Synthesis, characterization, crystal structure, in-vitro antimicrobial evaluation and molecular docking studies of 1-(furan-2-carbonyl)-3-alkyl-2,6-diphenylpiperidin-4-one derivatives

Article abstract of DOI:10.1016/j.molstruc.2016.07.023

A new class of various furoyl derivatives of 2,6-disubstituted piperidin-4-ones were synthesized and characterized by FTIR, NMR, mass and single crystal X-ray diffraction methods. The synthesized compounds were subjected to in-vitro antibacterial and antifungal activities against pathogenic microbial strains. The results pointed out that compounds 11, 12 & 14 displayed pronounced activity towards gram positive bacteria, whereas the compounds 9, 13 & 14 showed a superior inhibition activity against gram negative bacteria. The compound 9 showed a moderate activity towards the fungi. In addition, molecular docking experiments were also carried out.

Full text of DOI:10.1016/j.molstruc.2016.07.023

Accepted Manuscript
Synthesis, characterization, crystal structure, in-vitro antimicrobial evaluation and
molecular docking studies of 1-(furan-2-carbonyl)-3-alkyl-2,6-diphenylpiperidin-4-one
derivatives
R. Srikanth, A. Sivarajan, C.S. Venkatesan, V. Maheshwaran, P. Sugumar, G.
Rajitha, J.C. Varalakshmi, M.N. Ponnuswamy
PII:
S0022-2860(16)30694-9
10.1016/j.molstruc.2016.07.023
MOLSTR 22726
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 21 May 2016
Revised Date: 5 July 2016
Accepted Date: 8 July 2016
Please cite this article as: R. Srikanth, A. Sivarajan, C.S. Venkatesan, V. Maheshwaran, P.
Sugumar, G. Rajitha, J.C. Varalakshmi, M.N. Ponnuswamy, Synthesis, characterization, crystal
structure, in-vitro antimicrobial evaluation and molecular docking studies of 1-(furan-2-carbonyl)-3-
alkyl-2,6-diphenylpiperidin-4-one derivatives, Journal of Molecular Structure (2016), doi: 10.1016/
j.molstruc.2016.07.023.
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ACCEPTED MANUSCRIPT
Synthesis, characterization, crystal structure, in-vitro antimicrobial
evaluation and molecular docking studies of 1-(furan-2-carbonyl)-3-alkyl-2,6-
diphenylpiperidin-4-one derivatives
R. Srikantha,b*
,
A. Sivarajana, C.S.Venkatesanb, V. Maheshwaranc P. Sugumarc,
G. Rajithad, J. C. Varalakshmid and M. N. Ponnuswamyc*
aDepartment of Chemistry, Government Arts College, Tiruchirappali – 620 022, India.
bResearch and Development, Gland Pharma Ltd., Hyderabad 500 049, India.
cCentre of Advanced Study in Crystallography & Biophysics, University of Madras, Guindy
Campus, Chennai-600 025, India.
dInstitute of Pharmaceutical Technology, Sri Padmavathi Mahila VisvaVidyalayam (Women’s
University), Tirupati – 517502, Andhra Pradesh, India.
*Corresponding authors:
R. Srikanth
Research and Development, Gland pharma limited,
Hyderabad – 500 049, India.
Tel: +91-40-30510999
Fax: + 91-40-30510800
E-mail address: rangacharisrikanth@yahoo.com (R. Srikanth)
M. N. Ponnuswamy
Centre of Advanced Study in Crystallography & Biophysics,
University of Madras,
Guindy Campus,
Chennai-600 025, India.
E-mail address:mnpsy2004@yahoo.com (M. N. Ponnuswamy)
1

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ABSTRACT
A new class of various furoyl derivatives of 2,6-disubstituted piperidin-4-ones were
synthesized and characterized by FTIR, NMR, mass and single crystal X-ray diffraction
methods. The synthesized compounds were subjected to in-vitro antibacterial and antifungal
activities against pathogenic microbial strains. The results pointed out that compounds 11, 12 &
14 displayed pronounced activity towards gram positive bacteria, whereas the compounds 9, 13
& 14 showed a superior inhibition activity against gram negative bacteria. The compound 9
showed a moderate activity towards the fungi. In addition, molecular docking experiments were
also carried out.
Key words: piperidone; cyclo condensation; growth; crystal structure; antimicrobial activity;
molecular docking.
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1. Introduction
Small heterocyclic systems act as highly functionalized scaffolds and known as
pharmacophores of a number of biologically active molecules. Baliah and his coworkers have
reviewed the importance of piperidin-4-ones as intermediates in the synthesis of several
physiologically active compounds [1, 2]. Similarly, Lijinsky and Taylor [3] have found that the
presence of substituents at both the α-positions to that of N in piperidin-4-ones is important to
exert marked biological properties. Bioactive heterocyclic ring systems having 2,6-diaryl-
piperidine-4-one nucleus with different substituents at 3- and 5-positions of the ring have
aroused great interest due to their wide variety of biological properties such as antiviral,
antitumor [4,5], central nervous system [6], local anesthetic [7], anticancer [8], antimicrobial
activities [9] and their derivatives piperidine are also biologically important and act as
neurokinin receptor antagonists [10], analgesic and anti-hypertensive agents [11].
For the last few decades, a considerable amount of attention has been focussed on the
synthesis of furan derivatives and screening them for different pharmacological activities. The
furan ring system is the basic skeleton of numerous compounds possessing cardiovascular
activities. An iodinated lipophilic furan derivative is widely used in the treatment of ventricular
and atrial fibrillation. These moieties are widely used as antibacterial, antiviral, anti-
inflammatory, antifungal, antitumor, antihyperglycemic, analgesic, anticonvulsant [12] etc., but a
slight change in the substitution pattern in furan nucleus causes distinguishable differences in
their biological activities.
In the present study, we report the synthesis, characterization, crystal structure and
antimicrobial activity of the compounds 1-(furan-2-carbonyl)-3-alkyl-2,6-diphenylpiperidin-4-
1
13
one derivatives. The structural confirmation was carried out using FT-IR, H NMR, C NMR,
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2D-NMR and X-ray crystallographic methods. Molecular docking study was also performed on
1-(furan-2-carbonyl)-3-alkyl-2,6-diphenylpiperidin-4-one derivatives with the targeted GTP
binding protein.
2. Experimental procedure
2.1. General
The chemicals, 2-pentanone, 2-octanone, 4-flurobenzaldehyde, 4-bromobenzaldehyde
and 2-furoyl chloride were purchased from Sigma Aldrich and used without further purification.
Benzaldehyde, Triethylamine and Ammonium acetate were purchased from Spectrochem Pvt
Ltd. Melting points were determined in open capillary tubes and are uncorrected. IR spectra
1
were taken as KBr pellets for solids on a Shimadzu IR Prestige-21 model. H NMR (300 MHz)
13
and C NMR (75 MHz) spectra were recorded in DMSO-d6 solutions with TMS as an internal
standard on a Bruker Avance instrument. Mass spectra were recorded on an Agilent
Technologies 6310 Ion trap LC/MS.
2.2. Synthesis of 1-furoyl -2,6-diphenyl-3ethylpiperidin-4-one, 9
To a stirred solution of 2,6-diphenyl-3-ethylpiperidin-4-one (1g, 3.58 mmoles) in toluene
(15 mL), triethyl amine (1.9 mL, 14.34 mmoles) was added and the resultant reaction mixture
was cooled to 0-5°C. To this, 2-furoyl chloride (1.1 mL, 10.74 mmoles) was added and the
reaction was continued for stirring about 12 hrs at room temperature. The precipitated salts were
filtered off. The filtrate was treated with water and extracted with ethyl acetate (3 x 5 mL), the
organic layer was washed with aqueous sodium bicarbonate solution, followed by brine solution.
The resultant organic layer was evaporated to obtain crude compound, which on treatment with
ethyl acetate and n-hexane resulted in a white colour solid (yield: 65%). The compounds 10-14
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were obtained using the same procedure. The chemical structure and synthesis procedure of the
compounds 9-14 are given in Table 1 and shown in Scheme 1.
2.3. Crystal growth
The solubility of the compound is determined by adding the solvent to a known amount till
it completely dissolved. A supersaturated solution was prepared by dissolving the sample in
methanol at ambient temperature. The prepared solution was filtered, slightly warmed and
allowed to evaporate slowly at room temperature, in a dust free atmosphere [13]. After about 3
days, good quality tiny crystals appeared and were allowed to grow to a maximum possible
dimension and then harvested. The grown transparent crystals are used for X-ray diffraction
studies.
3. Results and discussion
The present study describes the synthesis and structural characterization of furoyl
derivatives of piperdin-4-ones. The furoyl derivatives 9-14 were synthesized by the condensation
of 2,6-diarylpiperidin-4-ones (3-8) with 2-furoyl chloride in the presence of triethylamine. The
compounds (3-8) were prepared according to the literature procedure and recrystallized from
ethanol. The formation of furoyl derivatives were confirmed by comparing the spectral data of
the furoyl compounds with the corresponding precursors of piperidone derivatives. The
molecular structure of compound 10 was confirmed by single crystal X-ray structure analysis.
The results are presented in the experimental section.
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Table 1
Structure of compounds 9-14; the numbering assignment is shown in compound 10
Compound 9
Compound 10
O
O
19
4
5
6
3
2
14
8
1
15
16
9
N
13
18
7
N
20
12O
10
22
17
23
11
O
O
21
O
24
Compound 11
Compound 12
O
O
N
N
F
O
O
F
O
O
Compound 13
Compound 14
O
O
N
N
Br
O
O
Br
O
O
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3.1 FTIR spectral analysis
The IR spectral analysis of compounds 9-14 were carried out to investigate the presence of
functional groups and their vibration modes. The IR spectrum was recorded in the range 400–
4000 cm-1 at room temperature using Shimadzu IR Prestige-21 model spectrophotometer. The IR
spectrum of all compounds showed a characteristic signal at around 1600-1630 cm-1 attributing
for amide carbonyl stretching, which is an evidence for the formation of furoyl substitution at the
1st position. In addition, a signal around 1710–1725 cm-1 corroborates for keto functionality in
piperidine ring. Besides, a band at 3065-3030 cm-1 indicates the aromatic C-H stretching
vibrations.
3.2 1H and 13C NMR analysis
1
The H NMR spectrum of compound 10 showed a doublet at δ 0.83 ppm corresponding to
methyl side chain of piperidin-4-one ring. In addition, a multiplet at δ 2.78-2.81 (J=14.7 Hz) and
3.05-3.09 (J = 10.8 Hz) correspond to the proton at C-3 and C-5 positions, respectively. The
aromatic protons and an AMX splitting pattern were observed for phenyl and furoyl rings
protons, respectively. The 13C NMR spectrum of compound 10 showed a signal at δ 161.9 ppm,
which is indicative of amide carbonyl attached to the furoyl ring. The signal at 208.4 ppm
indicates the presence of keto group in the piperidin-4-one ring. The signal observed at δ 12.9
ppm was attributed for the methyl side chain of piperidone ring carbons. Besides, the other
signals were also observed due to phenyl and furoyl ring carbons. This was further confirmed by
1
DEPT-135 NMR and Mass spectral analysis. The H NMR, 13C NMR and DEPT-135 NMR
spectra of compound 10 are shown in Figs. 1, 2 & 3, respectively.
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Fig. 1. 1H NMR spectrum of 1-Furoyl-2,6-diphenyl-3-methylpiperidin-4-one
Fig. 2. 13C NMR spectrum of 1-Furoyl-2,6-diphenyl-3-methylpiperidin-4-one
8

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Fig. 3. DEPT-135 NMR spectrum of 1-Furoyl-2,6-diphenyl-3-methylpiperidin-4-one
For 1-furoyl-2,6-diphenyl-3-methylpiperidin-4-one (10), 1H-1H COSY and 1H-13C HSQC
spectra were recorded to confirm the assignments. The COSY spectrum reveals that the upfield
signal at 0.83 ppm is unambiguously assigned at side chain methyl hydrogen H(19) and it shows
a cross peak with the multiplet at 2.78-2.81 ppm. Therefore, the signal at 2.76-2.81 ppm is
obviously due to H(3) only. In addition, a correlation with 5.41 ppm confirms H(3) attached to
H(2). The signal at 3.05-3.09 ppm H(5), a multiplet shows cross peak with 5.91 ppm for H(2),
indicating that both are adjacent to each other. Besides, other correlations also confirmed the
structure of the compound. 1H-13C HSQC shows a cross peak at 0.83 ppm and 12.9 ppm
indicates the –CH3 group. Similarly H(3), H(5), H(6), H(2), H(22), H(23) and H(24) were
9

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correlated with the corresponding carbons, further confirming the structure of the compound.
The observed correlations in the HOMOCOSY and HSQC spectra are given in Table 2. The
COSY and HSQC spectra of compound 10 are shown in Figs. 4 & 5, respectively. The IR
spectral values and analytical data of compounds 9-14 are presented in Tables 3 & 4,
respectively.
Table 2
Correlation in HOMOCOSY and HSQC of compound 10 (δ, ppm).
1H NMR signal
Correlation in HSQC Correlation in HOMOCOSY
12.9 (C(19))
2.78-2.81 (H(3)), 5.41 (H(2))
0.83 (H(19))
2.76-2.81 (H(3))
3.05-3.09 (H(5))
5.41 (H(2))
6.54 (H(23))
6.94 (H(22))
46.0 (C(3))
42.8 (C(5))
54.8 (C(2))
111.6 (C(23))
115.8 (C(22))
0.83 (H(19)), 5.41 (H(2))
5.91 (H(6))
2.76-2.81 (H(3))
6.94 (H(22))
6.54 (H(23))
-
7.19-7.46 (Aromatic protons) -
7.75 (H(24)) 145.0 (C(24))
6.94 (H(23))
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Fig. 4. COSY spectrum of 1-Furoyl-2,6-diphenyl-3-methylpiperidin-4-one
Fig. 5. HSQC spectrum of 1-Furoyl-2,6-diphenyl-3-methylpiperidin-4-one
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1
1-Furoyl-2,6-diphenyl-3-ethylpiperidin-4-one (9). H NMR (300 MHz, DMSO-d6): δ 0.84 (t,
3H, 20-CH3), 1.56 (m, 2H, 19-CH2), 2.62 – 2.88 (dd, 2H, J=5.1 & 17.4 Hz, 5-CH2), 2.98-3.00
(m, 1H, J = 3.6 Hz, 3-CH), 5.78-5.79 (m, 2H, J = 4.5 Hz, 2 & 6-CH), 6.58 (s, 1H, 24-CH furan),
6.99 (d, J = 3.3 Hz 1H, 23-CH furan), 7.16-7.41 (m, 10H, aromatic), 7.79 (bs, 1H, 25-CH
furan); 13C NMR (75 MHz, DMSO-d6): δ 11.2 (C-20), 22.1(C-19), 43.5 (C-5), 52.7 (C-2),
55.1(C-3), 58.8 (C-6), 111.6 (C-24, furan b), 116.1 (C-23, furan c), 126.5 (C-10, C-16, p ), 127.3
(C-8,12-o and C-14, 18-o), 128.4 (C-9, 11-m and C-15, 17-m), 140.8 (C-7), 141.4 (C-13), 145.2
(C-25, furan a), 147.1(C-22), 161.9(21-C=O), 208.3(C-4 C=0) ppm; MS (ESI): calculated for
C24H23NO3 373.4; Observed Mass: 374.4 (M+H)+
1
1-Furoyl-2,6-diphenyl-3-methylpiperidin-4-one (10). H NMR (300 MHz, DMSO-d6): δ 0.83
(d, 3H, J = 6.9 Hz, 19-CH3), 2.76-2.81 (m, 1H, J=14.7 Hz, 3-CH), 3.05-3.09 (m, 2H,
J = 10.8 Hz, 5-CH2), 5.41 (d, 1H, J = 8.4 Hz, 2-CH), 5.91 (t, 1H, J = 10.8 & 5.4 Hz, 6-CH), 6.54
(dd, 1H, J = 4.8 & 3.3 Hz, 1H, 23-CH furan), 6.94 (d, 1H, J = 3.3 Hz, 22-CH furan), 7.19-7.46
(m, 10H, aromatic), 7.75 (bs, 1H, 24-CH Furan); 13C NMR (75 MHz, DMSO-d6): δ 12.9 (C-19),
42.8 (C-5), 46.0 (C-3), 54.8 (C-2), 62.0 (C-6), 111.6 (C-23, furan b), 115.8 (C-22, furan a), 126.8
(C-16, aromatic-p), 127.1 (C-10, aromatic-p), 127.3 (C-8 & C-12 aromatic-o), 127.5 (C-14 & C-
18, aromatic-o), 128.1 (C-9 & C-11, aromatic-m), 128.5 (C-15 & C-17, aromatic-m), 141.1(C-7),
141.4 (C-13), 145.0 (C-24, furan c), 147.2 (C-21), 161.9 (20-C=O), 208.4 (C-4 C=0) ppm; MS
(ESI): calculated for C23H21NO3, 359.15; Observed Mass: 382.2 [M+Na adduct].
1
1-Furoyl-2,6-diphenyl-3-pentylpiperidin-4-one (11). H NMR (300 MHz, DMSO-d6): δ 0.73
(t, 3H, J=6.6 & 13.8 Hz, 23-CH3), 0.83-1.49 (m, 8H, 19, 20, 21 & 22 CH2), 2.39-2.44 (2d, 1H,
J = 2.7&12.6 Hz, 5-CH2), 2.63-2.80 (m, 2H, J = 8.4&12.3 Hz, 3-CH & 5-CH2), 3.64-3.68 (d, 1H,
J=10.5Hz, 2-CH), 3.98-4.03 (d, 1H, J=2.4 & 11.7Hz, 6-CH), 6.84 (dd, 1H, 27-CH furan), 7.4 (s,
12

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1H, 26-CH furan), 7.19-7.35 (m, 10H, aromatic), 8.19 (s, 1H, 28-CH furan); 13C NMR
(75 MHz, DMSO-d6): δ 13.7 (C-23), 21.7 (C-22), 24.3 (C-21), 26.6 (C-20), 31.3 (C-19), 50.7
(C-5), 55.9 (C-2), 60.9 (C-3), 66.4 (C-6), 117.6 (C-27 furan), 123.1 (C-26 furan), 126.6 (C-13),
127.2 (C-7), 127.5 (C-8 & C-12), 127.9 (C-14 & C-18), 128.2 (C-9 & C-12), 128.3 (C-15 & C-
16), 146.9 (C-25), 150.6 (C-28), 159.4 (C-24 C=O,), 208.8 (C-4 C=O); MS (ESI): calculated for
C27H29NO3: 415.5; Observed Mass: 416.6 (M+H)+
1
1-Furoyl-2,6-Fluoro-diphenyl-3-methylpiperidin-4-one (12). H NMR (300 MHz, DMSO-
d6): δ 0.85 (d, 3H, J = 6.6 Hz, 19-CH3), 2.74-2.79 (m, 1H, 3-CH), 3.07-3.09 (m, 2H, 5-CH2),
5.41 (d, 1H, J = 8.4 Hz, 2-CH), 5.89 (t, 1H, J =5.1 Hz, 6-CH), 6.55 (dd, 1H, J = 1.5 & 3.0 Hz,
1H, 23-CH furan), 6.97 (d, 1H, J = 3.3 Hz, 22-CH furan), 7.05-7.46 (m, 8H, 8-12 & 14-18
aromatic), 7.77 (s, 1H, 24-CH Furan); 13C NMR (75 MHz, DMSO-d6): δ 12.9 (C-19), 42.5 (C-
5), 46.0 (C-3), 54.3 (C-6), 62.0 (C-2), 111.7 (C-23, furan), 114.8 (C-22, furan), 115.0 (C-15),
115.2 (C-9), 115.5 (C-11), 116.2 (C-17), 128.9 (C-14), 129.0 (C-8), 129.5 (C-21), 129.6 (C-18),
137.1 (C-13), 137.2 (C-7), 145.1 (C-24), 147.1 (C-21), 159.4 (C-10), 159.6 (C-16), 161.8 (C-20,
C=O), 208.3 (C-4, C=O); MS (ESI): calculated for C23H19F2NO3: 395.4; Observed Mass:
396.1(M+H)+
1-Furoyl-2,6-bromo-diphenyl-3-methylpiperidin-4-one (13). 1H NMR (300 MHz, DMSO-d6):
δ 0.77 (d, 3H, J = 6.6 Hz, 19-CH3), 2.70-2.75 (m, 2H, 5-CH2), 3.07-3.09 (m, 1H, 3-CH2), 5.38
(d, 1H, J = 8.4 Hz, 2-CH), 5.86 (t, 1H, J =10.2 Hz, 6-CH), 6.57 (dd, 1H, J = 1.8 & 3.3 Hz, 1H,
23-CH furan), 6.97 (d, 1H, J = 3.3 Hz, 22-CH furan), 7.2-7.79 (m, 9H, 8-12 & 14-18 aromatic &
24-CH Furan); 13C NMR (75 MHz, DMSO-d6): δ 10.2 (C-19), 42.5 (C-5), 45.9 (C-3), 54.5 (C-
6), 61.3 (C-2), 111.7 (C-23, furan), 116.5 (C-22, furan), 117.7 (C-15), 120.3 (C-9), 120.5 (C-11),
122.7 (C-17), 129.9 (C-14), 129.8 (C-8), 130.7 (C-21), 131.1 (C-18), 134.7 (C-13), 140.3 (C-7),
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140.7 (C-24), 145.3 (C-21), 147.0 (C-10), 161.8 (C-20, C=O), 208.0 (C-4, C=O); MS (ESI):
calculated for C23H19Br2NO3: 517.2; Observed Mass: 518.0 (M+H)+
1
1-Furoyl-2,6-diphenyl-3,3'dimethylpiperidin-4-one (14). H NMR (300 MHz, DMSO-d6): δ
1.31 (s, 3H, 25-CH3), 1.35 (s, 3H, 26-CH3), 2.86-2.95 & 3.19-3.27 (2d, 2H, J = 9.6 & 18.3Hz, 5-
CH2), 5.8 (bs, 1H, 2-CH), 6.0 (m, 1H, J = 8.1 & 16.2 Hz, 6-CH), 6.52-7.04 (m, 2H, 23-CH & 22-
CH furan), 7.21-7.92 (m, 11H, aromatic & 24-CH Furan) ; 13C NMR (75 MHz, DMSO-d6): δ
20.39 (C-25), 21.1 (C-26), 43.6 (C-5), 47.8 (C-3), 58.8 (C-6), 67.1 (C-2), 111.4 (C-23), 115.8 (C-
22), 126.4 (C-10), 127.5 (C-15), 128.0 (C-8), 128.1 (C-9), 128.3 (C-14), 128.8 (C-12), 129.1 (C-
18), 138.9 (C-7), 142.5 (C-13), 146.9 (C-24), 147.0 (C-21), 161.5 (C-20, C=O), 210.3 (C-4,
C=O), MS (ESI): calculated for C24H23NO3: 373.4; Observed Mass: 374.2.
Table 3
Characteristic IR stretching frequencies (cm-1) of compounds 9–14
Compound
Aromatic C-H stretching
Aliphatic C-H stretching
C=O
Amide carbonyl
No
3065, 3034
3071, 3034
3134
3124
3105
3107, 3040
2972, 2931, 2875
2974, 2914, 2822
2957, 2926, 2858
2916, 2851
2993, 2974
2993, 2916, 2806
1714
1719
1717
1719
1722
1629
1639, 1625
1620
9
10
11
12
13
14
1643
1633
1610
1718, 1705
Table 4
Analytical data of compounds (9-14) 1-furoyl substituted 2,6-diarylpiperidin-4-one derivatives
ESI Mass
observed/(Calculated)
374.4
Entry
9
R1
CH2CH3
CH3
R2
H
H
H
F
Yield (%)
m.p (°C)
170.2
142.5
210.5
145.2
178.5
200.9
65
72
69
62
66
71
(373.4)
382.2 [M+Na]
(359.4)
10
416.6
(415.5)
396.1
(395.4)
518.0
(517.2)
374.2
(373.4)
11
CH3(CH2)4
CH3
12
CH3
Br
H
13
CH(CH3)2
14
14

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Scheme 1. Synthesis of furoyl analogue substituted 2,6-diarylpiperidin-4-ones.
O
R1
CHO
O
NH4OAc, 70-80°C
EtOH
N
R1
+
2
H
R2
R2
R2
3-8
2
1
2-Furoyl chloride/TEA
3h, reflux
O
R1
N
R2
O
R2
O
9-14
15

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3.3 Single-crystal X-ray diffraction studies
The single crystal X-ray diffraction data were collected on a Bruker axs Kappa APEXII CCD
diffractometer employing graphite-monochromatized MoKα radiation (λ = 0.71073 Å). The data
were processed using the SAINT software program [14]. The structure was solved by the direct
methods using SHELXS-97, and refined on F2 by full-matrix least-squares technique using the
SHELXL-97 package [15, 16]. The molecular graphics plots were drawn using PLATON [17]
and ORTEP-3 [18]. All H atoms were fixed geometrically and allowed to ride on their parent C
atoms, with C—H distance fixed in the range 0.93–0.97 Å. The H atom displacement parameters
were restricted to be 1.2Ueq for the parent atom. The details of X-ray data collection, structure
solution and structure refinement are given in Table 5. Bond distances, bond angles and torsion
angles of the 1-furoyl-2,6-diphenyl-3-methylpiperidin-4-one derivative are listed in Tables 6, 7
& 8, respectively. The ORTEP plot of compound 10 with the atom-numbering and displacement
ellipsoids drawn at 30% probability level is shown in Fig. 6 [18].
The compound 10 crystallizes in triclinic space group P-1. The bond lengths and bond
angles agree with those observed in other related structure [19]. The piperidine ring is in
distorted boat conformation. The puckering [20] and the asymmetry parameters are [21]: q2=
0.709 (17) Å; q3= −0.026 (16)Å and phi2= 255.0 (13)°, respectively. The attached phenyl rings
[C7—C12 & C13—C18] are in axial orientation as can be seen from the dihedral angles of 74.49
(9)° & 84.34 (8)° with respect to piperidine ring.
The furan ring [C21—C24/O3(Major) & C21/C22′-C24′/O3′(Minor)] is planar and
disordered over two set of positions 0.599(8)Å: 0.401(8)Å. The dihedral angle between the furan
ring and piperidine ring is 70.5 (3)° and 60.1 (4)°, respectively.
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The methyl atom (C19) substituted at 5th position of the piperidine ring is equatorially
oriented which can be seen from the torsion angle value of [N1/C6/C5/C19=] −178.17 (12)°. In
the molecule, the sum of bond angles around N1 [352.2(1)°] of the piperidine ring is in
accordance with sp2 hybridization [22].
The packing of the molecules viewed down a-axis is shown in Fig. 7. The crystal packing
was controlled by C—H…O type of intermolecular interactions in addition to van der Waals
forces. A graph-set motif of R2 (12) dimer formation [23] by a combination of C—H···O
2
hydrogen bond stabilizes the molecules as shown in Fig. 8. The C—H...π interactions occur
between C23’ and the centroid Cg (1-x,-y,2-z;) of the neighboring benzene ring (C7-C12), the
distance between C23’ and Cg is 3.899(13)Å. Relevant hydrogen bonding geometry is given in
Table 9.
Fig. 6. The molecular structure of compound 10 with the displacement ellipsoids drawn at 30%
probability level (ORTEP plot).
17

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Fig. 7. Packing of the molecules viewed down a-axis. Dashed lines indicate the intra-molecular
hydrogen bonds
Fig. 8. A graph-set motif of R2 (12) dimer formation.
2
18

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Table 5
Crystal data for Compound 10
Parameters
Values
Empirical formula
Formula weight
Temperature
C23 H21 N O3
359.41
296(2) K
0.71073 Å
Wavelength
Crystal system, space group
Unit cell dimensions
Triclinic, Pī
a = 8.2615(4)Å
b = 10.5017(5)Å
c = 11.3420(5)Å
α= 70.383(2)°
β= 88.937(3)°
γ = 83.447(3)°
Volume
920.65(7) Å3
Z, Calculated density
Absorption coefficient
F(000)
2, 1.296 Mg/m3
0.086 mm-1
380
Crystal size
Theta range for data collection
Limiting indices
Reflections collected / unique
Rint
0.35 x 0.25 x 0.25 mm
2.07 to 29.14 °
-11<=h<=11, -13<=k<=14, -15<=l<=15
23614 / 4577
0.0236
Completeness to theta = 25.00
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
100.00%
0.9789 and 0.9706
Full-matrix least-squares on F2
4577 / 51 / 282
1.037
R1 = 0.0452, wR2 = 0.1058
R1 = 0.0786, wR2 = 0.1301
0.154 and -0.194 e.Å-3
Largest diff. peak and hole
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Table 6
Bond lengths (Å) involving non-hydrogen atoms of Compound 10
Atoms
C6-N1
C6-C7
Length
1.4811(18) C20-C21
1.514(2) C21-C22
1.5373(19) C21-C22'
Atoms
Length
1.474(2)
1.346(7)
1.355(8)
1.373(4)
1.377(8)
1.405(7)
1.325(8)
1.357(5)
1.410(9)
1.321(9)
1.373(6)
1.386(2)
1.389(2)
1.379(2)
1.372(3)
1.373(2)
1.379(2)
C6-C5
C5-C4
1.511(2)
1.516(2)
C21-O3
C21-O3'
C5-C19
C4-O1
C4-C3
1.2048(19) C22-C23
1.491(2)
1.523(2)
C23-C24
C24-O3
C3-C2
C2-N1
C2-C13
C7-C8
1.4787(17) C22'-C23'
1.523(2)
1.376(2)
1.376(2)
1.381(2)
1.362(3)
1.365(3)
1.385(3)
C23'-C24'
C24'-O3'
C13-C18
C13-C14
C18-C17
C17-C16
C16-C15
C7-C12
C12-C11
C11-C10
C10-C9
C9-C8
C20-O2
C20-N1
1.2197(17) C15-C14
1.3707(17)
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Table 7
Bond angles (°) involving non-hydrogen atoms of Compound 10
Atoms
Angle
Atoms
Angle
N1-C6-C7
N1-C6-C5
C7-C6-C5
C4-C5-C19
C4-C5-C6
C19-C5-C6
O1-C4-C3
O1-C4-C5
C3-C4-C5
C4-C3-C2
N1-C2-C13
N1-C2-C3
C13-C2-C3
C8-C7-C12
C8-C7-C6
C12-C7-C6
C7-C12-C11
C10-C11-C12
C11-C10-C9
C10-C9-C8
C7-C8-C9
O2-C20-N1
O2-C20-C21
N1-C20-C21
C22-C21-C22'
C2-N1-C6
C22-C21-O3
110.46(11) C22'-C21-O3
111.88(11) C22-C21-O3'
111.50(12) C22'-C21-O3'
112.75(14) O3-C21-O3'
110.36(12) C22-C21-C20
110.99(13) C22'-C21-C20
122.39(16) O3-C21-C20
121.89(17) O3'-C21-C20
115.72(13) C21-C22-C23
112.59(13) C24-C23-C22
113.56(11) C23-C24-O3
107.85(12) C24-O3-C21
115.02(12) C21-C22'-C23'
24.0(3)
20.3(4)
106.8(4)
128.2(3)
137.8(3)
131.8(5)
111.0(2)
120.7(3)
105.4(6)
108.1(5)
110.4(4)
105.6(3)
109.1(7)
118.20(15) C24'-C23'-C22' 106.0(8)
120.67(14) C23'-C24'-O3'
121.10(13) C24'-O3'-C21
121.04(16) C18-C13-C14
120.07(19) C18-C13-C2
119.82(18) C14-C13-C2
120.17(18) C17-C18-C13
120.70(18) C16-C17-C18
121.35(13) C17-C16-C15
118.74(13) C16-C15-C14
119.70(13) C15-C14-C13
110.5(8)
107.5(5)
117.57(14)
121.99(14)
120.28(13)
121.13(16)
120.39(16)
119.43(16)
120.24(16)
121.19(15)
121.60(12)
113.69(11)
87.6(5)
C20-N1-C2
118.09(11) C20-N1-C6
110.5(3)
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Table 8
Torsion angles (°) for the non-hydrogen atoms of Compound 10
Atoms
Angle
Atoms
Angle
N1-C6-C5-C4
C7-C6-C5-C4
-52.42(16)
-176.70(12) C23-C24-O3-C21
-178.17(13) C22-C21-O3-C24
C22-C23-C24-O3
2.2(11)
-0.9(8)
N1-C6-C5-C19
C7-C6-C5-C19
C19-C5-C4-O1
C6-C5-C4-O1
-0.8(6)
57.55(17)
-16.6(2)
C22'-C21-O3-C24
O3'-C21-O3-C24
18.0(12)
-12.3(8)
171.3(3)
9.5(10)
-153(2)
2.7(11)
172.9(8)
-141.36(16) C20-C21-O3-C24
C19-C5-C4-C3
C6-C5-C4-C3
162.34(14)
37.60(18)
C22-C21-C22'-C23'
O3-C21-C22'-C23'
O1-C4-C3-C2
-163.45(16) O3'-C21-C22'-C23'
C5-C4-C3-C2
C4-C3-C2-N1
17.60(19)
-58.71(16)
69.14(16)
123.51(14)
C20-C21-C22'-C23'
C21-C22'-C23'-C24' -3.5(15)
C4-C3-C2-C13
N1-C6-C7-C8
C22'-C23'-C24'-O3'
C23'-C24'-O3'-C21
2.9(17)
-1.4(14)
C5-C6-C7-C8
-111.42(15) C22-C21-O3'-C24'
-21.0(19)
-0.9(10)
N1-C6-C7-C12
C5-C6-C7-C12
C8-C7-C12-C11
C12-C11-C10-C9
C11-C10-C9-C8
C12-C7-C8-C9
C6-C7-C8-C9
-58.55(17)
66.53(17)
-0.2(2)
C22'-C21-O3'-C24'
O3-C21-O3'-C24'
C20-C21-O3'-C24'
N1-C2-C13-C18
C3-C2-C13-C18
N1-C2-C13-C14
C3-C2-C13-C14
C14-C13-C18-C17
C2-C13-C18-C17
C17-C16-C15-C14
C16-C15-C14-C13
C18-C13-C14-C15
C2-C13-C14-C15
O2-C20-N1-C2
C21-C20-N1-C2
O2-C20-N1-C6
C21-C20-N1-C6
C13-C2-N1-C20
C3-C2-N1-C20
C13-C2-N1-C6
C3-C2-N1-C6
11.5(11)
-172.4(5)
141.65(14)
16.7(2)
-43.11(19)
-168.03(14)
-0.6(2)
0.9(3)
-0.5(3)
0.6(2)
178.61(15)
-0.3(3)
150.6(6)
-24.2(6)
-4.2(6)
-179.0(6)
-18.4(3)
166.8(2)
165.0(6)
-9.9(6)
C10-C9-C8-C7
O2-C20-C21-C22
N1-C20-C21-C22
O2-C20-C21-C22'
N1-C20-C21-C22'
O2-C20-C21-O3
N1-C20-C21-O3
O2-C20-C21-O3'
N1-C20-C21-O3'
C22'-C21-C22-C23
O3-C21-C22-C23
O3'-C21-C22-C23
C20-C21-C22-C23
C21-C22-C23-C24
C5-C6-N1-C20
C7-C6-N1-C2
174.75(15)
-1.4(3)
-0.2(3)
1.2(2)
-174.23(15)
147.82(14)
-37.50(19)
-3.05(19)
171.63(12)
125.61(14)
-105.70(15)
-84.74(15)
43.95(16)
-72.51(14)
10.66(17)
-5.5(8)
2.1(9)
155(3)
-167.0(5)
-2.6(11)
162.63(12)
135.52(12)
C7-C6-N1-C20
C5-C6-N1-C2
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Table 9 Hydrogen bonds for Compound 10 [Å and °]
D-H...A
C3-H3A...O2i
C23'-H23'… Cg4ii 0.93
d(D-H) d(H...A) d(D...A) <(DHA)
0.97
2.42
2.96
3.349(2) 159
3.899(2) 174
Symmetry Equivalent Positions: (i) -x,-y,2-z, ( ii) 1-x,-y,2-z
Cg4 is centroid of phenyl ring [C7-C12]
3.4 Microbiological screening
Antibacterial activity by cup plate method
The antimicrobial activity of the newly synthesized furoyl substituted piperidine-4-one
compounds were screened against the following species:
Gram positive bacteria: Bacillus subtilis and Staphylococcus aureus.
Gram negative bacteria: Escherichia coli and Klebsiella pneumonia (MTCC 109)
Standard: Streptomycin and penicillin
The species were obtained from Microbial Type Culture Collection (MTCC),
Chandigarh, India. The commercially available Nutrient Agar and Potato Dextrose Agar (PDA)
media used in this study were purchased from Hi Media Pvt. Ltd, Mumbai, India.
Antibacterial activity was performed by cup plate method by measuring zone of
inhibition [24]. All the test compounds were screened for antibacterial activity against bacterial
strains Bacillus subtilis, Staphylococcus aureus (gram-positive), Escherichia coli and
K.pneumonia (gram negative) at a concentration of 100 ꢀg/ml. Streptomycin and penicillin were
used as standard drugs at a concentration of 100 ꢀg/ml. Nutrient agar was used as culture
medium and dimethylsulfoxide (DMSO-D6) was used as solvent control. Laminar airflow bench
was swabbed with 70 % alcohol and UV lamp was switched on. After 30 min, the UV lamp was
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switched off. All the reagents, media, inoculums and glassware were placed in laminar airflow
bench observing all aseptic conditions. The plates were inoculated within minutes of the
preparation of suspension, so that the density does not change. A sterile cotton swab over was
dipped into the suspension and the medium was inoculated by even streaking of the swab over
the entire surface of the plate in three directions. After the inoculums had dried, cups of diameter
6mm were made in the agar plate with a sterile cork borer. The drug solutions were added to
these cups with a micropipette and the plates were then incubated at 37°C for 24 hours. The
development of inhibition zone around the well was measured in triplicate and recorded using
mm scale as (Mean±SD. The antibacterial activity of the compounds 9-14 are given in Table 10.
Table 10
Antibacterial activity of furoyl substituted 2,6-diarylpiperidin-4-one derivatives
Zone of inhibition (mm)
Test pathogens
Gram positive bacteria
Gram negative bacteria
B.subtilis
12±0.09
10±0.42
14±0.22
15±0.23
09±0.21
16±0.43
24±0.06
--
S.aureus
11±0.08
09±0.21
13±0.23
16±0.32
18±0.42
10±0.42
26±0.14
--
E.coli
K.pneumonia
19±0.42
12±0.18
11±0.18
12±0.19
10±0.14
14±0.08
--
Compound 9
Compound 10
Compound 11
Compound 12
Compound 13
Compound 14
Penicillin
13±0.27
11±0.08
09±0.16
13±0.14
16±0.21
15±0.47
--
Streptomycin
23±0.35
21±0.08
The test compounds 11, 12 and 14 displayed a significant antibacterial activity against S.
Subtilis. Compound 12 displayed good antibacterial activity against S. Aureus. Compound 13
displayed good antibacterial activity against S. Aureus. Compounds 13 and 14 exhibited
significant antibacterial activity against E.Coli. Compound 10 showed good antibacterial activity
against K.Pneumonia. Compound 14 also exhibited significant antibacterial activity against
24

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K.Pneumonia. The results of these compounds are promising as antimicrobial therapeutic agents.
Hence, the obtained results may be used as a key step for the designing of novel chemical
compounds with interesting antimicrobial profiles comparable to that of the standard drug.
Antifungal activity by disc diffusion method
All the compounds were screened for antifungal activity by disc diffusion technique.
Compounds are screened invitro for their antifungal activity against Candida albicans and
Aspergillus Niger and compared with the standard drug Ketaconozole. The zone of inhibition
formed for the compounds against organisms were calculated.
Name of the organism: Candida albicans (MTCC-227) and Aspergillus Niger ((MTCC-281)
Growth media:
Potato Dextrose Agar (PDA) media was used for fungal cultures. The culture medium
was inoculated with the fungal strains separately suspended in Potato dextrose broth. The
synthesized compounds were applied on sterile disc. Standard antibiotic (Ketaconozole 30µg)
was used as positive control and fungal plates were incubated at 37°C for 72 h. The diameters of
zone of inhibition observed were measured. The antifungal activity of the compounds 9-14 are
given in Table 11.
Table 11
Antifungal activity of furoyl substituted 2,6-diarylpiperidin-4-one derivatives
Zone of inhibition (mm)
Test pathogens
Candida albicans
500µg 1000µg
Aspergillus Niger
500µg 1000µg
Compound 9
14
11
8
8
7
16
13
9
9
8
10
8
7
8
9
12
9
8
9
12
11
Compound 10
Compound 11
Compound 12
Compound 13
Compound 14
Ketaconozole (30 µg)
6
7
9
28
26
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The test compound 9 displayed a moderate antifungal activity against Candida albicans
but all other compounds do not exhibit activity against both the fungi.
3.5 Molecular docking studies of 1-furoyl substituted 2,6-diarylpiperidin-4-one derivatives with
the target GTP binding protein
3.5.1 Target protein structure preparation
The X-ray crystal structure of GTP binding protein complex (PDB ID: 1LNZ) was
obtained from the Protein Data Bank (PDB) [25]. GTP binding proteins are conserved right
through life and widely used as binary switches for cellular processes that comprise signal
transduction, protein translocation, trafficking and cell cycle control [26].
All docking calculations and computational work were performed using various modules
of Schrödinger Suite 2011 using Red Hat Enterprise Linux 5.0 interface running on Pentium D
workstation.
Hydrogen bonds play a major role in the structure and function of biological molecules,
the ligand-receptor interactions were analyzed on the basis of hydrogen bond interactions. In
this study, we have used glide docking to study the binding orientations and expect binding
affinities of the piperidine compounds. The results obtained from this study would be helpful in
both understanding the inhibitory mode of the furan substituted piperidine derivatives as well in
predicting the activities of newly designed inhibitors on the basis of docking scores. They would
also provide some beneficial clues in structural modification for designing new inhibitors against
the treatment of cancers.
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Docking study was performed in order to analyze the suitability of the structure
conformation of the drug molecule in the protein environment. The docking was performed
maintaining the important hydrogen bonds between the drug molecule and its protein target.
The keto group of the furan substituted piperidine derivatives and the amino group
present in the active site residues of GTP binding protein plays an important role of hydrogen
bond interaction with the active site amino acid residues of ASN282, ASN283, LYS283 &
VAL312, respectively.
The docking score and glide energy values of compound 12 is minimum when compared
to the other ligands in both rigid and flexible docking. The study reveals that the molecule
compound 12 has good binding capability with the active site amino acids of GTP binding
protein.
In the flexible docking, notable interactions are observed with moderate energy values in
compounds 12 & 14. In all these complexes, the non-bonded interaction limits are varied from
2.5Å to 3.5Å, which reveals that the ligands may result in a strong inhibition.
Hydrogen bond interactions of the furan substituted piperidine compounds with amino
acids at the active site of GTP binding protein are given in Table 12. X-ray crystal structure of
the title compound 10 in the GTP active site showing the key hydrogen contacts between the
furan substituted piperidine derivative and enzyme is shown in Fig. 9a, b & c.
27

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Table 12
Hydrogen bond interactions of the furan substituted piperidine derivatives
with amino acids at the active site of GTP binding protein
Distance between
Docking Glide Interaction at the
Ligand
Donor and
Acceptor (Å)
2.90
Score Energy
active site
Compound 9 -4.7395 -33.645
Compound 10 -2.9811 -33.242
ASN282
N-H…O
ASN282
N-H…O
-
ASN282
N-H…F
LYS283
N-H…O
LYS283
N-H…O
LYS283
N-H…O
VAL312
N-H…O
2.96
Compound 11 -3.3363 -32.707
Compound 12 -3.8655 -37.662
-
2.90
3.35
3.18
3.19
2.94
Compound 13 -4.5582 -35.550
Compound 14 -4.6855 -32.184
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Fig. 9a. Ligplot of the furan substituted piperidine derivatives in the GTP active site showing
the key hydrogen contacts between compounds (9-10) and the enzyme.
29