Synthesis, crystal structure and anti-breast cancer activity of some enaminone derivatives

Article abstract of DOI:10.14233/ajchem.2014.17171

The present work reports the synthesis of some enaminone derivatives bearing a biologically active 3,4-dimethoxyphenyl (3) or 3,4,5-trimethoxyphenyl moieties (5 and 7), respectively. The trimethoxybenzene moiety has been previously reported to confer cyto

Full text of DOI:10.14233/ajchem.2014.17171

Asian Journal of Chemistry; Vol. 26, No. 21 (2014), 7424-7430
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.17171
Synthesis, Crystal Structure and Anti-Breast Cancer Activity of Some Enaminone Derivatives
1,*
1
2
2
MOSTAFA M. GHORAB , MANSOUR S. ALSAID , HAZEM A. GHABOUR and HOONG-KUN FUN
1Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Kingdom of Saudi Arabia
2Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Kingdom of SaudiArabia
*Corresponding author: Fax: +966 1 4670560; Tel: +966 534292860; E-mail: mmsghorab@yahoo.com
Received: 6 February 2014;
Accepted: 13 May 2014;
Published online: 30 September 2014;
AJC-16153
The present work reports the synthesis of some enaminone derivatives bearing a biologically active 3,4-dimethoxyphenyl (3) or 3,4,5-
trimethoxyphenyl moieties (5 and 7), respectively. The trimethoxybenzene moiety has been previously reported to confer cytotoxic
activity. The structure of the newly synthesized compounds was verified by elemental analyses, IR, 1H NMR, 13C NMR spectra and X-ray
analysis. The anti-breast cancer activity of the enaminone derivatives were evaluated. Compounds 3, 5 and 7 showed excellent anti-breast
cancer activity with IC50 values (55.2, 79.06 and 50.49 µM) compared with doxorubicin with IC50 value (71.80 µM) as reference drug.
Keywords: Synthesis, Enaminones, X-ray analysis, Anti-breast cancer activity.
and used without further purification. Melting points were
INTRODUCTION
determined on an electrothermal melting point apparatus
Enaminones are a group of organic compounds carrying
(Stuart Scientific, Stone) and were uncorrected. Precoated
the conjugated system N-C=C-C=O1. The chemistry of
Silica gel plates ( Kiesel gel 0.25 mm, 60 GF 254, Merck)
enaminones, their physicochemical properties and biological
were used for thin layer chromatography (TLC). The deve-
activities has been extensively reported in the literatures2-10. In
loping solvent system was chloroform/methanol (10:3) and
addition, cyclohex-2-enone exhibited a wide range of biolo-
the spot were detected by ultraviolet light. The infrared (IR)
gical activities such as anticancer11 and antimicrobial acti-
spectra ( KBr disc) were recorded on FT- IR spectrophotometer
vities12. On the other hand, enaminones have been used as key
(Perkin Elmer) at the Research Center, College of Pharmacy,
intermediates in organic synthesis13-18 and the chemistry of
1
King Saud University, Saudi Arabia. H-NMR spectra were
these compounds have been reviewed19. In particular they have
scanned in dimethylsulfoxide (DMSO-d6) on a NMR spectro-
photometer (Bruker AXS Inc.) operating at 500 MHz for 1H
been employed as synthons of a wide variety of biologically
active heterocyclic compounds20, as pharmaceutical com-
pounds having anticancer21, antibacterial22, antiinflammatory23
and other therapeutic agents24-26. During the last decade we
have been involved in a program aimed at exploring the
potentials of enaminone as a building block for hetero-
aromatics27 and we have successfully synthesized and reported
the corresponding quinoline derivatives13-18 utilizing enami-
nones as starting materials. Based on the above information
and 125.76 MHz for 13C at the aforementioned Research
Center. Chemical shifts are expressed in δ-values (ppm) relative
to tetramethylsilane (TMS) as an internal standard. Exchan-
geable protons were confirmed by addition of drop of D2O.
Elemental analyses were done on a model 2400 CHNSO
analyzer (Perkin Elmer).
X-ray crystallography: Single crystal suitable for X-ray
diffraction was mounted on glass fibres. The diffraction data
were collected on BrukerAPEX-II CCD area-detector diffrac-
tometer with CuKα radiation (λ = 1.54178 Å) at a temperature
of 296(2) K. The data for these compounds were processed
with SAINT and corrected for absorption using multi-scan34.
The structures were solved by direct methods using the program
SHELXTL9735 and refined by full-matrix least squares tech-
nique on F2 using anisotropic displacement parameters using
SHELXTL program35. All geometrical calculations were
carried out using the program PLATON36. Molcular graphics
and as a continuation of previous work on anticancer agents28-33
,
we report here the synthesis, spectral characterization and
X-ray crystal structures of the three enaminone derivatives of
expected anticancer activity.
EXPERIMENTAL
The starting materials cyclohexane-1,3-dione, 5,5-
dimethylcyclohexane-1,3- dione, 3,4-dimethoxyaniline and
3,4,5-trimethoxyaniline were purchased from Sigma-Aldrich

Vol. 26, No. 21 (2014)
Synthesis, Crystal Structure and Anti-Breast Cancer Activity of Some Enaminone Derivatives 7425
were drawn using SHELXTL35 and PLATON36 programs. All
the hydrogen atoms were fixed at calculated positions with a
common isotropic displacement parameters set to 1.2 (1.5 for
methyl groups) times the equivalent isotropic U values of the
parent carbon atoms. A rotating group model was applied to
the methyl groups. The crystallographic data are given in
Table-1. Hydrogen bonding interactions are shown in Table-2.
The selected bond lengths and bond angles are listed in Table-3.
The scheme of the synthesis of the compounds is shown in
Scheme-I.
Synthesis of 3-(3,4,5-trimethoxyphenylamino) cyclohex-
2-enone (5): A mixture of cyclohexane-1,3-dione 1 (1.12 g,
0.01 mol) and 3,4,5-trimethoxyaniline 4 (1.83 g, 0.01 mol) in
absolute ethanol (30 mL) containing 3 drops of triethylamine
was refluxed for 6 h. The reaction mixture was cooled and the
solid obtained was recrystallized from ethanol. Crystals were
harvested after a month on slow evaporation the solution.Yield
89 %; m.p. 205-207 °C; IR (KBr, νmax, cm-1): 3270 (NH), 3100
1
(CH arom.), 2966, 2836 (CH aliph.), 1653 (C=O). H NMR
spectrum in (DMSO-d6): 1.8-2.4 [m, 6H, 3CH2 cyclo.], 3.70,
3.78 [2s, 9H, 3 OCH3], 5.2 [s, 1H, CH cyclo.], 6.4 [s, 2H, Ar-
H], 8.7 [s, 1H, NH, D2O- exchangeable ]. 13C-NMR spectrum
of 5 in (DMSO-d6): 21.5, 28.4, 36.3, 55.8 (2), 60.0, 98.0 (2),
101.1, 134.4, 135.6, 153.0 (2), 162.2, 195.7 (C=O). Anal.13
Calcd for C15H19NO4 (277.32): C, 64.97; H, 6.91; N, 5.05.
Found: C, 64.69; H, 6.59; N, 5.31.
O
O
O
HN
O
. H2O
Abs. EtOH
TEA
Synthesis of 3-(3,4,5-trimethoxyphenylamino)-5,5-
dimethylcyclohex-2-enone (7): A mixture of 5,5- dimethyl-
cyclohexane-1,3-dione 6 (1.40 g, 0.01 mol) and 3,4,5- trimeth-
oxyaniline 4 (1.83 g, 0.01 mol) in absolute ethanol (30 mL)
containing three drops of triethylamine was refluxed for 6 h.
The reaction mixture was cooled and the obtained solid was
recrystallized from dioxane. Crystals suitable for X-ray diff-
raction was obtained after a week on slow evaporation of the
solution14.
H2N
+
O
O
O
( 1 )
( 3 )
( 2 )
O
+
O
O
NH2
HN
in vitro Cytotoxic activity: The human tumor breast
cancer cell line (MCF7) was obtained from the National Cancer
Institute, Cairo, Egypt. The cytotoxic activity of the synthesized
compounds was measured by the Sulfo-Rhodamine-B stain
(SRB) assay as reported byAlsaid et al.29. Cells were plated in
96-multiwell plate (104 cells per well) for 24 h before treatment
with the compounds to allow attachment of cell to the wall of
the plate. Tested compounds were dissolved in DMSO and
diluted with saline. Different concentrations of the compounds
under test (5, 12.5, 25 and 40 µmol L-1) were added to the cell
monolayer. Triplicate wells were prepared for each individual
dose. Monolayer cells were incubated with the compounds
for 48 h at 37 °C and in atmosphere of 5 % CO2. After 48 h,
cells were fixed, washed and stained for 0.5 h. with 0.4 %
(m/v) SRB dissolved in 1 % acetic acid. Unbounded dye was
removed by four washes with 1 % acetic acid and attached
stain was recovered with tris-EDTA buffer. Colour intensity
was measured in an ELISA reader (sunostick medical
technology, SPR-960B, U.K.). Negative control was added by
using the cell lines with the solvent without drug. The relation
between surviving fraction and drug concentration was plotted
to get the survival curve of each tumor cell line after the
specified time. The concentration required for 50 % inhibition
of cell viability (IC50) was calculated and compared with the
reference drug doxorubicin and the results are given in Table-1.
Abs. EtOH
TEA.
O
O
O
O
( 4 )
( 5 )
O
O
O
+
O
HN
Abs EtOH
TEA.
O
O
( 7 )
( 6 )
Scheme-I: Formation of enaminone derivatives
Synthesis of 3-( 3,5-dimethoxyphenylamino) cyclohex-
2-enone (3): A mixture of cyclohexane-1,3-dione 1 (1.22 g,
0.01 mol) and 3,5- dimethoxyaniline 2 (1.53 g, 0.01 mol) in
absolute ethanol (30 mL) containing 3 drops of triethylamine
was refluxed for 8 h. The reaction mixture was cooled and the
solid obtained was recrystallized from dioxane. Crystals
suitable for X-ray diffraction were obtained after a week on
slow evaporation the solution. Yield 94 %; m.p. 138-140 °C;
IR (KBr, νmax, cm-1): 3298 (NH), 3086 ( CH arom.), 2972,
2876 (CH aliph.), 1652 (C=O). 1H-NMR spectrum in (DMSO-
d6): 1.39, 1.87, 2.99 [ m, 6H, 3CH2 cyclo.], 3.70 [ s, 6H, 2
OCH3], 5.7 [s, 1H, CH cyclo.], 5.9-6.3 [m, 3H, Ar-H], 9.7
[s, 1H, NH, D2O-exchangeable]. 13C-NMR spectrum in
(DMSO-d6): 19.6, 28.3, 38.8, 56.4 (2), 91.2, 92.6, 101.6, 145.9,
161.4, 163.7 (2), 200.6 (C=O). Anal. Calcd for C14H17NO3
(247.29): C, 68.00; H, 6.93; N, 5.66. Found: C, 68.31; H, 6.64;
N, 5.93 %.
RESULTS AND DISCUSSION
The aim of the present work was to design, synthesis eluci-
dation of some enaminone derivatives carrying a biologically
active 3,5-dimethoxyphenyl moiety 3 and 3,4,5-trimethoxy-
phenyl moieties 5 and 7 with expected anticancer activity
(Scheme-I). 3-(3,5-Dimethoxyphenyl-amino)-cyclohex-2-enone
3 was obtained in good yield via reaction of cyclohexane-1,3-

7426 Ghorab et al.
Asian J. Chem.
TABLE-1
in vitro CYTOTOXIC ACTIVITY OF SOME NEWLY SYNTHESIZED
COMPOUNDS AGAINST HUMAN BREAST CANCER CELL LINE (MCF7)
Compound Concentration (µmol L-1)
Compd. No.
Control
IC50
5
12.5
25
40
Surviving Fraction (mean SE)a
DOX
3
5
7
1.00
1.00
1.00
1.00
0.721 0.020
0.614 0.002
0.806 0.008
0.577 0.044
0.546 0.020
0.519 0.009
0.631 0.033
0.421 0.012
0.461 0.010
0.365 0.028
0.418 0.032
0.369 0.014
0.494 0.030
0.279 0.047
0.332 0.081
0.211 0.065
71.8
55.2
79.06
50.49
an = 3
dione 1 with 3,5- dimethoxyaniline 2 in refluxing ethanol
containing a few drops of triethylamine as catalyst (Scheme-
I). The structure of compound 3 was supported by elemental
analysis, IR, 1H-NMR, 13C-NMR spectra and X-ray data. IR
spectrum of 3 revealed the presence of characteristic bands
for NH at 3310 cm-1, (CH arom.) at 3096 cm-1, (CH aliph.) at
molcules are linked together by N-H…O hydrogen bonds
[symmetry code: x,-1 + y, z] to form infinite one dimensional
chain along the [100] direction (Fig. 2). Symmetry related
O–H···O [symmetry code: 1-x, 2-y, 1-z] hydrogen bonds
further strengthen the hydrogen bonding. The molcules are
stacked along the a-axis (Fig. 3). Even though the molcules
are stacked along the a-axis from the packing mode, there is
no significant π-π stacking interaction. The geometrical
bonding of the hydrogen is shown in Table-2.
1
2977, 2866 cm-1 and ( C=O ) at 1647 cm-1. Also, H-NMR
spectrum in (DMSO-d6) indicated the presence of a signals at
3,71 ppm which could be assigned to two methoxyl groups,
5.7 ppm due to CH cyclo. and 9.7 ppm for NH of enaminone
3. 13C-NMR spectrum of 3 in (DMSO-d6) showed signals at
19.6, 28.3, 38.8, 56.4 (2), 91.2, 92.6 (2), 101.6, 145.9, 161.4,
163.7 (2), 200.6 (C=O).
In addition, interaction of 1 with 3,4,5-trimethoxyaniline
4 in refluxing ethanol13 afforded the corresponding 3-(3,4,5-
trimethoxyphenylamino)-cyclohex-2- enone 5 in good yield.
The structure of 5 was confirmed from its microanalysis, IR,
1H-NMR, 13C-NMR and X-ray data. Thus, IR spectrum of 5
exhibited the presence of characteristic bands for NH, CH
1
aromatic, CH aliphatic and (C=O). H-NMR spectrum of 5
revealed signals at 3.70, 3.78 ppm corresponding to three
methoxy groups, 5.2 ppm due to CH cyclo and 8.7 ppm for
NH group. 13C-NMR spectrum of 5 in (DMSO-d6) showed
signal at 195.7 (C=O). On the other hand, condensation of
5,5-dimethyl-cyclohexane-1,3-dione (6) with 3,4,5-trimethoxy-
aniline (4) yielded the corresponding 3-(3,4,5- trimethoxy-
phenylamino)-5,5- dimethylcyclohex-2-enone (7) in good
yield14. The structure of compound 7 was proved on the basis
Fig. 1. Thermal ellipsoidal plot of compound 3, ellipsoids are drawn at
the 50 % probability level
1
of elemental analysis, IR, H-NMR, 13C-NMR and X-ray
analysis. The IR sectrum of 7 showed bands for (NH), (CH
aromatic), (CH aliphatic) and (C=O).Also, 1H-NMR spectrum
in (DMSO-d6) indicated the presence of a singlet at 8.7 ppm
which could be assigned to NH of enaminone 3.
Crystal structure of 3-(3, 5-dimethoxyphenylamino)
cyclohex-2-enone monohydrate (3): In the crystal structure
of 3 (Fig. 1), the asymmetric unit comprises of one molcule of
3-(3, 5-dimethoxyphenylamino) cyclohex-2-enone and a water
molcule 3. The mean plane of dimethoxyphenylamino unit
and the mean plane of cyclohex-2-enone unit are twisted by
an angle of 38.23(12) °. The phenyl ring is essentially planar
with the maximum deviation from planarity being 0.014(2) Å
for the atom C9. In cyclohex-2-enone unit, the atom C4
deviates from planarity of -0.313(3) Å. The cyclohex-2-enone
unit adopts the envelope conformation with the puckering
amplitude of Q = 0.440(3) Å; θ = 51.9(4)°; φ = 176.4(4)° 37.
The C1-C6 ring has an envelope on C4. Symmetry related
Fig. 2. Perspective view of the packing diagram of compound 3, the
molcules are stacked along the a-axis

Vol. 26, No. 21 (2014)
Synthesis, Crystal Structure and Anti-Breast Cancer Activity of Some Enaminone Derivatives 7427
TABLE-2
CRYSTAL DATA AND PARAMETERS FOR STRUCTURE REFINEMENT OF COMPOUNDS 3, 5 AND 7
Parameters
Compound 3
Compound 5
Compound 7
CCDC deposition numbers
Empirical formula
Formula weight
922316
C14H19NO4
265.30
922317
C15H19NO4
277.31
922318
C17H23NO4
305.36
Temperature
296(2) K
296(2) K
296(2) K
Wavelength
1.54178 Å
1.54178 Å
1.54178Å
Crystal system, space group
Triclinic P-1
a = 4.792(3) Å
b = 7.209(3) Å
c = 202(10) Å
α = 97.169(3)°
β = 95.977(4)°
γ = 95.030(4)°
685.29(6) Å3
2, 1.286 Mg m-3
0.776 mm-1
284
Triclinic P-1
a = 7.173(10) Å
b = 10.258(10) Å
c = 11.325(10) Å
α = 113. 5(10)°
β = 107. 5(10)°
γ = 93.83(10)°
711.17(17) Å3
2, 1.295 Mg m-3
0.773 mm-1
296
Triclinic P-1
a = 7.048(2) Å
b = 11.849(3) Å
c = 11.876(3) Å
α = 115.712(10)°
β = 104. 136(2)°
γ = 96.427(2)°
839.31(4) Å3
2, 1.208 Mg m-3
0.699 mm-1
328
Unit cell dimensions
Volume
Z, calculated density
Absorption coefficient
F(000)
4.44-64.96°
8107/2286
0.0890
4.82-64.98°
6674/2347
0.0191
4.37-64.99°
8605/2775
0.0201
Θ Range for data collection
Reflections collected/Unique
Rint
64.96 97.3
64.98 96.7 %
64.99, 97.2 %
Completeness to Θ
Absorption correction
Max and Min Transmission
Refinement method
Data/restraints/parameters
Goodness of fit on F2
R1, wR2 [I ≥ 2σ(I)]
R1 and wR2 (all data)
Largest diff. peak and hole
Semi-empirical from equivalents
0.9405/0.6920
Full matrix least squares on F2
2286/0/174
Semi-empirical from equivalents
0.7311/0.6888
Full matrix least squares on F2
2347/0/183
Semi-empirical from equivalents
0.8683/0.6740
Full matrix least squares on F2
2775/0/209
1.096
1.117
1.094
0.0536, 0.1464
0.0752, 0.1599
0.238 and -0.252
0.0656, 0.1803
0.0683, 0.1834
0.356 and -0.441
0.0441, 0.1325
0.0484, 0.1370
0.185 and -0.183
hydrogen bonding is shown in (Fig. 5). There is no significant
π-π stacking interaction, as the shortest centroid to centroid
separation involving aromatic rings being longer than 4.2 Å.
Fig. 3. Hydrogen bonding diagram showing the molcules are linked into
one dimensional chain along the [100] direction. The packing is
further strengthened by weak O---H...O hydrogen bonding
Fig. 4. ORTEP diagram of compound 5 drawn at 50 % ellipsoids for non-
hydrogen atoms
Crystal structure of 3-(3, 4, 5-trimethoxyphenylamino)
cyclohex-2-enone (5): In the asymmetric unit of 5 (Fig. 4),
the trimethoxyphenyl ring forms a dihedral angle of 36.35
(16)° with the cyclohex-2-enone unit. The cyclohex-2-enone
unit adopts the envelope conformation with the puckering
parameters Q = 0.145(5) Å θ = 57.7(16)° and [φ = 190.8(18)°.
The molcules are linked together by symmetry related N-H…O
hydrogen bonds [symmetry code: 1 + x, y] to form infinite
one dimensional chain along the [100] direction. The N-H…O
Crystal structure of 3-(3, 4, 5-trimethoxyphenylamino)-
5,5-dimethylcyclohex-2-enone (7): In the crystal structure 7
(Fig. 6), the trimethoxyphenyl unit and the cyclohex-2-enone
are twisted to each other by an angle of 35.65(8)°. The
cyclohex-2-enone unit adopts the envelope conformation with
the puckering parameters Q = 0.4589 (18) Å; θ = 128.9 (2)°
and φ = 354.8(3)°. The molcules are linked together by symmetry
related N-H…O hydrogen bonds [symmetry code: 1 + x, y, z]
to form infinite one dimensional chain along the [100] direction

7428 Ghorab et al.
Asian J. Chem.
Fig. 7. Molcular packing of compound 7 showing N---H...O hydrogen bonds
in vitro Cytotoxic activity: The enaminone derivatives
3, 5 and 7 were evaluated for their in vitro cytotoxic activity
against human breast cancer cell line (MCF7). Doxorubicin
which is one of the most effective anticancer agents was used
as the reference drug in this study. The relationship between
surviving fraction and drug concentration was plotted to obtain
the survival curve of breast cancer cell line (MCF7). The response
parameter calculated was the IC50 value, which corresponds
to the concentration required for 50 % inhibition of cell
viability. Table-1 shows the in vitro cytotoxic activity of the
tested compounds compared to the reference drug. It was found
that, in the negative control, solvent has no effect on the cells
as the surviving fraction is 1.0, the most potent compounds
were the 3-(3,4,5-trimethoxyphenylamino)-5,5-dimethyl-
cyclohex-2-enone 7 having 3,4,5-trimethoxyphenyl group at
3-position (IC50 = 50.49 µM) and the 3-(3,5-dimethoxy-
phenylamino) cyclohex-2-enone 3 carrying 3,5-dimethoxy-
phenyl moiety (IC50 = 55.20 µM) which were found to be more
potent than the doxorubicin as positive control (IC50 = 71.8
µM), also, 3-(3,4,5-trimethoxyphenylamino) cyclohex-2-
enone 5 (IC50 = 79.06 µM) which was found to be nearly as
potent as the reference drug. Isosteric replacement of the 1,3-
cyclohexanone ring with 5,5-dimethylcyclohexane-1,3-dione
led to a drop in the activity as in compound 3 (IC50 = 55.20
Fig. 5. N---H...O hydrogen bonding linking the symmetry related molcules
into one dimensional chain along the [100] direction
(Fig. 7). There is no significant π-π stacking interaction, as the
centroid to centroid distance is longer than 5.48(10) Å. 1H-NMR
spectrum in (DMSO-d6) indicated the presence of a singlet at
8.7 ppm which could be assigned to NH of enaminone.
Fig. 6. Molcular structure of compound 7, ellipsoids drawn at the 40 %
probability level
TABLE-3
GEOMETRY OF THE HYDROGEN BONDS (Å, °)
Compound
D-H…A
N1-H1B…O1(a)
O1W-H1W1...O1(b)
N1-H1N...O1(c)
N-H...Od
d(D-H)
0.86
0.86
0.91(4)
0.81(2)
d(H-A)
2.14
2.45
1.92(4)
2.00(2)
d(D-A)
2.941(2)
2.931(3)
2.819(4)
2.809(2)
<(D-H…A)
156
116
174(3)
178(2)
3
3
5
7
Symmetry code: a[1-x, 2-y, 1-z]; b [1-x, 2-y, 1-z] c[1 + x,y,z]; d[1 + x,y,z]

Vol. 26, No. 21 (2014)
Synthesis, Crystal Structure and Anti-Breast Cancer Activity of Some Enaminone Derivatives 7429
TABLE-4
SELECTED BOND LENGTHS [Å] AND BOND ANGLES [DEG] FOR COMPOUNDS 3, 5 AND 7
3
5
7
O1- C2
O2- C9
O3- C11
O3- C14
N1- C6
N1- C7
C1- C6
C1- C2
C2- C3
C3- C4
C4- C5
C5- C6
C7- C12
C7- C8
1.252(3)
1.359(3)
1.372(3)
1.429(3)
1.351(3)
1.417(3)
1.364(3)
1.419(3)
1.499(4)
1.507(4)
1.514(3)
1.500(3)
1.377(3)
1.395(3)
1.376(3)
1.399(3)
1.371(3)
1.386(3)
0.8600
O2- C9
O2- C13
O3- C14
O4- C11
O4- C15
N1- C6
N1- C7
N1- H1N
C1- C6
C1- C2
C2- C3
C3- C4
C4- C5
1.364(3)
1.422(3)
1.407(4)
1.362(3)
1.415(4)
1.350(3)
1.411(3)
0.91(3)
1.359(3)
1.411(4)
1.490(4)
1.362(5)
1.450(4)
1.500(3)
1.384(4)
1.389(3)
1.387(3)
1.393(3)
1.391(4)
1.390(3)
O1- C2
O2- C13
O3- C12
O3- C16
O4- C11
O4- C17
N1- C6
N1- C9
C1- C6
C1- C2
N1- H1N
C2- C3
C3- C4
C4- C7
C4- C5
C4- C8
C9- C14
C5- C6
C9- C10
C10- C11
1.235(2)
1.360(2)
1.376(2)
1.403(3)
1.363(2)
1.411(2)
1.352(2)
1.409(2)
1.363(2)
1.422(2)
0.81(2)
1.502(2)
1.521(2)
1.518(2)
1.527(2)
1.530(2)
1.386(2)
1.506(2)
1.389(2)
1.387(2)
C5- C6
C7- C12
C7 C8
C8- C9
C9- C10
C10- C11
C11- C12
O1W- H1W1
O1W- H2W1
C8 C9
C9- C10
C10- C11
C11- C12
0.8440
Bond Angles
C9- O2- C13
C11- O3- C14
C6- N1- C7
C6- C1- C2
O1- C2- C1
O1- C2- C3
C1- C2- C3
C2- C3- C4
C3- C4- C5
C6- C5- C4
N1- C6- C1
N1- C6- C5
C1- C6- C5
C12- C7- C8
C12- C7- N1
C8- C7- N1
C9- C8- C7
O2- C9- C8
O2- C9- C10
C8- C9- C10
C11- C10- C9
C10- C11- C12
118.4(2)
117.0(2)
128.7(2)
122.7(2)
121.4(2)
120.3(2)
118.3(2)
112.3(2)
111.3(2)
111.9(2)
125.0(2)
114.1(2)
120.8(2)
120.8(2)
121.8(2)
117.2(2)
118.8(2)
124.9(2)
114.2(2)
120.9(2)
119.1(2)
120.9(2)
C6- N1- C7
130.2(2)
117.6(2)
122.5(2)
121.9(3)
126.5(2)
120.7(2)
122.7(3)
114.9(2)
118.3(2)
119.8(3)
118.3(2)
118.5(3)
114.8(2)
112.8(2)
120.6(2)
123.1(2)
116.2(2)
124.4(2)
115.4(2)
120.2(2)
124.2(2)
121.4(2)
C13- O2- C15
C6- N1- C9
N1- C6- C1
C12- O3- C16
C11- O4- C17
C6 -C1- C2
O1- C2- C1
O1- C2- C3
C1- C2- C3
C2- C3- C4
C7- C4- C3
C7- C4-C5
C3- C4-C5
C7- C4-C8
C3- C4-C8
C5- C4-C8
C6- C5-C4
N1- C6-C5
C1- C6-C5
C14- C9-C10
C14- C9-N1
O4- C11-C10
117.3(2)
129.0(2)
125.8(2)
114.4(2)
118.1(2)
121.7(2)
121.5(2)
119.6(2)
118.7(2)
113.2(2)
110.4(2)
110.4(2)
107.7(2)
108.5(2)
110.3(2)
109.2(2)
113.8(2)
113.7(2)
120.4(2)
120.7(2)
121.6(2)
124.1(2)
C9- O2- C13
C6- C1- C2
O1- C2- C1
N1- C6- C1
C1- C6- C5
C3- C4- C5
C10- O3-C14
C11- O4- C15
O1- C2- C3
C1- C2- C3
C4- C3- C2
C4- C5- C6
N1- C6- C5
C12- C7- C8
C12- C7- N
C8- C7- N1
O2- C9- C8
O2- C9- C10
C8- C9- C10
O4- C11- C12
O3- C10- C11
µM) and also a drop in the activity was shown by replacing
the 1,3-cyclohexanone ring with 5,5-dimethylcyc-lohexane-
1,3-dione moiety as in compound 5 (IC50 = 79.06 µM), an
improvement in the activity was observed upon incorporation
of 3,4,5-trimethoxyanilino combined with dimedone moiety
in compound 7 (IC50 = 50.49 µM).
lines showed promising cytotoxic activity, the most potent
compounds are 3-(3,4,5-trimethoxyphenylamino)-5,5-
dimethylcyclohex-2-enone (7) (IC50 = 50.49 µM) and 3-(3,5-
dimethoxyphenylamino) cyclohex-2-enone (3) (IC50 = 55.20
µM ) which were found to be more potent than doxorubicin
(IC50 = 71.8 µM) and 3-(3,4,5-trimethoxyphenylamino)
cyclohex-2-enone 5 carrying 3,4,5-trimethoxyphenyl moiety
at 3-position (IC50 = 79.06 µM) which is nearly as active as
the reference drug.
Conclusion
The synthesized enaminone derivatives have been spectro-
1
scopically characterized by FT IR, H, 13C-NMR and single
crystal X-ray diffraction studies. The structural elucidation is
used to explore the conformation features of the enaminone
derivatives.All the synthesized compounds adopt the envelope
conformation. In the crystal packing, the molcules are linked
together by N-H…O hydrogen bonds to form one dimensional
chain. From the above results, it is concluded that adminis-
tration of the tested compounds on human breast (MCF7) cell
ACKNOWLEDGEMENTS
The authors would like to extend their sincere appreciation
to the Deanship of Scientific Research at King Saud University
for funding of this research through the Research Group Project
no. RGP-VPP-302.

7430 Ghorab et al.
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