Syntheses, Structures, and Bioactivity Evaluation of some Transition Metal Complexes with Aroylbis(N,N-diethylthioureas) Derived from Natural Compounds

Article abstract of DOI:10.1002/zaac.202100063

Two novel benzoylthioureas derived from gallic acid, (tri-O-acetyl)galloyl-N,N-diethylthiourea HL¹, and cinnamic acid, cinnamoyl-N,N-diethylthiourea HL² have been successfully prepared and characterized by means of elemental analysis

Full text of DOI:10.1002/zaac.202100063

Journal of Inorganic and General Chemistry
DOI: 10.1002/zaac.202100063
ARTICLE
Zeitschrift für anorganische und allgemeine Chemie
Syntheses, Structures, and Bioactivity Evaluation of some
Transition Metal Complexes with Aroylbis(N,N-
diethylthioureas) Derived from Natural Compounds
Chien Thang Pham,[a] Thu Thuy Pham,[a] Viet Ha Nguyen,[b] Thi Nguyet Trieu,*[a] and
Hung Huy Nguyen*[a]
Two novel benzoylthioureas derived from gallic acid, (tri-O-
acetyl)galloyl-N,N-diethylthiourea HL1, and cinnamic acid, cinna-
moyl-N,N-diethylthiourea HL2 have been successfully prepared
and characterized by means of elemental analysis, IR, NMR,
high-resolution MS, and X-ray crystallography. The organic
ligands react with Ni(AcO)2 and Cu(AcO)2 in MeOH under
formation of bis-complexes with the compositions of [M(L)2]
(M=Ni2+, Cu2+; L=L1, L2). Similar reactions with Co(AcO)2,
however, result in Co(III) tris-complexes [Co(L)3] (L=L1, L2) with
the metal ions oxidized presumably by atmospheric dioxygen.
X-ray crystallography and spectroscopic characterization reveal
a cis square-planar coordination in the bis-complexes and facial
octahedral geometry in the tris-complexes. In all of metal
complexes, the deprotonated organic compounds ({L1}À and
{L2}À ) serve as (S,O)-bidentate ligands. The ligand HL1 and its
Ni(II) and Cu(II) complexes exhibit weak antiproliferative effects
on the human MCF7 breast and HepG2 liver cancer cells with
IC50 values in the range of 60–115 μM. Surprisingly, the tris-
complex [Co(L1)3] exhibits high cytotoxicity with IC50 values of
22.23�1.58 μM for MCF7 and 28.30�3.09 μM for HepG2 cancer
cells. The activity against MCF7 cells is even more than that of
cisplatin under the same conditions.
Introduction
pounds with even better biological activities.[5] Furthermore,
higher stability of resulting metal complexes compared with
the parent organic ligands could overcome the disadvantage of
rapid degradation in clinical applications.[5b]
Gallic acid and cinnamic acid (Figure 1) are common natural
phenolic acids found in free form or as derivatives in a wide
variety of plants and food sources. Over the past few decades, a
large number of research explorations have illustrated numer-
ous biological activities of the phenolic acids and their
derivatives, including antioxidant, antibacterial, anti-fungal,
antiviral, anti-inflammatory and anticancer.[6]
It is widely known that since long ago, plants and herbs have
been used through the world as food supplements and drugs
for traditional medicine.[1] Nowadays, such natural products
have been the basis of not only treatment of various diseases,
but also the modern medicine and drug therapeutics.[2] Natural
products display enormous structural diversity as well as
molecular and pharmaceutical characteristics, which can be
advantages in drug discovery.[3] A great number of medicines
are developed either in the form of pharmacologically active
natural products or semisynthetic derivatives.[1b,4] Besides organ-
ic derivatization, another potential approach to derive natural
products is allowing them to bind with metal ions to form
coordination compounds. This modification will affect structural
and electronic features of the organic frameworks, which in
turn will cause alteration in physiochemical as well as bio-
medicinal properties. Deliberate combination of metals with
biologically active natural products may produce new com-
Benzoyl(N,N-dialkylthioureas) HL0 are known as versatile
ligands which can form stable complexes with various transition
metal ions. In the majority of structurally characterized com-
plexes, the ligands predominantly serve as monoanionic,
bidentate (S,O)-chelators (Figure 2).[7] In addition to the wide
spectrum of compositions and structures, benzoylthioureas and
their transition metal complexes have been demonstrated
potential applications in various fields such as catalysts,
materials, metal extractions and pharmaceutical discovery.[8]
Taking into consideration the diverse structures and bio-
activities of benzoylthiourea complexes and the considered
phenolic acid derivatives, the combination of such two
[a] Prof. Dr. C. Thang Pham, T. Thuy Pham, Prof. Dr. T. Nguyet Trieu,
Prof. Dr. H. Huy Nguyen
Department of Inorganic Chemistry
VNU University of Science, Vietnam National University, Hanoi
19 Le Thanh Tong, Hoan Kiem, 10021 Hanoi, Vietnam
E-mail: nguyenhunghuy@hus.edu.vn
trieuthinguyet@hus.edu.vn
[b] V. Ha Nguyen
Faculty of Education
Hanoi Metropolitan University
98 Duong Quang Ham, Cau Giay, 11306 Hanoi, Vietnam
Supporting information for this article is available on the WWW
under https://doi.org/10.1002/zaac.202100063
Figure 1. Natural phenolic acids considered in this work.
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prepared from a two-step, one-pot synthesis starting from
commercially available starting materials, namely cinnamoyl
chloride, NH4SCN, and diethylamine (Scheme 1b). The pure
ligand is obtained with 62% yield.
The results of elemental analyses and the existence of the
molecular ions [HL1 +H]+ or [HL2 +H]+ in mass spectra are
indicative for the expected compositions of the ligands. The IR
spectra of HL1 and HL2 show characteristic strong absorptions
near 1660 cmÀ 1, which can be attributed to ketone νCO
stretches. The additional strong absorption at 1769 cmÀ 1 in the
spectrum of HL1 is assigned to ester νCO stretches. In addition to
the characteristic C=O bands, broad absorptions in the region
above 3100 cmÀ 1 indicate the presence of NH groups in the
organic compounds, which is confirmed by broad singlet
Figure 2. Benzoyl(N,N-dialkylthioureas) HL0, the predominant coor-
dination mode (I) and the ligands used in this work HL1 and HL2.
1
signals around 8.5 ppm in the H NMR spectra of the ligands in
CDCl3. Signal belonging to the protons of the phenyl rings are
detected in the range of 7.2–7.7 ppm. The CH2 groups show
two separate signals in the region of 3.0–4.0 ppm. This feature
reflects hindered rotation around the C(S)À NEt2 bond due to
the partial multiple-bond character, which is frequently ob-
served for benzoylthioureas.[7g,8a,11] This structural aspect also
influences the resonance of the CH3 protons in HL1, which is
found as two most upfield signals. In contrast to this well
separation, only one broad singlet signal corresponds to the
components could give access to tuning a great number of
biologically and pharmaceutically active compounds. Surpris-
ingly, a survey of literature reveals only a few reports on
synthesis and characterization of some benzoylthioureas de-
rived from O-methylated gallic acid and the related metal
complexes.[7i,9] None of these works provides structures of the
obtained complexes.
As part of our ongoing effort to explore the coordination
chemistry and bioactivity of benzoylthioureas derived from
natural compounds, we report herein the syntheses, structures
and in vitro anticancer activities against human MCF7 and
HepG2 cancer cells of several metal complexes of two new
ligands (tri-O-acetyl)galloyl-N,N-diethylthiourea HL1 and cinna-
moyl-N,N-diethylthiourea HL2 (Figure 2) with Ni2+, Cu2+ and
1
CH3 groups in HL2. Besides mutual details, the H NMR spectra
also reveal characteristic structural features of each ligand. In
particular, the resonances of the acetyl protons in HL1 are
detected as a multiplet in the range of 2.33–2.35 ppm. The
resonance of protons in the aliphatic double bond in HL2
appears as two doublets at 7.68 ppm and 6.68 ppm with the
typical trans vicinal spin coupling constant of 15.5 Hz. The 13C
{1H} NMR spectra of the ligands strongly support their expected
structures. The resonance of each CH2 and CH3 carbon atom of
the peripheral ethyl residues appears as two separate signals in
the upfield regions around 50 ppm and 10 ppm, respectively.
The signals around 20 ppm in the spectrum of HL1 are assigned
to the CH3 carbon atoms of the acetyl groups, while the
chemical shifts of the corresponding C=O groups occur about
165 ppm. In both ligands, the C=O and C=S carbon atoms of
benzoylthiourea moieties give weak resonance signals near
178 ppm and 163 ppm, respectively. The aromatic carbon
atoms of HL1 show resonances in the range of 120–150 ppm,
while those of HL2 appear in the region between the two
signals assignable to carbon atoms of the aliphatic double
bond at 144.0 ppm and 127.7 ppm.
Co3+
.
Results and Discussion
The ligands HL1 and HL2
The ligands HL1 and HL2 were synthesized in good yields
following reported procedures.[10] The synthesis of HL1 starts
with the O-acetylation of gallic acid using acetic anhydride.
Then, the acetylated acid is refluxed in an excess of SOCl2 to
convert into the corresponding acyl chloride. The reaction of
the acyl chloride with N,N-diethylthiourea in dry THF with the
presence of a stoichiometric amount of the supporting base
Et3N gives rise to HL1 in 60% yield (Scheme 1a). HL2 can be
Single crystals of the ligand HL2 suitable for X-ray diffraction
were obtained by slow evaporation of its MeOH/water solution.
The compound crystallizes in the monoclinic space group P21/c
with two crystallographically independent molecules in the
asymmetric unit (Figure 3). Selected bond lengths are listed in
Table 1. The ligand HL2 has a non-planar structure with carbonyl
and thiocarbonyl groups in virtually opposite orientations. Such
conformation is normally observed for other aroyl-(N,N-disub-
stituted)thioureas.[8d] The N,N-diethylthiourea groups are twisted
from the corresponding cinnamoyl moieties with the angles of
°
°
63.17(5) and 60.45(9) between the mean least-square planes
formed by the NC(S)N unit of the thiourea substituents and the
Scheme 1. Syntheses of the ligands (a) HL1 and (b) HL2.
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The bis-complexes [M(L)2] (M=Ni2+, Cu2+; L=L1, L2)
Two equivalents of the ligands HL1 or HL2 readily react with one
equivalent of Ni(AcO)2 or Cu(AcO)2 in MeOH in the presence of
a weak base like NaAcO. Pure products directly deposited from
the corresponding reaction mixtures. The chemical composi-
tions of [M(L)2] (M=Ni2+, Cu2+; L=L1, L2) are confirmed by the
results of the elemental analyses and the presence of peaks
associated with the expected molecular ions [M(L)2 +H]+ in the
high resolution mass spectra. In the IR spectra of the complexes,
the absence of broad absorptions in the region above
3100 cmÀ 1 assigned to νNH stretches suggests the successful
deprotonation of the ligands during complexation. In contrast
to modest shifts of about 30 cmÀ 1 of the carbonyl C=O bands in
complexes derived from HL2, such characteristic bands in
complexes based on HL1 show remarkable bathochromic shifts
of approximately 140 cmÀ 1, which are clear evidence for the
formation of the chelating (S,O)-benzoylthiourea. These struc-
tural features in the Ni(II) complexes are also observed in the
NMR spectra, in particular, the disappearance of the broad
singlet signal of the NH proton and the downfield shift of C=O
signal with respect to the uncoordinated ligands. Additionally,
the well-resolved splitting pattern of signals associated with
ethyl residues in 1H NMR spectrum of [Ni(L1)2] reveals an
increase in rotation barrier around C(S)-NEt2 bonds. Further-
more, the NMR spectra of the Ni(II) complexes strongly reflect
their diamagnetism, thereby pointing out the square planar
coordination geometry of the Ni atoms. The structural con-
clusions drawn from spectroscopic studies are verified by X-ray
diffraction analyses. Figure 4 presents the molecular structures
of the compounds [Cu(L1)2] and [Cu(L2)2]. Because the structure
of the Ni(II) complex [Ni(L1)2] is virtually identical with that of
[Cu(L1)2], no extra Figure is shown here. Selected bond lengths
Figure 3. Molecular structure of the asymmetric unit of (HL2)2.
Hydrogen atoms bonded to carbons are omitted for clarity. The
dashed line presents the hydrogen bond.
Table 1. Selected bond length/Å in the unit (HL2)2.
Bond lengths/Å
C10À O10
C10À N10
C11À N10
C11À N11
C11À S10
C1À C2
1.240(3)
1.369(3)
1.424(3)
1.336(3)
1.660(2)
1.331(3)
C30À O30
C30À N30
C31À N30
C31À N31
C31À S30
C21À C22
1.236(3)
1.376(3)
1.420(3)
1.328(3)
1.672(2)
1.327(3)
aroyl moieties. The CÀ O, CÀ S and CÀ N bond lengths resemble
those in analogous aroy(N,N-disubstituted)thioureas (Table 1).[12]
The partial double bond character of C(S)À NEt2 distances is a
confirmation of the hindered rotation around these bonds,
which is detected in the NMR spectra. The supramolecular
structure of HL2 is stabilized by the intermolecular C=O…HN
hydrogen bonds and π-π stacking (Figure S29).
and angles are given in Table 2. The [M(L1)2] (M=Ni2+, Cu2+
)
1
Table 2. Selected bond lengths/Å and bond angles/ in [M(L )2] (M=Ni2+, Cu2+) and [Cu(L2)2].
°
Bond lengths/Å
[Ni(L1)2]
[Cu(L1)2]
[Cu(L2)2]
MÀ O10
1.8613(17)
1.9262(17)
CuÀ O10/
CuÀ O30
1.9157(14)/1.9248(13)
MÀ S10
2.1514(7)
1.268(3)
1.313(3)
1.348(3)
1.734(2)
1.336(3)
2.2360(7)
1.263(3)
1.312(3)
1.351(3)
1.729(2)
1.339(3)
CuÀ S10/
CuÀ S30
2.2334(6)/2.2357(7)
1.258(2)/1.259(2)
1.336(2)/1.340(2)
1.343(2)/1.343(2)
C10À O10
C10À N10
N10À C11
C11À S10
C11À N11
C10À O10/
C30À O30
C10À N10/
C30À N30
N10À C11/
N30À C31
C11À S10/
C31À S30
C11À N11/
C31À N31
1.7415(17)/
1.7427(18)
1.345(2)/
1.341(2)
[Ni(L1)2]
95.43(6)
[Cu(L1)2]
93.97(6)
[Cu(L2)2]
°
Bond angles/
O10À MÀ S10
O10À CuÀ S10/
O30À CuÀ S30
O10À CuÀ S30/
O30À CuÀ S10/
93.00(4)/
93.56(4)
176.27(6)/
176.18(5)
O10À MÀ S10i
178.68(6)
178.26(6)
i
Symmetry operations used to generate equivalent atoms: À x, y, À z+1/2.
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structural determination indicates mononuclear square planar
complexes with cis configuration, in which divalent metal ions
are coordinated by two deprotonated ligands {L1}À or {L2}À
through two (S,O)-chelates. Such bidentate cis-L(S,O) coordina-
tion which is more thermodynamically favorable than trans-
L(S,O) fashion, has been observed in majority of reported
benzoylthiourea complexes with divalent metal ions.[8c,13] The
MÀ O and MÀ S bond lengths (M=Ni2+, Cu2+) are in the same
ranges as those found in the analogous complexes with other
benzoylthiourea ligands.[7b,c,h,14] The planarity of the six-mem-
bered chelate rings as well as the partial double bond character
CÀ S, CÀ O and CÀ N bonds in all complexes (Table 2) is in line
with the well-known extended π-systems in chelating ben-
zoylthiourea moieties.[7g]
In comparison to the counterparts in the uncoordinated
ligand HL2, the elongation of the CÀ O and CÀ S bonds and the
contraction of the CÀ N distances within the chelate rings in the
structure of the complex [Cu(L2)2] strongly suggest the higher
delocalization of π-electrons within the thiourea moieties by
the complexation.
The tris-complexes [Co(L)3] (L=L1, L2)
The tris-complexes [Co(L)3] (L=L1, L2) are readily formed in the
reaction of Co(AcO)2 (1 equiv.) with the corresponding organic
ligands (3 equiv.) in MeOH. Addition of a weak base like NaAcO
could accelerate the complex formation. The color change of
the reaction mixture is a visible sign of the oxidation of Co(II)
ions probably by atmospheric dioxygen during the complex-
ation. Similar redox reactions have been reported in the
preparation of Co(III) tris-complexes with other benzoylthiourea
ligands.[15] The result of elemental analysis and the presence of
the predicted ions [Co(L1)3 +H]+ and [Co(L2)3 +Na]+ in the mass
spectra confirm the chemical composition of the neutral tris-
complexes. In their IR spectra, the disappearance of the broad
absorption in the region above 3100 cmÀ 1 and the bath-
ochromic shift of the intense absorption corresponding to the
ketone νC=O vibrations illustrate the successful deprotonation of
the ligand and the chelate formation with π-electron delocaliza-
tion. The formal oxidation state “+3” of the cobalt ion is
validated by the diamagnetism of the products. It comes as no
1
surprise that the H NMR spectra measured in CDCl3 show no
signal accounting for NH proton in the downfield region 8.0–
9.0 ppm, which confirms the deprotonation of the ligands.
Similarly to the situation in the complex [Ni(L1)2], a considerable
increase of the rotational barrier around C(S)À NEt2 bonds upon
Figure 4. Molecular structures of the bis complexes (a) [Cu(L1)2] and
(b) [Cu(L2)2. Symmetry operations used to generate equivalent
1
coordination is observed in the H NMR spectra of both Co(III)
atoms: i À x, y, À z+1/2. Hydrogen atoms are omitted for clarity.
complexes. By comparison with the simple splitting patterns of
the same protons in the uncoordinated ligands and in the Ni(II)
complexes, the more delicate fine structures of the CH2 protons
of the ethyl residues presumably resulting from geminal and
vicinal couplings in combination with the overlap of resulting
signals apparently reflect the substantial increase of rigid
arrangement around the tertiary nitrogen atoms.[16] In contrast
complexes crystallize isomorphic as dichloromethane solvates
in the monoclinic space group C2/c with a half unit of
[M(L1)2]·CH2Cl2 in the asymmetric unit. For the [M(L2)2] series,
we could only successfully crystallize the [Cu(L2)2] complex,
which crystallizes in the solvent-free form in the triclinic space
group P-1 with one molecule in the asymmetric unit. The
1
to the complexity of H NMR spectra, the 13C{1H} NMR spectra
are straightforward. Except the significant downfield shifts of
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the resonance for carbonyl C=O groups because of the
elucidated using the spectroscopic data are confirmed by X-ray
coordination with the Co(III) ions, the 13C{1H} NMR spectra of the
complexes and the free ligands closely resemble. The structures
structure determination. Figure 5 depicts the structures of the
complexes, and selected structural parameters are listed in
Table 3.
The complex [Co(L1)3] crystallizes in the solvent-free form in
the triclinic space group P-1 with one molecule in the
asymmetric unit. Whereas the remaining complex crystallizes in
the solvated form in the non-centrosymmetric trigonal space
group R3 with one-third unit of [Co(L2)3]·CH2Cl2 in the
asymmetric unit, in which a crystallographic C3-axis passes
through the Co atom and the carbon atom of the co-crystalized
solvent molecule. The complexes are mononuclear with Co(III)
ions octahedrally coordinated by three deprotonated (S,O)-
bidentate ligands {L1}À or {L2}À with a facial arrangement of
donor atoms. Hitherto, this type of arrangement is the unique
coordination geometry known for homoleptic tris-complexes of
benzoylthioureas and trivalent metal ions.[13] The CoÀ O and
CoÀ S bond lengths are in the range of 1.915(2)–1.936(4) Å and
2.2034(9)–2.2120(2) Å, respectively. This is in good agreement
with the values observed in the Co(III) tris-complexes with other
benzoylthioureato ligands.[15,17] The planarity of chelate rings
and the partial double bond character of the CÀ O, CÀ N, and
CÀ S bonds within the benzoylthiourea moieties imply the
existence of typical extended π-systems, which are detected in
the IR spectra. In the supramolecular structure of [Co(L1)3], two
neighboring structural units interact with each other by a π–π
stacking (Figure S30).
Anticancer activity studies
Recent literature reviews witness wide spectrum of bioactivities
of aroyl/acylthiourea ligands and their transition metal
complexes.[8b–d] However, there are only several reports on
antitumor activities of this family of ligands,[18] and their
homoleptic complexes.[18a,19] In the present study, antiprolifer-
ative effects of the ligands and their metal complexes on
human MCF7 breast and HepG2 liver cancer cells were
inspected using dose-response assays. Table 4 lists the IC50
Figure 5. Molecular structure of the tris complexes (a) [Co(L1)3] and
(b) [Co(L2)3]. Symmetry operations used to generate equivalent
atoms: i 1À y, xÀ y, z and ii 1+yÀ x, 1À x, z. Hydrogen atoms are
omitted for clarity.
1
2
°
Table 3. Selected bond lengths/Å and bond angles/ in [Co(L )3] and [Co(L )3].
Bond lengths/Å
[Co(L1)3]
[Co(L2)3]
CoÀ O10
CoÀ S10
CoÀ O10
1.936(4)
2.2120(2)
1.259(7)
1.327(7)
1.343(8)
1.730(7)
1.349(7)
CoÀ O30
CoÀ S30
1.924(4)
2.206(2)
1.269(7)
1.327(8)
1.350(8)
1.732(7)
1.318(8)
CoÀ O50
CoÀ S50
1.918(4)
2.2047(2)
1.265(7)
1.316(7)
1.357(7)
1.725(6)
1.344(7)
1.915(2)
2.2034(9)
1.267(4)
1.327(4)
1.337(4)
1.726(3)
1.341(4)
CoÀ S10
C10À O10
C10À N10
N10À C11
C11À S10
C30À O30
C30À N30
N30À C31
C31À S30
C31À N31
C50À O50
C50À N50
N50À C51
C51À S50
C51À N51
C10À O10
C10À N10
N10À C11
C11À S10
C11À N11
C11À N11
Bond angles/
[Co(L1)3]
°
[Co(L2)3]
O10À CoÀ S10
93.03(13)
176.16(13)
O30À CoÀ S30
O30À CoÀ S50
96.32(13)
175.88(14)
O50À CoÀ S50
O50À CoÀ S10
92.83(13)
177.59(14)
O10À CoÀ S10
94.24(7)
176.98(7)
O10À CoÀ S30
O10À CoÀ S10ii
ii
Symmetry operations used to generate equivalent atoms: 1+yÀ x, 1À x, z.
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Table 4. IC50 values/μM of the ligands and complexes.
Tested compounds
MCF7
HepG2
Tested compounds
MCF7
HepG2
HL1
70.17�5.80
64.84�6.94
94.21�2.46
22.23�1.58
45.7�1.2
97.63�9.65
89.42�2.20
113.2�1.14
28.30�3.09
13.3�1.1
HL2
>380
>170
>170
>100
>380
>170
>170
>100
[Ni(L1)2]
[Cu(L1)2]
[Co(L1)3]
cisplatin[20]
[Ni(L2)2]
[Cu(L2)2]
[Co(L2)3]
values obtained and that of cisplatin determined under the
same condition.[20]
selectively form cis square planar and facial octahedral com-
plexes with di- and tri-valent metal ions, respectively. Anti-
cancer activity studies demonstrate that the ligand HL1 and its
Ni(II) and Cu(II) complexes show weak growth inhibition of the
human MCF7 breast and HepG2 liver cancer cells, while the
corresponding Co(III) complex presents considerable antiproli-
ferative effects against the two tested cancer cell lines. Its
cytotoxicity against MCF7 cells even more than that of cisplatin
under the same condition.
The results indicate that the ligand HL1 and its complexes
cause remarkable antiproliferative effects on the two tested cell
lines, while the remaining compounds have almost no activity
against the cancer cells. Although HL1 and its Ni(II) and Cu(II)
complexes (IC50 values>50 μM) show weak growth inhibition
for both HepG2 and MCF7 cancer cells, the IC50 values are
comparable with those of some aroylthioureas,[18c,d] and similar
homoleptic complexes tested against the same cell lines
(Figure 6).[19e,g] Surprisingly, the tris-complex [Co(L1)3] exhibits
high cytotoxicity. The activity against MCF7 cells is even more Experimental Section
than that of cisplatin under the same experimental condition. In
Materials: All chemicals used in this study were reagent grade and
used without further purification. Solvents were dried and used
freshly distilled unless otherwise stated.
comparison with IC50 values of the uncoordinated ligand, those
of the Co(III) complex decrease by a factor about 3.5. The
enhanced activities of the Co(III) complex with respect to the
uncoordinated ligand HL1 indicate the synergistic effect of
metal ion.[5a,21]
Physical Measurements: Infrared spectra were measured as KBr
pellets on an Affinity-1S FTIR-spectrometer between 400 and
4000 cmÀ 1. NMR spectra were taken with an AscendTM 500 MHz
(Bruker) multinuclear spectrometer. ESI high resolution mass
spectra were measured with an LTQ Orbitrap XLTM and SCIEX X500
QTOF instruments. All MS results are given in the form: m/z,
assignment. Elemental analyses of carbon, hydrogen, nitrogen and
sulfur were determined using a Heraeus (Germany) vario EL
elemental analyzer. Reproductions of the IR, NMR and MS spectra
are given as Supplementary Material.
Conclusions
Two new benzoylthioureas bearing natural compounds derived
moieties, namely gallic acid, HL1, and cinnamic acid, HL2, have
been synthesized and examined for their coordination potential
with Ni2+, Cu2+ and Co3+ ions. In all complexes, the ligands act
as monoanionic chelators with the (S,O) donor sets and
Synthesis of the ligand HL1: The ligand was synthesized following
the method reported by Dixon and Taylor with some modification-
s.[10a] A mixture of the anhydrous acetylated gallic acid (3.40 g,
0.02 mol) prepared according to the procedure adapted from Ye
et al.[22] and an excess amount of SOCl2 (15 mL, 0.2 mol) was heated
°
at 80 C under nitrogen atmosphere for 3 h to obtain a clear
solution. After that, the residual SOCl2 was removed under reduced
pressure. The resulting solid was dissolved in dry THF (50 mL) and
then added dropwise to a mixture of N,N-diethylthiourea (2.64 g,
0.02 mol) and Et3N (6.4 mL, 0.02 mol) in dry THF (20 mL). The
°
reaction mixture was heated up to 40–50 C and stirred for 2 h.
After cooling, the mixture to room temperature, a colorless
precipitate of Et3N·HCl was filtered off, and THF was removed under
low pressure. The obtained solid was washed with MeOH to give
the HL ligand as a colourless solid. Yield: 60% (4.93 g). Elemental
analysis Calcd. for C18H22O7N2S: C, 52.67; H, 5.40; N, 6.83; S, 7.81%.
Found: C, 52.48; H, 5.57; N, 6.65; S, 7.65%. IR (KBr, cmÀ 1): 3234 (w),
2974 (w), 2934 (w), 1769 (s), 1663 (m), 1528 (m), 1468 (m), 1423 (s),
1369 (s), 1329 (m), 1285 (m), 1204 (s), 1186 (s), 1167 (s), 1126 (s)
1059 (s), 1013 (s), 897 (m), 878 (m), 856 (w), 760 (w), 698 (w), 604
(w), 557 (w), 415 (w). 1H NMR (500 MHz, CDCl3, ppm): 8.32 (br, s, 1H,
NH), 7.66 (s, 2H, Ph), 4.05 (br, s, 2H, CH2), 3.60 (br, s, 2H, CH2), 2.35–
2.33 (br, m, 9H, CH3COO), 1.39 (br, s, 3H, CH3), 1.32 (br, s, 3H, CH3).
13C{1H} NMR (CDCl3, ppm): 178.7 (CS), 167.6 (m-CH3COO), 166.4 (p-
CH3COO), 161.5 (CO), 143.8, 138.4, 130.8, 120.5 (Ph), 48.0, 47.7 (CH2),
Figure 6. Structures and IC50 values of some aroylthioureas and
homoleptic complexes previously reported.
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20.6 (m-CH3COO), 20.2 (p-CH3COO), 13.3, 11.4 (CH3). +ESI MS (m/z):
Data for [Ni(L2)2]: Reddish brown. Yield: 83% (48.1 mg). Elemental
411.1219 (calcd. 411.1226), 100% [HL1 +H]+.
analysis Calcd. for C28H34O2N4S2Ni: C, 57.84; H, 5.89; N, 9.64; S,
11.03%. Found: C, 57.97; H, 5.72; N, 9.58; S, 10.91%. IR (KBr, cmÀ 1):
2978 (w), 2932 (w), 1634 (m), 1489 (s), 1408 (s), 1352 (s), 1296 (m),
1260 (m), 1236 (m), 1184 (m), 1128 (m), 1076 (m), 1016 (m), 989 (w),
879 (w), 760 (m), 713 (w), 683 (m), 600 (w), 488 (w). 1H NMR
(500 MHz, CDCl3, ppm): 7.65 (d, J=11.0 Hz, 1H, trans-CH=CH), 7.57–
7.38 (m, 5H, Ph), 6.61 (d, J=11.0 Hz, 1H, trans-CH=CH), 3.77 (br, s,
4H, CH2), 1.29 (br, s, 3H, CH3), 1.24 (br, s, 3H, CH3). 13C{1H} NMR
(CDCl3, ppm): 173.1 (CS), 172.0 (CO), 140.8 (trans-CH=CH), 135.7,
129.2, 128.7, 127.9 (Ph), 127.2 (trans-CH=CH), 45.9, 45.2 (CH2), 13.1,
12.6 (CH3). +ESI MS (m/z): 603.1382 (calcd. 603.1374), 14% [Ni(L2)2
+Na]+; 581.1538 (calcd. 581.1555), 75% [Ni(L2)2 +H]+; 285.1013
(calcd. 285.1038), 100% [HL2 +Na]+.
Synthesis of the ligand HL2: The ligand was synthesized following
the standard procedure proposed by Douglass and Dain.[10b] To a
suspension of NH4SCN (1.52 g, 0.02 mol) in 20 mL dry acetone was
added dropwise solution of cinnamoyl chloride (3.33 g, 0.02 mol) in
20 mL dry acetone. The reaction mixture was then heated up to
°
50 C and stirred for 1 h. After cooling the mixture to room
temperature, 20 mL dry acetone containing diethylamine (2.1 mL,
0.02 mol) were added dropwise. After that, the reaction mixture
was refluxed for 2 h and then poured into 500 mL water with
vigorous stirring. The isolated solid was collected by filtration and
washed with water. Recrystallization of the obtained pale-yellow
solid from hot MeOH and water afforded the ligand as a colorless
solid. Yield: 62% (3.25 g). Elemental analysis Calcd. for C14H18ON2S:
C, 64.09; H, 6,92; N, 10.68; S, 12.22%. Found: C, 63.94; H, 7.12; N,
10.46; S, 11.96%. IR (KBr, cmÀ 1): 3250 (w), 2976 (w), 2935 (w), 1665
(s), 1626 (s), 1531 (s), 1449 (s), 1421 (s), 1344 (s), 1283 (s), 1233 (s),
1192 (s), 1126 (s), 1072 (m), 1003 (s), 905 (w), 873 (w), 766 (s), 714
Data for [Cu(L2)2]: Brownish grey. Yield: 75% (43.9 mg). Elemental
analysis Calcd. for C28H34O2N4S2Cu: C, 57.36; H, 5.85; N, 9.56; S,
10.94%. Found: C, 57.54; H, 5.67; N, 9.38; S, 10.78%. IR (KBr, cmÀ 1):
2968 (w), 2932 (w), 1634 (m), 1512 (s), 1491 (s), 1412 (s), 1352 (m),
1294 (w), 1260 (w), 1176 (w), 1128 (w), 1070 (w), 1011 (w), 972 (w),
768 (w), 687 (w), 588 (w), 548 (w). +ESI MS (m/z): 608.1334 (calcd.
608.1317), 12% [Cu(L2)2 +Na]+; 586.1496 (calcd. 586.1497), 42%
[Cu(L2)2 +H]+; 285.1032 (calcd. 285.1038), 100% [HL2 +Na]+. Single
crystals suitable for X-ray analysis were obtained by slow evapo-
ration of the filtrate.
1
(m), 683 (m), 565 (m), 536 (m), 486 (m). H NMR (500 MHz, CDCl3,
ppm): 8.77 (br, s, 1H, NH), 7.68 (d, J=15.5 Hz, 1H, trans-CH=CH),
7.54–7.52 (m, 2H, Ph), 7.39–7.38 (m, 3H, Ph), 6.68 (d, J=15.5 Hz, 1H,
trans-CH=CH), 4.02 (br, s, 2H, CH2), 3.63 (br, s, 2H, CH2), 1.33 (br, s,
6H, CH3). 13C{1H} NMR (CDCl3, ppm): 179.2 (CS), 166.9 (CO), 144.0
(trans-CH=CH), 134.4, 129.2, 128.9, 128.2 (Ph), 127.7 (trans-CH=CH),
47.7, 44.6 (CH2), 13.2, 13.0 (CH3). +ESI MS (m/z): 263.1210 (calcd.
263.1218), 15% [HL2 +H]+; 285.1027 (calcd. 285.1038), 100% [HL2 +
Na]+. Single crystals suitable for X-ray analysis were obtained by
recrystallization of the compound from a mixture of MeOH and
water.
Syntheses of [Co(L)3]: HL1 or HL2 (0,3 mmol) were added to a
solution of Co(OAc)2 ·4 H2O (25.0 mg, 0.1 mmol) in MeOH (1 mL).
During stirring of reaction mixtures at room temperature for
15 min, the colour of the solutions changed gradually to green.
After the addition of NaOAc (24.6 mg, 0.3 mmol), the reaction
°
mixtures were stirred at 40 C for 1 h. The final solution was slowly
Syntheses of [M(L)2] (M=Ni2+, Cu2+): Ni(OAc)2 ·4 H2O or Cu-
(OAc)2 ·2H2O were dissolved in 1 mL of MeOH. The ligands HL1 or
HL2 (0.2 mmol) were added and the reaction mixtures were kept
evaporated at room temperature. During this process, the pure
products deposited as green solids, which were then filtered off,
washed with cold MeOH and dried in vacuum.
°
stirring at 40 C for 30 min before the addition of NaOAc (16.4 mg,
Data for [Co(L1)3]: Yield: 70% (90.1 mg). Elemental analysis Calcd.
for C54H63O21N6S3Co: C, 50.39; H, 4.93; N, 6.53; S, 7.47%. Found: C,
50.12; H, 5.06; N, 6.28; S, 7.22%. IR (KBr, cmÀ 1): 2976 (w), 2932 (w),
1770 (s), 1530 (m), 1495 (s), 1406 (s), 1371 (s), 1354 (s), 1279 (m),
1238 (m), 1179 (s), 1155 (s), 1128 (s), 1045 (s), 1007 (s), 899 (m), 880
(m), 847 (m), 797 (w), 737 (w), 687 (w), 590 (w), 548 (w), 488 (w), 422
°
0.2 mmol). During an additional stirring at 40 C for 1 h, the pure
products deposited from the solution and were then collected by
filtration, washed with cold MeOH and dried in vacuum.
Data for [Ni(L1)2]: Purple. Yield: 75% (65.8 mg). Elemental analysis
Calcd. for C36H42O14N4S2Ni: C, 49.27; H, 4.82; N, 6.38; S, 7.31%. Found:
C, 49.03; H, 5.02; N, 6.17; S, 7.01%. IR (KBr, cmÀ 1): 2976 (w), 2934 (w),
1771 (s), 1528 (m), 1499 (s), 1418 (s), 1371 (s), 1279 (m), 1242 (m),
1180 (s), 1153 (s), 1076 (m), 1047 (s), 1009 (s), 899 (m), 847 (m), 800
1
(w). H NMR (500 MHz, CDCl3, ppm): 7.91 (s, 2H, Ph), 3.86–3.73 (m,
4H, CH2), 2.29 (s, 3H, p-CH3COO), 2.27 (s, 6H, m-CH3COO), 1.21 (t, J=
7.0 Hz, 3H, CH3). 13C{1H} NMR (CDCl3, ppm): 174.8 (CS), 172.3 (CO),
167.7 (m-CH3COO), 166.6 (p-CH3COO), 142.6, 137.0, 136.9, 121.6
(Ph), 45.9, 45.8 (CH2), 20.6 (m-CH3COO), 20.2 (p-CH3COO), 13.1, 12.8
(CH3). +ESI MS (m/z): 1287.2653 (calcd. 1287.2619), 100% [Co(L1)3 +
H]+. Single crystals suitable for X-ray analysis were obtained by
slow evaporation of a solution of the complex in DMF.
1
(m), 762 (m), 735 (w), 664 (w), 586 (w), 550 (w), 501 (w), 415 (s). H
NMR (500 MHz, CDCl3, ppm): 7.79 (s, 2H, Ph), 3.74 (q, J=7.0 Hz, 4H,
CH2), 2.28 (br, s, 3H, p-CH3COO), 2.27 (br, s, 6H, m-CH3COO), 1.27 (t,
J=7.0 Hz, 3H, CH3), 1.23 (t, J=7.0 Hz, 3H, CH3). 13C{1H} NMR (CDCl3,
ppm): 172.8 (CS), 169.9 (CO), 167.8 (m-CH3COO), 166.6 (p-CH3COO),
142.8, 137.1, 135.2, 121.5 (Ph), 46.3, 45.8 (CH2), 20.6 (m-CH3COO),
20.2 (p-CH3COO), 13.1, 12.5 (CH3). +ESI MS (m/z): 877.1526 (calcd.
877.1571), 100% [Ni(L1)2 +H]+. Single crystals suitable for X-ray
analysis were obtained by slow evaporation of a solution of the
complex in a mixture of MeOH and CH2Cl2.
Data for [Co(L2)3]: Yield: 88% (74.1 mg). Elemental analysis Calcd.
for C42H51O3N6S3Co: C, 59.84; H, 6.10; N, 9.97; S, 11.41%. Found: C,
59.67; H, 6.25; N, 9.82; S, 11.53%. IR (KBr, cmÀ 1): 2980 (w), 2930 (w),
1634 (s), 1510 (s), 1485 (s), 1422 (s), 1404 (s), 1350 (s), 1248 (m),
1190 (m), 1128 (m), 1072 (m), 1011 (m), 978 (m), 874 (w), 843 (w),
762 (m), 727 (w), 685 (w), 613 (w), 486 (w). 1H NMR (500 MHz, CDCl3,
ppm): 7.71 (d, J=16.0 Hz, 1H, trans-CH=CH), 7.51 (s, 2H, Ph), 7.33–
7.32 (m, 3H, Ph), 6.84 (d, J=16.0 Hz, 1H, trans-CH=CH), 3.95–3.77
(m, 4H, CH2), 1.28 (br, s, 3H, CH3), 1.20 (br, s, 3H, CH3). 13C{1H} NMR
(CDCl3, ppm): 175.9 (CS), 174.2 (CO), 140.2 (trans-CH=CH), 136.1,
129.1, 128.9, 128.6 (Ph), 127.9 (trans-CH=CH), 45.5, 45.1 (CH2), 13.3,
13.1 (CH3). +ESI MS (m/z): 865.2479 (calcd. 865.2414), 63% [Co(L2)3
+Na]+. Single crystals suitable for X-ray analysis were obtained by
slow evaporation of a solution of the complex in a mixture of
MeOH and CH2Cl2.
Data for [Cu(L1)2]: Brownish grey. Yield: 70% (61.8 mg). Elemental
analysis Calcd. for C36H42O14N4S2Cu: C, 49.00; H, 4.80; N, 6.35; S,
7.27%. Found: C, 48.72; H, 4.91; N, 6.08; S, 7.13%. IR (KBr, cmÀ 1):
2974 (w), 2936 (w), 1771 (s), 1543 (w), 1518 (m), 1495 (s), 1423 (s),
1371 (s), 1279 (m), 1238 (w), 1179 (s), 1153 (s), 1074 (m), 1045 (s),
1009 (s), 899 (m), 847 (m), 797 (m), 764 (m), 735 (w), 687 (w), 588
(w), 546 (m), 486 (m), 415 (s). +ESI MS (m/z): 904.1334 (calcd.
904.1333), 100% [Cu(L1)2 +Na]+; 882.1552 (calcd. 882.1513), 25%
[Cu(L1)2 +H]+. Single crystals suitable for X-ray analysis were
obtained by slow evaporation of a solution of the complex in a
mixture of MeOH and CH2Cl2.
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X-ray crystallography: The intensities for the X-ray determinations
E. A. Bayer, M. Majeed, A. Bishayee, V. Bochkov, G. K. Bonn, N.
of [Co(L1)3], [Ni(L1)2]·CH2Cl2, [Cu(L1)2]·CH2Cl2, HL2, [Co(L2)3]·CH2Cl2
and [Cu(L2)2] were collected on a Bruker D8 QUEST instrument at
170 K with Mo Kα radiation (λ=0.71073 Å) using a TRIUMPH
monochromator. Standard procedures were applied for data
reduction and absorption correction.[23] Structure solution and
refinement were performed with the SHELXT and SHELXL 2014/7
programs.[24] Hydrogen atoms were calculated for idealized posi-
tions and treated with the ‘riding model’ option of SHELXL. The
program OLEX2-1.2 was used for the molecular representation.[25]
More details on data collections and structure calculations are
contained in Table S1. Crystallographic data for the structures in
this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre, CCDC, 12 Union Road, Cambridge CB21EZ, UK.
Copies of the data can be obtained free of charge on quoting the
depository numbers CCDC-1995471 [Co(L1)3], CCDC-1995472 {[Ni-
(L1)2]·CH2Cl2}, CCDC-1995473 {[Cu(L1)2]·CH2Cl2}, CCDC-2055051
(HL2)2, CCDC-2055052 {[Co(L2)3]·CH2Cl2} and CCDC-2055053 [Cu(L2)2]
(Fax: +44-1223-336-033; E-Mail: deposit@ccdc.cam.ac.uk, http://
www.ccdc.cam.ac.uk).
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determined using a MTT assay. Human MCF-7 and HepG2 cancer
cells were obtained from the American Type Culture Collection
(Manassas, VA) ATCC. Cells were cultured in standard procedure
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Acknowledgements
This research is funded by Vietnam National Foundation for
Science and Technology Development (NAFOSTED) under grant
number 104.03-2016.48.
Keywords: Benzoylthiourea
complexes · Co(III) complexes · anticancer activities
·
Ni(II) complexes
·
Cu(II)
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Manuscript received: February 22, 2021
Revised manuscript received: April 4, 2021
Z. Anorg. Allg. Chem. 2021, 1–10
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© 2021 Wiley-VCH GmbH
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These are not the final page numbers!

ARTICLE
Prof. Dr. C. Thang Pham, T.
Thuy Pham, V. Ha Nguyen,
Prof. Dr. T. Nguyet Trieu*, Prof. Dr. H.
Huy Nguyen*
1 – 10
Syntheses, Structures, and Bioac-
tivity Evaluation of some Transi-
tion Metal Complexes with
Aroylbis(N,N-diethylthioureas)
Derived from Natural Compounds