Synthesis, human topoisomerase IIα inhibitory properties and molecular modeling studies of anti-proliferative curcumin mimics

Article abstract of DOI:10.1039/c9ra05661k

3,5-Bis(arylidene)-N-substituted-4-oxo-piperidine-1-carboxamides 24-51 were synthesized as curcumin mimics in a facile pathway through reaction of 3,5-bis(arylidene)-4-piperidones with the appropriate isocyanate in the presence of triethylamine. The 3E,5E′-stereochemical configuration was conclusively supported by single crystal X-ray studies of compounds 25 and 34. Most of the synthesized piperidinecarboxamides showed high anti-proliferative properties with potency higher than that of 5-fluorouracil (clinically approved drug against colon, breast and skin cancers) through in vitro MTT bio-assay. Some of them revealed anti-proliferative properties at sub-micromolar values (IC₅₀ = 0.56-0.70 μM for compounds 29, 30 and 34-38 against HCT116; and IC₅₀ = 0.64 μM for compound 30 against A431 cell lines) with promising inhibitory properties against human DNA topoisomerase IIα. The safe profile of the anti-proliferative active agents against the RPE1 normal cell line may prove their selectivity towards carcinoma cells. Robust molecular models (2D-QSAR, 3D-pharmacophore) supported the SAR and validated the observed bio-properties.

Full text of DOI:10.1039/c9ra05661k

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Synthesis, human topoisomerase IIa inhibitory
properties and molecular modeling studies of anti-
proliferative curcumin mimics†
Cite this: RSC Adv., 2019, 9, 33761
a
b
c
d
Nehmedo G. Fawzy, Siva S. Panda,
Aladdin M. Srour
Walid Fayad, ElSayed M. Shalaby,
*
e
a
and Adel S. Girgis
3
,5-Bis(arylidene)-N-substituted-4-oxo-piperidine-1-carboxamides 24–51 were synthesized as curcumin
mimics in a facile pathway through reaction of 3,5-bis(arylidene)-4-piperidones with the appropriate
0
isocyanate in the presence of triethylamine. The 3E,5E -stereochemical configuration was conclusively
supported by single crystal X-ray studies of compounds 25 and 34. Most of the synthesized
piperidinecarboxamides showed high anti-proliferative properties with potency higher than that of 5-
fluorouracil (clinically approved drug against colon, breast and skin cancers) through in vitro MTT bio-
assay. Some of them revealed anti-proliferative properties at sub-micromolar values (IC50 ¼ 0.56–0.70
mM for compounds 29, 30 and 34–38 against HCT116; and IC50 ¼ 0.64 mM for compound 30 against
A431 cell lines) with promising inhibitory properties against human DNA topoisomerase IIa. The safe
profile of the anti-proliferative active agents against the RPE1 normal cell line may prove their selectivity
towards carcinoma cells. Robust molecular models (2D-QSAR, 3D-pharmacophore) supported the SAR
and validated the observed bio-properties.
Received 22nd July 2019
Accepted 12th October 2019
DOI: 10.1039/c9ra05661k
rsc.li/rsc-advances
13,14
bioavailability.
The presence of an active methylene group
Introduction
conjugated with the two b-diketones reduce the stability of
15–17
Dienone is an attractive chemical motif utilized by many curcumin.
Due to these facts, the present study is directed
researchers
for
designing
promising
biologically/ towards the investigation of novel 4-piperidone-1-carboxamides
1–4
pharmacologically active agents. Curcumin 1 is one of the as curcumin mimics (Fig. 1). In other words, a slight modi-
most famous dietary natural product dienones isolated from cation of the curcumin pharmacophoric skeleton is considered
Curcuma longa and used in many Asian countries for its anti- utilizing only one ketonic function conjugated with the two
inammatory and wound healing properties (Ayurvedic medi- unsaturated olenic linkages.
5–7
cine). Curcumin analogues exhibit an extensive broad spec-
Interest in the piperidone ring system originate from the
trum of biological properties such as antibacterial, anti- diverse biological properties showed by 1,3-diarylidene-4-
8
9
10
11
7
18–24
25
tubercular, anti-HIV, antioxidant, antitumor, and anti- piperidones as antitumor,
inammatory activities and exhibit a potential therapeutic larial
anti-mycobacterial, antima-
12
26
and acetylcholinesterase inhibitor suggesting the
4
27
effect on Alzheimer's disease. Despite the safety prole and usefulness for Alzheimer's disease treatment. The promising
broad spectrum biological properties of curcumin, it could not properties of 2,4-bis(arylidene)-8-methyl-8-azabicyclo[3.2.1]
be approved as a therapeutic agent due to its high metabolic octan-3-ones against MCF7 (breast) and HepG2 (liver) carci-
28
instability, low water/plasma solubility and poor systemic noma cell lines also prompted the present study.
Rational for insertion of carboxamide residue at N-1 of the
targeted 3,5-bis(arylidene)-4-piperidones is stemmed from the
fact that many clinically approved cancer drugs possess 1,3-
disubstituted urea function of which, Sorafenib 2, (Nexavar,
Bayer Healthcare Pharmaceuticals Inc.) that was approved by
the U. S. Food and Drug Administration (US-FDA on November
a
Department of Pesticide Chemistry, National Research Centre, Dokki, Giza 12622,
Egypt. E-mail: girgisas10@yahoo.com
b
Department of Chemistry & Physics, Augusta University, Augusta, GA 30912, USA
c
Drug Bioassay-Cell Culture Laboratory, Pharmacognosy Department, National
Research Centre, Dokki, Giza, 12622, Egypt
d
X-Ray Crystallography Lab., Physics Division, National Research Centre, Dokki, Giza 22, 2013) for the treatment of locally recurrent or metastatic,
1
2622, Egypt
progressive, differentiated thyroid carcinoma along with its
previous approval for the treatment of advanced renal cell
carcinoma (2005) and advanced hepatocellular carcinoma
e
Department of Therapeutic Chemistry, National Research Centre, Dokki, Giza 12622,
Egypt
†
Electronic supplementary information (ESI) available. CCDC 1855508, 1855509.
29–31
(2007).
Lenvatinib 3, was approved by US-FDA (2015) for the
For ESI and crystallographic data in CIF or other electronic format see DOI:
treatment of locally recurrent or metastatic, progressive thyroid
1
0.1039/c9ra05661k
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Fig. 1 Rational design of 4-piperidone-1-carboxamides 5 as curccumin mimics.
cancer and recently in 2016 in combination with everolimus for
treatment of advanced renal cancer following one prior anti-
32
angiogenic therapy. Regorafenib 4, (Stivarga, Bayer Health-
Care Pharmaceuticals Inc) approved by US-FDA in 2017 for
33
treatment of hepatocellular carcinoma.
Generally, rational design of the targeted agents 5 can be
recognized as molecular conjugation of pharmacophoric units
derived from modied curcuminoid scaffold 1 and uranyl
fragment which is the bio-active residue of antitumor drugs
sorafenib 2, lenvatinib 3 and regorafenib 4 (Fig. 1).
The targeted 4-piperidone-1-carboxamides 5 are screened
against colon, breast and skin human carcinoma cell lines. 5-
Fluorouracil (injection) is approved by FDA for clinical treat-
ment of colorectal and breast cancer and topically for skin
34,35
(basal cell) cancer.
Additionally, pyrimidine scaffold of 5-

uorouracil can be recognized as bio-isosteric form to the tar-
36,37
geted skeleton/ring system (piperidine).
For these reasons,
5-uorouracil is considered as a positive control in the present
study.
Results and discussion
Chemistry
The synthetic pathway for the targeted 3,5-bis(arylidene)-N-
substituted-4-oxo-piperidine-1-carboxamides 24–51 is depicted
in Scheme 1, through reaction of the appropriate 3,5-
bis(arylidene)-4-piperidone 13–18 with the corresponding
isocyanate 19–23 in N,N-dimethylformamide (DMF) in the Scheme 1 Synthetic route towards 3,5-bis(arylidene)-4-piperidone-
presence of quantitative amount of triethylamine. Spectro- 1-carboxamides 24–51.
1
13
scopic (IR, H-NMR and C-NMR; ESI Fig. S1–S84†) and
elemental analysis data support the structure. IR spectrum of
compound 24 (representative of the synthesized family), X-ray crystallography
exhibits the ketonic and amidic carbonyls at n ¼ 1666,
Compounds 25 and 34 are presented in ESI Fig. S85 and S86,†
respectively (ORTEP preview). The two compounds were found to
be crystallized in the monoclinic system with space group C2/c
ꢀ
1
1
651 cm , respectively. The piperidinyl methylene protons are
1
observed as singlet signal at d
The exocyclic olenic protons are revealed as singlet signal at d
7.69 supporting the presence of E, E -conguration.
NMR spectrum of compound 24 shows the amidic and
H
¼ 4.88 in H-NMR spectrum.
H
1
for compound 25 and P2 /n for compound 34 and with one
0
38 13
¼
C-
molecule per asymmetric unit cell. The structures are central 4-
oxopiperidine-1-carboxamide heterocycle attached at C17 and
C19 to two benzylidenes in compound 25 and two 4-uo-
ketonic carbonyl carbons at d ¼ 155.1 and 186.8, respectively in
C
addition to the piperidinyl methylene carbon at d ¼ 45.5.
0
C
robenzylidines in compound 34 forming E,E -conguration. The
Single crystal X-ray studies of compounds 25 and 34 add
carboxamide group is connected to 4-chlorophenyl and phenyl in
conclusive support for the structure.
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compound 25 and 34, respectively. The geometrical parameters proliferative properties observed, structure–activity relation-
of the two compounds were found to be comparable to each other ships (SAR) could be attained. Attachment of electron-
38,39
and with similar reported structures.
All aryl rings in both withdrawing function (e.g. chlorine or uorine) to the phenyl
compounds are planar as expected. The piperidine ring adopts ring of exocyclic olenic linkages oriented at C-3 and C-5 of
a half-chair conguration with maximum deviation of 0.379 (3), piperidinecarboxamides, enhances the anti-proliferative prop-
ꢀ
0
.373 (2) A at atom N
2
for compounds 25 and 34, respectively erties relative to the electron-donating functions (methyl or
ꢀ
(
1
puckering parameters, Q ¼ 0.556 (3), 0.539 (2) A, Q ¼ 115.6 (3), methoxy). Insertion of benzylidene fragment at C-3 and C-5 of
ꢁ
ꢁ
16.1 (3) and F ¼ 166.0 (4), 171.1 (2) for compounds 25 and 34, the targeted piperidones is important for developing antitumor
respectively). In compound 25, the dihedral angles between the active agents compared to the 2-thienylidene residue. Fluorine
least-square plane of the central piperidinyl heterocycle and the containing-compounds reveal higher anti-proliferative efficacy
phenyl rings (C1–C6, C10–C15 and C21–C26) are 51.89 (13), 47.92 than the chlorine analogues against HCT116 cell line. Mean-
ꢁ
(
12) and 26.65 (14) , respectively, and for compound 34, these while, better antitumor properties were shown by the chlorine
ꢁ
dihedral angles are 54.23 (12), 38.27 (12) and 21.31 (14) , substituted-compounds compared to their uorine analogues
respectively. Molecules in compound 25 are forming a supramo- against MCF7 and A431 cell lines [compound 32 (IC50 ¼ 2.35
lecular chain via intermolecular C26–H261/O1 interaction (ESI mM) is an exception, exhibiting potency close to the corre-
Fig. S87 and Table S1†). Similar supramolecular assembly is sponding analogue 37 (IC50 ¼ 2.32 mM) against MCF7 cell line.
formed in compound 34 via intermolecular C23–H23/O1 The same observations for compounds 29 and 34 (IC50 ¼ 1.29,
interaction (ESI Fig. S88 and Table S2†).
1.27 mM, respectively) against A431 cell line].
Screening the synthesized piperidinecarboxamides 24–51
against normal (non-cancer) RPE1 (human immortalized
retinal pigment epithelial cell line) can prove the selectivity
towards carcinoma cells. From the results obtained (Table 1, ESI
Fig. S96†), it has been noticed that the promising anti-
proliferative agents synthesized have IC50 towards RPE1 7–32,
Structure optimization studies
The computational studies in the current study are directed to
determine the difference(s) between optimized geometric
parameters (utilizing DFT, dentistry function theory technique
by B3LYP method with 3-21G* basis set, ESI Fig. S89 and S90†)
for compounds 25 and 34 and those experimentally observed
4–11 and 5–14 folds relative to that of HCT116, MCF7 and A431
cell lines, respectively. Additionally, it has been noticed that
most of the synthesized agents with methyl/methoxy benzyli-
denes have high selectivity towards the cancer cell lines relative
to the normal/non-cancer cell (therapeutic index).
(single crystal X-ray data). This will identify the effect(s) of
40,41
lattice form (solid state) on these parameters.
The optimized
structures of compounds 25 and 34 reveal bond distances and
angles comparable to the experimental values (ESI Tables S3
and S4†). The maximum difference in bond lengths and angles
ꢀ
ꢁ
ꢀ
ꢁ
are 0.036 A, 3.9 and 0.052 A, 4.2 for compounds 25 and 34,
respectively. The root-mean square errors (RMSE) in bond
lengths and angles for compounds 25 and 34 are 0.018, 1.602;
Molecular modeling
2D-QSAR study. Correlation between the biological proper-
ties and chemical structures can be identied by QSAR (quan-
titative structure–activity relationship) modeling in terms of
physico-chemical parameters (descriptors). QSAR modeling is
widely utilized by medicinal chemistry researchers for
understanding/determining the rules governing the biological
properties, validating the biological observations and predi-
0.022 and 1.493, respectively. The central piperidinyl hetero-
cycle of the structures obtained theoretically and experimentally
have been superimposed in order to globally compare their
conformations (ESI Fig. S91 and S92†). The difference(s) in
alignment observed can be explained in terms of crystal packing
effects in the solid state which are not present in the gaseous
state considered by DFT optimization.
42
cating promising hits/leads.
D-QSAR modelling. The synthesized 3,5-bis(arylidene)-N-
2
substituted-4-oxo-piperidine-1-carboxamides 24–47 revealing
variable anti-proliferative properties were employed for QSAR
Anti-proliferative activity
Anti-proliferative properties of the synthesized piper- modeling (CODESSA-Pro soware). Promising three descriptor
2
idinecarboxamides 24–51 were investigated against HCT116 BMLR-QSAR models were obtained with R (squared correlation
(
colon), MCF7 (breast) and A431 (squamous skin) carcinoma coefficient) ¼ 0.934, 0.951, 0.901 for HCT116, MCF7 and A431
cell lines by the standard MTT bio-assay utilizing 5-uorouracil cell lines, respectively (ESI Tables S5–S7,† Fig. S97–S99†).
as a reference standard. From the results observed (Table 1,
28
HCT116 cell line 2D-QSAR modelling. Total molecular 1-
ESI Fig. S93–S95†), it has been noticed that most of the center E–E repulsion/# of atoms is the rst semi-empirical
synthesized piperidinecarboxamides show potent anti- descriptor of the HCT116 2D-QSAR model (t-criterion ¼
proliferative properties higher than that of 5-uorouracil (clin- 15.070). The descriptor positively participates in the QSAR model
34,35
ically approved drug against colon, breast and skin cancers
)
determining 1/IC50 value in other words, the high descriptor
and curcumin (mimic scaffold). Some of the synthesized value observes high potent agent as exhibited in compounds 35
compounds reveal anti-proliferative properties at sub- and 41 [with descriptor values ¼ 68.54209, 47.42904, respectively
micromolar values (IC50 ¼ 0.56–0.70 mM for compounds 29, (ESI Table S8†)] that reveal estimated IC values 0.53 and 3.71
50
3
0 and 34–38 against HCT116; and IC50 ¼ 0.64 mM for mM, respectively (Table 2). Total molecular one-center electron–
43
compound 30 against A431 cell lines). Based on the anti- electron repulsion energy is determined by eqn (1).
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Table 1 Anti-proliferative properties of the synthesized compounds
a
b
IC50 , mM ꢂ SD (therapeutic index)
ID
Compd
HCT116
MCF7
A431
RPE1
1
2
3
4
5
6
7
8
9
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
1.08 ꢂ 0.18 (15.40)
1.03 ꢂ 0.29 (21.43)
1.43 ꢂ 0.20 (12.39)
1.61 ꢂ 0.14 (<31.06)
1.31 ꢂ 0.22 (9.13)
0.70 ꢂ 0.06 (13.81)
0.58 ꢂ 0.07 (8.43)
1.03 ꢂ 0.13 (7.28)
1.04 ꢂ 0.11 (11.61)
1.13 ꢂ 0.19 (10.10)
0.56 ꢂ 0.04 (31.25)
0.56 ꢂ 0.06 (14.75)
0.62 ꢂ 0.05 (15.26)
0.57 ꢂ 0.07 (17.16)
0.56 ꢂ 0.03 (19.41)
1.44 ꢂ 0.17 (<34.72)
2.73 ꢂ 0.20 (<18.32)
2.26 ꢂ 0.23 (8.37)
22.98 ꢂ 1.82 (2.04)
1.23 ꢂ 0.15 (<40.65)
1.11 ꢂ 0.09 (<45.05)
1.38 ꢂ 0.15 (<36.23)
1.50 ꢂ 0.14 (31.81)
1.29 ꢂ 0.19 (<38.76)
>50.00 ꢂ 1.01 (—)
40.83 ꢂ 2.61 (<1.22)
20.09 ꢂ 2.44 (2.36)
>50.00 ꢂ 2.90 (—)
20.43 ꢂ 1.99
1.83 ꢂ 0.14 (9.09)
2.09 ꢂ 0.26 (10.56)
2.48 ꢂ 0.31 (7.15)
2.95 ꢂ 0.24 (<16.95)
2.58 ꢂ 0.30 (4.64)
1.33 ꢂ 0.24 (7.27)
1.13 ꢂ 0.29 (4.33)
1.44 ꢂ 0.19 (5.21)
2.35 ꢂ 0.23 (5.14)
2.14 ꢂ 0.26 (5.33)
2.34 ꢂ 0.29 (7.48)
1.36 ꢂ 0.17 (6.07)
1.71 ꢂ 0.12 (5.53)
2.32 ꢂ 0.30 (4.22)
2.16 ꢂ 0.15 (5.03)
3.96 ꢂ 0.29 (<12.63)
5.10 ꢂ 0.30 (<9.80)
4.58 ꢂ 0.28 (4.13)
4.90 ꢂ 0.26 (9.58)
3.96 ꢂ 0.23 (<12.63)
4.17 ꢂ 0.27 (<11.99)
5.85 ꢂ 0.31 (<8.55)
5.73 ꢂ 0.33 (8.33)
4.89 ꢂ 0.25 (<10.22)
33.72 ꢂ 1.38 (<1.48)
24.68 ꢂ 1.99 (<2.03)
21.67 ꢂ 2.78 (2.19)
>50.00 ꢂ 3.01 (—)
3.15 ꢂ 0.44
2.49 ꢂ 0.31 (6.68)
2.51 ꢂ 0.24 (8.79)
2.83 ꢂ 0.36 (6.26)
2.56 ꢂ 0.29 (<19.53)
2.58 ꢂ 0.27 (4.64)
1.29 ꢂ 0.15 (7.50)
0.64 ꢂ 0.08 (7.64)
1.24 ꢂ 0.14 (6.05)
1.31 ꢂ 0.09 (9.21)
1.45 ꢂ 0.12 (7.87)
1.27 ꢂ 0.09 (13.78)
1.20 ꢂ 0.14 (6.88)
1.31 ꢂ 0.08 (7.22)
1.18 ꢂ 0.11 (8.29)
1.33 ꢂ 0.17 (8.17)
2.57 ꢂ 0.15 (<19.46)
4.90 ꢂ 0.34 (<10.20)
2.64 ꢂ 0.27 (7.16)
8.75 ꢂ 0.40 (5.37)
2.72 ꢂ 0.20 (<18.38)
2.85 ꢂ 0.16 (<17.54)
11.35 ꢂ 1.10 (<4.41)
8.83 ꢂ 1.26 (5.40)
7.98 ꢂ 1.34 (<6.27)
>50.00 ꢂ 3.65 (—)
>50.00 ꢂ 2.08 (—)
40.63 ꢂ 2.88 (1.17)
>50.00 ꢂ 2.38 (—)
23.44 ꢂ 2.09
16.63 ꢂ 1.57
22.07 ꢂ 2.06
17.72 ꢂ 1.98
>50.00 ꢂ 3.02
11.96 ꢂ 1.76
9.67 ꢂ 2.03
4.89 ꢂ 1.97
7.50 ꢂ 1.75
12.07 ꢂ 1.76
11.41 ꢂ 1.68
17.50 ꢂ 2.16
8.26 ꢂ 2.33
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
9.46 ꢂ 1.86
9.78 ꢂ 1.53
10.87 ꢂ 1.42
>50.00 ꢂ 3.16
>50.00 ꢂ 2.96
18.91 ꢂ 1.33
46.96 ꢂ 2.17
>50.00 ꢂ 3.43
>50.00 ꢂ 2.76
>50.00 ꢂ 3.76
47.72 ꢂ 3.05
>50.00 ꢂ 3.99
>50.00 ꢂ 4.16
>50.00 ꢂ 4.22
47.39 ꢂ 2.66
>50.00 ꢂ 2.34
c
d
5-FU
Curcumin
NT
d
d
38.25 ꢂ 2.36
16.00 ꢂ 2.04
NT
NT
a
b
IC50 is the concentration producing 50% inhibition of cell growth relative to the control ꢂ standard deviation (SD). Therapeutic index is the IC50
c
d
in normal cell (RPE1)/IC50 in cancer cell. 5-FU is 5-uorouracil (standard reference). NT is not tested.
X
k
X
E
eeðtotÞ ¼
E
eeðAÞ
(1)
ni
n
ni
n
k
IC ¼ ꢀ
log2
(3)
A
i¼1
where, A is a given atomic species. E (A) is the electron–elec-
tron repulsion energy for atom A.
ee
th
i
where, n is the number of atoms in the i class. n is the total
number of atoms in the molecule. k is the number of atomic
layers in the coordination sphere around a given atom that are
accounted for.
MCF7 cell line 2D-QSAR modelling. FPSA-2 Fractional PPSA
PPSA-2/TMSA) (MOPAC PC) is a geometrical descriptor (t-
Minimum 1-electron reaction index for atom O is an atomic
type descriptor (t-criterion ¼ ꢀ4.497) participating negatively in
the QSAR model (coefficient ¼ ꢀ88.6353). Because most of the
descriptor values for the tested compounds are with negative
sign, the low descriptor value reveals potent anti-proliferative
agent as shown for compounds 35 and 41 (descriptor values ¼
(
criterion ¼ 16.432) positively participated in the 2D-QSAR
model expressing the IC50 values i.e., the high descriptor
value describes the low potent anti-proliferative agent as shown
in compounds 30 and 45 [descriptor values ¼ 1.3958, 2.85685
(2) (ESI Table S9†) for estimated IC values 0.89, 5.82 mM,
ꢀ
0.00024, ꢀ0.00261, respectively). Fukui atomic one-electron
43
reactivity index can be calculated by eqn (2).
XX
ꢀ
R
A
¼
c
iHOMO
c
jLUMO ð3LUMO ꢀ 3HOMO
Þ
5
0
i˛A j˛A
respectively (Table 2)]. Fractional total charge weighted partial
positive surface area determines by eqn (4).
43
where, ciHOMO stands for the highest occupied molecular orbital
HOMO) coefficients. cjLUMO is the lowest unoccupied molecular
orbital (LUMO) coefficients. 3LUMO is the LUMO energy and
(
PPSA2
FPSA2 ¼
(4)
TMSA
3
HOMO is for the HOMO energy.
Average information content (order 0) is a topological
where, PPSA2 is the total weighed partial positively charged
molecular surface area. TMSA is the total molecular surface
area.
descriptor. Mean information content index can be calculated
by eqn (3).
43
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Table 2 Observed and estimated anti-proliferative activity values for the tested piperidinecarboxamides 24–47 according to the BMLR-QSAR
models
HCT116
MCF7
A431
Observed IC50
Entry Compd mM
,
Estimated IC50
mM
,
Observed IC50
Error mM
,
Estimated IC50
mM
,
Observed IC50
Error mM
,
Estimated IC50,
mM
a
a
a
Error
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
1.08
1.03
1.43
1.61
1.31
0.70
0.58
1.03
1.04
1.13
0.56
0.56
0.62
0.57
0.56
1.44
2.73
2.26
22.98
1.23
1.11
1.38
1.50
1.29
1.17
0.95
1.39
1.29
1.60
0.72
0.60
0.88
0.91
0.93
0.59
0.53
0.69
0.63
0.56
1.36
2.87
3.71
3.43
1.29
0.94
1.55
1.71
1.72
ꢀ0.09 1.83
0.08 2.09
0.04 2.48
0.32 2.95
ꢀ0.29 2.58
ꢀ0.02 1.33
ꢀ0.02 1.13
0.15 1.44
0.13 2.35
0.20 2.14
ꢀ0.03 2.34
0.03 1.36
ꢀ0.07 1.71
ꢀ0.06 2.32
0.00 2.16
0.08 3.96
ꢀ0.14 5.10
ꢀ1.45 4.58
19.55 4.90
ꢀ0.06 3.96
0.17 4.17
ꢀ0.17 5.85
ꢀ0.21 5.73
ꢀ0.43 4.89
1.39
2.50
2.50
2.62
2.51
1.58
0.89
1.54
2.12
2.00
2.07
1.46
2.18
2.51
2.53
4.46
4.52
4.87
5.10
4.38
3.94
5.82
5.13
4.74
0.44
ꢀ0.41
ꢀ0.02
0.33
2.49
1.94
2.21
2.80
4.25
2.65
1.08
0.92
1.81
1.39
1.76
1.00
1.07
0.98
1.03
1.38
2.79
6.04
3.32
6.78
3.09
3.18
10.62
5.63
6.53
0.55
0.30
0.03
2.51
2.83
2.56
2.58
1.29
0.64
1.24
1.31
1.45
1.27
1.20
1.31
1.18
1.33
2.57
4.90
2.64
8.75
2.72
2.85
ꢀ1.69
ꢀ0.07
0.21
ꢀ0.28
ꢀ0.57
ꢀ0.08
ꢀ0.31
0.27
0.07
ꢀ0.25
0.24
ꢀ0.10
0.23
0.14
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
0.27
ꢀ0.10
ꢀ0.47
ꢀ0.19
ꢀ0.37
ꢀ0.50
0.58
ꢀ0.29
ꢀ0.20
ꢀ0.42
0.23
0.13
0.33
0.15
ꢀ0.05
ꢀ0.22
ꢀ1.14
ꢀ0.68
1.97
ꢀ0.37
ꢀ0.33
0.73
0.03 11.35
0.60
0.15
8.83
7.98
3.20
1.45
a
Error is the difference between the observed and estimated bio-activity values.
HA dependent HDSA-1 (Zerov PC) is a charge-related charge weighted partial negatively charged surface area can be
43
descriptor has a mild power in the QSAR model due to its calculated by eqn (6) and (7), respectively.
X
lowest coefficient value (ꢀ0.0318232) among all the descriptors
PPSA3 ¼
q
A
S
A
A˛fd
A
. 0g
(6)
of the attained model. This observation is consistent with the
assigned SAR where, attachment of the benzylidene fragment
oriented at the C-3 and C-5 of the constructed piperidones with
electron-donating function (methyl or methoxy) decreases the
anti-proliferative properties (IC50 of compounds 39–47 ¼ 3.96–
A
Where, S
A
is the positively charged solvent-accessible atomic
surface area and q
A
is the atomic partial charge.
X
PNSA3 ¼
q
A
S
A
A˛fd
A
\0g
(7)
5.85 mM) relative to the electron-withdrawing function (IC50 of
A
compounds 29–38 with chlorine or uorine atoms ¼ 1.13–2.35
where, SA is the negatively charged solvent-accessible atomic
surface area and q is the atomic partial charge.
mM). Hydrogen bonding donor ability of the molecule (HDSA1)
A
43
can be calculated by eqn (5).
A431 cell line 2D-QSAR modelling. Count of H-donors sites
(5) (MOPAC PC) is a charge-related descriptor with the highest level
of signicance (t-criterion ¼ 10.621) among all the QSAR model
descriptors. Although, this descriptor has the lowest coefficient
value among all the descriptors of the model (coefficient ¼
X
HDSA1 ¼
S
D
D˛HHꢀdonor
D
D
where, S is the solvent accessible surface area of H-bonding
donor H atoms.
0
.068221), it seems one of the most important effective
Partial charged surface area (MOPAC PC) for atom C is also
a charge-related descriptor. Although this descriptor has the
lowest value among all the descriptors of the 2D-QSAR model
attained, it observes high effect to the estimated anti-
proliferative properties due to its high coefficient value
parameters controlling the estimated biological properties as
shown by compounds 36 and 45 [descriptor values ¼ 10, 16 (ESI
Table S10†) for estimated IC50 values 0.98, 10.62 mM, respec-
tively (Table 2)]. This descriptor supports the SAR assumptions
regarding the effect of electron-donating groups (methyl or
methoxy) versus electron-withdrawing elements (uorine or
chlorine) attaching to the exocyclic benzylidene residue of the
synthesized piperidones.
(
ꢀ866.471) as shown in compounds 30 and 45 (descriptor
values 0.00317, 0.00256, respectively). Atomic charge
weighted partial positively charged surface area and atomic
¼
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Table 3 Best fit values and estimated anti-proliferative activity values for the tested piperidinecarboxamides 24–47 according to the 3D-
pharmacophore modeling
HCT116
MCF7
A431
Observed IC50, Estimated IC50
,
Observed IC50, Estimated IC50
,
Observed IC50, Estimated IC50,
Entry Compd mM
mM
Fit value mM
mM
Fit value mM
mM
Fit value
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
1.08
1.03
1.43
1.61
1.31
0.70
0.58
1.03
1.04
1.13
0.56
0.56
0.62
0.57
0.56
1.44
2.73
2.26
22.98
1.23
1.11
1.38
1.50
1.29
0.86
6.951
6.874
6.885
7.043
6.731
6.917
7.029
6.643
6.521
6.780
6.942
7.040
7.094
7.198
7.203
6.574
6.730
6.581
5.824
6.814
6.500
6.808
6.791
6.411
1.83
2.09
2.48
2.95
2.58
1.33
1.13
1.44
2.35
2.14
2.34
1.36
1.71
2.32
2.16
3.96
5.1
2.25
2.80
2.62
2.64
2.19
2.93
2.59
2.89
3.14
3.08
2.03
1.82
1.84
2.21
2.46
3.74
3.04
3.85
3.21
2.76
3.45
3.10
3.65
3.72
6.069
5.975
6.002
5.999
6.082
5.954
6.008
5.960
5.924
5.933
6.114
6.162
6.156
6.077
6.030
5.848
5.939
5.836
5.914
5.981
5.883
5.929
5.859
5.850
2.49
2.51
2.83
2.56
2.58
1.29
0.64
1.24
1.31
1.45
1.27
1.2
1.31
1.18
1.33
2.57
4.9
2.64
8.75
2.72
2.85
11.35
8.83
7.98
3.77
1.25
1.21
2.58
3.74
2.31
1.56
2.02
1.65
3.86
2.42
1.46
1.84
1.62
1.46
3.62
1.87
3.58
5.18
2.61
1.60
5.11
5.26
3.07
7.029
7.508
7.524
7.194
7.032
7.242
7.412
7.300
7.387
7.019
7.221
7.442
7.341
7.396
7.440
7.046
7.333
7.052
6.891
7.189
7.401
6.897
6.885
7.118
1.03
1.00
0.69
1.43
0.93
0.72
1.75
2.31
1.27
0.88
0.70
0.62
0.49
0.48
2.05
1.43
2.02
11.50
1.18
2.43
1.19
1.24
2.98
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
4.58
4.9
3.96
4.17
5.85
5.73
4.89
2
Minimum resonance energy for bond H–C is a semi- and standard deviation (s ) are also good indications for the
43
2
empirical descriptor can be calculated by eqn (8).
goodness of QSAR models (F ¼ 93.751, 130.382, 60.784; s ¼
XX
0
.019, 0.125, 0.012 for HCT116, MCF7 and A431 carcinoma cell
E
R
ðABÞ ¼
P
mnbmn
(8)
m˛A m˛B
Table 4 Inhibitory properties of human DNA topoisomerase IIa for the
tested piperidinecarboxamides, Methotrexate and Combretastatin
Where, A is a given atomic species. B is another atomic species.
mn is the density matrix elements over atomic basis {mn}. bmn is
P
the resonance integrals on atomic basis {mn}.
a
Entry
Compound
IC50 (mM ꢂ SD)
Minimum e–n attraction for atom N is also a semi-empirical
descriptor. Nuclear-electron attraction energy for a given atomic
1
2
3
4
5
6
7
8
9
27
29
30
34
35
36
37
38
39
40
41
42
43
44
45
46
33.64 ꢂ 1.30
28.97 ꢂ 1.39
41.79 ꢂ 2.42
30.69 ꢂ 1.32
26.39 ꢂ 1.61
23.04 ꢂ 1.37
27.23 ꢂ 1.72
35.01 ꢂ 2.08
41.30 ꢂ 1.60
40.35 ꢂ 1.56
50.17 ꢂ 1.94
31.49 ꢂ 1.22
28.30 ꢂ 1.09
46.18 ꢂ 1.79
39.31 ꢂ 1.52
56.23 ꢂ 2.18
33.01 ꢂ 1.28
23.25 ꢂ 1.31
22.02 ꢂ 0.85
43
species can be determined by eqn (9).
ꢁ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ ꢃ
ꢂ
X X
Z
B
ꢂ
E
neðABÞ ¼
P
m;n˛A
mn
m
n
ꢂ
(9)
R
iB
B
Where, A is a given atomic species, B other atoms. Pmnis the
B
density matrix elements over atomic basis {mn}. Z is the charge
of atomic nucleus B. RiB is the distance between the electron
1
1
0
1
ZB
and atomic nucleus B. hm| |ni is the electron-nuclear attrac-
RiB
12
13
tion integrals on atomic basis {mn}.
1
1
1
1
4
5
6
7
Validation of QSAR models. Internal validation technique is
the most appropriate for the QSAR studies due to the short data
37
set utilized. Reliability of the 2D-QSAR models is achieved
47
2
based on the statistical parameters observed (R ¼ 0.934, 0.951, 18
Methotrexate (Met)
Combretastatin A-4 (CA-4)
2
2
0
0
.901; R cvOO ¼ 0.905, 0.931, 0.859; R cvMO ¼ 0.909, 0.933, 19
.861 for HCT116, MCF7 and A431 carcinoma cell lines,
a
IC50 is the concentration producing 50% inhibition of the tested
respectively). High value differences between Fisher criteria (F) enzyme, SD is the standard division.
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lines, respectively). Additionally, most of the estimated/ 5 are aligned with hydrophobics H-2 and H-3. However, the
predicted biological properties are close to the experimentally amidic carbonyl oxygen and the substituent of amidic group are
observed values (Table 2) including the potent, mild and weak aligned with hydrogen bonding acceptor (HBA) and hydro-
anti-proliferative agents tested.
D-Pharmacophore modeling. Discovery Studio 2.5 soware
phobic H-1, respectively (ESI Fig. 102†).
3
Pharmacophoric model of the anti-proliferative active agents
was utilized for 3D-pharmacophore modeling. 3D- 24–47 against breast (MCF7) carcinoma cell line shows three
Pharmacophore modeling is an important computational chemical features [two hydrophobics (H-1, H-2) and one
technique used intensively in medicinal chemistry research to hydrogen bonding acceptor (HBA)] (ESI Fig. S103 and S104†).
explore the parameters controlling biological properties in The substituent of the amidic fragment and aryl group of
terms of interaction taking place between variable pharmaco- exocyclic olenic linkage are tted with hydrophobics H-1 and
phoric features (e.g. hydrogen bonding acceptor/donor, hydro- H-2, respectively. While the ketonic oxygen gives interaction
phobic, positive/negative ionizable. etc.) with functional with HBA for all the tested compounds (ESI Fig. S105†).
44
groups or elemental of bio-active molecules.
Piper-
Two hydrogen bonding acceptors (HBA-1, HBA-2) and two
idinecarboxamides 24–47 exhibiting variable anti-proliferative hydrophobics (H-1, H-2) were viewed by the 3D-pharmacophore
properties against the tested cell lines were employed for 3D- of the tested compounds 24–47 against squamous skin (A431)
pharmacophore modeling. 3D-pharmacophore modeling of carcinoma cell line (ESI Fig. S106 and S107†). Ketonic and
the tested compounds 24–47 against HCT116 (colon) carcinoma amidic oxygens are tted with HBA-1 and HBA-2, respectively.
cell line shows HYPOGEN with 3D-array of four chemical However, the exocyclic olenic linkage and substituent of the
features [three hydrophobics (H-1, H-2, H-3) and one hydrogen amidic fragment are tted with hydrophobics H-1 and H-2,
bonding acceptor (HBA)] (ESI Fig. S100 and S101†). Typical respectively for all the tested agents (ESI Fig. S108†).
alignments were observed by all the tested compounds 24–47 in
Most of the estimated biological data are correlated with the
the hypothesized 3D-pharmacophore. The aryl groups of experimental observations (Table 3). It has been also noticed
exocyclic olenic linkages attached to the piperidinyl C-3 and C- that all the functions/elements interacted with the
Fig. 2 Gel assay for human DNA Topo IIa inhibition by the tested piperidinecarboxamides, Methotrexate (Met) and Combretastatin A4 (CA4).
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pharmacophoric features for all the tested HCT116, MCF7 or
A431 cell lines are the controlling parameters governing bio-
Experimental section
observations mentioned in SAR. This does not only support Melting points were recorded on a Stuart SMP3 melting point
the mentioned SAR but also strengthen the assumptions for apparatus. IR spectra (KBr) were recorded on a Shimadzu FT-IR
optimizing more potent anti-proliferative active hits.
Human DNA topoisomerase IIa inhibitory properties. DNA in a Bruker 500 ( H: 500, C: 125 MHz) spectrometer. The
6
8400S spectrophotometer. NMR spectra (DMSO-d ) were taken
1
13
46,47
topoisomerases are the enzymes regulate DNA replication, starting compounds 13–18
were prepared according to the
transcription and repair. Inhibitors of topoisomerases I and II reported procedures.
45
(
Topo I, II) are effectively used as anticancer agents. The
inhibitory properties of the promising anti-proliferative agents
synthesized (29, 30 and 34–38) and those exhibited high safety
prole against RPE1 (non-cancer cell line) relative to the tested
cancer cell (27, 39–47), against human DNA topoisomerase IIa
were investigated. Reports described the topoisomerase IIa
inhibitory properties of 1,3-ylidene-4-piperidones encouraged
Synthesis of 3,5-bis(arylidene)-N-substituted-4-oxo-piperidine-
-carboxamides 24–51 (general procedure)
1
A mixture of equimolar amounts of the appropriate 3,5-
bis(arylidene)-4-piperidone 13–18 (2.5 mmol) and the corre-
sponding isocyanate 19–23 in N,N-dimethylformamide (10 ml)
containing triethylamine (2.5 mmol) was stirred at room
21,22
these studies.
From the results obtained (Table 4 and Fig. 2),
ꢁ
temperature (25–30 C) for the appropriate time (TLC control).
it has been noticed that compound 36 reveals inhibitory prop-
erties against the tested enzyme with potency comparable to
that of the standard references used (IC50 ¼ 23.04, 22.02, 23.25
mM for compound 36, Combretastatin A-4 and Methotrexate,
respectively). Promising inhibitory properties were also revealed
by compounds 35, 37, 43 and 29 relative to the standard used
The separated solid upon pouring the reaction mixture into
water (200 ml) containing sodium chloride (1 g) was collected,
washed with water and crystallized from a suitable solvent
affording the corresponding 24–51.
3,5-Di[(E)-benzylidene]-4-oxo-N-phenylpiperidine-1-
(
IC50 ¼ 26.39, 27.23, 28.30, 28.97 mM, respectively). The slight
carboxamide (24)
differences shown due to the anti-proliferative properties of the
tested compounds relative to their topoisomerase IIa inhibitory Obtained from reaction of 13 and 19. Reaction time 10 h. Yellow
ꢁ
properties (Table 1 and 4) can be attributed to the fact that some microcrystals from n-butanol, mp 179–181 C, yield 94% (0.93
ꢀ
1
1
tested analogues may have functional activities than the adop- g). IR: nmax/cm 1666, 1651, 1605, 1535. H-NMR d (ppm): 4.88
ted topoisomerase IIa inhibitory activity considered in the (s, 4H, 2 NCH ), 6.92 (t, J ¼ 7.0 Hz, 1H, arom. H), 7.18 (t, J ¼
2
current study. Generally, the topoisomerase IIa inhibitory 7.2 Hz, 2H, arom. H), 7.29 (d, J ¼ 7.7 Hz, 2H, arom. H), 7.46–7.53
properties of the tested compounds support the anti- (m, 6H, arom. H), 7.60 (d, J ¼ 7.1 Hz, 4H, arom. H), 7.69 (s, 2H, 2
1
3
proliferative properties observed with good sign indication for olenic CH), 8.89 (s, 1H, NH). C-NMR d (ppm): 45.5 (NCH ),
2
their mode of action that may assist in developing better hits/ 119.9, 122.1, 128.3, 128.8, 129.5, 130.7, 133.1, 134.4, 135.8, 140.0
leads.
(arom. C + olenic C), 155.1 (amidic CO), 186.8 (ketonic CO).
Elemental analysis: C26 (394.47) required C, 79.17; H,
.62; N, 7.10, found C, 79.34; H, 5.71; N, 7.29.
22 2 2
H N O
5
Conclusion
3,5-Di[(E)-benzylidene]-N-(4-chlorophenyl)-4-oxopiperidine-1-
(
3E,5E)-3,5-Bis(arylidene)-N-substituted-4-oxo-piperidine-1-
carboxamides 24–51 were synthesized in excellent yield (80–
8%) through reaction of the appropriate 3,5-bis(arylidene)-4-
carboxamide (25)
Obtained from reaction of 13 and 20. Reaction time 10 h. Yellow
9
ꢁ
microcrystals from n-butanol, mp 186–188 C, yield 80% (0.86
piperidone 13–18 with the corresponding isocyanate 19–23 in
DMF in the presence of triethylamine. Single crystal X-ray
studies of compounds 25, 34 add good support for the
geometrical stereoisomerism. Most of the synthesized piper-
idinecarboxamides show potent anti-proliferative properties
higher than that of 5-uorouracil (standard reference) through
in vitro MTT testing against HCT116 (colon), MCF7 (breast) and
A431 (squamous skin) carcinoma cell lines. Promising inhibi-
tory properties were observed against DNA topoisomerase IIa by
the tested anti-proliferative agents synthesized. Robust 2D-
QSAR and 3D-pharmacophore modeling support the observed
anti-proliferative properties. Eventually, it can be concluded
that, the series of synthesized compounds may be considered
ꢀ
1
1
g). IR: nmax/cm 1674, 1655, 1609, 1578. H-NMR d (ppm): 4.87
(
7
7
s, 4H, 2 NCH ), 7.22 (d, J ¼ 7.9 Hz, 2H, arom. H), 7.32 (d, J ¼
2
.8 Hz, 2H, arom. H), 7.46–7.53 (m, 6H, arom. H), 7.59 (d, J ¼
.0 Hz, 4H, arom. H), 7.67 (s, 2H, 2 olenic CH), 9.01 (s, 1H,
1
3
NH). C-NMR d (ppm): 45.5 (NCH
2
), 121.3, 125.7, 128.1, 128.8,
29.5, 130.7, 133.0, 134.4, 135.8, 139.0 (arom. C + olenic C),
54.9 (amidic CO), 186.7 (ketonic CO). Elemental analysis:
21ClN (428.92) required C, 72.81; H, 4.94; N, 6.53, found
C, 72.89; H, 5.00; N, 6.64.
1
1
C
26
H
2 2
O
3
1
,5-Di[(E)-benzylidene]-N-(4-methoxyphenyl)-4-oxopiperidine-
-carboxamide (26)
a promising starting point for design of novel highly effective Obtained from reaction of 13 and 21. Reaction time 12 h. Yellow
ꢁ
anti-proliferative small molecules based on the high biological microcrystals from n-butanol, mp 184–186 C, yield 94% (1.00
ꢀ
1
1
activity exhibited towards cancer cells and safety prole against g). IR: nmax/cm 1670, 1624, 1612, 1531. H-NMR d (ppm): 3.67
normal cell studied. (s, 3H, OCH ), 4.85 (s, 4H, 2 NCH
), 6.77 (d, J ¼ 7.9 Hz, 2H,
3
2
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arom. H), 7.16 (d, J ¼ 8.0 Hz, 2H, arom. H), 7.46–7.53 (m, 6H, ¼ 7.8 Hz, 2H, arom. H), 7.51–7.65 (m, 10H, 8 arom. H + 2
1
3
arom. H), 7.59 (d, J ¼ 7.3 Hz, 4H, arom. H), 7.67 (s, 2H, 2 olenic olenic CH), 9.00 (s, 1H, NH). C-NMR d (ppm): 45.4 (NCH ),
2
1
3
CH), 8.71 (s, 1H, NH). C-NMR d (ppm): 45.4 (NCH ), 55.1 121.3, 125.8, 128.2, 128.7, 128.8, 132.2, 132.36, 132.45, 133.2,
2
(
OCH ), 113.5, 122.0, 128.8, 129.5, 130.7, 132.8, 133.2, 134.4, 133.5, 133.69, 133.72, 134.2, 134.6, 136.5, 138.9 (arom. C +
3
1
35.7, 154.7 (arom. C + olenic C), 155.3 (amidic CO), 186.9 olenic C), 154.9 (amidic CO), 186.4 (ketonic CO). Elemental
ketonic CO). Elemental analysis: C27 (424.50) required analysis: C26 (497.80) required C, 62.73; H, 3.85; N,
C, 76.40; H, 5.70; N, 6.60, found C, 76.63; H, 5.79; N, 6.66.
(
H
24
N
2
O
3
3 2 2
H19Cl N O
5.63, found C, 62.61; H, 3.71; N, 5.47.
3,5-Di[(E)-benzylidene]-N-ethyl-4-oxopiperidine-1-
3,5-Bis[(E)-4-chlorobenzylidene]-N-(4-methoxyphenyl)-4-
carboxamide (27)
oxopiperidine-1-carboxamide (31)
Obtained from reaction of 13 and 22. Reaction time 24 h. Yellow Obtained from reaction of 14 and 21. Reaction time 12 h. Pale
ꢁ
ꢁ
microcrystals from benzene, mp 172–174 C, yield 92% (0.80 g). yellow microcrystals from n-butanol, mp 210–212 C, yield 91%
ꢀ1
1
ꢀ1
1
IR: nmax/cm 1674, 1620, 1535, 1447. H-NMR d (ppm): 0.92 (t, J (1.12 g). IR: nmax/cm 1670, 1636, 1605, 1589. H-NMR d (ppm):
6.8 Hz, 3H, CH ), 2.97 (quintet, J ¼ 6.4 Hz, 2H, NCH CH ), 3.67 (s, 3H, OCH ), 4.81 (s, 4H, 2 NCH ), 6.77 (d, J ¼ 7.9 Hz, 2H,
¼
3
2
3
3
2
4
.71 (s, 4H, 2 NCH ), 6.82 (s, 1H, NH), 7.44–7.52 (m, 6H, arom. arom. H), 7.16 (d, J ¼ 7.9 Hz, 2H, arom. H), 7.51–7.64 (m, 10H, 8
2
13
H), 7.57 (d, J ¼ 7.3 Hz, 4H, arom. H), 7.63 (s, 2H, 2 olenic CH). arom. H + 2 olenic CH), 8.69 (s, 1H, NH). C-NMR d (ppm):
1
3
3 2 3 2 2 3
C-NMR d (ppm): 15.4 (CH ), 35.0 (NCH CH ), 45.0 (NCH ), 45.4 (NCH ), 55.1 (OCH ), 113.5, 122.1, 128.7, 128.8, 132.2,
1
1
28.7, 129.4, 130.7, 133.3, 134.5, 135.4 (arom. C + olenic C), 132.4, 132.5, 132.7, 133.3, 133.67, 133.72, 134.2, 134.5, 136.5,
57.0 (amidic CO), 187.0 (ketonic CO). Elemental analysis: 154.8 (arom. C + olenic C), 155.3 (amidic CO), 186.6 (ketonic
22 22 2 2 2 2 3
C H N O (346.43) required C, 76.28; H, 6.40; N, 8.09, found CO). Elemental analysis: C27H22Cl N O (493.38) required C,
C, 76.39; H, 6.54; N, 7.95.
65.73; H, 4.49; N, 5.68, found C, 65.64; H, 4.38; N, 5.88.
N-Benzyl-3,5-di[(E)-benzylidene]-4-oxopiperidine-1-
3,5-Bis[(E)-4-chlorobenzylidene]-N-ethyl-4-oxopiperidine-1-
carboxamide (28)
carboxamide (32)
Obtained from reaction of 13 and 23. Reaction time 24 h. Pale Obtained from reaction of 14 and 22. Reaction time 24 h. Yellow
ꢁ
ꢁ
yellow microcrystals from benzene, mp 163–165 C, yield 98% microcrystals from n-butanol, mp 211–213 C, yield 88% (0.92
(
ꢀ1
1
ꢀ1
1
1.00 g). IR: nmax/cm 1651, 1605, 1574, 1531. H-NMR d (ppm): g). IR: nmax/cm 1670, 1628, 1612, 1535. H-NMR d (ppm): 0.91
4
.16 (s, 2H, PhCH ), 4.78 (s, 4H, 2 NCH ), 7.12–7.52 (m, 12H, 11 (t, J ¼ 6.7 Hz, 3H, CH ), 2.95 (quintet, J ¼ 6.0 Hz, 2H, NCH CH ),
2
2
3
2
3
arom. H + NH), 7.58 (d, J ¼ 7.2 Hz, 4H, arom. H), 7.65 (s, 2H, 2 4.67 (s, 4H, 2 NCH
2
), 6.80 (s, 1H, NH), 7.55–7.60 (m, 10H, 8
1
3
13
olenic CH). C-NMR d (ppm): 43.4 (PhCH
26.4, 126.8, 128.0, 128.7, 129.4, 130.7, 133.3, 134.5, 135.6, 140.6 (NCH
arom. C + olenic C), 157.3 (amidic CO), 186.9 (ketonic CO). (arom. C + olenic C), 156.9 (amidic CO), 186.8 (ketonic CO).
Elemental analysis: C27 (408.50) required C, 79.39; H, Elemental analysis: C22 (415.31) required C, 63.62;
2
), 45.2 (NCH
2
), arom. H + 2 olenic CH). C-NMR d (ppm): 15.4 (CH
3
), 34.9
1
(
2
CH ), 44.9 (NCH ), 128.8, 132.4, 133.3, 133.8, 134.1, 134.3
3
2
H
24
N
2
O
2
2 2 2
H20Cl N O
5.92; N, 6.86, found C, 79.59; H, 6.11; N, 7.03.
H, 4.85; N, 6.75, found C, 63.81; H, 4.93; N, 6.64.
3,5-Bis[(E)-4-chlorobenzylidene]-4-oxo-N-phenylpiperidine-1-
N-Benzyl-3,5-bis[(E)-4-chlorobenzylidene]-4-oxopiperidine-1-
carboxamide (29)
carboxamide (33)
Obtained from reaction of 14 and 19. Reaction time 12 h. Pale Obtained from reaction of 14 and 23. Reaction time 24 h. Yellow
ꢁ
ꢁ
yellow microcrystals from n-butanol, mp 205–207 C, yield 85% microcrystals from n-butanol, mp 199–201 C, yield 92% (1.10
(
ꢀ1
1
ꢀ1
1
0.99 g). IR: nmax/cm 1651, 1605, 1535, 1489. H-NMR d (ppm): g). IR: nmax/cm 1674, 1628, 1612, 1528. H-NMR d (ppm): 4.15
4
7
.84 (s, 4H, 2 NCH ), 6.92 (t, J ¼ 7.1 Hz, 1H, arom. H), 7.18 (t, J ¼ (s, 2H, PhCH ), 4.74 (s, 4H, 2 NCH ), 7.12 (d, J ¼ 7.2 Hz, 2H,
2
2
2
.4 Hz, 2H, arom. H), 7.28 (d, J ¼ 7.7 Hz, 2H, arom. H), 7.50–7.65 arom. H), 7.17 (t, J ¼ 7.0 Hz, 1H, arom. H), 7.24 (t, J ¼ 7.1 Hz, 2H,
1
3
(
m, 10H, 8 arom. H + 2 olenic CH), 8.87 (s, 1H, NH). C-NMR arom. H), 7.40 (br s, 1H, NH), 7.54 (d, J ¼ 7.9 Hz, 4H, arom. H),
13
d (ppm): 45.5 (NCH
2
), 120.0, 122.2, 128.3, 128.7, 128.8, 132.2, 7.59 (d, J ¼ 7.9 Hz, 4H, arom. H), 7.63 (s, 2H, 2 olenic CH). C-
), 45.2 (NCH ), 126.4, 126.7, 128.0,
arom. C + olenic C), 155.1 (amidic CO), 186.5 (ketonic CO). 128.7, 132.4, 133.3, 133.8, 134.1, 134.4, 140.5 (arom. C + olenic
Elemental analysis: C H Cl N O (463.36) required C, 67.40; C), 157.2 (amidic CO), 185.6 (ketonic CO). Elemental analysis:
1
(
32.4, 132.5, 133.3, 133.6, 133.7, 134.2, 134.6, 136.4, 139.9 NMR d (ppm): 43.4 (PhCH
2
2
2
6
20
2 2 2
H, 4.35; N, 6.05, found C, 67.27; H, 4.28; N, 6.17.
C H Cl N O (477.39) required C, 67.93; H, 4.65; N, 5.87,
27 22 2 2 2
found C, 68.00; H, 4.56; N, 5.73.
3,5-Bis[(E)-4-chlorobenzylidene]-N-(4-chlorophenyl)-4-
oxopiperidine-1-carboxamide (30)
3,5-Bis[(E)-4-uorobenzylidene]-4-oxo-N-phenylpiperidine-1-
carboxamide (34)
Obtained from reaction of 14 and 20. Reaction time 12 h. Pale
ꢁ
yellow microcrystals from n-butanol, mp 185–187 C, yield 87% Obtained from reaction of 15 and 19. Reaction time 12 h. Pale
1.08 g). IR: nmax/cm 1655, 1597, 1558, 1516. H-NMR d (ppm): yellow microcrystals from n-butanol, mp 191–193 C, yield 87%
ꢀ1
1
ꢁ
(
ꢀ1
1
4.83 (s, 4H, 2 NCH
2
), 7.23 (d, J ¼ 7.8 Hz, 2H, arom. H), 7.31 (d, J (0.94 g). IR: nmax/cm 1651, 1597, 1566, 1535. H-NMR d (ppm):
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Paper
ꢀ
1
1
4
7
4
4
1
1
.85 (s, 4H, 2 NCH
2
), 6.92 (t, J ¼ 7.0 Hz, 1H, arom. H), 7.18 (t, J ¼ (1.02 g). IR: nmax/cm 1674, 1606, 1582, 1543. H-NMR d (ppm):
.4 Hz, 2H, arom. H), 7.29–7.36 (m, 6H, arom. H), 7.67 (br s, 6H, 4.17 (s, 2H, PhCH ), 4.75 (s, 4H, 2 NCH ), 7.13 (d, J ¼ 7.2 Hz, 2H,
2
2
1
3
arom. H + 2 olenic CH), 8.88 (s, 1H, NH). C-NMR d (ppm): arom. H), 7.17 (t, J ¼ 7.1 Hz, 1H, arom. H), 7.24 (t, J ¼ 7.2 Hz, 2H,
5.4 (NCH ), 115.7, 115.9, 120.0, 122.2, 128.3, 131.0, 132.8, arom. H), 7.33 (t, J ¼ 8.3 Hz, 4H, arom. H), 7.41 (br s, 1H, NH),
2
1
3
33.0, 133.1, 134.7, 139.9, 161.5, 163.5 (arom. C + olenic C), 7.64 (br s, 6H, 4 arom. H + 2 olenic CH). C-NMR d (ppm): 43.4
55.1 (amidic CO), 186.6 (ketonic CO). Elemental analysis: (PhCH
2 2
), 45.1 (NCH ), 115.7, 115.8, 126.4, 126.8, 128.0, 131.0,
26 20 2 2 2
C H F N O
(430.45) required C, 72.55; H, 4.68; N, 6.51, 131.1, 132.99, 133.0, 133.04, 133.1, 134.5, 140.6, 161.5, 163.5
found: C, 72.41; H, 4.75; N, 6.59.
(arom. C + olenic C), 157.2 (amidic CO), 186.7 (ketonic CO).
Elemental analysis: C27 (444.48) required C, 72.96; H,
.99; N, 6.30, found C, 73.12; H, 4.92; N, 6.10.
22 2 2 2
H F N O
4
N-(4-Chlorophenyl)-3,5-bis[(E)-4-uorobenzylidene]-4-
oxopiperidine-1-carboxamide (35)
Obtained from reaction of 15 and 20. Reaction time 12 h. Pale
3
,5-Bis[(E)-4-methylbenzylidene]-4-oxo-N-phenylpiperidine-1-
ꢁ
yellow microcrystals from n-butanol, mp 192–194 C, yield 95%
carboxamide (39)
ꢀ1
1
(
1.10 g). IR: nmax/cm 1655, 1600, 1574, 1504. H-NMR d (ppm):
Obtained from reaction of 16 and 19. Reaction time 12 h. Pale
yellow microcrystals from n-butanol, mp 221–223 C, yield 87%
4
2
1
1
1
1
.85 (s, 4H, 2 NCH ), 7.22–7.37 (m, 7H, arom. H), 7.55–7.58 (br d,
2
ꢁ
H, arom. H), 7.66 (br s, 5H, 3 arom. H + 2 olenic CH), 9.00 (s,
ꢀ1
1
(0.92 g). IR: nmax/cm 1670, 1643, 1601, 1535. H-NMR d (ppm):
1
3
2
H, NH). C-NMR d (ppm): 45.4 (NCH ), 115.6, 115.7, 115.9,
2.37 (s, 6H, 2 ArCH
3
), 4.85 (s, 4H, 2 NCH
2
), 6.91 (t, J ¼ 7.1 Hz,
19.8, 121.3, 125.7, 128.2, 131.0, 132.6, 132.67, 132.72, 133.1,
34.8, 139.0, 161.5, 163.5 (arom. C + olenic C), 154.9 (amidic CO),
86.5 (ketonic CO). Elemental analysis: C26H19ClF N O (464.90)
2 2 2
1
H, arom. H), 7.18 (t, J ¼ 7.3 Hz, 2H, arom. H), 7.28–7.33 (m, 6H,
arom. H), 7.49 (d, J ¼ 7.5 Hz, 4H, arom. H), 7.64 (s, 2H, olenic
1
3
CH), 8.88 (s, 1H, NH). C-NMR d (ppm): 21.0 (ArCH ), 45.5
3
required C, 67.17; H, 4.12; N, 6.03, found C, 67.33; H, 4.17; N, 6.07.
(
1
(
NCH
39.4, 140.0 (arom. C + olenic C), 155.1 (amidic CO), 186.6
ketonic CO). Elemental analysis: C28 (422.53) required
2
), 119.9, 122.1, 128.3, 129.4, 130.8, 131.7, 132.3, 135.7,
3,5-Bis[(E)-4-uorobenzylidene]-N-(4-methoxyphenyl)-4-
26 2 2
H N O
oxopiperidine-1-carboxamide (36)
C, 79.59; H, 6.20; N, 6.63, found C, 79.66; H, 6.31; N, 6.60.
Obtained from reaction of 15 and 21. Reaction time 12 h. Pale
ꢁ
yellow microcrystals from n-butanol, mp 189–191 C, yield 97%
ꢀ1
1
N-(4-Methoxyphenyl)-3,5-bis[(E)-4-methylbenzylidene]-4-
oxopiperidine-1-carboxamide (40)
(1.12 g). IR: nmax/cm 1670, 1628, 1597, 1504. H-NMR d (ppm):
3
.67 (s, 3H, OCH ), 4.82 (s, 4H, 2 NCH ), 6.78 (d, J ¼ 7.8 Hz, 2H,
3
2
arom. H), 7.17 (d, J ¼ 7.8 Hz, 2H, arom. H), 7.34 (t, J ¼ 8.1 Hz, Obtained from reaction of 16 and 21. Reaction time 12 h. Pale
ꢁ
4
1
1
1
H, arom. H) 7.66 (br s, 6H, 4 arom. H + 2 olenic CH), 8.71 (s, yellow microcrystals from n-butanol, mp 230–232 C, yield 98%
1
3
ꢀ1
1
H, NH). C-NMR d (ppm): 45.3 (NCH
15.7, 115.9, 122.1, 131.02, 131.04, 132.8, 132.9, 133.0, 133.1, 2.36 (s, 6H, 2 ArCH
34.6, 154.8, 161.5, 163.5 (arom. C + olenic C), 155.3 (amidic 6.77 (d, J ¼ 7.7 Hz, 2H, arom. H), 7.18 (d, J ¼ 7.7 Hz, 2H, arom.
H), 7.31 (d, J ¼ 7.0 Hz, 4H, arom. H) 7.48 (d, J ¼ 7.1 Hz, 4H, rom.
2
), 55.1 (OCH
3
), 113.5, (1.11 g). IR: nmax/cm 1674, 1628, 1605, 1582. H-NMR d (ppm):
3
), 3.67 (s, 3H, OCH ), 4.83 (s, 4H, 2 NCH ),
3
2
22 2 2 3
CO), 186.7 (ketonic CO). Elemental analysis: for C27H F N O
1
3
(460.48) required C, 70.43; H, 4.82; N, 6.08, found C, 70.49; H, H), 7.63 (s, 2H, 2 olenic CH), 8.71 (s, 1H, NH). C-NMR
4.94; N, 6.01.
d (ppm): 21.0 (ArCH ), 45.5 (NCH ), 55.1 (OCH ), 113.5, 122.0,
3 2 3
1
29.4, 130.8, 131.7, 132.4, 132.9, 135.6, 139.4, 154.7 (arom. C +
olenic C), 155.3 (amidic CO), 186.7 (ketonic CO). Elemental
analysis: C29 (452.55) required C, 76.97; H, 6.24; N,
.19, found C, 76.81; H, 6.05; N, 6.10.
N-Ethyl-3,5-bis[(E)-4-uorobenzylidene]-4-oxopiperidine-1-
carboxamide (37)
28 2 3
H N O
6
Obtained from reaction of 15 and 22. Reaction time 24 h. Pale
ꢁ
yellow microcrystals from benzene, mp 180–182 C, yield 94%
ꢀ
1
1
(
0
0.90 g). IR: nmax/cm 1674, 1620, 1582, 1543. H-NMR d (ppm):
.92 (t, J ¼ 6.9 Hz, 3H, CH ), 2.96 (quintet, J ¼ 6.2 Hz, 2H,
NCH CH ), 4.68 (s, 4H, 2 NCH
), 6.81 (s, 1H, NH), 7.33 (t, J ¼
.3 Hz, 4H, arom. H) 7.62 (br d, 6H, 4 arom. H + 2 olenic CH).
N-Ethyl-3,5-bis[(E)-4-methylbenzylidene]-4-oxopiperidine-1-
carboxamide (41)
3
2
3
2
Obtained from reaction of 16 and 22. Reaction time 24 h. Yellow
8
ꢁ
microcrystals from benzene, mp 174–176 C, yield 88% (0.82 g).
1
3
3 2 3 2
C-NMR d (ppm): 15.4 (CH ), 34.9 (NCH CH ), 44.9 (NCH ),
15.9, 131.1, 133.0, 134.4, 161.5, 163.5 (arom. C + olenic C),
56.9 (amidic CO), 186.8 (ketonic CO). Elemental analysis:
C H F N O (382.41) required C, 69.10; H, 5.27; N, 7.33, found
C, 69.15; H, 5.36; N, 7.19.
ꢀ
1
1
IR: nmax/cm 1670, 1628, 1605, 1535. H-NMR d (ppm): 0.92 (t, J
6.6 Hz, 3H, CH ), 2.37 (s, 6H, 2 ArCH
.3 Hz, 2H, NCH CH ), 4.68 (s, 4H, 2 NCH
.31 (d, J ¼ 7.2 Hz, 4H, arom. H) 7.45 (d, J ¼ 7.3 Hz, 4H, arom.
1
1
¼
3
3
), 2.96 (quintet, J ¼
), 6.79 (s, 1H, NH),
6
7
2
3
2
2
2
20 2 2 2
1
3
H), 7.58 (s, 2H, 2 olenic CH). C-NMR d (ppm): 15.4
(
1
(
NCH CH ), 21.0 (ArCH ), 34.9 (NCH CH ), 45.0 (NCH ), 129.4,
30.8, 131.8, 132.5, 135.4, 139.3 (arom. C + olenic C), 157.0
amidic CO), 186.9 (ketonic CO). Elemental analysis:
2 3 3 2 3 2
N-Benzyl-3,5-bis[(E)-4-uorobenzylidene]-4-oxopiperidine-1-
carboxamide (38)
Obtained from reaction of 15 and 23. Reaction time 24 h. Pale
yellow microcrystals from n-butanol, mp 178–180 C, yield 97% C, 77.06; H, 6.94; N, 7.60.
C H N O (374.48) required C, 76.98; H, 7.00; N, 7.48, found
24 26 2 2
ꢁ
33770 | RSC Adv., 2019, 9, 33761–33774
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RSC Advances
N-Benzyl-3,5-bis[(E)-4-methylbenzylidene]-4-oxopiperidine-1-
carboxamide (42)
131.0, 132.7, 135.3, 155.3, 160.3 (arom. C + olenic C), 154.7
(amidic CO), 186.5 (ketonic CO). Elemental analysis:
C H N O (484.55) required C, 71.88; H, 5.82; N, 5.78, found
2
9
28 2 5
Obtained from reaction of 16 and 23. Reaction time 24 h. Yellow
ꢁ
C, 71.94; H, 5.95; N, 5.86.
microcrystals from methanol, mp 166–168 C, yield 92% (1.00
ꢀ
1
1
g). IR: nmax/cm 1651, 1601, 1566, 1512. H-NMR d (ppm): 2.36
N-Ethyl-3,5-bis[(E)-4-methoxybenzylidene]-4-oxopiperidine-1-
carboxamide (46)
3 2 2
(s, 6H, 2 ArCH ), 4.17 (s, 2H, PhCH ), 4.75 (s, 4H, 2 NCH ), 7.14
(
7
d, J ¼ 7.2 Hz, 2H, arom. H), 7.17 (d, J ¼ 7.1 Hz, 1H, arom. H),
.24 (t, J ¼ 7.2 Hz, 2H, arom. H), 7.31 (d, J ¼ 7.5 Hz, 4H, arom. Obtained from reaction of 17 and 22. Reaction time 24 h. Yellow
ꢁ
H), 7.40 (br s, 1H, NH), 7.46 (d, J ¼ 7.5 Hz, 4H, arom. H), 7.62 (s, microcrystals from benzene, mp 173–175 C, yield 98% (0.99 g).
1
3
ꢀ1
1
2
H, 2 olenic CH). C-NMR d (ppm): 21.0 (ArCH ), 43.5 IR: nmax/cm 1665, 1620, 1597, 1566. H-NMR d (ppm): 0.93 (t, J
3
(
1
PhCH
2
), 45.2 (NCH
2
), 126.4, 126.8, 128.0, 129.4, 130.8, 131.7, ¼ 6.4 Hz, 3H, CH ), 2.98 (br s, 2H, NCH CH ), 3.82 (s, 6H, 2
3
2
3
32.5, 135.5, 139.3, 140.6 (arom. C + olenic C), 157.2 (amidic OCH ), 4.67 (s, 4H, 2 NCH ), 6.81 (s, 1H, NH), 7.05 (d, J ¼ 7.9 Hz,
3
2
CO), 186.7 (ketonic CO). Elemental analysis: C29
(
H
28
N
2
O
2
4H, arom. H) 7.52 (d, J ¼ 7.9 Hz, 4H, arom. H), 7.57 (s, 2H, 2
13
436.56) required C, 79.79; H, 6.47; N, 6.42, found C, 79.92; H, olenic CH). C-NMR d (ppm): 15.5 (CH ), 35.0 (NCH CH ),
3 2 3
6.61; N, 6.48.
44.9 (NCH ), 55.3 (OCH ), 114.3, 127.2, 131.2, 132.7, 135.1, 160.2
2 3
(arom. C + olenic C), 157.0 (amidic CO), 186.6 (ketonic CO).
3
1
,5-Bis[(E)-4-methoxybenzylidene]-4-oxo-N-phenylpiperidine-
-carboxamide (43)
Elemental analysis: C24 (406.48) required C, 70.92; H,
6.45; N, 6.89, found C, 71.06; H, 6.51; N, 6.92.
26 2 4
H N O
Obtained from reaction of 17 and 19. Reaction time 12 h. Pale
ꢁ
N-Benzyl-3,5-bis[(E)-4-methoxybenzylidene]-4-oxopiperidine-
1-carboxamide (47)
yellow microcrystals from n-butanol, mp 190–192 C, yield 93%
ꢀ1
1
(
1.05 g). IR: nmax/cm 1670, 1643, 1597, 1558. H-NMR d (ppm):
3
.83 (s, 6H, 2 OCH
3
), 4.84 (s, 4H, 2 NCH
2
), 6.91 (t, J ¼ 6.5 Hz, 1H, Obtained from reaction of 17 and 23. Reaction time 24 h. Yellow
ꢁ
arom. H), 7.07 (d, J ¼ 7.6 Hz, 4H, arom. H), 7.18 (t, J ¼ 7.0 Hz, microcrystals from n-butanol, mp 177–179 C, yield 85% (1.00
ꢀ
1
1
2
H, arom. H), 7.30 (d, J ¼ 7.7 Hz, 2H, arom. H), 7.56 (d, J ¼ g). IR: nmax/cm 1670, 1628, 1597, 1535. H-NMR d (ppm): 3.82
7
.7 Hz, 4H, arom. H), 7.62 (s, 2H, olenic CH), 8.88 (s, 1H, NH). (s, 6H, 2 OCH ), 4.18 (s, 2H, PhCH ), 4.74 (s, 4H, 2 NCH ), 7.05
C-NMR d (ppm): 45.5 (NCH ), 55.4 (OCH ), 114.4, 119.9, 122.1, (d, J ¼ 7.9 Hz, 4H, arom. H), 7.14–7.18 (m, 3H, arom. H), 7.24 (t,
3
2
2
1
3
2
3
1
27.1, 128.3, 131.0, 132.7, 135.4, 140.1, 160.3 (arom. C + olenic J ¼ 7.2 Hz, 2H, arom. H), 7.41 (br s, 1H, NH), 7.54 (d, J ¼ 7.9 Hz,
13
C), 155.2 (amidic CO), 186.4 (ketonic CO). Elemental analysis: 4H, arom. H), 7.60 (s, 2H, 2 olenic CH). C-NMR d (ppm): 43.5
(454.53) required C, 73.99; H, 5.77; N, 6.16, found (PhCH ), 45.2 (NCH ), 55.3 (OCH ), 114.3, 126.4, 126.8, 127.1,
28 26 2 4
C H N O
2
2
3
C, 73.80; H, 5.82; N, 6.19.
128.0, 131.2, 132.7, 135.2, 140.7, 160.2 (arom. C + olenic C),
57.2 (amidic CO), 186.5 (ketonic CO). Elemental analysis:
29 28 2 4
C H N O (468.55) required C, 74.34; H, 6.02; N, 5.98, found
1
N-(4-Chlorophenyl)-3,5-bis[(E)-4-methoxybenzylidene]-4-
oxopiperidine-1-carboxamide (44)
C, 74.55; H, 6.06; N, 5.96.
Obtained from reaction of 17 and 20. Reaction time 12 h. Pale
ꢁ
(3E,5E)-4-Oxo-N-phenyl-3,5-bis(thiophen-2-ylmethylene)
piperidine-1-carboxamide (48)
yellow microcrystals from n-butanol, mp 185–187 C, yield 84%
ꢀ1
1
(
1.02 g). IR: nmax/cm 1663, 1636, 1597, 1566. H-NMR d (ppm):
3
.83 (s, 6H, 2 OCH
3
), 4.84 (s, 4H, 2 NCH
2
), 7.07 (br d, 4H, arom. Obtained from reaction of 18 and 19. Reaction time 12 h. Yellow
ꢁ
H), 7.24 (br s, 2H, arom. H), 7.34 (br s, 2H, arom. H) 7.55 (br s, microcrystals from n-butanol, mp 188–190 C, yield 87% (0.88
1
3
ꢀ1
1
4H, rom. H), 7.62 (s, 2H, 2 olenic CH), 9.01 (s, 1H, NH). C- g). IR: nmax/cm 1670, 1647, 1589, 1535. H-NMR d (ppm): 4.86
NMR d (ppm): 45.5 (NCH
2
), 55.3 (OCH
3
), 114.4, 121.3, 125.6, (s, 4H, 2 NCH ), 6.94 (t, J ¼ 7.0 Hz, 1H, arom. H), 7.21 (t, J ¼
2
1
27.1, 128.1, 130.8, 132.7, 135.5, 139.1, 160.3 (arom. C + olenic 7.4 Hz, 2H, arom. H), 7.29 (br s, 2H, arom. H), 7.36 (d, J ¼ 7.6 Hz,
C), 154.9 (amidic CO), 186.3 (ketonic CO). Elemental analysis: 2H, arom. H), 7.64 (s, 2H, olenic CH), 7.86 (br s, 2H, arom. H),
1
3
C H ClN O (488.97) required C, 68.78; H, 5.15; N, 5.73, found 7.96 (br s, 2H, arom. H), 9.08 (s, 1H, NH). C-NMR d (ppm): 46.0
2
8
25
2 4
C, 68.89; H, 5.07; N, 5.92.
2
(NCH ), 120.2, 122.6, 128.4, 128.8, 129.0, 130.3, 132.7, 134.7,
1
38.2, 140.6 (arom. C + olenic C), 156.0 (amidic CO), 185.9
ketonic CO). Elemental analysis: (406.52)
required C, 65.00; H, 4.46; N, 6.89, found C, 64.93; H, 4.56; N,
.95.
(
22 18 2 2 2
C H N O S
3
,5-Bis[(E)-4-methoxybenzylidene]-N-(4-methoxyphenyl)-4-
oxopiperidine-1-carboxamide (45)
6
Obtained from reaction of 17 and 21. Reaction time 12 h. Yellow
microcrystals from n-butanol, mp 212–214 C, yield 80% (0.97
ꢁ
ꢀ
1
1
(3E,5E)-N-(4-Methoxyphenyl)-4-oxo-3,5-bis(thiophen-2-
ylmethylene)piperidine-1-carboxamide (49)
g). IR: nmax/cm 1670, 1628, 1597, 1558. H-NMR d (ppm): 3.67
s, 3H, OCH ), 3.83 (s, 6H, 2 OCH ), 4.82 (s, 4H, 2 NCH ), 6.77 (d,
(
3
3
2
J ¼ 8.0 Hz, 2H, arom. H), 7.06 (d, J ¼ 7.7 Hz, 4H, arom. H), 7.19 Obtained from reaction of 18 and 21. Reaction time 12 h. Yellow
ꢁ
(
(
(
d, J ¼ 8.1 Hz, 2H, arom. H) 7.56 (d, J ¼ 8.0 Hz, 4H, rom. H), 7.61 microcrystals from n-butanol, mp 194–196 C, yield 84% (0.92
1
3
ꢀ1
1
s, 2H, 2 olenic CH), 8.71 (s, 1H, NH). C-NMR d (ppm): 45.4 g). IR: nmax/cm 1667, 1651, 1593, 1535. H-NMR d (ppm): 3.68
NCH ), 55.1 (OCH ), 55.3 (OCH ), 113.5, 114.3, 122.0, 127.1, (s, 3H, OCH ), 4.83 (s, 4H, 2 NCH
), 6.80 (d, J ¼ 7.9 Hz, 2H,
2
3
3
3
2
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arom. H), 7.24 (d, J ¼ 7.7 Hz, 2H, arom. H), 7.28 (br s, 2H, arom.
H), 7.64 (s, 2H, 2 olenic CH), 7.84 (br s, 2H, arom. H), 7.96 (br s,
Conflicts of interest
1
3
2
5
1
1
H, arom. H), 8.90 (s, 1H, NH). C-NMR d (ppm): 45.4 (NCH2), There is no conict to declare.
5.1 (OCH ), 113.5, 121.7, 127.9, 128.6, 129.9, 132.2, 133.0,
3
34.2, 137.7, 154.7 (arom. C + olenic C), 155.7 (amidic CO),
Acknowledgements
85.5 (ketonic CO). Elemental analysis: C23H N O S (436.54)
20 2 3 2
required C, 63.28; H, 4.62; N, 6.42, found C, 63.12; H, 4.53; N, This work was supported nancially by National Research
6
.56.
Centre, Egypt, Project ID: 11010341. Thanks also to Dr Nicola
Demitri (Elettra-Sincrotrone Trieste S. C. p. A., Trieste, Italy) due
to his help in X-ray measument.
(
3E,5E)-N-Ethyl-4-oxo-3,5-bis(thiophen-2-ylmethylene)
piperidine-1-carboxamide (50)
Notes and references
Obtained from reaction of 18 and 22. Reaction time 24 h. Yellow
ꢁ
microcrystals from n-butanol, mp 197–199 C, yield 96% (0.86
1
2
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1
g). IR: nmax/cm 1670, 1636, 1589, 1551. H-NMR d (ppm): 0.97
t, J ¼ 6.5 Hz, 3H, CH ), 3.02 (br s, 2H, NCH CH ), 4.69 (s, 4H, 2
NCH ), 6.91 (s, 1H, NH), 7.28 (d, J ¼ 3.1 Hz, 2H, arom. H), 7.60
(
3
2
3
2
(
s, 2H, 2 olenic CH), 7.79 (br s, 2H, arom. H), 7.95 (br s, 2H,
1
3
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3
2
3
(
NCH
olenic C), 157.3 (amidic CO), 185.7 (ketonic CO). Elemental
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4
2
(
3E,5E)-N-Benzyl-4-oxo-3,5-bis(thiophen-2-ylmethylene)
piperidine-1-carboxamide (51)
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