Synthesis, Structure, and Biological Activity of Copper and Cobalt Coordination Compounds with Substituted 2-(2-Hydroxybenzylidene)-N-(prop-2-en-1-yl)hydrazinecarbothioamides

Article abstract of DOI:10.1134/S1070363219050153

The reaction of N-(prop-2-en-1-yl)hydrazinecarbothioamide with substituted 2-hydroxybenzaldehydes afforded the corresponding Schiff bases which were used as ligands to obtain copper and cobalt coordination compounds Cu(NL^1–6)X · n H₂O (X = Cl^?, NO3?; n = 0–3), Co(HL²)₂NO₃, and Co(NL⁶)₂Cl. The structure of the isolated complexes was determined by NMR spectroscopy and X-ray analysis. The complexes were tested for antimicrobial and antifungal activity against S. aureus, E. coli, and yeast-like fungi. Inhibitory effect of the initial thioamides and their complexes against human myeloid leukemia HL-60 cancer cell line was also studied.

Full text of DOI:10.1134/S1070363219050153

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 5, pp. 953–964. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Authors(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 5, pp. 766–778.
Synthesis, Structure, and Biological Activity
of Copper and Cobalt Coordination Compounds with Substituted
2-(2-Hydroxybenzylidene)-N-(prop-2-en-1-yl)hydrazine-
carbothioamides
A. P. Guleaa, V. O. Graura, Yu. M. Chumakovb, c, P. A. Petrenkob, G. G. Baland,
O. S. Burduniucd, e, V. I. Tsapkova*, and V. F. Rudicf
a State University of Moldova, ul. Mateevicha 60, Kishinev, Moldova
*e-mail: vtsapkov@gmail.com
b Institute of Applied Physics, Kishinev, Moldova
c Gebze Institute of Technology, Gebze/Kocaeli, Ҫayirova, Turkey
d Testemitanu State University of Medicine and Pharmacy, Kishinev, Moldova
e National Agency of Public Health, Kishinev, Moldova
f Institute of Microbiology and Biotechnology, Academy of Sciences of Moldova, Kishinev, Moldova
Received November 29, 2018; revised November 29, 2018; accepted February 22, 2019
Abstract—The reaction of N-(prop-2-en-1-yl)hydrazinecarbothioamide with substituted 2-hydroxybenzalde-
hydes afforded the corresponding Schiff bases which were used as ligands to obtain copper and cobalt
coordination compounds Cu(NL1–6)X · n H2O (X = Cl–, NO3–; n = 0–3), Co(HL2)2NO3, and Co(NL6)2Cl. The
structure of the isolated complexes was determined by NMR spectroscopy and X-ray analysis. The complexes
were tested for antimicrobial and antifungal activity against S. aureus, E. coli, and yeast-like fungi. Inhibitory
effect of the initial thioamides and their complexes against human myeloid leukemia HL-60 cancer cell line
was also studied.
Keywords: coordination compounds, 2-hydroxybenzaldehyde, allylthiosemicarbazones, antimicrobial activity,
anticancer activity
DOI: 10.1134/S1070363219050153
2-(2-Hydroxybenzylidene)-N-(prop-2-en-1-yl)hyd-
razinecarbothioamide possesses a number of donor
atoms and is capable of forming structurally diverse
coordination compounds with transition metals [1–6];
such complexes showed selective anticancer activity
[7, 8]. It was found that their biological activity
correlates with their structure. Therefore, synthesis and
study of new metal complexes with 2-(2-hydroxy-
benzylidene)-N-(prop-2-en-1-yl)hydrazinecarbothioamide
and its derivatives attract interest from both theoretical
and practical viewpoints.
(H2L3), 2-(2,4-dihydroxybenzylidene)- (H2L4), 2-(2-hyd-
roxy-3-nitrobenzylidene)- (H2L5), and 2-(2-hydroxy-3-
methoxybenzylidene)-N-(prop-2-en-1-yl)hydrazinecarbo-
thioamides (H2L6) (Scheme 1) and studying their struc-
ture, physicochemical properties, and biological activity.
Thioamides H2L1–H2L6 were synthesized by
condensation of equimolar amounts of N-(prop-2-en-1-
yl)hydrazinecarbothioamide (4-allylthiosemicarbazide)
and substituted 2-hydroxybenzaldehydes in ethanol.
The yields, melting points, and elemental analyses of
ligands H2L1–H2L6 are given in Table 1, and their
NMR spectral data are collected in Table 2. We suc-
ceeded in obtaining single crystals of H2L4–H2L6
suitable for X-ray analysis (Table 3) by recrystal-
lization from ethanol.
The present work was aimed at synthesizing copper
and cobalt coordination compounds with 2-(5-bromo-2-
hydroxybenzilidene)- (H2L1), 2-(3,5-dibromo-2-hydroxy-
benzylidene)- (H2L2), 2-(2,3-dihydroxybenzylidene)-
953

954
GULEA et al.
Molecules H2L4 in crystal are linked through inter-
Scheme 1.
molecular hydrogen bonds O1–H···S1 i C2–H···O1 to
form chains along the b axis due to double screw
molecular axis (Fig. 3, Table. 5). Owing to the
symmetry center, the chains are linked to each other
through hydrogen bonds N2–H···S1. Molecules H2L5
and H2L6 in crystal form centrosymmetric dimers
through hydrogen bonds N2–H···S1, N2–H···O1, and
O1–H···S1 (Figs. 4, 5; Table 5). The dimers interact
with each other mainly through van der Waals forces.
In keeping with the criterion proposed in [16]
(CgI···CgJ < 6.0 Å, β < 60.0°, where β is the angle
formed by the CgICgJ vector and normal to the
aromatic ring CgI), the crystal structure of thioamides
H2L4–H2L6 is also characterized by π–π stacking
between the benzene rings (C6–C11) related to each
other through the symmetry center in H2L4 and H2L5 or
through the double screw axis in H2L6. The distances
between the centroids of these fragments are 5.334,
5.613, and 4.46 Å, and the angles β are 53.5°, 57.0°,
and 12.2°, respectively. Apart from the above π–π
interactions, ligand H2L5 features Y–X···Cg (π-ring)
interaction (X···Cg < 4.0 Å, γ < 30.0°, where γ is the
angle between the XCg vector and normal to the
aromatic ring), and X–H···Cg (π-ring) interaction
(H···Cg < 3.0 Å, γ < 30.0°, where γ is the angle
between the HCg vector and normal to the aromatic
ring [16, 17]) is observed in the crystal structure of
H2L6. For the C1–S1···Cg (C6–C11) interaction (–x, –y,
1 – z), the distance between the S1 atom and centroid
of the benzene ring is 3.489 Å, and the angle γ is 2.7°.
The C9–H···Cg (C6–C11) (–x, 0.5 + y, 0.5 – z)
interaction in H2L6 is characterized by H···Cg 2.83 Å
and γ 7.6°.
R1
R3
OH
N NH
R2
NH
S
H2L1−6
R1 = R2 =H, R3 = Br (H2L1); R1 = R3 = Br, R2 = H (H2L2);
R1 = OH, R2 = R3 = H (H2L3); R1 = R3 = H, R2 = OH (H2L4);
R1 = NO2, R2 = R3 = H (H2L5); R1 = OCH3, R2 = R3 =
H (H2L6).
Figures 1 and 2 show the structures of hydrazine-
carbothioamides H2L4–H2L6 in crystal according to the
X-ray diffraction data (arbitrary atom numbering).
Unlike previously described thiosemicarbazides and
thiosemicarbazones [12–15], the N1–C1 bond has Z
configuration. However, the N3=C5 bond has E
configuration, which is consistent with published data.
The C1N1N2N3S1C5 fragment (A) in thioamides H2L4–
H2L6 is almost planar; the maximum deviations of
atoms from the corresponding mean-square planes are
0.053, 0.07, and 0.062 Å, respectively. On the other
hand, the entire molecules H2L4–H2L6 are non-planar.
The mean-square planes of the benzene rings (C6–C11)
are turned through angles of 17.3°, 11.2°, and 10.7°
with respect to the A planes, and the torsion angles
C1N1C2C3 and C1C2C3C4 are 92.2, –134.7°, 109.6,
2.9°, and 142.1, 128.8°, respectively. The S1–C1 and
N1–C1 distances in H2L6 are shorter than those in H2L4
and H2L5 by 0.021, 0.026 Å and 0.024, 0.035 Å,
respectively (Table 4).
Table 1. Yields, melting points, and elemental analyses of substituted 2-(2-hydroxybenzylidene)-N-(prop-2-en-1-yl)hydra-
zinecarbothioamides H2L1–H2L6 a
Found, %
H
Calculated, %
H N
Thioamide
Yield, %
mp, °C
Formula
C
N
C
H2L1
H2L2
H2L3
H2L4
H2L5
H2L6
87
90
75
78
85
92
172–174
210–212
198–200
186–188
151–153
225–227
41.82 3.73
33.72 2.65
52.76 5.35
52.36 5.18
47.00 4.02
54.14 5.54
13.21
10.93
16.44
16.56
20.24
15.77
C11H12BrN3OS
C11H11Br2N3OS
C11H13N3O2S
C11H13N3O2S
C11H12N4O3S
C12H15N3O2S
42.05 3.85 13.37
33.61 2.82 10.69
52.57 5.21 16.72
52.57 5.21 16.72
47.13 4.32 19.99
54.32 5.70 15.84
a Some characteristics of thioamides H2L1, H2L4, and H2L6 were given in [9–11].
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019

SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF COPPER AND COBALT
955
Table 2. 1H and 13C NMR spectra (acetone-d6) of thioamides H2L1–H2L6 a
Thioamide
H2L1
δ, ppm
δC, ppm
10.56 br.s ( 1H, OH), 9.41 br.s (1H, NH), 8.47 br.s (1H, NH),
177.42 (C=S); 155.74, 133.52, 129.87,
8.45 s (1H, CH=N), 7.90 d (1H, Harom, J = 2.5 Hz), 7.38 m (1H, 122.24, 118.30, 111.44 (Carom); 139.48
Harom), 6.91 d (1H, Harom, J = 8.8 Hz), 5.97 m (1H, CH=CH2),
(CH=N), 134.73 (CH=CH2), 115.24 (CH2=),
5.15 m (2H, CH2=), 4.35 m (2H, CH2N)
46.37 (CH2N)
H2L2
H2L3
H2L4
H2L5
10.71 br.s (1H, OH), 9.88 br.s (1H, NH), 8.45 br.s (1H, NH),
177.43 (C=S); 152.49, 135.66, 131.14,
122.35, 111.49, 111.35 (Carom); 141.38
8.40 s (1H, CH=N), 7.77 d (1H, Harom, J = 2.4 Hz), 7.73 d (1H,
Harom, J = 2.4 Hz), 5.98 m (1H, CH=CH2), 5.16 m (2H, CH2=), (CH=N), 134.51 (CH=CH2), 115.41 (CH2=),
4.37 m (2H, CH2N)
46.58 (CH2N)
10.48 br.s (1H, OH), 8.73 br.s (1H, OH), 8.47 s (1H, CH=N),
8.27 br.s (2H, NH), 7.15 d (1H, Harom, J = 7.9 Hz), 6.91 d (1H,
Harom, J = 7.9 Hz), 6.76 t (1H, Harom, J = 7.9 Hz), 5.99 m (1H,
CH=CH2), 5.17 m (2H, CH2=), 4.36 m (2H, CH2N)
178.32 (C=S); 145.31, 145.06, 142.92,
119.66, 119.61, 116.79 (Carom); 142.96
(CH=N), 134.75 (CH=CH2), 115.26 (CH2=),
46.40 (CH2N)
10.29 br.s (1H, OH), 9.44 br.s (1H, OH), 8.92 br.s (1H, NH),
177.85 (C=S); 160.84, 158.84, 131.50,
111.22, 108.10, 102.71 (Carom); 145.01
8.35 s (1H, CH=N), 8.11 br.s (1H, NH), 7.38 d (1H, Harom, J =
8.5 Hz), 6.45 d (1H, Harom, J = 8.5 Hz), 6.41 s (1H, Harom), 5.98 (CH=N), 134.86 (CH=CH2), 115.15 (CH2=),
m (1H, CH=CH2), 5.15 m (2H, CH2=), 4.35 m (2H, CH2N)
46.41 (CH2N)
10.80 br.s (1H, OH), 10.69 br.s (1H, NH), 8.52 br.s (1H, NH),
178.56 (C=S); 161.61, 135.83, 133.55,
8.58 s (1H, CH=N); 8.37 m, 8.16 m, 7.13 m (3H, Harom); 5.98 m 126.21, 119.85, 116.74 (Carom); 152.76
(1H, CH=CH2), 5.16 m (2H, CH2=), 4.36 m (2H, CH2N)
(CH=N), 134.63 (CH=CH2), 115.33 (CH2=),
46.31 (CH2N)
H2L6 b 11.52 br.s (1H, OH), 9.23 br.s (1H, NH), 8.62 br.s (1H, NH),
8.42 s (1H, CH=N), 7.58 d (1H, Harom, J = 7.9 Hz), 6.97 d (1H,
Harom, J = 7.9 Hz), 6.79 t (1H, Harom, J = 7.9 Hz), 5.92 m (1H,
177.46 (C=S); 148.39, 139.62, 121.30,
119.40, 118.57, 113.23 (Carom); 146.42
(CH=N), 135.66 (CH=CH2), 115.94 (CH2=),
CH=CH2), 5.13 m (2H, CH2=), 4.22 m (2H, CH2N), 3.82 s (3H, 56.35 (CH3), 46.22 (CH2N)
CH3)
Some characteristics of thioamides H2L1, H2L4, and H2L6 were given in [9–11].
a
b
In DMSO-d6.
By mixing hot (50–55°C) ethanolic solutions of
compositions (Table 6) corresponded to the formulas
copper and cobalt chlorides or nitrates and thioamides
H2L1–H2L6 at a molar ratio of 1:1 or 1:2 and
subsequent heating for 50–60 min we obtained
coordination compounds 1–10 whose elemental
Cu(HL1–6)X·nH2O (1, 3–9) [X = Cl– (1, 5, 7, 8), NO3–
(3, 4, 6, 9); n = 0 (1, 5, 7, 8), 1 (3, 4, 6), 3 (9)],
Co(HL2)2NO3 (2), and Co(HL6)2Cl (10). Complexes
1–10 are insoluble in diethyl ether, poorly soluble in
Fig. 2. Structure of the molecule of 2-(2-hydroxy-3-methoxy-
benzyl-idene)-N-(prop-2-en-1-yl)hydrazinecarbothioamide
(H2L6) in crystal according to the X-ray diffraction data.
Fig. 1. Structure of the molecule of 2-(2,4-dihydroxybenzyl-
idene)-N-(prop-2-en-1-yl)hydrazinecarbothioamide (H2L4) in
crystal according to the X-ray diffraction data.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019

956
GULEA et al.
Table 3. Crystallographic data and parameters of X-ray diffraction experiments and structure refinement for compounds H2L4–
H2L6 and 9
Parameter
H2L4
C11H13N3O2.75
263.30
H2L5
H2L6
9
Formula
S
C11H12N4O3S
280.31
C12H15N3O2S
265.33
C12H20N4O8SCu
443.92
M
Crystal system
Monoclinic
Monoclinic
Monoclinic
Triclinic
Space group
Z
P21/c
4
P21/c
4
P21/c
4
P-1
4
a, Å
15.236(4)
4.5098(13)
20.553(5)
90
8.9728(5)
16.6764(7)
8.8395(5)
90
13.661(14)
5.978(4)
16.834(6)
90
6.8720(7)
14.0564(18)
18.901(2)
79.178(10)
89.523(9)
87.640(10)
1791.8(4)
1.646
b, Å
c, Å
α, deg
β, deg
γ, deg
V, Å 3
95.65(2)
90
104.396(6)
90
108.17(6)
90
1405.4(6)
1.244
1281.16(12)
1.453
1306.2(17)
1.349
d
calc, g/cm3
λ, Å
μ, cm–1
0.71073
0.232
0.71073
0.263
0.71073
0.246
0.71073
1.384
Temperature, K
Crystal dimensions, mm
293(2)
293(2)
293(2)
293(2)
0.80×0.05×0.02
25.05
0.20×0.18×0.30
25.04
0.40×0.03×0.01
28.96
0.50×0.27×0.04
25.05
θ
max, deg
h, k, l
–16 ≤ h ≤ 18
–3 ≤ k ≤ 5
–7 ≤ h ≤ 10
–17 ≤ k ≤ 19
–9 ≤ l ≤ 10
–18 ≤ h ≤ 18
–7 ≤ k ≤ 7
–8 ≤ h ≤ 8
–16 ≤ k ≤ 15
–22 ≤ l ≤ 14
–24 ≤ l ≤ 15
–22 ≤ l ≤ 22
Number of independent
reflections (Rint)
4482/ 2409
2785/1926
4767/4915
9835/6197
Number of reflections with
I > 2σ(I)
0.0699
0.0186
0.00
0.0507
Number of refined parameters
R1/wR2 (independent reflections)
R1/wR2 (reflections with I > 2σ(I)]
Goodness of fit S
156
172
150
485
0.0739/0.1345
0.1822/0.1703
0.883
0.0425/0.0851
0.0657/0.0960
1.004
0.0736/0.1064
0.2974/0.2091
0.828
0.0866/0.1625
0.1751/0.2013
0.962
Δρmax/Δρmin, ē/A3
0.291/–0.224
0.144/–0.201
0.310/–0.304
1.776/–0.473
water, better soluble in alcohols, and readily soluble in
DMF, DMSO, and acetonitrile. Their yields and some
physicochemical characteristics are given in Table 6.
obtained by recrystallization from ethanol (Table 3).
A unit cell of 9 contains two nonequivalent
[Cu(HL6)H2O]+ cations, two nitrate ions, and four
water molecules. The copper atom in each cation
coordinates singly deprotonated H2L6 molecule acting
as a tridentate ligand to form two chelate rings, as well
The structure of copper complex 9 was determined
by X-ray analysis of its single crystal which was
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019

SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF COPPER AND COBALT
957
Table 4. Selected bond lengths and bond angles in
as a water molecule (Fig. 6). The lengths of the
coordination bonds are as follows: Cu1–O1 1.9152(2)
[1.9112(2)], Cu1–S1 2.2636(3) [2.2591(3)], Cu1–N3
1.9270(2) [1.9331(2)], and Cu1–OW 1.9430(2) Å
[1.9605(3) Å] (Table 7). The six- and five-membered
chelate rings lie virtually in one plane; the
corresponding dihedral angles are 3.83 and 3.79°.
Molecules 9 in crystal are linked to each other through
the nitrate anions and water molecules to form a three-
dimensional intermolecular hydrogen bond system
(Fig. 7). In keeping with the above noted criterion
(CgI···CgJ < 6.0 Å, β < 60.0°, where β is the angle
between the CgICgJ vector and normal to the aromatic
ring CgI) [16], there exists π–π-stacking interaction
between the Cu2O1AC11AC6AC5AN3A metallacycles
related through a symmetry center. The distance
Cg1···Cg1 (1 – x, 1 – y, –z) between the centroids of
these fragments is 3.513 Å, and the angle β is equal to
13.8°. Apart from the π–π stacking, metal–Cg (π-ring)
interaction (Cu···Cg < 4.0 Å) is observed in the crystal
structure of complex 9. The Cu···Cg distances for the
Cu1···Cg (C6C7C8C9C10C11) (–x, 1 – y, 1 – z) and
Cu2···Cg (C6AC7AC8AC9AC10AC11A) (1 – x, 1 – y, –z)
interactions are 3.517 and 3.487 Å, respectively.
molecules H2L4–H2L6 in crystal
d, Å
H2L5
Bond
H2L4
H2L6
S1–C1
C5–N3
C5–C6
N3–N2
N1–C1
N1–C2
N2–C1
C2–C3
1.687(5)
1.283(5)
1.460(6)
1.397(5)
1.330(5)
1.437(5)
1.355(5)
1.463(7)
1.683(3)
1.276(3)
1.461(3)
1.374(3)
1.325(3)
1.455(3)
1.354(3)
1.662(7)
1.264(7)
1.448(8)
1.399(6)
1.295(8)
1.476(9)
1.356(8)
1.478(4) 1.462(10)
Angle
ω, deg
N3C5C6
C5N3N2
C1N1C2
C1N2N3
N1C1N2
N1C1S1
N2C1S1
C9C8C7
N1C2C3
C4C3C2
122.0(4)
115.9(4)
125.3(4)
120.1(4)
117.0(4)
121.4(2)
115.4(2)
123.9(2)
121.1(2)
115.7(2)
121.0(6)
115.9(5)
124.2(7)
122.4(5)
115.5(6)
Complexes 1–10 were characterized by elemental
123.9(4) 125.43(19) 125.0(6)
119.1(4) 118.87(18) 119.5(5)
analyses, molar electrical conductivities, magneto-
119.3(5)
115.6(5)
127.2(5)
119.6(2)
112.3(2)
119.8(6)
112.3(7)
126.0(3) 125.7(10)
chemical data, and IR spectra (Table 6). According to
the molar conductivity measurements, compounds 1, 5,
7, and 8 in DMF solution are nonelectrolytes (æ = 2–
4 Ω–1 cm2 mol–1), and complexes 2–4, 6, 9, and 10 are
binary electrolytes (æ = 54–70 Ω–1 cm2 mol–1). Cobalt
complexes 2 and 10 are diamagnetic at room
Fig. 4. H-Bonded chains in the crystal structure of 2-(2-hyd-
roxy-3-nitrobenzylidene)-N-(prop-2-en-1-yl)hydrazinecarbo-
thioamide (H2L5).
Fig. 3. A fragment of crystal packing of 2-(2,4-dihydroxy-
benzylidene)-N-(prop-2-en-1-yl)hydrazinecarbothioamide
(H2L4).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019

958
GULEA et al.
Table 5. Geometric parameters of hydrogen bonds in the crystal structures of compounds H2L4–H2L6 and 9
Distance, Å
Bond D–H···A
∠DHA, deg
Coordinates of A
D–H
H···A
D···A
H2L4
O1–H···N3
N2···H···S1
N1···H···N3
C2···H···S1
0.82
0.86
0.86
0.97
1.95
2.60
2.26
2.61
2.672
3.448
2.659
3.109
147
171
108
112
x, y, z
1–x, 2–y, 1–z
x, y, z
x, y, z
H2L5
O1···H···O3
O1···H···S1
N1···H···N3
N2···H···S1
C2···H···O1
0.82
0.82
0.86
0.86
0.97
1.90
2.82
2.25
2.72
2.46
2.594
3.367
2.638
3.479
3.349
142
126
107
148
153
x, y, z
–x, –1/2+y, 1/2–z
x, y, z
–x, –y, –z
–x, 1/2+y, 1/2–z
H2L6
N2···H···O1
O1···H···O2
O1···H···S1
N1···H···N3
C5···H···O1
C2···H···S1
0.86
0.82
0.82
0.86
0.93
0.97
2.19
2.18
2.52
2.26
2.43
2.64
2.978
2.637
3.184
2.664
2.754
3.081
151
116
139
109
100
108
–x, 2–y, –z
x, y, z
–x, 2–y, –z
x, y, z
x, y, z
x, y, z
9
N1···H···O2N2
N1A···H···O2N1
N2···H···O1N2
N2A···H···O1N1
O1W···H···O4W
O1W···H···O4W
O1WA···H···O2W
O1WA···H···O5W
O2W···H···O1N1
O2W···H···O1A
O2W···H···O2A
O3W···H···O5W
O4W···H···O1A
O4W···H···O2A
O5W···H···O1N2
O5W···H···O1
C2A···H···S1A
C2···H···S1
0.86
0.86
0.86
0.86
0.85
0.85
0.87
0.87
0.85
0.85
0.85
0.85
0.85
0.85
0.85
0.85
0.97
0.97
2.04
2.02
1.93
1.96
2.21
2.41
1.88
190
2.34
2.22
2.27
2.51
2.23
2.48
206
2.897
2.870
2.783
2.815
2.685
2.685
2.743
2.655
3.090
2.926
3.022
3.343
2.977
3.233
2.893
3.005
3.089
3.112
174
169
169
170
115
100
171
144
148
141
147
167
146
147
167
163
110
113
x, y, z
1–x, 1–y, –z
x, y, z
1–x, 1–y, –z
–x, 1–y, 1–z
–x, 1–y, 1–z
x, y, z
x, y, z
x, y, z
x, y, z
x, y, z
–1+x, y, z
x, y, z
x, y, z
x, y, z
1–x, 1–y, 1–z
x, y, z
2.18
2.62
2.60
x, y, z
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019

SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF COPPER AND COBALT
Table 6. Selected bond lengths and bond angles in molecule 9
959
Bond
Cu1–O1
d, Å
1.915(5)
Bond
S1–C1
d, Å
Angle
O1Cu1N3
O1Cu1O1W
N3Cu1O1W
O1Cu1S1
ω, deg
93.6(3)
86.6(2)
175.4(3)
173.98(19) C1N1C2
86.7(2)
C1N2N3
93.54(17) N1C1N2
Angle
O1WACu2S1A
N3C5C6
ω, deg
1.705(8)
1.277(9)
1.458(10)
1.393(8)
1.325(9)
1.472(10)
1.325(9)
1.389(14)
92.68(18)
126.1(8)
116.5(6)
125.6(8)
118.7(7)
116.1(8)
122.6(7)
121.3(6)
120.7(8)
113.2(9)
125.7(13)
Cu1–N3
1.927(6)
2.264(2)
1.943(5)
1.911(5)
1.933(6)
2.259(2)
1.961(6)
C5–N3
C5–C6
N3–N2
N1–C1
N1–C2
N2–C1
C2–C3
Cu1–S1
C5N3N2
Cu1–O1W
Cu2–O1A
Cu2–N3A
Cu2–S1A
Cu2–O1WA
N3Cu1S1
O1WCu1S1
O1ACu2N3A
O1ACu2O1WA
N3ACu2O1WA
O1ACu2S1A
N3ACu2S1A
93.8(2)
86.8(2)
N1C1S1
N2C1S1
C9C8C7
176.8(3)
174.74(17) N1C2C3
86.99(19) C4C3C2
temperature (294 K), and the central metal atom
therein has a degree of oxidation of 3+ and a pseudo-
octahedral ligand environment (Table 6). The effective
magnetic moments of the copper complexes correspond
to spin values for one unpaired electron. These findings
suggest monomeric structure of the complexes.
The mode of ligand coordination to the central
metal ion in complexes 1–10 was determined by
comparing their IR spectra with the spectra of initial
thioamides H2L1–H2L6 with account taken of the X-ray
diffraction data for compound 9. The IR spectra of
initial ligands H2L1–H2L6 contained absorption bands
Fig. 5. A fragment of crystal packing of 2-(2-hydroxy-3-
methoxybenzylidene)-N-(prop-2-en-1-yl)hydrazinecarbothio-
amide (H2L6).
Fig. 6. Structure of the molecule of complex 9 in crystal
according to the X-ray diffraction data.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019

960
GULEA et al.
Table 7. Yields, effective magnetic moments, electrical conductivities, and elemental analyses of copper and cobalt
coordination compounds 1–10
Found, %
Calculated, %
a
Yield, μef,
æ,a
Formula
%
B.M.
Ω–1 cm2 mol–1
Cl
M
N
S
Cl
M
N
S
1
2
3
4
5
6
7
8
9
80
75
82
67
78
69
77
73
69
1.75
4
70
57
65
4
8.47 15.19 9.90 7.48 C11H11BrClCuN3OS
8.60 15.42 10.19 7.78
б
–
–
–
6.25 10.57 6.94 С22H20Br4CoN7O5S2
11.60 10.17 5.70 C11H12Br2CuN4O5S
15.87 13.98 7.91 C11H14CuN4O6S
–
–
–
6.51 10.83 7.09
11.86 10.46 5.99
16.13 14.22 8.14
1.82
1.81
1.92
1.83
1.79
1.78
9.88 17.93 11.94 8.89 C11H12ClCuN3O2S
15.87 14.01 7.99 C11H14CuN4O6S
10.15 18.19 12.03 9.18
16.13 14.22 8.14
67
2
–
–
9.14 16.59 14.60 8.31 C11H11ClCuN4O3S
9.55 17.32 11.39 8.74 C12H14ClCuN3O2S
9.37 16.80 14.81 8.48
9.76 17.49 11.57 8.83
3
1.87
b
61
–
14.17 12.47 6.98 C12H20CuN4O6S
9.17 13.32 10.07 C24H28ClCoN6O4S2
–
14.31 12.62 7.22
10
72
54
5.47
5.69 9.46 13.49 10.29
a
At 294 K.
b
Diamagnetic.
at 3450–3100, 1660–1580, and 1400–1100 cm–1. The
IR spectra of all complexes lacked absorption in the
region 3450–3100 cm–1, which is typical of phenolic
O–H stretchings of the free ligands. This indicates
deprotonation of the OH group upon coordination. The
same conclusion follows from the 40–50 cm–1 low-
frequency shift of the ν(C–O) band observed at 1260–
1190 cm–1 in the spectra of H2L1–H2L6. In addition, the
complexation is accompanied by low-frequency shift
of the ν(C=N) band (by 20–30 cm–1) and high-
frequency shift of the ν(C=C) band (by 25–40 cm–1).
These data suggest coordination of deprotonated
ligands HL1–HL6 to the metal ion through phenolic
oxygen atom, nitrogen atom of the azomethine group,
and thionic sulfur atom. This coordination mode is also
supported by the appearance in the IR spectra of all
Fig. 7. A fragment of crystal packing of complex 9.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019

SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF COPPER AND COBALT
961
Table 8. Minimum inhibitory concentrations (MIC, μg/mL) and minimum bactericidal concentrations (MBC, μg/mL) of
ligands H2L1–H2L6 and coordination compounds 1–10
Staphylococcus
Bacillus cereus
Escherichia coli Salmonella abony Candida albicans
aureus ATCC 25923
GISK 8035
ATCC 25922 GISK 03/03 ATCC 90028
Compound
MIC
MBC
˃1000
60
MIC
˃1000
1.5
1.5
1.5
˃1000
1.5
30
MBC
MIC MBC
MIC
MBC
˃1000
˃1000
˃1000
>1000
˃1000
>1000
500
MIC
MBC
Initial saltsa
H2L1
˃1000
˃1000 ˃1000 ˃1000 ˃1000
˃1000
˃1000
15
3
15
3
˃1000 ˃1000 ˃1000
˃1000 ˃1000 ˃1000
>1000 >1000 >1000
3
3
3
30
3
1
H2L2
15
1.5
3
3
3
1.5
1.5
1.5
30
7
2
7
˃1000 ˃1000 ˃1000 ˃1000
3
3
H2L3
1.5
15
7
1.5
30
3
60
15
60
15
7
>1000 >1000 >1000
3
120
30
250
60
250
60
120
7
4
H2L4
15
7
120
3
15
30
˃1000 ˃1000 ˃1000
˃1000
500
3
15
7
5
7
15
7
500
12
500
250
500
120
250
12
3
6
H2L5
3
7
3
60
3
7
60
15
˃1000
7
250
120
˃1000
60
15
120
15
120
15
120
120
500
3
30
15
˃1000
60
7
7
H2L6
1.5
˃1000
7
120
3
˃1000 ˃1000 ˃1000 ˃1000
˃1000
60
˃1000
15
7
8
9
30
30
120
500
15
7
7
120
120
500
500
500
a
CuCl2·2H2O; Cu(NO3)2·3H2O; CoCl2·6H2O; Co(NO3)2·6H2O.
complexes of new bands in the region 530–405 cm–1,
in particular ν(M–N) bands at 525–505 and 430–
405 cm–1 and ν(M–S) bands at 450–440 cm–1. The other
functional groups of thioamides H2L1–H2L6 are not
involved in the complexation since the corresponding
characteristic bands of the complexes are observed in
the same regions as in the spectra of the initial
thiosemicarbazones. On the basis of the obtained data,
the synthesized complexes were assigned structures A
(1, 5, 7, 8), B (3, 4, 6, 9), and C (2, 10) (Scheme 2).
aureus, Bacillus cereus) and gram-negative bacteria
(Escherichia coli, Salmonella abony) and yeast-like
fungi (Candida albicans). The results are summarized
in Table 8. It is seen that all initial copper and cobalt
salts showed no activity against the above listed
microorganisms and that ligands H2L1, H2L2, and H2L4
were active only against gram-positive bacteria and
fungi and low active against gram-negative bacteria.
Complexes 1–10 showed selective bacteriostatic and
and bactericidal activities against S. aureus and C.
albicans in the concentration range 1.5–120 μg/mL and
against E. coli in the concentration range 15–500 μg/mL.
The minimum inhibitory concentration (MIC) and
minimum bactericidal concentration (MBC) of the
complexes depended on the nature of the central metal
ion and substituents in thiosemicarbazones H2L1–H2L6.
Complex 3 turned out to be the most active against
gram-positive bacteria, and complex 8, against gram-
negative bacteria. Furthermore, similarity of the MIC
As shown in [7, 8] complexes of biometals with 2-
(2-hydroxybenzylidene)-N-(prop-2-en-1-yl)hydrazine-
carbothioamide selectively inhibit the growth and
proliferation of some cancer cell lines and some
microorganisms. In this work we tested initial metal
salts and ligands and coordination compounds 1–10 for
in vitro antimicrobial and antifungal activities against
standard strains of gram-positive (Staphylococcus
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019

962
GULEA et al.
Scheme 2.
R2
R1
R2
R1
R3
O
Cl
S
R3
O
OH2
S
.
NO3
nH2O
Cu
Cu
N
N
N
H
N
H
N
H
N
H
А
B
R2
R3
R1
NH
O
Co
N NH
HN
S
X
HN N
S
O
R1
R3
R2
C
Table 9. Antiproliferation activity of ligands H2L1–H2L6 and
coordination compounds 1–10 against cancer (HL-60) and
healthy cells (MDCK)
and MBC values for many compounds indicated
bactericidal character of their action.
IC50 , μM
As reported previously for 3d metal complexes with
2-(2-hydroxybenzylidene)-N-(prop-2-en-1-yl)hydrazine-
carbothioamide, complexes 1–10 at a concentration of
0.1–10 μM showed antiproliferative activity against
HL-60 human myeloid leukemia cancer cell line and
model MDCK (Madin–Darby canine kidney) normal
cell line (Table 9). The activity of both ligands and
complexes derived therefrom strongly depended on the
substituent in the salicylidene fragment. For example,
introduction of two bromine atoms into the benzene
ring (H2L2) led to complete loss of activity. The
highest activity was observed for the ligands
containing a bromine atom in the 5-position and a
methoxy group in the 3-position, which inhibited
cancer cell proliferation by more than 50% at a
concentration of 10 μM. Copper complexes with these
ligands showed the highest activity in the examined
series. The activity of the copper complexes was
higher than that of the corresponding ligand, whereas
the cobalt complexes were low active. The highest
Compound
HL-60
8.0
MDCK
˃100
18
H2L1
1
1.8
H2L2
2
>10
>10
3.8
>10
3.8
>10
>10
>10
0.6
˃ 100
>100
92
>100
4.8
3
H2L3
4
H2L4
6
˃100
50
H2L5
7
>100
˃100
˃100
˃100
˃100
H2L6
8
7.2
0.4
>10
10
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019

SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF COPPER AND COBALT
963
cytostatic activity was found for complex 8 which
completely inhibited proliferation of cancer cells at
concentrations of 10 and 1 μM; however, it showed
almost no activity at lower concentrations.
Bruker ALPHA spectrometer. The effective magnetic
moments were measured by the Gouy method. The
molar magnetic susceptibilities were calculated with a
correction for diamagnetism on the basis of theoretical
magnetic susceptibilities of organic compounds.
The selectivity of action of thioamides H2L1–H2L6
and complexes 1–10 was assayed by estimating their
antiproliferative activity healthy MDCK cells. Table 9
contains IC50 values characterizing the cytostatic effect
of these compounds with respect to HL-60 and MDCK
cells. It is seen that in most cases the antiproliferative
activity against healthy cells is lower by a factor of 10
and more than their effect on HL-60 cancer cells. Thus,
the synthesized compounds selectively inhibit
proliferation of HL-60 cancer cells without appreciable
negative effect on healthy cells.
The antimicrobial, antifungal, and anticancer activities
were assessed according to standard procedures [22].
2-(5-Bromo-2-hydroxybenzylidene)-N-(prop-2-en-
1-yl)hydrazinecarbothioamide (H2L1) was synthesized
as described in [9].
2-(3,5-Dibromo-2-hydroxybenzylidene)-N-(prop-
2-en-1-yl)hydrazinecarbothioamide (H2L2). A solu-
tion of 10 mmol of N-(prop-2-en-1-yl)hydrazine-
carbothioamide in 35 mL of ethanol was added to a hot
(55–60°C) solution of 10 mmol of 3,5-dibromo-2-
hydroxybenzaldehyde in 15 mL of ethanol. After
cooling, light yellow solid precipitated and was filtered
off on a glass filter, washed with a small amount of
ethanol, and dried in air.
Ligands H2L3 i H2L5 were synthesized in a similar
way from N-(prop-2-en-1-yl)hydrazinecarbothioamide
and 2,3-dihydroxy- or 2-hydroxy-3-nitrobenzaldehyde,
respectively, at a molar ratio of 1:1. Compounds H2L4
and H2L6 were prepared according to the procedures
described in [10, 11]. Some characteristics of
thioamides H2L1–H2L6 are given in Tables 1 and 2.
Thioamides H2L1–H2L6 are readily soluble in DMF
and DMSO, as well as in alcohols on heating.
Our results indicate promise of further search for
antimicrobial, antifungal, and anticancer agents among
coordination compounds of biometals with thioamide-
based ligands.
EXPERIMENTAL
The X-ray diffraction data for compounds H2L4–
H2L6 and 9 were obtained with an Oxford Diffraction
Xcalibur diffractometer [18]. The structures were
solved by the direct method and were refined by the
least-squares method in anisotropic approximation for
non-hydrogen atoms using SHELX-97 software [19];
the crystal structure of H2L4 was refined as racemic
twin. Hydrogen atoms were placed in geometrically
calculated positions, and their temperature factors UH
were assumed to be higher by a factor of 1.2 than those
of the corresponding carbon and oxygen atoms. The
principal crystallographic data and parameters of X-ray
diffraction experiments and structure refinement are
given in Table 1, and selected interatomic distances
and bond angles are given in Table 2. The coordinates
of atoms in structures H2L4–H2L6 and 9 were deposited
to the Cambridge Crystallographic Data Centre
(CCDC entry nos. 929459–929461, 1872426). The
geometry calculations and were performed, and the
molecular structures were plotted, using PLATON
[16]; only those hydrogen atoms which are involved in
hydrogen bonds are shown in the crystal packing
images. The structures were analyzed using the CCDC
data (versiin 5.39) [20, 21].
[2-(5-Bromo-2-hydroxybenzylidene)-N-(prop-2-
en-1-yl)hydrazinecarbothioamido]chlorocopper(II)
(1). A solution of 10 mmol of ligand H2L1 in 50 mL of
ethanol was heated to 50–55°C, and a solution of
10 mmol of copper(II) chloride dihydrate in 20 mL of
ethanol was added with continuous stirring. The
mixture was refluxed for 50–60 min. After cooling to
room temperature, the precipitate was filtered on a
glass filter, washed with small amounts of alcohol and
diethyl ether, and dried in air until constant weight.
Complexes 2–10 were synthesized in a similar way
from thioamides H2L2–H2L6 and the corresponding
cobalt(II) and copper(II) salts taken at a ratio of 2:1 or 1:1.
ACKNOWLEDGMENTS
The electrical conductivity of solutions of com-
plexes 1–10 in DMF with a concentration of 0.001 M
were measured at 20°C with an R-38 rheochord bridge.
The IR spectra (4000–400 cm–1) were recorded on an
The authors thank Prof. D. Poirier (Laval
University, Quebec, Canada) and O.S. Garbuz for their
help in performing biological testing.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019

964
GULEA et al.
11. Bal-Demirci, T., Akkurt, M., Yalcm, S.P., and
CONFLICT OF INTERESTS
Buyukgungor, O., Transition Met. Chem., 2010, vol. 35,
No conflict of interest was declared by the authors.
REFERENCES
p. 95. doi 10.1007/s11243-009-9300-2
12. Duan, C.-Y., Tian, Y.-P., Zhao, C.-Y., You, X.-Z., and
Mak, T.C.W., Polyhedron, 1997, vol. 16, p. 2857. doi
10.1016/S0277-5387(97)00013-2
13. Vrdoljak, V., Cindric, M., Milic, D., Dubravka, M.C.,
Predrag, N., and Kamenar, B., Polyhedron, 2005,
vol. 24, p. 1717. doi 10.1016/j.poly.2005.05.002
14. Bourosh, P.N., Revenko, M.D., Gdaniec, M., Stratulat, E.F.,
and Simonov, Yu.A., J. Struct. Chem., 2009, vol. 50,
no. 3, p. 510. doi 10.1007/s10947-009-0078–z
15. Chumakov, Yu.M., Biyushkin, V.N., and Bodyu, V.G.,
J. Struct. Chem., 1985, vol. 26, no. 6, p. 929. doi
10.1007/BF00748365
1. Bal-Demirci, T., Polyhedron, 2008, vol. 27, p. 440. doi
10.1016/j.poly.2007.10.001
2. Orysyk, S.I., Bon, V.V., Zholob, O.O., Pekhnyo, V.I.,
Orysyk, V.V., Zborovskii, Yu.L., and Vovk, M.V.,
Polyhedron, 2013, vol. 51, p. 211. doi 10.1016/
j.poly.2012.12.021
3. Bon, V.V., Orysyk, S.I., and Pekhnyo, V.I., Russ. J.
Coord. Chem., 2011, vol. 37, no. 2, p. 149. doi 10.1134/
s1070328411010027
4. Bon, V.V., Acta Crystallogr., Sect. C, 2010, vol. 66,
p. 300. doi 10.1107/S0108270110035754
16. Spek, A.L., J. Appl. Crystallogr., 2003, vol. 36, p. 7. doi
5. Orysyk, S.I., Bon, V.V., Obolentseva. O.O., Zborovskii, Yu.L.,
Orysyk, V.V., Pekhnyo, V.I., Staninets, V.I., and Vovk, M.V.,
Inorg. Chim. Acta, 2012, vol. 382, p. 127. doi 10.1016/
j.ica.2011.10.027
10.1107/S0021889802022112
17. Malone, J.F., Murray, C.M., Charlton, M.H., Docherty, R.,
and Lavery, A.J., J. Chem. Soc., Faraday Trans., 1997,
vol. 93, p. 3429. doi 10.1039/A700669A
6. Orysyk, S.I., Repich, G.G., Bon, V.V., Dyakonenko, V.V.,
Orysyk, V.V., Zborovskii, Yu.I., Shishkin, O.V.,
Pekhnyo, V.I., and Vovk, M.V., Inorg. Chim. Acta, 2014,
vol. 423, p. 496. doi 10.1016/j.ica.2014.08.056
18. CrysAlisPro, Version 1.171.33.52 (release 06-11-2009
CrysAlis171.NET). Oxford Diffraction.
19. Sheldrick, G.M., Acta Crystallogr., Sect. A, 2008,
vol. 64, p. 112. doi 10.1107/S0108767307043930
7. Kalinowski, D.S., Quach, P., and Richardson, D.R.,
Future Med. Chem., 2009, vol. 1, no. 6, p. 1143. doi
10.4155/FMC.09.80
20. Allen, F.H., Acta Crystallogr., Sect. B, 2002, vol. 58,
p. 380. doi 10.1107/S0108768102003890
21. Addison, A.W., Rao, T.N., Reedijk, J., and Verschoor, G.C.,
J. Chem. Soc., Dalton Trans., 1984, no. 7, p. 1349. doi
10.1039/DT9840001349
22. Gulea, A., Poirier, D., Roy, J., Stavila, V., Bulimestru, I.,
Tapcov, V., Birca, M., and Popovschi, L., J. Enzyme
Inhib. Med. Chem., 2008, vol. 23, no. 6, p. 806. doi
101080/147563607017443002
8. Lovejoy, D.B. and Richardson, D.R., Blood, 2002,
vol. 100, p. 666. doi 10.1182/blood.V100.2.666
9. Ülküseven, B., Bal-Demirci, T., Akkurt, M., Yalçın, Ş.P.,
and Büyükgüngör, O., Polyhedron, 2008, vol. 27,
no. 18, p. 3646. doi 10.1016/j.poly.2008.08.024
10. Scott, A.W. and McCall, M.A., J. Am. Chem. Soc., 1945,
vol. 67, no. 10, p. 1767. doi 10.1021/ja01226a043
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019