Novel 3-benzyl-2,6-diarylpiperidin-4-one derivatives: Syntheses, characterization, and antimicrobial profile

Article abstract of DOI:10.1007/s00044-013-0624-2

The study was aimed at the syntheses and evaluation of a series of novel 3-benzyl-2,6-diarylpiperidine-4-ones. The newly synthesized compounds were characterized by elemental analysis, infrared, ¹H NMR, ¹³C NMR, and mass spectral analyses. These compounds were screened for their inhibiting potential against various bacterial and fungal strains. The antimicrobial activity was performed against four Gram positive bacteria (S. aureus, B. subtilis, B. pumilus, and M. luteus), three Gram negative bacteria (P. aeruginosa, P. fluorescens, and E. coli), and two fungal strains (A. niger and P. chrysogenum) by cup-plate method and tube assay method. The results reveal that some of these compounds exhibited remarkable activity against the selected bacterial and fungal strains, with MIC values as low as 50 μg/mL. Interestingly, all the compounds exhibited better antifungal activity than antibacterial activity. Thus, it can be concluded that 3-benzyl-2,6- diarylpiperidine-4-ones may exhibit potent antifungal activity.

Full text of DOI:10.1007/s00044-013-0624-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0624-2
ORIGINAL RESEARCH
Novel 3-benzyl-2,6-diarylpiperidin-4-one derivatives: syntheses,
characterization, and antimicrobial profile
•
Shashi Kant Sahu Avinash C. Tripathi
•
•
Mary Koshy Shailendra K. Saraf
Received: 16 February 2013 / Accepted: 6 May 2013
Ó Springer Science+Business Media New York 2013
Abstract The study was aimed at the syntheses and
evaluation of a series of novel 3-benzyl-2,6-diarylpiper-
idine-4-ones. The newly synthesized compounds were
Introduction
The widespread use of heterocyclic compounds is because
their structures can be subtly manipulated to achieve the
required modification in function (Gilchrist, 1997). Het-
erocyclic ring systems having piperidin-4-one nucleus have
generated great interest in the past and recent years due to
their wide variety of biological properties (Sahu et al.,
2013) such as antibacterial (Ramalingan et al., 2004; Jay-
abharathi et al., 2007a, b; Gopalakrishnan et al., 2009;
Srinivasan et al., 2006), antifungal (Aridoss et al., 2006,
2007a, b, 2009; Jayabharathi et al., 2005), analgesic and
antipyretic (Kalaiselvan et al., 2004; Rameshkumar et al.,
2003; Salima et al., 1986), anticancer (Dimmock et al.,
1990, 2002; Das et al., 2007; Pati et al., 2008, 2009;
Makarov et al., 2009; Patel et al., 2007), antiviral (Artico
et al., 1998; Santo et al., 2003; El-Subbagh et al., 2000),
antihypertensive (Zhang et al., 2009), and antimycobacte-
rial activities (Das et al., 2008; Aridoss et al., 2008).
Piperidine-4-one nucleus is generally synthesized by
Mannich reaction, producing b-amino-carbonyl compound,
also known as a Mannich base. The biological activities of
piperidones are associated with substitutions at 2, 3, and 6
positions. The biological activity was found to be significant
in compounds possessing aromatic substituents at 2 and/or 6
positions (Rameshkumar et al., 2003). The substituted
piperidin-4-ones, such as 1,3-dimethyl-2,6-diphenyl-4-pip-
eridone, have been found to be versatile intermediates in
different types of reactions since they have two reactive sites,
carbonyl and keto methylene groups. This paved the pathway
for the synthesis of some heterocyclic compounds such as
tetrahydropyridine, diazepanone, oxazepanone, piperidone,
pyridopyrimidone, pyrido-pyrimidinethione, thiazolopyri-
dine, furanylmethylene, and pyridoindole (Padmavathi
et al., 2005). Piperidin-4-one, when reacted with
characterized by elemental analysis, infrared, 1H NMR, 13
C
NMR, and mass spectral analyses. These compounds were
screened for their inhibiting potential against various bac-
terial and fungal strains. The antimicrobial activity was
performed against four Gram positive bacteria (S. aureus,
B. subtilis, B. pumilus, and M. luteus), three Gram negative
bacteria (P. aeruginosa, P. fluorescens, and E. coli), and
two fungal strains (A. niger and P. chrysogenum) by cup-
plate method and tube assay method. The results reveal that
some of these compounds exhibited remarkable activity
against the selected bacterial and fungal strains, with MIC
values as low as 50 lg/mL. Interestingly, all the com-
pounds exhibited better antifungal activity than antibacte-
rial activity. Thus, it can be concluded that 3-benzyl-2,6-
diarylpiperidine-4-ones may exhibit potent antifungal
activity.
Keywords Piperidin-4-ones ꢀ Mannich reaction ꢀ
Antifungal ꢀ Antibacterial ꢀ Antimicrobial
S. K. Sahu ꢀ A. C. Tripathi ꢀ M. Koshy ꢀ S. K. Saraf (&)
Faculty of Pharmacy, Babu Banarasi Das Northern India
Institute of Technology, BBD City, Faizabad Road,
Chinhut, Lucknow 227105, U.P, India
e-mail: dirpharmniec@gmail.com
S. K. Sahu
e-mail: shashikant1505@gmail.com
A. C. Tripathi
e-mail: aviniec31@gmail.com
M. Koshy
e-mail: marymary@rediffmail.com
123

Med Chem Res
O
C
hydroxylamine hydrochloride, generates piperidin-4-one
oxime which shows potent antimicrobial activity (Bala-
subramanian et al., 2006). Similarly, piperidin-4-one when
refluxed with hydrazine hydrate, yields bispiperidine which
shows anticonvulsant activity (Krapcho and Turk, 1979).
Using piperidin-4-one as intermediate bicyclic pyrazolines,
piperidin-4-one semicarbazones, thiosemicarbazones, and
piperidin-4-one oxime ethers have also been synthesized
which show central nervous system depressant, anti-
inflammatory (Hemalatha et al., 2008), and antibacterial
activity (Ramalingan et al., 2006), respectively. The aryl-
piperidine scaffold is a key element involved in binding to a
variety of receptors and therefore can be described as a
privileged structure (Horton et al., 2003). Similarly, piperi-
done derivatives have also received wide interest among
chemists and biologists due to their envisaged mode of
interaction with cellular thiols, with modest or no affinity for
the hydroxy and amine groups found in nucleic acids (Mutus
et al., 1989; Ramachandran et al., 2008).
H3C
O
Reflux
O
C
O
C
C2H5OH
Ar1
N
H
Ar2
H
Ar2
Ar1
H
NH4OAc
Ar1
Ar2
O
O
SP1
SP2
O
O
F
F
SP3
SP4
SP5
F
H3C
H3C
S
S
Materials and methods
H3C
S
The chemicals and reagents were procured from S.D. Fine and
Sigma-Aldrich and were used as such. Melting points were
determinedusingmeltingpointapparatusandareuncorrected.
Progress of the reactions was monitored by thin layer chro-
matographyonsilicagel G plates, using iodine vapors and UV
chamber as visualizing agents. The synthesized compounds
were subjected to physical and spectral analysis.
SP6
SP7
H3C
S
F
Br
Br
SP8
O
Synthesis
SP9
O
O
The synthesis of 3-benzyl-2,6-diarylpiperidin-4-ones was
achieved with a versatile and efficient synthetic route
outlined in Scheme 1.
SP10
O
F
General procedure for the synthesis of 3-benzyl-
2,6-diarylpiperidin-4-ones
Scheme 1 Synthesis of 3-benzyl-2,6-diarylpiperidin-4-one derivatives
Dry ammonium acetate (0.01 mol.) was dissolved in ethanol
(3 ml), mixed with different aromatic/heteroaromatic alde-
hydes (0.02 mol.) and benzylacetone (0.01 mol.), refluxed for
10 min and allowed to stand at room temperature overnight.
Then, ether (5 ml) was added followed by concentrated
hydrochloric acid (3 ml) and cooled in ice water. The precip-
itated hydrochloride was filtered and washed with ethanol–
ether (1:5) mixture. The hydrochloride was suspended in
acetone and made alkaline using strong ammonia solution. On
dilution with excess of water, the base was precipitated which
was filtered and dried and recrystallized from chloroform. The
purity of compounds was confirmed by thin layer chroma-
tographyusing precoated silicagelG plates (20 920 cm)anda
solventsystem ofdichloromethaneand chloroform (1:99). The
spots were developed in UV chamber (long and short wave-
length) and Iodine chamber. Only SP-1 was recrystallized
from ethanol and its melting range was determined by open
capillary method and is uncorrected. The other compounds
were obtained as highly viscous sticky solids (Jayabharathi
et al., 2007a; Rameshkumar et al., 2003).
Spectral data of synthesized compounds
Compound SP-1: 3-benzyl-2,6-bis-(4-oxo-4H-
chromen-3-yl)-piperidin-4-one
% Yield (w/w): 27.10, Melting range (°C): 128–130, Ele-
mental Analysis: C = 68.34 % H = 03.67 % N = 02.45 %;
123

Med Chem Res
IR KBr (cm-1): 1,693.38 (C=O stretching), 3,415.70 (N–H
stretching), 1,271.00 (C–N stretching); Mass m/e [M?1]?:
478, 1H NMR(CDCl3, d ppm): 2.17(t, 1H, amine)2.67(s, 4H,
methylene), 7.49–7.79 (m, 14H, benzene); 13C NMR (CDCl3,
ppm): 33.7 (CH2 aliphatic), 42.29 (CH2 piperidine), 51.06
(CH piperidine), 56.86 (CH piperidine), 61.22 (CH piperi-
dine), 117.66 (2CH chromene), 125.53 (2CH chromene),
126.12 (2CH chromene),125.91 (2C chromene), 126.44 (2C
chromene), 134.21 (2CH chromene), 154.72 (2C chromene),
155.94 (2C chromene), 127.22 (CH benzene), 128.73–129.50
(4CH benzene), 138.86 (C benzene), 174.86 (2C chromene
carbonyl), 204.53 (C piperidin carbonyl)
3.45–4.14 (m, 3H, methine), 7.18–7.74 (m, 7H, naphtha-
lene), 6.92–7.16 (m, 9H, benzene); 13C NMR (CDCl3,
ppm): 33.26 (CH2 aliphatic), 44.9 0 (CH2 piperidine),
59.41 (CH piperidine), 60.21 (CH piperidine), 64.73 (CH
piperidine), 115.29 (2CH benzene), 130.55 (2CH benzene),
136.48 (C benzene),162.70 (C benzene), 128.73–129.50
(4CH benzene), 127.22 (CH benzene), 138.86 (C ben-
zene),125.6–127.22 (8CH naphthalene), 123.60 (CH
naphthalene), 134.27 (C naphthalene), 207.08 (C piperidine
carbonyl).
Compound SP-5: 3-benzyl-2,6-bis-(5-methyl-
thiophen-2-yl)-piperidin-4-one
Compound SP-2: 3-benzyl-2,6-bis-(4-fluorophenyl)-
piperidin-4-one
% Yield (w/w): 13.91; Elemental Analysis: C = 70.36 %
H = 05.88 % N = 02.98 %; IR KBr (cm-1): 1,712.67
(C=O stretching), 3,456.20 (N–H stretching), 1,224.71 (C–
N stretching); Mass m/e [M?1]?: 382; 1H NMR (CDCl3, d
ppm): 2.43–2.52 (d, 6H, methyl), 2.87–3.05 (m, 4H,
methylene), 3.98–4.01 (d, 1H, methine), 4.25–4.29 (t, 1H,
methine), 6.56–6.81 (m, 4H, thiophene), 7.06–7.25 (m, 5H,
benzene); 13C NMR (CDCl3, ppm): 16.83 (2CH3), 33.70
(CH2 aliphatic), 44.31 (CH2 piperidine), 56.82 (CH piper-
idine), 59.70 (CH piperidine), 62.92 (CH piperidine),
122.98 (2CH thiophene), 126.70–128.10 (2CH thiophene),
141.84 (2C thiophene),147.03–149.61 (2C thiophene),
128.10–129.50 (4CH benzene), 127.22 (CH benzene),
138.86 (C benzene), 204.53 (C piperidine carbonyl).
% Yield (w/w): 22.54; IR KBr (cm-1): 1,712.67 (C=O
stretching), 3,415.70 (N–H stretching), 1,230.50 (C–N
1
stretching); Mass m/e [M?1]?: 378; H NMR (CDCl3, d
ppm): 2.07–2.29 (m, 1H, amine), 3.75 (d, 1H, methine),
4.05 (d, 1H, methine), 6.91–7.27 (m, 12H, benzene); 13C
NMR (CDCl3, ppm): 33.24 (CH2 aliphatic), 45.81 (CH2
piperidine), 58.68 (CH piperidine), 60.86 (CH piperidine),
64.73 (CH piperidine), 115.29 (4CH benzene), 127.22 (CH
benzene), 128.73-130.55 (8CH benzene), 136.48 (C ben-
zene), 138.53 (C benzene), 162.70 (C benzene), 207.08 (C
piperidine carbonyl).
Compound SP-3: 3-benzyl-2,6-di-naphthalen-1-yl-
piperidin-4-one
Compound SP-6: 3-benzyl-2-(5-methyl-thiophen-2-yl)-
6-naphthalen-2-yl-piperidin-4-one
% Yield (w/w): 17.68; Elemental Analysis: C = 80.63 %
H = 06.22 % N = 02.42 %; IR KBr (cm-1): 1,708.81
(C=O stretching), 3,309.62 (N–H stretching), 1,217.00 (C–
N stretching); Mass m/e [M?1]?: 442, 1H NMR (CDCl3, d
ppm): 2.28–2.32 (d, 1H, amine), 2.92 (s, 4H, methylene),
3.37 (s, 1H, methine), 4.35 (d, 1H, methine), 7.08–7.10 (d,
5H, benzene), 7.18–7.68 (m, 12H, naphthalene); 13C NMR
(CDCl3, ppm): 33.24 (CH2 aliphatic), 44.90 (CH2 piperi-
dine), 59.41 (CH piperidine), 60.55 (CH piperidine), 63.66
(CH piperidine), 123.60–124.12 (2CH naphthalene),
125.68–126.26 (8CH naphthalene), 132.79–134.27 (8CH
naphthalene), 132.89–134.37 (2C naphthalene), 127.22
(CH benzene), 128.73–129.50 (4CH benzene), 138.86 (C
benzene), 207.08 (C piperidine carbonyl).
% Yield (w/w), 29.19; Elemental Analysis: C = 79.15 %
H = 06.32 % N = 02.36 %; IR KBr (cm-1): 1,708.81 (C=O
stretching), 3,407.98 (N–H stretching), 1,217.00 (C–N stretch-
1
ing); Mass m/e [M?1]?: 412; H NMR (CDCl3, d ppm):
2.08–2.32 (m, 1H, amine), 2.42–2.66 (m, 3H, methyl),
2.73–2.93 (m, 4H, methylene), 3.39–4.28 (m, 2H, methine),
6.68 (m, 2H, thiophene), 7.08–7.21 (m, 5H, benzene), 7.38–7.59
(m, 7H, naphthalene); 13C NMR (CDCl3, ppm): 16.83 (CH3),
33.70 (CH2 aliphatic), 44.31 (CH2 piperidine), 56.62 (CH
piperidine), 59.81 (CH piperidine), 62.71 (CH piperidine),
122.96 (CH thiophene), 126.67 (CH thiophene), 142.84 (C
thiophene), 149.58 (C thiophene), 128.32–129.50 (4CH ben-
zene), 127.22 (CH benzene), 138.86 (C benzene),
125.68–127.22 (8CH naphthalene), 123.60 (CH naphthalene),
134.27 (C naphthalene), 205.14 (C piperidine carbonyl).
Compound SP-4: 3-benzyl-2-(4-fluorophenyl)-6-
naphthalen-2-yl-piperidin-4-one
Compound SP-7: 3-benzyl-6-(4-fluorophenyl)-2-
(5-methyl-thiophen-2-yl)-piperidin-4-one
% Yield (w/w): 36.37; IR KBr (cm-1): 1,710.74 (C=O
stretching), 3,311.55 (N–H stretching), 1,224.71 (C–N
stretching); Mass m/e [M?1]?: 410; H NMR (CDCl3, d
ppm): 2.12 (s, 1H, amine), 2.72–2.90 (m, 4H, methylene),
% Yield (w/w): 09.23; IR KBr (cm-1): 1,711.10 (C=O
stretching), 3,400.30 (N–H stretching), 1,217.50 (C–N
1
123

Med Chem Res
1
stretching); Mass m/e [M?1]?: 380; H NMR (CDCl3,d
Compound SP-10: 3-benzyl-2-(4-fluorophenyl)-6-(4-oxo-
4H-chromen-3-yl)-piperidin-4-one
ppm): 2.24–2.29 (d, 1H, amine), 2.39–2.43 (d, 3H, methyl),
2.80–2.96 (m, 4H, methylene), 3.75 (m, 1H, methine) 4.04
(m, 1H, methine), 6.60 (d, 2H, thiophene), 6.94–7.29 (m,
9H, benzene), 7.47–6.94; 13C NMR (CDCl3, ppm): 16.83
(CH3), 33.70 (CH2 aliphatic), 44.31 (CH2 piperidine),
56.62 (CH piperidine), 59.81 (CH piperidine), 62.71 (CH
piperidine), 122.96 (CH thiophene), 126.67 (CH thio-
phene), 142.84 (C thiophene), 149.58 (C thiophene),
128.32–129.50 (4CH benzene), 127.22 (CH benzene),
138.86 (C benzene), 115.38 (2CH benzene), 129.39 (2CH
benzene), 138.53 (C benzene), 162.85 (C benzene), 205.14
(C piperidine carbonyl).
% Yield (w/w): 21.31; IR KBr (cm-1): 1,700.00 (C=O
stretching), 3,402.30 (N–H stretching), 1,219.50 (C–N
1
stretching); Mass m/e [M?1]?: 428; H NMR (CDCl3,d
ppm): 2.14–2.19 (d, 1H, amine), 2.55–2.62 (t, 2H, methy-
lene), 2.82–2.87 (t, 2H, methylene), 3.90 (d, 1H, methine),
4.06 (s, 1H, methine), 7.07–7.76 m,
(13H, benzene); 13C NMR (CDCl3, ppm): 33.24 (CH2
aliphatic), 42.29 (CH2 piperidine), 51.55 (CH piperidine),
60.55 (CH piperidine), 64.19 (CH piperidine), 117.66 (CH
chromene), 127.20 (C chromene), 125.53–125.91 (2CH
chromene), 126.12 (CH chromene), 134.21 (CH chro-
mene), 151.04 (CH chromene), 155.94 (C chromene),
127.22 (CH benzene), 128.73–129.50 (4CH benzene),
138.86 (C benzene), 115.29 (2CH benzene), 130.55 (2CH
benzene), 136.48 (C benzene),162.70 (C benzene), 174.86
(C chromene carbonyl), 206.85 (C piperidin carbonyl),
Compound SP-8: 3-benzyl-2,6-bis-(2-bromo-phenyl)-
piperidin-4-one
% Yield (w/w): 51.50; Elemental Analysis: C = 56.57 %
H = 04.41 % N = 01.31 %; IR KBr (cm-1): 1,709.60
(C=O stretching), 3,435.60 (N–H stretching), 1,216.80 (C–
1
N stretching); Mass m/e [M?1]?: 500; H NMR (CDCl3,d
In vitro evaluation of antimicrobial activity
ppm): 2.13–2.25 (d, 1H, amine), 2.89–2.97 (m, 4H, meth-
ylene), 4.48–4.53 (t, 2H, methine), 6.90–7.39 (m, 13H,
benzene); 13C NMR (CDCl3, ppm): 33.24 (CH2 aliphatic),
44.66 (CH2 piperidine), 56.83 (CH piperidine), 60.83 (CH
piperidine), 63.50 (CH piperidine), 127.04–128.29 (5CH
benzene), 127.11–128.29 (2C benzene), 138.65–140.99
(2C benzene), 128.29–129.50 (4CH benzene), 138.86 (C
benzene), 130.77–133.78 (4CH benzene), 207.08 (C
piperidine carbonyl).
The synthesized compound was tested for in vitro antimi-
crobial activity against Staphylococcus aureus, Bacillus
subtilis, B. pumilus, Micrococcus luteus, Pseudomonas
aeruginosa, P. fluorescens, Escherichia coli, Aspergillus
niger, and Penicillium chrysogenum using cup-plate and
tube assay method. A previously liquefied medium with the
requisite quantity of suspension of the microorganism was
inoculated. Then, the suspension was added to the medium
at room temperature and the inoculated medium was
poured immediately into Petri dishes with uniform thick-
ness, by placing the dishes on a uniform level surface. The
prepared dishes were stored in a manner so as to ensure that
no significant growth or death of test organism occurred
before the dishes were used and that surface of agar layer
was dry at the time of use. The solutions of antimicrobial
agents SP-1 to SP-10 (25–250 lg/mL in DMSO) were
applied to the surface of the solid medium in cavities
(6 mm) prepared in the agar. Standard drugs used (nor-
floxacin and fluconazole) were taken in reported quantities,
i.e., 50 lg/mL. The volumes of the solutions were added to
each cavity in uniform and sufficient quantities to almost
fill the holes. The plates were left for 1–4 h at room tem-
perature, as a period of pre-incubation diffusion, to mini-
mize the effects of variation in the time between the
applications of the different solutions. They were incubated
for 18 h at the temperature suitable for individual micro-
organism. The diameters of the circular zones of inhibition
were measured (Indian Pharmacopoeia, Ministry of Health
and Family Welfare, Controller of Publications, Govt. of
India, Delhi, II (P-Z) 1996).
Compound SP-9: 3-benzyl-2-naphthalen-1-yl-6-
(4-oxo-4H-chromen-3-yl)-piperidin-4-one
% Yield (w/w): 20.69; Elemental Analysis: C = 70.32 %
H = 04.81 % N = 00.50 %; IR KBr (cm-1): 1,690.90
(C=O stretching), 3,392.30 (N–H stretching), 1,217.50 (C–
1
N stretching); Mass m/e [M?1]?: 460; H NMR (CDCl3,d
ppm): 2.14 (s, 1H, amine), 2.56–2.60 (t, 2H, methylene),
2.73–2.78 (t, 2H, methylene), 3.90 (s, 1H, methine), 4.06
(s, 1H, methine), 7.16–7.30 (m, 9H, benzene), 7.41–7.72
(m, 7H, naphthalene); 13C NMR (CDCl3, ppm): 33.24
(CH2 aliphatic), 42.29 (CH2 piperidine), 51.55 (CH piper-
idine), 60.55 (CH piperidine), 63.39 (CH piperidine),
117.66
(CH chromene), 127.20 (C chromene), 125.53–125.91
(2CH chromene), 126.12 (CH chromene), 134.21 (CH
chromene), 151.04 (CH chromene), 155.94 (C chromene),
127.22 (CH benzene), 128.73–129.50 (4CH benzene),
138.86 (C benzene), 124.12 (CH naphthalene),
125.70–128.34 (6CH naphthalene), 132.20–134.15 (3C
naphthalene), 174.86 (C chromene carbonyl), 206.85 (C
piperidin carbonyl),
123

Med Chem Res
Table 1 In vitro antifungal and antibacterial activities of compounds SP-1 to SP-10
Diameter of zone of inhibition (mm)
Compounds Concn. Fungal strains
(lg/mL)
Bacterial strains
SA BS
AN
PC
BP
ML
PA
PF
EC
SP-1
SP-2
SP-3
SP-4
SP-5
SP-6
SP-7
SP-8
25
50
–
–
–
–
–
–
–
12.1 0.1
–
13.3 0.1 12.0 1.0 12.37 0.2 12.2 0.1 12.3 0.3 14.9 0.5 12.0 0.4 15.0 0.2 12.3 0.2
14.2 0.2 14.1 0.1 13.1 0.6 14.3 0.2 13.6 0.7 17.0 0.5 14.1 0.2 16.8 0.3 15.1 0.5
15.2 0.5 15.0 0.1 15.7 0.6 17.3 1.0 13.7 0.7 18.1 0.3 16.1 0.6 19.5 0.5 17.2 0.3
17.1 0.3 16.0 0.2 17.1 0.2 18.9 0.1 15.3 0.2 19.4 0.3 18.5 0.5 21.2 1.0 18.1 0.1
100
150
200
250
25
19.4 1.0 18.3 0.5 18.1 0.1 20.8 1.0
14.0 1.0 14.4 0.1 12.9 0.6
17 1.0 21.0 0.5 21.1 0.2 23.0 1.0 20.5 0.5
13.1 0.2
–
–
–
–
–
50
15.0 1.0 15.1 0.7 11.4 0.1 15.4 0.1 14.1 0.2 11.2 0.1 14.1 1.0 15.5 0.3 16.2 0.3
16.2 0.4 17.5 0.4 12.2 0.5 16.4 0.1 15.1 0.4 16.0 0.5 17.3 0.3 18.1 0.8 17.0 1.0
18.5 0.1 18.1 0.2 14.0 1.0 17.5 0.2 16.3 0.1 18.1 0.3 18.4 0.5 20.0 0.5 18.2 0.4
19.0 1.0 19.6 0.5 15.3 0.3 18.5 0.4 17.0 0.5 20.1 0.1 19.0 1.0 21.2 0.1 19.3 0.5
20.1 0.6 21.3 0.2 18.0 1.0 20.1 0.1 19.3 0.4 22.0 1.0 21.1 0.4 24.3 0.1 22.0 1.0
100
150
200
250
25
13.2 0.2 13.0 0.4
–
12.1 0.3
–
–
–
–
14.5 0.6
50
15.0 1.0 16.9 0.5 12.1 0.1 14.7 0.5 15.2 0.4 11.6 0.7 15.3 0.2 14.5 0.3 16.4 0.1
17.6 0.2 18.3 0.1 13.5 0.8 16.1 0.4 17.3 0.5 15.1 0.2 17.3 0.1 16.5 1.0 18.1 0.3
18.0 2.0 19.8 0.3 14.5 0.1 17.3 0.2 18.2 0.3 16.3 0.3 19.1 0.8 18.6 0.3 19.0 1.0
19.5 0.5 20.5 0.5 16.1 0.2 19.0 0.1 19.1 0.5 18.6 0.1 20.6 0.6 20.2 0.7 20.3 0.4
20.4 0.1 21.0 1.0 18.8 0.9 21.0 0.2 20.5 0.5 23.0 0.1 22.4 0.5 23.0 1.0 22.2 0.5
100
150
200
250
25
13.1 0.2 13.2 0.3
–
12.4 0.5
–
–
–
–
14.5 0.2
50
16.4 0.8 15.0 0.5 12.5 0.7 14.9 0.2 13.4 0.2 14.1 0.2 14.5 0.5 14.3 0.4 16.0 1.0
17.1 0.1 17.0 0.5 14.3 0.1 15.2 0.0 15.2 0.1 15.0 0.5 15.1 0.4 16.5 0.5 18.5 0.1
19.0 0.1 18.3 0.2 16.8 0.3 17.2 0.7 16.1 0.3 17.0 0.8 18.4 0.2 19.1 0.2 19.3 0.4
20.5 0.4 19.1 0.6 18.0 1.0 18..5 0.3 17.0 1.0 19.9 0.2 20.4 0.7 21.3 0.4 20.2 0.1
21.7 0.3 20.2 0.5 21.1 0.2 20.0 1.0 18.2 0.5 23.6 0.4 22.0 0.1 23.2 0.2 22.5 0.8
100
150
200
250
25
–
–
–
–
–
–
–
12.0 0.1
–
50
14.0 0.9 13.8 0.3 11.2 0.6 13.5 1.0 13.2 0.7 15.0 0.5 14.1 0.3 15.7 0.2 13.9 0.4
16.2 0.7 14.2 0.4 13.1 0.5 15.2 0.7 15.5 0.3 16.4 0.4 15.1 0.3 17.4 0.8 15.3 0.6
17.4 0.3 16.0 0.5 14.4 0.1 16.0 0.5 16.2 0.3 18.2 0.2 16.0 1.0 19.5 0.1 17.3 0.1
19.2 0.6 18.1 0.3 17.0 0.7 18.2 0.9 17.0 0.3 19.4 0.8 18.6 0.3 20.4 0.5 19.6 0.1
20.0 0.1 19.5 0.8 19.1 1.0 20.0 0.5 19.0 0.5 22.1 0.7 19.6 0.1 23.0 0.5 22.5 0.3
100
150
200
250
25
–
–
–
–
11.1 0.5
–
–
–
–
50
14.1 0.3 13.4 0.5 13.1 0.7 12.1 0.9 13.5 0.3 14.0 0.5 13.5 0.2 15.0 0.0 12.1 0.2
15.5 0.4 14.0 0.5 14.3 0.4 14.1 0.1 15.0 0.7 16.2 0.3 15.1 0.4 17.4 0.5 14.3 0.5
16.5 0.1 15.2 0.2 15.5 0.5 16.6 0.6 16.6 0.8 18.0 1.0 16.2 0.6 18.2 0.2 16.2 0.3
18.3 0.3 17.0 1.0 16.1 0.9 17.1 0.7 18.5 0.1 20.0 1.0 17.0 0.5 20.5 0.3 18.2 0.7
19.0 0.1 19.3 0.2 20.4 0.7 19.5 0.1 20.6 0.5 23.0 0.1 18.4 0.8 22.1 0.6 21.0 1.0
100
150
200
250
25
13.0 0.1 13.6 0.3
–
12.2 0.5 12.0 1.0
–
12.1 0.3
–
–
50
14.0 0.3 15.1 0.4 11.2 0.8 14.4 0.3 14.0 0.4 14.3 0.5 14.4 0.2 14.5 0.3 12.1 0.3
15.3 0.7 16.1 0.3 13.0 0.6 15.2 0.9 16.1 0.5 17.4 0.3 16.0 0.5 16.2 1.0 13.0 0.5
16.6 0.8 17.0 0.1 16.5 0.2 17.5 0.1 17.3 0.8 18.2 0.7 17.0 0.1 18.4 0.4 14.3 1.0
18.3 0.5 19.3 0.3 18.0 1.0 19.3 0.4 18.2 0.2 19.3 0.5 18.1 0.8 20.0 0.1 16.5 0.6
19.2 0.8 20.2 0.5 19.7 0.3 21.3 0.2 20.0 0.5 23.1 0.5 19.1 0.3 22.3 0.5 18.1 0.5
100
150
200
250
25
12.5 0.2
–
–
–
12.0 1.0
–
–
–
–
–
50
14.0 0.5 14.4 0.2 12.2 0.1 13.5 0.5 14.6 0.2 13.3 0.6 12.5 1.0
12.1 0.2
100
150
15.5 1.0 15.1 0.5 13.4 0.6 15.1 0.3 15.5 0.2 15.0 0.7 13.2 0.1 15.6 0.4 14.0 0.5
17.2 0.7 16.2 0.1 16.2 1.0 16.3 0.5 16.5 0.3 19.1 0.7 14.2 0.0 18.1 0.9 15.3 0.6
123

Med Chem Res
Table 1 continued
Diameter of zone of inhibition (mm)
Compounds Concn. Fungal strains
(lg/mL)
Bacterial strains
SA BS
AN
PC
BP
ML
PA
PF
EC
200
250
25
18.2 0.5 18.4 0.7 18.3 0.2 18.1 0.2 18.5 0.5 21.0 0.1 16.2 0.4 20.4 0.1 17.1 0.7
20.4 0.1 19.4 0.8 20.5 0.2 20.0 1.0 19.3 0.8 24.5 0.5 18.2 0.3 23.3 0.2 18.0 1.0
SP-9
12.3 0.3
–
–
12.1 0.7 11.2 0.4
–
–
–
–
50
14.1 0.0 12.1 0.1 12.0 0.3 14.3 0.8 12.2 0.2 14.1 0.2 12.2 0.7 12.0 0.5 13.2 0.6
15.2 0.7 15.5 0.1 14.3 0.8 16.2 0.2 14.5 1.0 16.2 0.5 15.3 0.5 15.1 0.2 15.1 0.4
17.1 0.6 16.2 0.1 15.1 0.1 18.5 0.3 15.4 0.3 20.5 0.1 17.0 0.1 17.3 1.0 16.0 0.2
18.0 0.3 18.1 0.9 17.2 0.7 20.1 0.5 17.3 0.7 22.3 0.3 18.1 0.3 20.5 0.5 18.5 0.1
19.4 0.1 19.0 0.5 19.3 0.3 22.1 0.4 18.5 0.1 24.3 0.5 21.2 0.3 22.1 0.2 20.2 0.5
100
150
200
250
25
SP-10
12.2 0.2
–
–
–
–
–
–
–
–
50
13.0 0.5 12.0 0.5 12.1 0.7 14.0 0.9 12.1 0.5 18.1 0.4 12.1 0.1 11.1 0.4 13.1 0.5
15.3 0.4 14.2 0.2 14.5 0.1 16.1 0.4 15.5 1.0 20.4 0.4 15.4 0.4 16.2 0.6 15.5 0.1
16.4 0.9 15.5 1.0 16.4 0.6 17.2 0.6 16.1 0.5 21.1 0.3 16.3 0.7 18.1 0.5 17.2 0.4
17.1 0.3 17.3 1.0 18.1 0.2 20.0 0.2 18.0 1.0 22.0 0.2 18.1 0.2 20.0 1.0 19.1 0.3
19.1 0.8 19.3 0.4 21.2 0.5 22.5 0.1 19.2 0.6 24.2 0.7 21.0 0.5 23.1 0.4 21.5 0.1
100
150
200
250
50
A
B
C
–
–
25.3 0.5 23.5 0.2 28.2 0.5 26.3 0.7 28.3 1.0 25.5 1.0 36.2 0.4
50
28.8 0.2 20.0 1.0
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Values are expressed in triplicates, i.e., mean SD (n = 3)
A norfloxacin, B fluconazole, C control (DMSO)
AN Aspergillus niger (MTCC No. 2546), PC Penicillium chrysogenum (MTCC No. 161), SA Staphylococcus aureus (MTCC No. 1430), BS
Bacillus subtilis (MTCC No. 441), BP Bacillus pumilus (MTCC No. 1456), ML Micrococcus luteus (MTCC No. 1538), PA Pseudomonas
aeruginosa (MTCC No. 424), PF Pseudomonas fluorescens (MTCC No. 2421), EC Escherichia coli (MTCC No. 1573)
Determination of minimum inhibitory concentration
(MIC)
Results and discussion
A series of novel 3-benzyl-2,6-diarylpiperidine-4-one
derivatives were synthesized by reacting dry ammonium
acetate, different aromatic/heteroaromatic aldehydes, and
benzylacetone in ethanol. All the synthesized compounds
were characterized by IR, MS, and 1H NMR spectra as well
as elemental analysis so as to assign the structures. IR
spectra were recorded on Shimadzu 8400S and Perkin
Elmer Spectrum RX1 FTIR spectrophotometers. The KBr
pellet technique was adopted to record the spectra. The
tentative assignment of the vibrational frequencies of the
synthesized compounds were compared with those reported
in the literature. The spectral shifts and intensity changes
observed explain the influence of the substituents. Mass
spectra were recorded on JEOL-AccuTOF JMS-T100LC
spectrometer from Central Drug Research Institute, Luc-
Tube assay method was performed to determine the
MICs of the synthesized compounds. MICs are consid-
ered the ‘‘gold standard’’ for determining the suscepti-
bility of organisms to antimicrobials and are therefore
used to judge the performance of all other methods of
susceptibility testing. To the test tubes containing 4.5 mL
of nutrient medium previously seeded with the appro-
priate test organism, 1.0 mL of each concentration (25,
50, 100, 150, 200, and 250 lg/mL) of the sample solu-
tion was added. Standard drugs used (norfloxacin and
fluconazole) were taken in reported quantities, i.e.,
50 lg/mL. An inoculated broth containing no antibiotic
was included as growth control and a tube of uninocu-
lated broth was used as sterility control. These test tubes
were then, incubated for 24 h at suitable temperature.
Then, optical density was recorded using Labotronics
Digital Photo Colorimeter Model No. 13 at 530 nm. The
sharp fall in the readings of optical density was con-
sidered as MIC.
1
know, India. H NMR spectra were recorded at 400 MHz
on Bruker DRX-300 spectrometer and 13C NMR data were
recorded on Advance-400 MHz, Bruker (Switzerland)
spectrometer using tetramethyl silane as internal standard
1
from Central Drug Research Institute, Lucknow, India. H
123

Med Chem Res
Table 2 In vitro antifungal and antibacterial activities of compounds SP-1 to SP-10
Minimum inhibitory concentration (MIC, lg/mL)
Fungal strains
Compounds
Bacterial strains
AN
PC
SA
BS
BP
ML
PA
PF
50
EC
SP-1
SP-2
SP-3
SP-4
SP-5
SP-6
SP-7
SP-8
SP-9
SP-10
A
150
50
200
50
150
250
150
200
200
150
200
150
200
200
50
150
50
150
200
150
200
200
100
50
150
250
250
150
150
150
150
150
150
150
50
150
150
150
150
150
150
100
150
150
200
50
150
50
150
150
150
100
150
150
200
150
200
50
50
50
50
50
50
50
50
100
150
150
150
150
150
150
50
150
150
50
150
150
100
150
200
150
–
150
150
50
100
50
150
50
100
50
100
–
150
50
50
50
B
50
50
–
–
–
–
–
–
–
Each value is mean of three independent experiments (n = 3). Minimum inhibitory concentrations were determined by seriel dilution method for
microdilution plates
A norfloxacin, B fluconazole
AN Aspergillus niger (MTCC No. 2546), PC Penicillium chrysogenum (MTCC No. 161), SA Staphylococcus aureus (MTCC No. 1430), BS
Bacillus subtilis (MTCC No. 441), BP Bacillus pumilus (MTCC No. 1456), ML Micrococcus luteus (MTCC No. 1538), PA Pseudomonas
aeruginosa (MTCC No. 424), PF Pseudomonas fluorescens (MTCC No. 2421), EC Escherichia coli (MTCC No. 1573)
NMR and 13C NMR spectra of 3-benzyl-2,6-diaryl-4-pip-
eridones were analyzed and effect of varying the substit-
uents was observed on the 1H and 13C chemical shifts. The
signals in the region of 6.32–7.8 ppm are due to the aryl/
heteroaryl group protons at C-2, C-6 merged together to
give multiplet with benzylic protons. Deshielding of the
ortho protons of aryl/heteroaryl and benzylic protons can
be attributed to the lone pair of electrons on the nitrogen in
piperidone. Elemental analysis was carried out on Ele-
mental Vario EL III analyzer from Central Drug Research
Institute, Lucknow, India.
compounds showed moderate to good activity against all
the bacterial strains.
The in vitro antifungal activity of compounds was
examined against the fungal strains A. niger (MTCC No.
2546) and P. chrysogenum (MTCC No. 161). Fluconazole
was chosen as the standard drug for the antifungal study.
MIC values of all the compounds fall in the range of
50–250 lg/mL. Compounds SP-2, SP-3, SP-4, SP-7,
and SP-9 showed maximum activity against A. niger
(50 lg/mL); SP-2, SP-3, and SP-4 against P. chrysogenum
(50 lg/mL), whereas the remaining compounds exhibited
moderate to good activity (Tables 1, 2).
The in vitro antibacterial activity of the compounds was
studied by cup-plate method as well as by tube assay
method against S. aureus (MTCC No. 1430), B. subtilis
(MTCC No. 441), B. pumilus (MTCC No. 1456), M. luteus
(MTCC No. 1538), P. aeruginosa (MTCC No. 424), P.
fluorescens (MTCC No. 2421), and E. coli (MTCC No.
1573). Norfloxacin was taken as the standard drug for the
antibacterial activity studies. All of the synthesized com-
pounds demonstrated antimicrobial activity as shown in
Table 1. A close examination of MIC values indicates that
all the compounds exhibited a varied range (50–250 lg/
mL) of antibacterial potency against the tested bacterial
strains (Table 2). Compounds SP-2, SP-3, SP-4, SP-7, and
SP-9 exhibited maximum activity against B. subtilis
(50 lg/mL); SP-7 and SP-9 against B. pumilus (50 lg/
mL); and compounds SP-2 and SP-3 showed maximum
activity against E. coli (50 lg/mL). The remaining
Conclusions
Among the compounds tested for antibacterial activity,
compounds with symmetrical substitution at C-2 and C-6
by aryl groups exhibited promising activity. Further, it was
found that 4-fluorophenyl, naphthalen-1-yl, and 4-oxo-4H-
chromen-3-yl groups were important in eliciting good
antibacterial activity. Similarly, among the antifungal
profile of the compounds tested, the presence of 4-fluoro-
phenyl and naphthalen-1-yl groups at C-2 and C-6 posi-
tions of piperidin-4-one ring played an important role in
eliciting inhibition of all the fungi under test. Thus, a close
examination of in vitro antibacterial and antifungal activity
profiles for the 3-benzyl-2,6-diarylpiperidin-4-ones, against
123

Med Chem Res
Dimmock JR, Arora VK, Wonko SL, Hamon NW, Quail JW, Jia Z,
Warrington RC, Fang WD, Lee JS (1990) 3,5-Bis-benzylidene-
4-piperidones and related compounds with high activity towards
P388 leukemia cells. Drug Des Deliv 6(3):183–194
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Kowalczyk ES, Allen TM, Santos CL, De Clercq E, Balzarini J,
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the tested bacterial and fungal strains, clearly indicates that
compounds SP-2 and SP-3 were the most potent antimi-
crobial agents in the series. Significantly, all the com-
pounds showed better antifungal activity as compared to
the antibacterial activity and may thus hold promise as
antifungal agents. This finding increases the importance of
this work because most of the antimicrobial agents are
antibacterial, rather than antifungal, and there is an urgent
need for antifungal agents.
The study reveals that several modifications are possible
in the piperidin-4-one ring system. Piperidin-4-ones when
reacted with thiosemicarbazide and hydroxylamine hydro-
chloride give thiosemicarbazone and oxime, respectively,
which themselves have their own activity and could lead to
more potent and highly active compounds.
as antiviral and cytotoxic agents.
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Acknowledgments We express our sincere gratitude to Central
Drugs Research Institute, Lucknow, India for providing the library
facilities and sophisticated analytical instrument facilities.
Hemalatha T, Imran PK, Gnanamani A, Nagarajan
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