowed to stand at room temperature overnight. The reaction mix-
ture was diluted with ether (100 ml) and treated with Conc. HCl
(20 ml). The precipitated hydrochloride was washed with etha-
nol–ether mixture. The hydrochloride was suspended in acetone
and neutralized with aqueous ammonia. Dilution with water gave
the free base which was recrystallized from ethanol.
The spectroscopic numbering of carbon atoms in 13–23 is
shown in Scheme 1. Protons are numbered accordingly. Thus, the
proton at C-2 is denoted as H-2 and that at C-50 is denoted as H-
50. Compound 18, was taken as a representative and the signals
were assigned based on the correlations in the 2D spectra. For
the remaining compounds the signals were assigned based on their
positions, multiplicity and integral values and by comparing with
18 and previous piperidone analogues using known effects
[32,33] of the OMe and F substituent in the aryl rings. The observed
1H and 13C chemical shifts are given in Tables 3 and 5 respectively.
The 1H–1H coupling constants and 2D spectral correlations are gi-
ven in Tables 4 and 6 respectively. The 1D and 2D NMR spectra of
compound 18 were shown in Figs. 1–6.
2.2.2. 2,6-Diarylpiperidin-4-one N(40)-cyclohexylthiosemicarbazones
(13–23)
Thiosemicarbazones (13–23) were synthesized by refluxing a
mixture of respective 2,6-diarylpiperidin-4-one (1–11) (25 mmol)
and cyclohexylthiosemicarbazide 12 (25 mmol) in methanol
(10 ml) containing few drops of acetic acid for 1 h. The separated
solid was washed with ice-cold water and was recrystallized from
methanol. The physical data for the synthesized compounds (13–
23) are given in Table 1.
The 1H NMR spectrum of compound 18 showed two broad sig-
nals in the downfield region. The singlet at 8.44 ppm with one pro-
ton integral, and a doublet at 7.54 ppm with one proton integral
are due to NH proton of –NHCS and CSNH–Cy group respectively
in the thiosemicarbazone moiety. The piperidin NH proton reso-
nate in up field region of 1.93 ppm as singlet. Methyl group (a,e)
protons at C-3, appear as two separate singlets due to c-gauche ef-

A. Sethukumar et al. / Journal of Molecular Structure 1047 (2013) 237–248
239
Table 1
Physical data of compounds 13–23.
Compound
R1
R2
R3
X
Yield (%)
Melting point (°C)
Mass
13
14
15
16
17
18
19
20
21
22
23
CH3
CH3
CH3
CH(CH3)2
CH(CH3)2
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
F
OCH3
H
F
H
F
OCH3
H
F
86
80
80
85
85
90
85
86
85
80
80
172–174
198–200
184–186
202–204
192–194
194–196
198–200
188–190
208–210
204–206
198–200
420.4
457.1
481.0
448.4
485.0
434.8
471.0
495.0
434.6
–
H
CH3
CH3
CH3
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
OCH3
495.0
Table 2
IR spectral data of compounds 13–23.
Compound
mNAH
mCAH (Aromatic)
mCAH (Alipahatic)
mC=N
mC=S
13
3357
3216
2967
2934
2854
2810
1517
1516
1533
1527
1528
1525
1525
1221
14
15
16
17
18
19
3357
3214
2969
2936
2854
2810
1222
1246
1205
1219
1207
1218
3324
3194
2928
2854
2848
2852
2852
3330
3171
3030
2929
3342
3183
3030
2926
3319
3184
3030
2925
3319
3181
3046
2975
2930
2854
2810
20
21
3347
3183
2975
2926
2850
2852
1524
1527
1245
1205
3342
3194
3030
2969
2926
22
23
3342
3342
2926
2926
2853
2853
1516
1523
1231
1247
fect at 1.06 and 1.22 ppm and among the two signals the shielded
one is assigned to axial methyl protons.
A singlet at 3.76 ppm and a doublet of doublet at 3.86 ppm
are assigned for benzylic protons H-2a and H-6a, respectively.
Moreover, there are two double doublets one at 2.75 ppm with
coupling constant values 14.00 Hz J25a;5eÞ=3:00 Hz ðJ36a;5eÞ and the
other at 2.40 ppm with coupling constant values 14.00 Hz
ðJ25a;5eÞ=11:50 Hz ðJ63a;5aÞ. The large vicinal and germinal coupling
constant values reveal that the double doublet at 2.40 ppm is
due to the resonance of axial proton at C-5 (H-5a). The remaining
proton signal at 2.75 ppm is unambiguously assigned for H-5e.
Cyclohexyl ring protons appear in the down field region as they
are slightly deshielded. A multiplet at 4.31–4.35 ppm with one
proton integral is assigned to H-10a in C-10. The observed deshiel-
Scheme 1. Schematic diagram showing the synthesis of compounds 13–23.
3.2.1. Conformational analysis of 13–23
Based on a previous study [34], the parent piperidin-4-ones
(1–11) should exist in chair conformation. In these conformations
the aryl groups are equatorial and the alkyl group at C-3 is equato-
rial in the 3t-alkyl compounds. The coupling constant values and
position of the chemical shifts were used to predict the conforma-
tion of the compounds. The observations of large vicinal coupling
constant values between 9.20–10.0 ðJ32a;3aÞ and 11.20–11.60 Hz
ðJ36a;5aÞ and of small value of the vicinal coupling constants of 2.4–
3.2 Hz ðJ36a;5eÞ for the protons of C-6 and C-2 of the synthesized
compounds 13–20 indicate that the six-membered heterocyclic
ring of compounds 13–20 adopts normal chair conformation
(Fig. 7) with equatorial orientation of phenyl groups at C-2 and
C-6, and equatorial orientation of methyl group at C-3. However,
compounds 18–20, which have two methyl groups at C-3 carbon
and in these compounds one of the methyl group should have
the axial orientation and the remaining one is equatoraialy
oriented [35,36]. Furthermore, equatorial disposition of phenyl
ding is due to the presence of electronegative nitrogen atom at
a
position. H-20e/H-60e and H-20a/H-60a resonates at 2.09–2.14 and
1.35–1.38 ppm respectively as multiplets. In the up field region
there are two multiplets at 1.72–1.77 and 1.47–1.51 ppm due to
H-30e/H-50e and H-30a/H-50a protons. The H-40e and H-40a protons
were observed at 1.64–1.67 and 1.31–1.33 ppm respectively.
The ortho, meta and para protons of phenyl group attached at
C-2 and C-6 carbons of piperidin ring gives separate signals. ortho
protons are deshielded by the lone pair of electrons on the nitrogen
while the meta and para protons are shielded and resonate in the
upfield region.

Table 3
1H chemical shift (ppm) values of compounds 13–23.
Proton
Compound
13
14
15
16
17
18
19
20
21
22
23
–NHCS
8.54 (s)
8.58 (s)
8.50 (s)
8.54 (s)
8.44 (s)
8.44 (s)
8.59 (s)
8.43 (s)
8.53 (s)
8.57 (s)
8.52 (s)
CSNH–Cy
NH
7.51 (d)
1.79 (s)
7.49 (d)
1.99 (s)
7.51 (d)
1.96 (s)
7.50 (d)
–
8.74 (d)
1.80 (s)
7.54 (d)
1.93 (s)
7.50 (d)
1.93 (s)
7.51 (d)
1.81 (s)
7.56 (d)
1.83 (s)
7.56 (d)
1.80 (s)
7.58 (d)
1.79 (s)
H-2a
3.51 (d)
3.50 (d)
3.45 (d)
3.97 (d)
3.92 (d)
3.76 (s)
3.72 (s)
3.67 (s)
4.08 (d)
4.08 (d)
4.03 (d)
H-3a
H-5e
H-5a
2.54–2.63 (m)
2.87 (dd)
2.20 (dd)
2.48–2.55 (m)
2.86 (dd)
2.15 (dd)
2.48–2.56 (m)
2.83 (dd)
2.17 (dd)
2.64 (dd)
2.83 (dd)
2.35 (dd)
2.49 (dd)
2.76 (dd)
2.22 (dd)
–
–
–
2.69–2.77 (m)
2.94–2.99 (m)
–
2.67–2.71 (m)
2.95–2.97 (m)
–
2.68–2.71 (m)
2.91–2.93 (m)
–
2.75 (dd)
2.40 (dd)
2.76 (dd)
2.32 (dd)
2.68 (dd)
2.33 (dd)
H-6a
3.86 (dd)
3.84 (dd)
3.79 (dd)
3.99 (dd)
3.92 (dd)
3.86 (dd)
3.83 (d)
3.76 (d)
3.49 (d)
3.50 (d)
3.84 (d)
H-10a
4.27–4.34 (m)
2.04–2.11 (m)
1.28–1.36 (m)
1.69–1.73 (m)
1.42–1.47 (m)
1.60–1.63 (m)
1.23–1.27 (m)
7.44–7.46 (m)
7.44–7.46 (m)
7.32–7.37 (m)
7.32–7.37 (m)
7.26–7.29 (m)
4.24–4.33 (m)
2.05–2.09 (m)
1.26–1.36 (m)
1.69–1.73 (m)
1.39–1.50 (m)
1.61–1.65 (m)
1.20–1.24 (m)
7.02–7.07 (m)
7.02–7.07 (m)
7.40–7.50 (m)
7.40–7.50 (m)
–
4.26–4.34 (m)
2.05–2.10 (m)
1.26–1.36 (m)
1.65–1.75 (m)
1.43–1.50 (m)
1.61–1.64 (m)
1.20–1.28 (m)
7.35 (d)
7.35 (d)
6.87 (d)
6.88 (d)
–
4.27–4.37 (m)
2.08–2.12 (m)
1.32–1.36 (m)
1.73–1.76 (m)
1.44–1.50 (m)
1.64–1.76 (m)
1.27–1.30 (m)
7.44–7.46 (m)
7.51–7.52 (m)
7.35–7.37 (m)
7.38–7.41 (m)
7.29–7.34 (m)
4.24–4.31 (m)
2.05–2.08 (m)
1.26–1.31 (m)
1.68–1.72 (m)
1.41–1.49 (m)
1.60–1.64 (m)
1.20–1.24 (m)
7.36–7.39 (m)
7.41–7.43 (m)
7.00–7.03 (m)
7.04–7.06 (m)
–
4.31–4.35 (m)
2.09–2.14 (m)
1.35–1.38 (m)
1.72–1.77 (m)
1.47–1.51 (m)
1.64–1.67 (m)
1.31–1.33 (m)
7.46–7.47 (m)
7.51–7.53 (m)
7.33–7.36 (m)
7.38–7.41 (m)
7.31–7.33 (m)
4.26–4.30 (m)
2.01–2.12 (m)
1.31–1.37 (m)
1.68–1.77 (m)
1.41–1.51 (m)
1.60–1.67 (m)
1.25–1.28 (m)
7.39–7.42 (m)
7.47–7.49 (m)
6.99–7.03 (m)
7.03–7.08 (m)
–
4.28–4.34 (m)
2.04–2.12 (m)
1.32–1.37 (m)
1.72–1.78 (m)
1.42–1.52 (m)
1.60–1.66 (m)
1.25–1.29 (m)
6.84–6.86 (m)
7.39–7.41 (m)
6.88–6.91 (m)
7.33–7.35 (m)
–
4.27–4.35 (m)
2.06–2.11 (m)
1.41–1.51 (m)
1.70–1.74 (m)
1.29–1.37 (m)
1.61–1.65 (m)
1.23–1.27 (m)
7.25–7.26 (m)
7.47–7.49 (m)
7.31–7.40 (m)
7.31–7.40 (m)
7.31–7.40 (m)
4.30–4.34 (m)
2.07–2.12 (m)
1.31–1.35 (m)
1.71–1.75 (m)
1.45–1.50 (m)
1.63–1.66 (m)
1.23–1.26 (m)
7.36–7.39 (m)
7.45–7.47 (m)
7.04–7.07 (m)
7.08–7.11 (m)
–
4.32–4.35 (m)
2.08–2.14 (m)
1.31–1.36 (m)
1.73–1.76 (m)
1.46–1.51 (m)
1.64–1.66 (m)
1.23–1.29 (m)
7.30 (d)
7.41 (d)
6.89 (d)
6.93 (d)
–
H-20e, H-60e
H-20a, H-60a
H-30e, H-50e
H-30a, H-50a
H-40e
H-40a
H-200, H-600
H-2000, H-6000
H-300, H-500
H-3000, H-5000
H-400, H-4000
3-Alkyl protons
CH3
0.88 (d)
–
–
0.87 (d)
–
–
0.87 (d)
–
–
0.94 (d)
1.12 (d)
1.88–1.92 (m)
0.88 (d)
1.07 (d)
1.81–1.88 (m)
1.06 (s)
1.22 (s)
–
1.01 (s)
1.17 (s)
–
1.00 (s)
1.17 (s)
–
1.00 (d)
–
–
1.01 (d)
–
–
1.02 (d)
–
–
CH3
CH
5-Alkyl protons
CH3
p-OCH3
–
–
–
–
–
–
–
–
–
–
–
–
–
–
0.87 (d)
–
0.88 (d)
–
0.88 (d)
3.83 (s), 3.85 (s)
3.80 (s), 3.81 (s)
3.80 (s), 3.81 (s)

A. Sethukumar et al. / Journal of Molecular Structure 1047 (2013) 237–248
241
Table 4
tent of ꢃ15.0 ppm whereas C-3 is shielded only to a small extent of
ꢃ6.0 ppm. These observations are similar to those made in 3t-al-
kyl-2r,6c-diarylpiperidin-4-one oximes [37] with E configuration
about the C@N bond. Obviously, in 18–20 the configuration about
C@N bond is E (Fig. 7). In the other thiosemicarbazones also H-5e
has a higher chemical shift than H-5a and C-5 has a lower chemical
shift than C-3. Hence, in all the thiosemicarbazones (13–23) the
configuration about the C@N bond should be E and the six mem-
bered heterocyclic ring adopts chair conformation with the orien-
tation of N–NH–CS–NHCy moiety syn to the C-5 carbon (Fig. 7).
2D NMR spectral analysis suggested that the cyclohexane frag-
ment present in the compounds 13–23 also adopt a chair confor-
mation. The axial proton H-10a (at C-10 carbon in cyclohexyl ring)
orientated in anti to the NAH proton as shown in Fig. 7. It is evi-
denced that the NAH proton at 7.54 ppm has NOE with only axial
H-20a, H-60a around 1.35–1.38 ppm and there is no NOE with H-10a
around 4.31–4.35 ppm. It is also supported by the single crystal
XRD study of compound 18.
1H–1H coupling constant (Hz) values of compounds 13–23.
Compound
3J6a,5a
3J2a,3a
2J5e,5a
3J6a,5e
3J3a,alkyl
13
14
15
16
17
18
19
20
21
22
23
11.6
11.6
11.6
11.2
11.2
11.5
11.6
11.6
–
10.0
10.0
10.0
9.2
9.6
–
–
–
10.4
8.4
8.4
14.0
14.0
14.0
14.8
14.8
14.0
14.0
14.0
–
2.4
2.4
2.4
3.2
3.2
6.8
6.4
6.4
3.6
3.6
–
–
–
6.4
5.2
4.8
3.0
a
a
3.2
2.4
2.8
–
–
–
–
a
H-6 and H-5a were observed only as doublets due to poor resolution.
groups at C-2 and C-6 makes the chair conformation more rigid
thereby preventing inter-conversion from one chair into another.
In compounds 13–20 the heterocyclic ring may be flattened or dis-
torted about the C2AC3 bond to decrease gauche interaction be-
tween the equatorial phenyl group and the equatorial methyl
groups at C-2 and C-3 respectively.
3.3. 13C NMR spectral analysis of compounds 13–23
In the 13C NMR spectrum of compound 18, the aromatic carbons
are distinguished from other carbons by their characteristic
absorption in the region of 126.6–129.4 ppm. Ipso carbons of phe-
In the case compounds 21–23, which have methyl substituent
at C-3 and C-5 carbon, the methyl group at C-5 adopts axial orien-
tation in order to avoid the 1,3 spatial interaction between the
methyl and N–NH–CS–NHCy and to retain the chair conformation
(Fig. 8). The equatorial orientation of the H-5e proton is substanti-
ated from the vicinal coupling constant ðJ36a;5e ¼ 2:4—3:2 HzÞ. The
axial orientation of H-3a was confirmed from the diaxial coupling
constant value ðJ32a;3a ¼ 8:4—10:4 HzÞ. These observations suggest
that the six-membered heterocyclic ring for compounds 21–23
may take a chair conformation with equatorial orientation of the
aryl groups (C-2 and C-6), equatorial and axial orientations of
methyl groups at C-3 and C-5 respectively [35,36]. The axial orien-
tation of methyl group at C-5 carbon is in line with the previous
studies [35].
À
Á
nyl groups C010 and C0100 resonate at 140.0 and 143.0 ppm. Thiocar-
bonyl carbon (C@S) is absorbed at 177.0 ppm and the C-4 carbon
(C@N) resonated at 157.0 ppm. The cyclohexyl ring carbons reso-
nates in the lower frequency region and among the four carbons,
C-10 carbon is deshieled due to electronegative nitrogen atom at
a
position.
A set of signals in the upfield region of 43.3 and 32.4 ppm are
assigned to C-3 and C-5 carbons respectively. Among these two
carbons C-5 carbon is shielded due to -syn effect (the CAH bond
c
is polarized and the carbon (C-5) acquired negative charge as
shown in Fig. 7). Similarly, C-2 and C-6 carbon resonances were ob-
served at 70.5 and 61.2 ppm respectively and the observed shield-
Compared to 7–9, in 18–20 H-5e is deshielded by ꢃ0.5 ppm and
H-5a is shielded by ꢃ0.45 ppm. Similarly, C-5 is shielded to an ex-
ing of C-6 is due to extended
c
-syn effect.
Table 5
13C chemical shift (ppm) values of compounds 13–23.
Carbon
Compound
13
14
15
16
17
18
19
20
21
22
23
C@S
C-2
176.8
69.2
176.8
68.4
176.8
68.6
176.7
65.2
176.8
64.3
177.0
70.5
176.9
69.7
176.9
69.9
176.9
69.3
176.9
68.5
176.8
68.7
C-3
45.0
45.2
45.2
54.6
54.8
43.3
43.2
43.4
40.7
40.7
40.8
C-4
C-5
153.5
36.0
152.9
36.1
153.8
36.1
151.8
36.2
151.1
36.3
157.0
32.4
156.6
30.9
157.4
32.5
158.0
36.4
157.3
36.3
158.3
36.6
C-6
60.8
52.6
32.6
24.6
25.5
24.6
32.6
142.3
142.7
128.7
126.6
127.9
128.5
128.0
128.0
60.1
52.6
32.6
24.6
25.5
24.6
32.6
138.0
138.5
129.4
128.3
115.4
115.7
161.2
163.6
60.3
52.6
32.6
24.6
25.5
24.5
32.6
134.6
135.0
114.0
113.8
127.7
128.8
134.6
135.0
59.8
52.5
32.6
24.8
25.5
24.8
32.6
142.8
142.8
128.7
126.6
127.9
128.6
128.0
128.0
59.0
52.6
32.6
24.5
25.5
24.5
32.6
138.6
138.7
129.4
115.4
115.6
128.2
161.2
163.3
61.2
52.6
32.6
24.5
25.6
24.5
32.6
140.0
143.0
129.1
126.6
128.1
128.8
127.8
127.8
60.5
52.5
32.6
24.6
25.5
24.6
32.6
135.6
138.7
115.6
114.6
130.4
128.3
161.1
163.6
60.6
52.6
32.6
24.6
25.6
24.6
32.6
132.2
135.3
114.1
113.1
130.0
127.7
159.1
159.3
62.9
52.6
36.4
24.6
25.5
24.6
36.4
140.6
142.7
128.6
126.9
127.9
128.5
127.6
128.0
62.2
52.6
32.6
24.5
25.5
24.5
32.6
136.3
138.3
129.3
115.3
115.4
128.4
161.3
163.3
62.4
52.6
32.6
24.5
25.5
24.5
32.6
132.8
134.9
128.8
113.7
113.8
127.9
158.9
159.3
C-10
C-20
C-30
C-40
C-50
C-60
C-100
C-1000
C-200, C-600
C-2000, C-6000
C-300, C-500
C-3000, C-5000
C-400
C-4000
3-Alkyl carbons
CH3
CH3
12.0
–
–
11.9
–
–
12.0
–
–
18.6
20.8
32.6
18.7
21.1
32.6
21.0
22.5
–
20.9
22.4
–
20.9
22.5
–
12.0
–
–
11.9
–
–
11.9
–
–
CH
5-Alkyl carbons
CH3
p-OCH3
–
–
–
55.3
–
–
–
–
–
–
–
–
–
55.3
11.2
–
11.1
–
11.1
55.3
–

242
A. Sethukumar et al. / Journal of Molecular Structure 1047 (2013) 237–248
Table 6
Correlations in the 1H–1H COSY, NOESY, HSQC and HMBC spectra of compound 18.
Signals in the 1H
spectrum
Correlations in the 1H–1H Correlations in the NOESY Correlations in the
Correlations in the HMBC spectrum
COSY spectrum
spectrum
HSQC spectrum
1.06 (s, 3H, CH3)
–
3.76, 7.46–7.47, 7.51–
7.53,
2.40, 7.46–7.47
1.64–1.67
22.5 (CH3)
21.0 (CH3, b), 43.3 (C-3,
a
), 70.5 (C-2, b), 157.0 (C-4, b)
), 70.5 (C-2, b), 157.0 (C-4, b)
1.22 (s, 3H, CH3)
1.31–1.33 (m, 1H,
H-40a)
1.35–1.38 (m, 2H,
H-20a/H-60a)
1.47–1.51 (m, 2H,
H-30a/H-50a)
1.64–1.67 (m, 1H,
H-40e)
–
21.0 (CH3)
25.6 (C-40)
22.5 (CH3, b), 43.3 (C-3,
–
a
1.64–1.67
2.09–2.14, 4.31–4.35
1.72–1.77, 2.09–2.14
1.31–1.33
1.72–1.77, 2.09–2.14
32.6 (C-20)
24.5 (C-30)
25.6 (C-40)
24.5 (C-50)
–
24.5 (C-30,
a
a
), 24.5 (C-50,
a
)
)
1.72–1.77, 1.64–1.67,
2.09–2.14, 4.31–4.35
1.31–1.33
32.6 (C-20,
), 32.6 (C-60,
a
–
1.72–1.77 (m, 2H,
H-30e/H-50e)
1.93 (s, 1H, NH)
1.47–1.51, 2.09–2.14
–
1.35–1.38, 1.47–1.51
32.6 (C-20,
a
), 32.6 (C-60,
a
), 52.6 (C-10, b)
3.76, 3.86, 7.46–7.47,
7.51–7.53
1.35–1.38, 1.47–1.51,
1.72–1.77, 4.31–4.35
1.22, 2.75, 3.76, 7.51–7.53 32.4 (C-5)
2.40, 3.86, 8.44 32.4 (C-5)
–
2.09–2.14 (m, 2H,
H-20e/H-60e)
2.40 (dd, 1H, H-5a) 3.86, 2.75
2.75 (dd, 1H, H-
5e)
3.76 (s, 1H, H-2a)
1.35–1.38, 1.47–1.51,
1.72–1.77, 4.31–4.35
32.6 (C-60)
–
61.2 (C-6,
43.3 (C-3, b), 61.2 (C-6,
a
), 143.1 (C-1000, b), 157.0 (C-4,
), 157.0 (C-4, a)
a)
3.86, 2.40
–
a
1.06, 1.93, 3.86, 7.46–7.47 70.5 (C-2)
21.0 (CH3, b), 22.5 (CH3, b), 43.3 (C-3,
100, ), 157.0 (C-4, b) 129.1 (C-200/C-600, b)
143.1 (C-1000, b), 70.5 (C-2, b), 126.6 (C-2000/C-6000, b)
a), 61.2 (C-6, b), 140.0 (C-
a
3.86 (dd, 1H, H-
6a)
4.31–4.35 (m, 1H,
H-10a)
2.40, 2.75
1.93, 2.40, 2.75,3.76,
7.51–7.53
1.47–1.51, 2.09–2.14
61.2 (C-6)
1.35–1.38, 2.09–2.14,
7.54
7.33–7.3, 7.38–7.41
52.6 (C-10)
32.6 (C-20,
a
), 32.6 (C-60,
a)
7.31–7.33 (m, 2H,
7.33–7.36, 7.38–7.41
7.31–7.33, 7.46–7.47
7.31–7.33, 7.51–7.53
127.8 (C-400/C-4000
)
128.1 (C-300/C-500,
a
) 128.8 (C-3000/C-5000
, a)
H-400/H-4000
)
7.33–7.36 (m, H-
300/H-500)
7.31–7.33, 7.46–7.47
7.31–7.33, 7.51–7.53
7.33–7.36
128.1 (C-300/C-500)
128.8 (C-3000/C-5000
129.1 (C-200/C-600)
127.8 (C-400/C-4000 ), 129.1 (C-200/C-600,
,
a
a
), 140.0 (C-100, b)
), 143.1 (C-1000, b)
7.38–7.41 (m, H-
)
)
127.8 (C-400/C-4000 ), 126.6 (C-200/C-600,
, a
a
3
000/H-5000
)
7.46–7.47 (m, H-
200/H-600)
1.06, 1.22, 1.93, 3.76,
7.33–7.36
1.06, 2.40, 3.86, 7.38–7.41 126.6 (C-2000/C-6000
70.5 (C-2,b), 128.1(C-300/C-500,
a)
7.51–7.53 (m, H-
7.38–7.41
61.2 (C-6, b) 128.8 (C-3000/C-5000
,
a
)
2
000/H-6000
)
7.54 (d, 1H,
C@SNH)
8.44 (s, 1H,
C@NANH)
4.31–4.35
1.06, 1.35–1.38
2.75
–
–
–
–
157.0 (C-4, b), 177.0 (AC@S,
a
)
Fig. 1. 1H NMR spectrum of compound 18.

A. Sethukumar et al. / Journal of Molecular Structure 1047 (2013) 237–248
243
Fig. 2. 1H–1H COSY spectrum of compound 18.
Fig. 3. NOESY spectrum of compound 18.

244
A. Sethukumar et al. / Journal of Molecular Structure 1047 (2013) 237–248
Fig. 4. 13C NMR spectrum of compound 18.
Fig. 5. HSQC (1H–13C one bond correlation) spectrum of compound 18.
It has been found that in cyclohexanes, the substituent (equato-
rial or axial) shields the d-carbon and this shielding has been
attributed to linear electric field effect. In these cases the d-carbons
are not involved in a steric interaction with the substituents. In 13–
23, the ortho carbons of aryl moiety C-200 and C-600 are at d-positions
relative to the alkyl groups at C-3. In these cases there is steric

A. Sethukumar et al. / Journal of Molecular Structure 1047 (2013) 237–248
245
Fig. 6. HMBC (1H–13C multiple bond correlation) spectrum of compound 18.
Fig. 7. Conformation of compounds 13–20.
Fig. 8. Conformation of compounds 21–23.
interaction between the d-carbons and the substituents. From Ta-
ble 5 it is seen that the ortho carbons C-200 and C-600 are deshielded
by the alkyl groups at C-3 and the observed deshielding is around
1 ppm compared to C-2000, C-6000 carbon chemical shifts.
a
-effect was analyzed. Due to the diminished electronegativity of
C@N compared with C@O, the -carbons are significantly shielded
in thiosemicarbazones compared with their respective parent pip-
eridones. Though the shielding of -carbons to C@N is in accord
with the expected electronegativity effect, the syn -carbon is
a
By comparing the chemical shifts of
a-carbons (C-3 and C-5) of
a
the thiosemicarbazones with the corresponding piperidones, the
a

246
A. Sethukumar et al. / Journal of Molecular Structure 1047 (2013) 237–248
Fig. 9. ORTEP diagram of the compound 18.
experienced on syn
pounds whereas the shielding experienced on anti
about ꢃ4–10 ppm. Particularly in 3-substituted compounds, the
shielding of anti
a
-carbon is about ꢃ11–18 ppm for all com-
Table 7
a
-carbon is only
Crystal data and structure refinement details for 18.
a
-carbon is about ꢃ7.5 ppm while in the symmet-
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system, space group
Unit cell dimensions
C26 H34 N4
434.63
293(2) K
0.71073 Å
Orthorhombic, Pca21
a = 23.8428(11) Å
S
ric thiosemicarbazone the shielding magnitude increased to ꢃ9–
10 ppm. This variation is solely due to the effect of the alkyl sub-
stituents at the anti
a
-carbon (C-3). 13C NMR spectral study sup-
ported the proposed chair conformation of the synthesized
compounds with the equatorial orientation of the bulky aryl
groups.
a
= 90°
b = 8.8422(4) Å
b = 90°
c = 23.0770(10) Å
c
= 90°
3.4. Single-crystal XRD study of 3,3-dimethyl-2,6-diarylpiperidin-4-
one N(40)-cyclohexyl thiosemicarbazone (18)
Volume
4865.2(4) Å3
Z, calculated density
Absorption coefficient
F(000)
Crystal size (mm)
Theta range for data collection
Limiting indices
Reflections collected/unique
Completeness to theta = 25.00
Absorption correction
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
8, 1.187 Mg/m3
0.153 mmꢁ1
1872
The structure and geometry of 18 in the solid state is estab-
lished by single crystal X-ray structural analysis. Compound 18,
crystallizes in an orthorhombic system with Pca21 space group
and there are two asymmetric molecules with very little differ-
ences in bond parameters. Eight molecules are present in the unit
cell. ORTEP of 18 is shown in Fig. 9. Crystal data, data collection and
structure refinement parameters are given in Table 7. Selected
bond distances and angles are given in Table 8.
The ketone condenses with thiosemicarbazide resulted a new
C@N bond whose bond length is 1.283(4) Å [C3AN2]. The configu-
ration about the C@N bond is E. Thiosemicarbazone moiety is pla-
nar and oriented to the best plane of piperidine ring at an angle of
24.45°. The observed dihedral angle between the S1 and N2 is
0.30 ꢂ 0.20 ꢂ 0.20
1.92–25.00°
ꢁ28 6 h 6 28, ꢁ10 6 k 6 10, ꢁ26 6 l 6 26
23,500/8113 [R(int) = 0.0305]
97.7%
Semi-empirical from equivalents
0.965 and 0.932
Full-matrix least-squares on F2
8113/439/696
1.013
R1 = 0.0435, wR2 = 0.0996
R1 = 0.0633, wR2 = 0.1102
0.0018(3)
Extinction coefficient
Largest diff. peak and hole
0.246 and ꢁ0.188 eAꢁ3
175.3(2)° [S1AC20AN3AN2]. The delocalization of
p electron den-
sity over thiosemicarbazone moiety resulted in variations of C@N,
NAN and C@S bond distances from the normal values [39]. From
the geometrical parameters it is observed that the piperidine ring
adopts chair conformation and the atoms N1 and C3 deviate from
the plane defined by C1/C2/C4/C5 to an extent of 0.668 and
ꢁ0.567 Å respectively [40] on either side of the plane. The phenyl
groups attached to C1 and C5 carbons are equatorially oriented
with the angle of 57.73 and 66.25° respectively from the mean
more shielded than that of anti
the interaction of the CNANHA bond with the syn
a
-carbon. This is substantiated by
CAH(e) bond
(Fig. 7). This interaction induces a polarity in the syn CAH(e)
bond, so that the syn -equatorial proton (H-5e) acquires a slight
positive charge and the C-5 carbon acquires a slight negative
charge. And, as consequence, the proton and carbon are
respectively deshielded and shielded [38]. The sum of shielding
a
a
a
a

A. Sethukumar et al. / Journal of Molecular Structure 1047 (2013) 237–248
247
Table 8
coli, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococ-
cus pyogenes. The antibacterial potency of the compounds were
compared with standard drug ampicillin, a broad spectrum antibi-
otic and their minimum inhibitory concentration (MIC) values are
summarized in Table 9. In general all the synthesized compounds
(13–23) exerted a wide range of modest antibacterial activity
in vitro against the tested organisms.
Selected bond distances (Å) and angles (°) for 18.
Bond length (Å)
C(1) AN(1)
C(1)AC(12)
C(1)AC(2)
C(2)AC(3)
C(3)AN(2)
1.455(4)
1.509(4)
1.527(4)
1.498(4)
1.283(4)
1.519(4)
1.523(5)
1.529(4)
1.555(4)
1.461(4)
1.519(4)
1.379(4)
1.382(4)
1.322(4)
1.368(4)
1.681(3)
1.462(4)
2.82(3)
C(3)AC(4)
Compound 13, without any substituent at para position of the
aryl moieties at C-2 and C-6 positions of the six membered hetero-
cyclic ring and with methyl group at C-3 position exhibited in vitro
C(4)AC(19)
C(4)AC(18)
C(4)AC(5)
C(5)AN(1)
C(5)AC(6)
antibacterial activity at 50 l
g mlꢁ1 against E. coli, S. pyogenes but in
the case of P. aeruginosa and B. subtilis increase in activity was ob-
served. However, the introduction of electronegative fluorine atom
in the para position (Compound 14) resulted in the almost same ef-
fect against all the tested strains except S. aureus. It inhibited S.
C(6)AC(7)
C(6)AC(11)
C(20)AN(4)
C(20)AN(3)
C(20)AS(1)
C(21)AN(4)
N(7)AH(7A)ꢄ ꢄ ꢄS(1)#1
aureus at a MIC of 12.5 l
g mlꢁ1. Replacement of fluorine group
present at the para position of the aryl moieties at C-2 and C-6
by electron donating methoxy functionalities (Compound 15)
yielded no improvement in activity against E. coli but the activity
decreased against S. aureus, B. subtilis, P. aeruginosa, and S.
pyogenes.
Bond angles (°)
N(1)AC(1)AC(12)
N(1)AC(1)AC(2)
C(12)AC(1)AC(2)
C(3)AC(2)AC(1)
N(2)AC(3)AC(2)
N(2)AC(3)AC(4)
C(2)AC(3)AC(4)
C(3)AC(4)AC(19)
C(3)AC(4)AC(18)
C(19)AC(4)AC(18)
C(3)AC(4)AC(5)
C(19)AC(4)AC(5)
C(18)AC(4)AC(5)
N(1)AC(5)AC(6)
N(1)AC(5)AC(4)
C(6)AC(5)AC(4)
N(4)AC(20)AN(3)
N(4)AC(20)AS(1)
N(3)AC(20)AS(1)
N(4)AC(21)AC(22)
N(4)AC(21)AC(26)
N(7)AH(7A)ꢄ ꢄ ꢄS(1)#1
111.1(2)
108.6(2)
109.6(2)
112.0(2)
126.2(2)
117.4(2)
116.4(2)
108.3(2)
111.0(2)
108.5(3)
107.2(2)
111.6(2)
110.1(2)
108.4(2)
110.3(2)
113.4(2)
115.6(3)
124.6(2)
119.8(2)
109.6(5)
110.7(3)
177(3)
Compound 16, exhibits same activity against B. subtilis and S.
aureus compared to 13 and there is no inhibitory effect against
E. coli, P. aeruginosa, and S. pyogenes even at maximum tested con-
centration of 200 l
g mlꢁ1. Introduction of fluoro functionalities at
para position of the aryl group and C-3 isopropyl group (Compound
17) enhances the activity against all the tested organisms except B.
subtilis.
Compound 18, with two methyl groups at C-3 and without sub-
stituents in the aryl groups showed excellent results against all the
tested bacterial strains, which are comparable with the standard
drug (ampicillin). It exhibits good activity than the other com-
pounds in this series also. However, 19 and 20 are less potent
against all the tested organisms.
Compound 21, exerted appreciable antibacterial activity against
all the tested microbes. Similarly, the introduction of fluro and
methoxy functionalities in aryl group of 21 (Compounds 22 and
23) shown one and twofold enhancement in the activity against
bacterial strains except S. aureus. 23 exert excellent activity and
it was the second best in this series.
plane of piperidine ring. The cyclohexyl ring in the thiosemicarba-
zone fragment also adopts chair conformation as expected and all
other bond parameters are normal.
3.5.2. Antifungal activity of compounds 13–23
In vitro antifungal activity of the synthesized compounds 13–
23, were examined against five fungal strains viz. Aspergillus flavus,
Aspergillus niger, Penicillium chryogenum, Trioderma veride and
Fusarium oxysporum. Amphotericin-B was used as the standard
drug. The MIC values of the test compounds and the standard are
furnished in Table 10.
3.5. In vitro antimicrobial activity
3.5.1. Antibacterial activity of compounds 13–23
All the synthesized compounds 13–23, were tested for their
antibacterial activity in vitro against Bacillus subtilis, Escherichia
Table 9
Antibacterial activity of compounds 13–23.
Compounds
MIC in lg/ml
Bacillus subtilis
Escherichia coli
Pseudomonas aeruginosa
Staphylococcus aureus
Streptococcus pyogenes
13
14
15
16
17
18
19
20
12.5
12.5
25
12.5
50
12.5
25
100
50
50
25
25
200
25
12.5
100
100
25
25
50
200
12.5
25
50
25
12.5
50
25
50
50
100
>200
100
12.5
50
100
>200
100
12.5
200
100
50
>200
50
21
50
22
23
25
12.5
12.5
50
12.5
12.5
25
12.5
12.5
100
200
12.5
12.5
12.5
12.5
Ampicillin

248
A. Sethukumar et al. / Journal of Molecular Structure 1047 (2013) 237–248
Table 10
Antifungal activity of compounds 13–23.
Compounds
MIC in lg/ml
Aspergillus flavus
Aspergillus niger
Penicillium chryogenum
Trioderma veride
Fusarium oxysporum
13
14
15
16
17
18
25
50
25
100
25
50
50
100
50
50
25
25
50
>200
50
50
50
25
25
50
50
>200
25
25
>200
50
100
100
25
25
19
20
21
22
25
>200
25
50
25
25
25
100
50
>200
100
25
100
50
100
>200
50
50
50
50
100
25
100
100
50
50
25
23
Amphotericin-B
25
25
25
[2] B.R. Jerom, K.H. Spencer, Eur. Pat. Appl. EP 277794 (1988).
[3] R.V. Perumal, M. Adiraj, P. Shanmugapandiyan, Indian Drugs 38 (2001) 156–
159.
Compound 13, with methyl group at C-3 in the heterocyclic ring
showed equivalent potency to the standard drug amphotericin-B
against all the fungal strains at MIC of 25
l
g mlꢁ1 level except
[4] C.F. Bochringer, G.M.B.H. Shochne, Brit. Pat. Appl. BP866488 (1961).
[5] C.R. Ganellin, R.G. Spickett, J. Med. Chem. 8 (1965) 619–625.
[6] M. Nikolov, D. Stefanora, D. Chardanov, Acta Nerv. Super. 16 (1974) 264–267.
[7] B. Kathleen, C. Jean-Peirre, H. Andre, Eur. Pat. Appl. EP169139 (1986).
[8] R.E. Hagenbach, H. Gysin, Experentia 8 (1952) 184–188.
[9] B. Ileana, V. Dobre, I. Niculescu-Duvaz, J. Prakt. Chem. 327 (1985) 667–674.
[10] I.G. Mobio, A.T. Soldatenkov, V.O. Federov, E.A. Ageev, N.D. Sergeeva, S. Lin, E.E.
Stashenko, N.S. Prostakov, E.I. Andreeva, Khim.-Farm. Zh. 23 (1989) 421–427.
[11] A.K. Srivastava, C.B. Suresh, J. Indian Chem. Soc. 53 (1976) 841–843.
[12] M.C. Frank, L.K. Daniel, E.M. Normal, J. Gen. Microbiol. 128 (1981) 1349–1354.
[13] M. Manowitz, G. Walter, J. Pharm. Sci. 54 (1965) 650–655.
[14] N. Fahmi, R.V. Singh, J. Indian Chem. Soc. 73 (1996) 257–259.
[15] D.L. Klayman, J.F. Bartosevich, T.S. Griffin, C.J. Mason, J.P. Scovill, J. Med. Chem.
22 (1979) 855–862.
against A. niger (MIC of 50
l
g mlꢁ1). Introduction of fluorine and
methoxy functionality at the para position of phenyl group (com-
pounds 14 and 15) resulted in minimum to moderate decrease in
inhibition potency against all the tested fungal organisms with
MIC ranging from 25 to 200 l
g mlꢁ1. Replacement of methyl group
by isopropyl group at C-3 position (compound 16) demonstrates
lesser activity against all the tested strains. Similarly, no improve-
ment in activity was noticed for 17.
Compound 18, with two methyl groups at C-3 position excreted
fine potency against A. niger, T. veride and F. oxysporum but one fold
lower activity against A. flavus, and P. chryogenum compared to the
reference. Compounds 19–23, exhibit decreased activity against all
the tested strains.
[16] S.N. Pandeya, I. Ponnilavarasan, A. Pandey, R. Lahan, J.P. Stables, Pharmazie 54
(1999) 923–925.
[17] S.N. Pandeya, H. Manjula, J.P. Stables, Pharmazie 56 (2001) 121–124.
[18] N. Bharti, K. Husain, M.T.G. Garza, D.E. Cruz-Vega, J. Castro-Garza, B.D. Mata-
Cardenas, F. Naqvia, A. Azama, Bioorg. Med. Chem. Lett. 12 (2002) 3475–3478.
[19] J.R. Dimmock, R.N. Puthucode, J.M. Smith, M. Hetherigton, J.W. Quail, U.
Pugazhenthi, J. Med. Chem. 39 (1996) 3984–3997.
4. Conclusion
[20] J.R. Dimmock, K.K. Sidhu, S.D. Tumber, S.K. Basran, M. Chen, J.W. Quail, Eur. J.
Med. Chem. 30 (1995) 287–301.
[21] J.R. Dimmock, S.N. Pandeya, J.W. Quail, U. Pugazhenthi, T.M. Allen, G.Y. Kao,
Eur. J. Med. Chem. 30 (1995) 303–314.
[22] J.R. Dimmock, K.K. Sidhu, R.S. Thayar, P. Mack, M.J. Dutty, R.S. Reid, J.W. Quail, J.
Med. Chem. 36 (1993) 2243–2252.
[23] J.R. Dimmock, G.B. Baker, Epilepsia 35 (3) (1994) 648–655.
[24] J.R. Dimmock, S.C. Vashishtha, J.P. Stables, Pharmacology 55 (2000) 490–494.
[25] S.N. Pandeya, P. Yogeeswari, J.P. Stables, Eur. J. Med. Chem. 35 (2000) 879–886.
[26] S.N. Pandeya, B. Mishra, P.N. Singh, D.C. Rupainwar, Pharmacol. Res. 37 (1)
(1998) 17–22.
[27] K. Hu, Z. Yang, S. Pan, H. Xu, J. Ren, Eur. J. Med. Chem. 45 (2010) 3453–3458.
[28] G.M. Sheldrick, Acta Crystallogr. 46 (1990) 467–473.
[29] G.M. Sheldrick, SHELXL-97, University of Gottingen, Gottingen, Germany,
1997.
A series of N(40)-cyclohexyl thiosemicarbazones have been syn-
thesized successfully in appreciable yields and were characterized
by IR, NMR and Mass spectra. Single crystal XRD analysis was also
performed for compound 18. The observed vicinal proton–proton
coupling constants suggest that in thiosemicarbazones 13–23,
the piperidine ring adopts chair conformation with equatorial ori-
entations of the aryl groups. The observed chemical shifts of H-5e,
H-5a and C-5 are in accord with E configuration about the C@N
bond. In 13–20, the equatorial alkyl carbon attached to C-3 is
shielded by the nitrogen atom of the C@N bond due to c-syn effect.
The cyclohexyl fragment present in thiosemicarbazone moiety also
exist normal chair conformation. The single-crystal XRD study of
compound 18, also evidences E configuration about the C@N bond
and the chair conformation of piperidin and cyclohexyl rings. Re-
sults of the biological studies suggested that the compounds 18
(against bacteria) and 13 (against fungi)P display antimicrobial
activity similar to that of standards ampicillin and amphotericin-
B respectively against all the tested strains. The other compounds
showed moderate to good inhibition against tested bacterial and
fungal strains.
[30] C.R. Noller, V. Baliah, J. Am. Chem. Soc. 70 (1948) 3853–3855.
[31] M.L. Dhar, M.M. Dhar, B.N. Dhawan, B.N. Mehrotra, C. Ray, Indian J. Exp. Biol. 6
(1968) 232–247.
[32] R.M. Silverstein, F.X. Webster, Spectrometric Identification of Organic
Compounds, sixth ed., Wiley, New York, 1998. p. 229.
[33] R.M. Silverstein, F.X. Webster, Spectrometric Identification of Organic
Compounds, sixth ed., Wiley, New York, 1998. p. 234.
[34] K. Pandiarajan, R. Sekar, R. Anantharaman, V. Ramalingam, D. Marko, Indian J.
Chem. B 30 (1991) 490–493.
[35] S. Umamatheswari, B. Balaji, M. Ramanathan, S. Kabilan, Eur. J. Med. Chem. 46
(2011) 1415–1424.
[36] J. Thanusu, V. Kanagarajan, M. Gopalakrishnan, Res. Chem. Intermed. 36 (2010)
1073–1084.
[37] K. Pandiarajan, R.T. Sabapathy Mohan, M.U. Hasan, Magn. Reson. Chem. 24
(1986) 312–316.
References
[38] S. Sylvestre, K. Pandiarajan, Spectrochim. Acta, Part A 78 (2011) 153–159.
[39] W.H. Haynes, CRC Handbook of Chemistry and Physics, 92nd ed., 2011–2012.
[40] Mercury, Crystallographic Software from CCDC. <www.ccdc.cam.ac.uk>.
[1] G.J. Richardo, B.C. Juan, R.A. Mario, M. Roldan, C.R. Peinado, Fernando Spen. 47
(1979) 168–172.