Synthesis of copper(II) and zinc(II) complexes with chalcone–thiosemicarbazone hybrid ligands: X-ray crystallography, spectroscopy and yeast activity

Article abstract of DOI:10.1007/s11243-018-0262-0

Four chalcone–thiosemicarbazones (C-TSCs) of the type 2-((E)-3-(4-R-phenyl)-1-phenylallylidene)-N-phenylhydrazinecarbothioamide, where R = Cl (HL1), NO₂ (HL2), CH₃ (HL3) or CN (HL4), were prepared in good yields from the reaction of the respective chalcone with 4-phenyl-3-thiosemicarbazide and HCl in EtOH. Reaction of HL with CuCl₂·2H₂O or ZnCl₂ in the presence of Et₃N afforded the complexes [M(L)₂], M = Cu(II) or Zn(II). X-ray diffraction analysis revealed that the ligands coordinate in their deprotonated form, in a bidentate fashion through the iminic nitrogen and sulfur atoms. Yeast activities of the compounds were tested, where the ligand HL4 was the most damaging derivative, exhibiting cell viability at about 50%. On the other hand, lipid peroxidation assays revealed that the ligand HL1 was able to better induce membrane damage compared to the other compounds. It has been found that coordination with Cu(II) and Zn(II) did not increase the biological activities of the C-TSCs.

Full text of DOI:10.1007/s11243-018-0262-0

Transition Metal Chemistry
https://doi.org/10.1007/s11243-018-0262-0
Synthesis of copper(II) and zinc(II) complexes
with chalcone–thiosemicarbazone hybrid ligands: X‑ray
crystallography, spectroscopy and yeast activity
Igor Resendes Barbosa1 · Isabela da Silva Pinheiro1 · Alan Douglas Lopes dos Santos1 ·
Aurea Echevarria1 · Carla Marins Goulart1 · Guilherme Pereira Guedes1,2 · Nathally Alves da Costa1 ·
Beatriz Martinez de Oliveira e Silva1 · Cristiano Jorge Riger1 · Amanda Porto Neves1
Received: 30 May 2018 / Accepted: 13 July 2018
© Springer Nature Switzerland AG 2018
Abstract
Four chalcone–thiosemicarbazones (C-TSCs) of the type 2-((E)-3-(4-R-phenyl)-1-phenylallylidene)-N-phenylhydra-
zinecarbothioamide, where R=Cl (HL1), NO2 (HL2), CH3 (HL3) or CN (HL4), were prepared in good yields from the
reaction of the respective chalcone with 4-phenyl-3-thiosemicarbazide and HCl in EtOH. Reaction of HL with CuCl2·2H2O
or ZnCl2 in the presence of Et3N aforded the complexes [M(L)2], M=Cu(II) or Zn(II). X-ray difraction analysis revealed
that the ligands coordinate in their deprotonated form, in a bidentate fashion through the iminic nitrogen and sulfur atoms.
Yeast activities of the compounds were tested, where the ligand HL4 was the most damaging derivative, exhibiting cell
viability at about 50%. On the other hand, lipid peroxidation assays revealed that the ligand HL1 was able to better induce
membrane damage compared to the other compounds. It has been found that coordination with Cu(II) and Zn(II) did not
increase the biological activities of the C-TSCs.
Introduction
breast cancer), T24 (bladder cancer) and L929 (mouse fbro-
blast), with IC50 values similar to or better than cisplatin, in
the range of 0.35–6.40 μM [4].
Thiosemicarbazones (TSCs) constitute a class of great inter-
est in medicinal chemistry due to their important pharmaco-
logical properties, such as antitumor, antimicrobial, antiviral
and antiparasitic activities [1]. They are also known for their
excellent ability to chelate a wide variety of transition met-
als, moreover their coordination is usually associated with
the improvement of their biological activities [2–4]. Zn(II)
complexes of pyridine-TSCs showed greater antiproliferative
activity compared to the free ligands, against MCF-7 (human
Also, the chalcones (1,3-diaryl-2-propen-1-ones) rep-
resent important natural compounds which have received,
along with their synthetic derivatives, considerable atten-
tion owing to their great range of bioactivities, such as anti-
infammatory, antimicrobial, antioxidant and anticancer
properties [5]. Because of the presence of chalcone deriva-
tives in diferent biologically active compounds, new com-
pounds bearing this moiety have been extensively exploited.
In this context, chalcone-derived thiosemicarbazones
have also been investigated as well as their metal com-
plexes [6–9]. They have demonstrated potential activities
like antimicrobial and cytotoxic. For instance, da Silva and
colleagues [8] obtained a series of C-TSCs and its Cu(II)
complexes whose cytotoxicity was tested against four tumor
cell lines. Overall, the cytotoxicity signifcantly increased
upon coordination, where the complexes exhibited very low
IC50 values, several of them at nanomolar concentrations.
A series of Zn(II) and Ga(III) complexes of C-TSCs
have shown antimicrobial activity, where the Zn(II) com-
pounds were more active than the ligands against one
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11243-018-0262-0) contains
supplementary material, which is available to authorized users.
* Amanda Porto Neves
amandanevess@gmail.com
1
Instituto de Química, Universidade Federal Rural do Rio
de Janeiro, BR-465, Km 7, Seropédica, RJ CEP 23890-000,
Brazil
2
Present Address: Instituto de Química, Universidade Federal
Fluminense, Campus do Valonguinho, Centro, Niterói,
RJ CEP 24020-150, Brazil
Vol.:(0123456789)
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Transition Metal Chemistry
bacteria strain. On the other hand, coordination to Ga(III)
resulted in activity improvement of all C-TSC ligands [9].
Thiosemicarbazones can exist as thione–thiol tautom-
ers and exhibit structural isomers (Z or E) in respect of
the iminic nitrogen [10, 11]. In the complexes, they can
bind to the metal either in neutral or in anionic form.
Versatility of the TSCs allows the incorporation of dif-
ferent substituents that can increase the coordination sites
of the derivatives, leading to complexes with different
geometries, where the TSCs can act mainly as bidentate,
tridentate or even tetradentate ligands [12]. It is known
that minor structural modifications can affect the chem-
istry of the complex, and such knowledge is of crucial
importance to understand their biological profiles. As
it is well documented that the biological properties of
C-TSC derivatives improve upon coordination to a transi-
tion metal, the present work aimed at synthesizing a new
series of Cu(II) and Zn(II) complexes containing C-TSC
ligands. In addition, toxicity of the compounds toward
the model organism Saccharomyces cerevisiae has also
been accessed.
Experimental
Materials and physical measurements
All commercial reagents and solvents were purchased from
Aldrich and used without any further purifcation. The sub-
stituted chalcones (Scheme 1) were prepared according to
the literature [17], and 4-phenyl-3-thiosemicarbazide was
synthesized as described [18]. Phosphate bufer (pH 6.0)
was prepared by dissolving 138 g of NaH2PO4.H2O and
142 g of Na2HPO4 in H2O to a fnal volume of 1 L. The
melting points were recorded on a PFM II capillary melt-
ing point apparatus. FTIR spectra were recorded on a FTIR
Bruker Vertex 70 Spectrophotometer, using KBr pellets and
scanned between 4000 and 600 cm−1. Microanalyses were
performed using a Perkin-Elmer CHN 2400 microanalyzer.
Electronic spectra were recorded on a UV-1800 Shimadzu
spectrophotometer with 1-cm quartz cells, using acetoni-
trile solutions of the compounds (1.0×10−5 mol L−1) within
the range 200–600 nm for the ligands and 200–900 nm for
1
the complexes. H (500 MHz) and 13C NMR (125 MHz)
Saccharomyces cerevisiae has become a useful and
convenient model for studying the cytotoxic potential of
synthetic drugs [13, 14]. Its resemblance to mammalian
cells in relation to organelles, macromolecules and cel-
lular structures has led to S. cerevisiae being one of the
most common eukaryotic model systems used in studies
related to cellular processes [15]. In addition, knowledge
of the yeast genome allows genetic manipulations to
obtain more sensitive strains to oxidative damage, such
as the mutant deficient in glutathione synthesis (Δgsh1),
which is a deficient strain in protection systems linked to
the cells redox homeostasis [16].
spectra were carried out with a Bruker Ultrashield Plus
in DMSO-d6 (Tedia Brazil) containing tetramethylsi-
lane as internal standard. Chemical shifts are reported in
parts per million (ppm). Wild-type yeast strain BY4741
(MATa; his3Δ1; leu2Δ0; met15Δ0; ura3Δ0) was purchased
from Euroscarf, Frankfurt, Germany.
Synthesis of the ligands
The substituted chalcone (2 mmol), 4-phenyl-3-thiosemicar-
bazide (0.501 g, 3 mmol) and drops of concentrated hydro-
chloric acid in 10 mL of ethanol were refuxed for 2–6 h.
After cooling, the formed precipitate was fltered of and
further recrystallized from ethanol. Scheme 1 shows the
synthetic route.
Ligands and complexes have been also studied by spec-
troscopic methods, and the crystalline structures of the
complexes were elucidated by X-ray diffraction analysis.
2-((E)-3-(4-chlorophenyl)-1-phenylallylidene)-N-phenyl-
hydrazinecarbothioamide, HL1.
Scheme 1 Synthetic route for the preparation of HL1–HL4
1 3

Transition Metal Chemistry
From 0.485 g of the respective chalcone. Yield 0.585 g,
75%; m.p. 159–160 °C. FTIR (KBr, cm−1): 3306, 3209 and
3156 (N–H), 3051 and 2942 ν(C–Hvinyl/C–Harom), 1593
ν(C=Cvinyl), 1519, 1482 and 1444 ν(C=N)+ ν(C=Carom),
140.6 (C9), 139.7, 139.4, 137.2, 133.6, 130.2 (C–Harom),
129.9 (2C–Harom), 129.7 (2C–Harom), 128.8 (2C–Harom),
128.6 (2C–Harom), 128.5 (2C–Harom), 127.3 (C–Harom),
125.8 (2C–Harom), 118.3 (C8), 21.5 (CH3). Minor isomer:
139.2, 139.1, 133.5, 130.5 (C–Harom), 130.0 (C–Harom),
129.6 (C–Harom), 128.7 (C–Harom), 127.9 (C–Harom), 125.7
(C–Harom), 21.4 (CH3). UV–Vis [CH3CN; λ/nm: 263, 340.
2-((E)-3-(4-Cyanophenyl)-1-phenylallylidene)-N-phenyl-
hydrazinecarbothioamide, HL4.
1
980 ν(C=Csubstituted trans), 771 ν(C=S). H NMR (DMSO-
d6): Major isomer: δ 11.54 (s, N2–H), 10.06 (s, N3–H),
7.89 (d, J = 16.10 Hz, H9), 7.84–7.14 (m, C–Harom), 6.84
(d, J = 16.10 Hz, H8). Minor isomer: 10.42 (s, N2–H),
9.03 (s, N3–H), 7.84–7.14 (m, C–Harom + H9), 6.49 (d,
J = 16.39 Hz, H8). 13C NMR (DMSO-d6): Major isomer:
177.2 (C=S), 148.9 (C=N), 139.4, 138.9 (C9), 137.0,
135.3, 134.3, 130.2 (2C–Harom), 129.9 (2C–Harom), 129.7
(C–Harom), 129.2 (2C–Harom), 128.8 (2C–Harom), 128.6
(2C–Harom), 125.9 (2C–Harom), 125.7 (C–Harom), 120.1 (C8).
Minor isomer: 139.2, 135.2, 133.7, 130.3, 129.8 (C–Harom),
129.4 (C–Harom), 129.1 (C–Harom), 128.7 (C–Harom), 125.5
(C–Harom) 125.3 (C–Harom). UV–Vis [CH3CN; λ/nm: 265,
343.
From 0.466 g of the respective chalcone. Yield 0.619 g,
81%; m.p. 176–177 °C. FTIR (KBr, cm−1): 3334, 3278
and 3213 ν(N–H), 3059, 2939 ν(C–Hvinyl/C–Harom),
2225 ν(C≡N), 1596 ν(C=Cvinyl), 1530, 1468 and 1439
ν(C=N)+ν(C=Carom), 973 ν(C=Csubstituted trans), 795 ν(C=S).
1H NMR (DMSO-d6): Major isomer: 10.46 (s, N2–H), 9.17
(s, N3–H), 7.99–7.19 (m, C–Harom), 7.47 (d, J=16.38 Hz,
H9), 6.56 (d, J = 16.38 Hz, H8). Minor isomer: δ 11.60
(s, N2–H), 10.10 (s, N3–H), 8.00 (d, J = 16.11 Hz, H9),
7.99–7.19 (m, C–Harom), 6.91 (d, J = 16.11 Hz, H8). 13C
NMR (DMSO-d6): Major isomer: 177.3 (C=S), 148.3
(C=N), 141.0, 139.4 (C-1′’’), 138.2 (C–Harom), 136.8,
132.9 (2C–Harom), 129.9 (2C–Harom), 129.8 (C–Harom),
129.1 (2C–Harom), 128.8 (C–Harom), 128.6 (2C–Harom), 126.0
(2C–Harom), 125.8 (C–Harom), 122.7 (C8), 119.3 (CN), 111.5.
Minor isomer: 140.9, 139.1, 135.1, 133.2 (C–Harom), 132.5,
130.3, 128.7 (C–Harom), 128.1 (C–Harom), 125.5 (C–Harom),
119.2 (CN), 111.1. UV–Vis [CH3CN; λ/nm: 266, 349.
2-((E)-3-(4-Nitrophenyl)-1-phenylallylidene)-N-phenyl-
hydrazinecarbothioamide, HL2.
From 0.506 g of the respective chalcone. Yield 0.660 g,
82%; m.p. 174–175 °C. FTIR (KBr, cm−1): 3332, 3276 and
3213 (N–H), 3060 and 2936 ν(C–Hvinyl/C–Harom), 1595
ν(C=Cvinyl), 1536, 1469 and 1441 ν(C=N)+ ν(C=Carom),
1340 (symmetrical N=O), 976 ν(C=Csubstituted trans), 789
1
ν(C=S). H NMR (DMSO-d6): Major isomer: δ 11.65 (s,
N2–H), 10.11 (s, N3–H), 8.29 (d, J = 8.91 Hz, 2Harom),
8.07–8.03 (m, C–Harom), 8.04 (d, J = 16.14 Hz, H9),
7.82–7.14 (m, C–Harom), 6.98 (d, J = 16.14 Hz, H8).
Minor isomer: 10.49 (s, N2–H), 9.19 (s, N3–H), 8.23 (d,
J=8.91 Hz, 2C–Harom), 8.07–8.03 (m, C–Harom), 7.82–7.14
(m, C–Harom + H9), 6.64 (d, J = 16.42 Hz, H8). 13C NMR
(DMSO-d6): Major isomer: 177.3 (C=S), 148.1 (C=N),
147.8, 143.0, 139.4, 137.7 (C9), 136.8, 129.9 (2C–Harom),
129.8 (C–Harom), 129.4 (2C–Harom), 128.8 (2C–Harom),
128.6 (2C–Harom), 126.0 (2C–Harom), 125.8 (C–Harom),
124.2 (2C–Harom), 123.5 (C8). Minor isomer: 177.3 (C=S),
147.3, 142.9, 139.1, 130.6 (C–Harom), 130.2 (C–Harom),
128.7 (C–Harom), 128.3 (C–Harom), 125.4 (C–Harom), 124.6
(2C–Harom). UV–Vis [CH3CN; λ/nm: 274, 370.
Synthesis of the complexes [Cu(L1–4)2] and [Zn(L1–
4)2]
Cu(II) and Zn(II) complexes were prepared from a general
procedure illustrated in Scheme 2. To a suspension of the
desired ligand HL1–HL4 (0.12 mmol) in 3 mL of metha-
nol was added Et3N (0.033 mL, 0.24 mmol), followed by
the addition of a previously prepared solution of the cor-
responding metal salt (0.010 g of CuCl2·2H2O or 0.008 g of
ZnCl2-0.06 mmol) in 2 mL of methanol. The resulting mix-
ture was stirred at room temperature for 2 h and centrifuged,
and the precipitate was washed with water and methanol and
dried. Crude products were purifed from diethyl ether by
crystallization and dried in open air.
2-((E)-3-(4-Tolyl)-1-phenylallylidene)-N-phenylhydrazi-
necarbothioamide, HL3.
From 0.444 g of the respective chalcone. Yield 0.505 g,
68%; m.p. 135–136 °C. FTIR (KBr, cm−1): 3308 and
3157 (N–H), 3049 ν(C–Hvinyl/C–Harom), 2950 and 2916
ν(C–Haliphatic), 1597 ν(C=Cvinyl), 1519, 1480 and 1444
ν(C=N)+ν(C=Carom), 981 ν(C=Csubstituted trans), 779 ν(C=S).
1H NMR (DMSO-d6): δ 11.48 (s, N2–H), 10.02 (s, N3–H),
7.86 (d, J = 16.07 Hz, H9), 7.73–7.14 (m, C–Harom), 6.80
(d, J=16.07 Hz, H8), 2.36 (s, CH3). Minor isomer: 10.39
(s, N2–H), 8.94 (s, N3-H), 7.73–7.14 (m, C–Harom + H9),
6.45 (d, J = 16.44 Hz, H8), 2.31 (s, CH3). 13C NMR
(DMSO-d6): Major isomer: 177.1 (C=S), 149.5 (C=N),
[Cu(L1)2], 1a. From 0.047 g of HL1. Yield 0.031 g,
61%; m.p. 140–142 °C. Anal. Calc. for C44H36Cl2N6S2Cu
· (CH3CH2)2O: C, 62.7; H, 4.8; N, 9.1%. Found: C, 63.2;
H, 5.0; N, 8.8%. FTIR (KBr, cm−1): 3406 (N–H); 3055 and
2924 ν(C–Hvinyl/C–Harom), 1597 ν(C=Cvinyl), 1526, 1495,
1475 and 1431 ν(C=N)+ν(C=Carom). UV–Vis [CH3CN; λ/
nm: 285, 323, 389.
[Cu(L2)2], 2a. From 0.048 g of HL2. Yield 0.040 g, 78%;
m.p. 134–135 °C. Anal. Calc. for C44H36N8O4S2Cu · 3/2
(CH3CH2)2O: C, 61.4; H, 5.1; N, 11.5. Found: C, 61.3; H,
5.2; N, 11.1%. FTIR (KBr, cm−1): 3336 and 3277 (N–H);
1 3

Transition Metal Chemistry
Scheme 2 Synthesis of Cu(II) and Zn(II) complexes containing chalcone–thiosemicarbazone ligands
3056 and 2927 ν(C–Hvinyl/C–Harom), 1595 ν(C=Cvinyl), 1517,
1495, 1470 and 1431 ν(C=N) + ν(C=Carom), 1340 (NO2).
UV–Vis [CH3CN; λ/nm: 292, 308, 410.
1H NMR (400 MHz, DMSO-d6): Major Z confguration: δ
10.06 (s, 1H, N3–H), 7.65 (d, J=15.82 Hz, H9), 7.55–7.49
(m, C–Harom), 7.45 (t, J=7.64; 7.13 Hz, C–Harom), 7.30 (d,
J=7.95 Hz, C–Harom), 7.19 (d, J=7.13 Hz, C–Harom), 6.92
(t, J=7.95; 7.45 Hz, C–Harom), 6.72 (d, J=15.82 Hz, H8).
UV–Vis [CH3CN; λ/nm: 306, 393.
[Cu(L3)2], 3a. From 0.044 g of HL3. Yield 0.041 g, 86%;
m.p. 159–160 °C. Anal. Calc. for C46H42N6S2Cu · C4H4O:
C, 68.8; H, 5.1; N, 9.6%. Found: C, 69.6; H, 5.0; N, 9.7%.
FTIR (KBr, cm−1): 3312 (N–H); 3053, 2921 and 2854
ν(C–Hvinyl/C–Harom), 1600 ν(C=Cvinyl), 1530, 1498, 1478
and 1433 ν(C=N) + ν(C=Carom). UV–Vis [CH3CN; λ/nm:
290, 327, 390.
[Zn(L3)2], 3b. From 0.044 g of HL3. Yield 0.025 g, 53%;
m.p. 210–212 °C. Anal. Calc. for C46H42N6S2Zn · H2O:
C, 67.0; H, 5.1; N, 10.2. Found: C, 67.7; H, 5.0; N, 9.9%.
FTIR (KBr, cm−1): 3345 and 3346 (N–H); 3051, 3023 and
2918 ν(C–Hvinyl/C–Harom), 1602 ν(C=Cvinyl), 1534, 1495,
1476 and 1429 ν(C=N)+ν(C=Carom). 1H NMR (400 MHz,
DMSO-d6): Major Z confguration: δ 9.82 (s, 1H, N3–H),
7.47 (d, J=15.62 Hz, 1H, H9), 7.45–6.85 (m, C–Harom), 6.54
(d, J=15.62 Hz, 1H, H8), 6.57–6.46 (m, C–Harom), 2.02 (s,
3H, CH3). UV–Vis [CH3CN; λ/nm: 345, 355, 390.
[Cu(L4)2], 4a. From 0.046 g of HL4. Yield 0.035 g,
70%; m.p. 192–193 °C. Anal. Calc. for C46H36N8S2Cu · 1/2
CH3OH: C, 66.3; H, 4.3; N, 13.3%. Found: C, 69.4; H, 4.3;
N, 13.1%. FTIR (KBr, cm−1): 3334 (N–H); 3053, 2971 and
2924 ν(C–Hvinyl/C–Harom), 2223 (C≡N), 1599 ν(C=Cvinyl),
1528, 1494, 1468 and 1430 ν(C=N)+ν(C=Carom). UV–Vis
[CH3CN; λ/nm: 285, 404.
[Zn(L4)2], 4b. From 0.046 g of HL4. Yield 0.038 g, 77%;
m.p. 249–250 °C. Anal. Calc. for C46H36N8S2Zn · ½ CH3OH:
C, 66.1; H, 4.3; N, 13.3. Found: C, 67.0; H, 4.3; N, 13.2%.
FTIR (KBr, cm−1): 3372 and 3338 (N–H); 3059, 2966 and
2923 ν(C–Hvinyl/C–Harom), 2222 (C≡N), 1599 ν(C=Cvinyl),
1534, 1496, 1468 and 1428 ν(C=N)+ν(C=Carom). 1H NMR
(DMSO-d6): δ 10.01 (s, 1H, N3–H), 7.59 (d, J=15.81 Hz,
1H, H9), 7.54 (t, J=7.78, 7.53 Hz, 1H, C–Harom), 7.48–7.39
(m, 4H, C–Harom), 7.31 (d, J = 8.03 Hz, 2H, C–Harom),
7.16 (d, J = 7.53 Hz, 2H, C–Harom), 7.05–6.93 (m, 4H,
C–Harom), 6.90 (t, J=7.28, 7.03 Hz, 1H, C–Harom), 6.66 (d,
J=15.81 Hz, 1H, H8). UV–Vis [CH3CN; λ/nm: 285, 371,
401.
[Zn(L1)2], 1b. From 0.047 g of HL1. Yield 0.031 g,
61%; m.p. 200–201 °C. Anal. Calc. for C44H36Cl2N6S2Zn
· CH3OH: C, 61.5; H, 4.4; N, 9.6%. Found: C, 61.6; H, 4.3;
N, 9.4%. FTIR (KBr, cm−1): 3332 (N–H); 3054, 2969 and
2923 ν(C–Hvinyl/C–Harom), 1596 ν(C=Cvinyl), 1533, 1494,
1475 and 1430 ν(C=N)+ν(C=Carom). 1H NMR (400 MHz,
DMSO-d6): Major Z confguration: δ 9.92 (s, 1H, N3–H),
7.46 (d, J = 16.05 Hz, H9), 7.60–7.41 (m, C–Harom), 7.34
(d, J = 7.60 Hz, C–Harom), 7.27 (d, J = 8.30 Hz, C–Harom),
7.16 (d, J=7.28 Hz, C–Harom), 6.97 (t, J=7.77; 7.41; Hz,
C–Harom), 6.93–6.73 (m, C–Harom), 6.65 (d, J = 8.30 Hz,
C–Harom), 6.59 (d, J=16.05 Hz, H8). UV–Vis [CH3CN; λ/
nm: 345, 356, 392.
[Zn(L2)2], 2b. From 0.048 g of HL2. Yield 0.031 g,
60%; m.p. 205–207 °C. Anal. Calc. for C44H36N8O4S2Zn
· CH3OH: C, 60.0; H, 4.3; N, 12.5. Found: C, 60.0; H, 4.2;
N, 12.1%. FTIR (KBr, cm−1): 3381, 3333 and 3276 (N–H);
3057 and 2925 ν(C–Hvinyl/C–Harom), 1595 ν(C=Cvinyl), 1534,
1495, 1468 and 1428 ν(C=N) + ν(C=Carom), 1340 (NO2).
X‑ray difraction
Single-crystal X-ray data were collected on a Bruker D8
Venture difractometer using graphite-monochromated Mo
Kα radiation (λ=0.71073 Å) at room temperature (1a, 1b
and 4b) and at 150 K for 3a. Data collection, cell refnement
1 3

Transition Metal Chemistry
and data reduction were performed with Bruker Instrument
Service v4.2.2, APEX2 [19] and SAINT [20], respectively.
The absorption correction using equivalent refections was
performed with the SADABS program [21]. The struc-
ture solutions and full-matrix least-squares refinements
based on F2 were performed with the SHELXS-97 and
SHELXL-2014 programs [22]. All atoms except hydrogen
were refned anisotropically. Hydrogen atoms were treated
using a constrained refnement. 1a displayed large accessible
voids, which are flled by disordered crystallization solvent
molecules. As the eforts to assign these solvent intensities
were unsuccessful, a solvent mask routine implemented
in the Olex2 program was used [23]. The total volume of
the voids and electrons per unit cell are 1761 Å3 and 442,
respectively. The number of electrons per asymmetric unit
corresponds to 55 (Z = 8), which are in good agreement
with one ethyl ether and one water as crystallization sol-
vent. Structure drawings were generated using MERCURY
program [24]. A summary of crystal structure, data collec-
tion and refnement for 1a, 1b, 3a and 4b is given in Table 1.
Selected bond lengths and angles are listed in Table 2, while
geometric parameters for hydrogen bonding and short con-
tacts are gathered in Table 3.
Biological assays
Growth conditions
Cells were grown up to stationary phase in liquid YPD 2%
medium (1% yeast extract, 2% glucose and 2% peptone),
using an orbital shaker at 28 °C and 160 rpm, with the
ratio of fask volume/medium of 5/1. Cellular density was
determined by measuring the optical density of cell suspen-
sions at 570 nm (OD570) and converting to dry weight mL−1
with a standard curve. Media components were obtained
from BD Difco (USA). Stock solution of the compounds
(0.002 g mL−1) was prepared in water containing 50%
DMSO.
Cell viability
Yeast cells were grown up to stationary phase (3.0 mg dry
weight/mL), harvested by centrifugation and washed twice
with 50 mmol L−1 phosphate bufer (pH 6.0). Thereafter,
cells (0.020 g) were resuspended in 20 mL of the same phos-
phate bufer containing 0.100 mmol L−1 of the synthetic sub-
stances maintained at 28 °C/160 rpm for 4 h. The presence
Table 1 Summary of crystal data, collection and refnement parameters for 1a, 1b, 3a and 4b
Compound reference
1a
1b
3a
4b
Chemical formula
Formula mass
Crystal system
Space group
C44H34Cl2CuN6S2
845.38
Orthorhombic
Pbcn
C48H42Cl2N6OS2Zn
919.29
Triclinic
P−1
C50H48CuN6OS2
876.60
Triclinic
P−1
C46H34N8S2Zn
828.32
Monoclinic
P21/n
a/Å
b/Å
c/Å
α/°
β/°
γ/°
18.7215(19)
28.170(4)
18.339(2)
90
90
90
10.5368(4)
14.7559(6)
15.2185(6)
91.301(2)
101.699(2)
95.566(2)
2303.91(16)
293
10.4366(6)
14.5686(7)
15.8398(9)
82.538(3)
71.727(3)
79.831(3)
2243.9(2)
150
13.9682(7)
15.8161(8)
19.6146(10)
90
108.592(2)
90
Unit cell volume/Å3
Temperature/K
9672(2)
293
4107.2(4)
293
Z
8
2
2
4
Radiation type
MoKα
0.68
49,824
8489
MoKα
0.78
56,310
9460
MoKα
0.62
49,091
9215
0.11
MoKα
0.74
29,180
7560
Absorption coefcient, μ/mm−1
No. of refections measured
No. of independent refections
Rint
0.061
0.086
0.058
Final R1 values (I > 2ꢀ(I))
Final wR(F2) values (I > 2ꢀ(I))
Final R1 values (all data)
Final wR(F2) values (all data)
Goodness of ft on F2
Largest dif. peak/hole/e Å−3
CCDC deposition
0.046
0.113
0.079
0.147
1.19
0.55/−0.56
1835514
0.043
0.083
0.086
0.098
1.01
0.29/−0.40
1835516
0.052
0.117
0.096
0.139
1.04
0.68/−0.58
1835515
0.044
0.091
0.084
0.112
1.05
0.43/−0.35
1835513
1 3

Transition Metal Chemistry
Table 2 Selected bond lengths
(Å) and angles (°) for 1a, 1b,
3a and 4b
Atom labels
1a (M=Cu)
1b (M=Zn)
3a (M=Cu)
4b (M=Zn)
M–S1a
M–S1b
M–N1a
M–N1b
N1a–N2a
N1b–N2b
N2a–C16a
N2b–C16b
C16a–N3a
C16b–N3b
C16a–S1a
C16b–S1b
C8a–C9a
2.222(1)
2.232(1)
1.996(3)
2.015(2)
1.390(4)
1.390(4)
1.309(4)
1.301(4)
1.365(4)
1.358(5)
1.738(3)
1.745(3)
1.327(5)
1.339(5)
98.0(1)
85.17(8)
150.74(8)
145.34(8)
84.86(8)
108.92(4)
−0.9(4)
0.8(4)
2.2636(7)
2.2529(9)
2.068(2)
2.041(2)
1.381(3)
1.384(3)
1.301(3)
1.304(4)
1.360(3)
1.362(3)
1.754(2)
1.757(3)
1.330(4)
1.334(4)
104.96(8)
86.41(6)
122.85(6)
128.29(6)
87.64(6)
128.25(3)
−2.3(3)
1.9(4)
2.226(1)
2.2293(9)
1.991(2)
1.982(3)
1.389(4)
1.388(4)
1.306(4)
1.304(4)
1.356(5)
1.363(4)
1.756(3)
1.748(4)
1.339(4)
1.339(4)
98.4(1)
85.26(8)
149.12(9)
147.02(9)
85.91(8)
107.59(4)
−0.5(4)
1.9(4)
2.252(1)
2.2493(9)
2.072(3)
2.060(2)
1.383(3)
1.380(3)
1.311(5)
1.311(4)
1.360(4)
1.367(4)
1.744(3)
1.753(3)
1.336(5)
1.336(4)
101.8(1)
87.06(7)
125.32(7)
127.47(7)
87.66(7)
128.55(4)
−0.3(4)
1.5(4)
C8b–C9b
N1a–M–N1b
N1a–M–S1a
N1a–M–S1b
N1b–M–S1a
N1b–M–S1b
S1a–M–S1b
N1a–N2a–C16a–S1a
N1b–N2b–C16b–S1b
of DMSO did not infuence the toxicity of the compounds
since the percentage remained below 3% [25]. To test cel-
lular tolerance against the substances, cells were diluted
with water and plated on solid 2% YPD (1% yeast extract,
2% glucose, 2% peptone and 2% agar), after 4 h. Hydrogen
peroxide was used as a positive control and the cells as the
experimental control in phosphate bufer. Plates were pre-
pared in triplicate. Colonies were counted after incubation
at 28 °C for at least 72 h. Tolerance was expressed as a
percentage of viable cells [26]. Assays were repeated three
independent times.
Table 3 Intermolecular and intramolecular contacts in 1a, 1b, 3a and
4b (values in Å and deg)
Compound D–H···A
D–H H···A D···A
<D–H···A
1a
1b
C22b–H22b···N2b 0.93 2.24 2.828(5) 120
C18a–H18a···N2a 0.93 2.27 2.868(4) 121
N3a–H3a···S1ai
0.86 2.84 3.411(2) 125
0.86 2.05 2.907(3) 173
N3b–H3b···O1sii
C22a–H22a···N2a 0.93 2.30 2.871(4) 120
C22b–H22b···N2b 0.93 2.29 2.868(3) 120
C18b–
0.93 2.92 3.595(3) 131
H18b···Cl1aiii
Lipid peroxidation levels
C8b–H8b···S1a
N3a–H3a···S1ai
N3b–H6b···O1s
0.93 2.95 3.848(3) 162
0.88 2.61 3.456(3) 163
0.88 2.05 2.930(4) 174
3a
4b
Lipid oxidation was measured by TBARS (thiobarbitu-
ric acid-reactive species) method, which detects malon-
dialdehyde (MDA). Cells (0.050 g-dry weight) were
resuspended in 20 mL of the phosphate bufer contain-
ing 0.100 mmol L−1 of the synthetic substances kept at
28 °C/160 rpm for 4 h. Hydrogen peroxide was used as a
positive control at the same concentration, and the cells
were tested in phosphate bufer as the experimental con-
trol. Cells were harvested by centrifugation and washed
twice with phosphate bufer. The pellets were resuspended
in 0.5 mL of the same bufer, followed by 10% trichlo-
roacetic acid, and then 1.5 g of glass beads was added.
The samples were lysed by 6 cycles of 20-s agitation on
C22a–H22a···S1ai 0.95 3.02 3.840(4) 145
C18a–H18a···N2a 0.95 2.27 2.872(4) 121
C8a–H8a···N1b
C8b–H8b···N1a
0.95 2.56 3.146(4) 120
0.95 2.57 3.165(4) 121
C18b–H18b···N2b 0.95 2.22 2.839(4) 122
N3b–H3b···N4bi
0.86 2.32 3.179(4) 174
N3a–H3a1···S1aii 0.86 2.82 3.426(3) 129
C18a–H18a···N2a 0.93 2.26 2.847(4) 120
C18b–H18b···N2b 0.93 2.31 2.865(4) 118
Symmetry codes: 1a (i) −x + 1, −y, −z + 1; (ii) x, y, z − 1; (iii)
−x, −y + 1, −z. 3a (i) −x + 1, −y + 1, −z + 1. 4b (i) x, y − 1, z; (ii)
−x + 2, −y + 2, −z + 2
1 3

Transition Metal Chemistry
1H NMR spectroscopy
a vortex mixer, followed by 20 s on ice. Extracts were
centrifuged (4000 rpm/4 min) and the supernatant mixed
with 0.1 mL of EDTA 0.1 mol L−1 and 0.6 mL of TBARS
1% (w/v), prepared in NaOH 0.05 mol L−1. The reaction
mixture was incubated in a boiling water bath for 15 min,
and after cooling, the absorbance was measured spectro-
photometrically at 532 nm. The results are expressed as
pmol MDA/mg cell [26]. Assays were repeated three inde-
pendent times.
The free proligands show the characteristic NH sig-
nals (N2–H and N3–H) within the range 10.4–11.7 and
9.0–10.1 ppm, respectively. The =C–H (H8 and H9) appear
in the regions of 6.5–7.0 and 7.4–8.1 ppm, respectively, as
duplets with coupling constants of 16 Hz, characteristic of
trans confguration. Aromatic hydrogens were all found
between 7 and 8 ppm, as expected.
Duplicated peaks in the spectra of all proligands are
observed, such as H8, H9, N2–H, N3–H and the -CH3 group
(H23–HL3), indicating the presence of two isomers in solu-
tion (1:3 proportion, see for HL4, Fig. 1). The literature
reports the possibility of formation of E and Z isomers for
similar chalcone–thiosemicarbazone compounds [9] that
depends on the R-substituent of the chalcone as well as how
long the substances remain in solution. Figure 1 illustrates
the comparison between the 1H NMR spectra of HL4 and
its Zn(II) complex, 4b.
Results and discussion
The proligands were prepared using an adapted meth-
odology [27] from a mixture of previously synthesized
substituted chalcones [17] and phenyl-thiosemicarbazide
[18] using few drops of concentrated HCl in ethanol. The
products were purifed by recrystallization from ethanol
in reasonable yields (68–82%). All metal complexes were
obtained in 2:1 (ligand:metal) proportion using excess
of Et3N in a suspension of the desired ligand to allow
deprotonation. After adding the metal salt, the complexes
precipitated immediately as brownish green, orange and
yellow solids, which were obtained in pure form by crys-
tallization from the diethyl ether solutions and confrmed
by elemental analysis. All complexes are poorly soluble
in polar organic solvents such as methanol, ethanol and
CH3CN.
After coordination, the N2–H in the spectra of 4b disap-
peared, confrming the anionic form of the thiosemicarba-
zone ligands. H9, H10 and aromatic hydrogens were found
in the characteristic regions.
It is interesting to note individual signals for each hydro-
gen in the spectra of 4b, implying the presence of one isomer
in solution. However, the 1H NMR spectra of the other Zn
complexes (1b–3b) exhibited some duplicated peaks in a
very small amount (~10%), which possibly might be related
to traces of the other isomer in solution. According to the
X-ray structures of 1a, 1b, 3a and 4b, all complexes exhib-
ited the ligands in the Z-confguration, where the phenyl ring
of the C7=N1 bond is orientated toward the thiosemicarba-
zone group. Thus, the Z-isomer must be the most stable form
for the complexes both in the solid state and in solution.
Suitable single-crystals for X-ray diffraction were
obtained by slow evaporation of the solutions of 3a and 1b
in methanol–THF (1:1). 4b crystals were obtained in metha-
nol–acetone (1:1) and 1a in diethyl ether.
Vibrational spectra
Electronic spectra
The IR spectra of the chalcone–thiosemicarbazones
exhibit the characteristic ν(NH) stretching vibrations in the
3334–3156 cm−1 range. For the complexes, the absence of
the least energetic NH band at about 3200 cm−1 confrmed
deprotonation of the thioamide NH function and coordina-
tion of the ligand in the anionic form [28]. The band around
1595 cm−1 attributed to the vinyl ν(C=C) was not shifted
upon complexation, as expected. A signifcant change was
observed in the bands associated with the νC=CAr +νC=N,
found in the range of 1545–1440 cm−1 for HL1–HL4 and
shifted to 1535–1430 cm−1 after coordination. In addition, a
new intense absorption at about 1595 cm−1 appeared in the
spectra of the complexes, confrming coordination through
the iminic nitrogen [29]. HL4, 4a and 4b have the ν(C≡N)
assigned at 2224 cm−1. Finally, HL2, 2a and 2b display an
intense band at 1340 cm−1 characteristic of nitro group.
The electronic spectra of the proligands show very similar
profles, with two main absorptions around 270 nm and in
the 340–370 nm range. The frst transition of medium inten-
sity has been attributed in the literature as π–π* transitions
of the aromatic rings [8, 9]. The most energetic absorption at
340–370 nm has been usually assigned as n-π* bands from
the azomethine and thioamide functions [8]. As pointed
out in the literature, it is also possible that these intense
absorptions are a result of both π–π* and n–π* transitions
overlapped in the same envelope [9]. The Cu(II) complexes
exhibit two broad bands from 285 to 320 nm that can be
assigned as ligand π–π* transitions. The presence of a new
absorption around 389–410 nm could be associated with
the shift of the n–π* transitions attributed to C=N and C=S
upon coordination and the formation of higher conjugated
system after deprotonation of the ligands [9]. Some studies
1 3

Transition Metal Chemistry
Fig. 1 1H NMR spectra of HL4 and its Zn complex, in DMSO-d6, from 6.0 to 12.0 ppm
also suggest that these bands may be probably overlapped
with ligand-to-metal charge transfer (LMCT) transitions [8].
The presence of the Cu(II) has been confrmed by the char-
acteristic broad d–d transitions around 610 nm, from the
concentrated solutions. For the Zn(II) complexes, the π–π*
and n–π* transitions of the ligands have been shifted after
coordination, appearing as broad bands in the 343–370 and
391–421 nm ranges, toward the visible region, as expected.
displays the asymmetric unit of all compounds with main
atom numbering.
In all complexes, two chalcone-thiosemicarbazonate
ligands (L−) are coordinated to the metal in a bidentate mode
via the azomethine nitrogen (N1a and N1b) and the S-thi-
olate (S1a and S1b) atoms, leading to a 5-membered che-
late. The deprotonation of the thiosemicarbazone moieties
was confrmed by the double-bond character of N2a–C16a,
N2b–C16b, N1a–C7a, N1b–C7b, which present lengths
around 1.30 Å. Besides, the C16a–S1a and C16b–S1b bond
lengths are in the range 1.738(3)–1.757(3) Å, also support-
ing the evidence of the thiolate formation. The metal atoms
are four-coordinated, and the complexes exhibit a seesaw
geometry, determined by the calculation of τ4 parameter
[30] (1a 0.45; 1b 0.73; 3a 0.45; and 4b 0.73). The M–N and
M–S bond lengths are typical when compared to other com-
pounds previously reported [3, 10], being slightly shorter
Crystal structure descriptions
Suitable single-crystals for X-ray difraction of the com-
plexes 1a, 1b, 3a and 4b were obtained by slow solvent
evaporation at 10 °C. A summary of crystal data, collec-
tion and refnement parameters is listed in Table 1. Selected
bond lengths and angles are gathered in Table 2. Figure 2a–d
1 3

Transition Metal Chemistry
Fig. 2 Crystal structures of compounds 1a (a), 1b (b), 3a (c) and 4b (d). Hydrogen atoms and solvent molecules are omitted for the sake of clar-
ity. Color codes: C (gray), N (blue), S (yellow), Cl (green), Zn (magenta) and Cu (cyan). (Color fgure online)
for the Cu(II) complexes. Both ligands in the coordina-
tion sphere adopt the ZZ-confguration with respect to the
C7a–N1a and C16a–N2a or C7b–N1b and C16b–N2b bond
pairs. It is important to stress that the Z-orientation related to
the C16a–N2a and C16b–N2b bonds is required to allow the
simultaneous coordination from sulfur and nitrogen atoms.
In the compounds 1a and 3a, both phenyl rings on the C7a
or C7b are orientated almost perpendicular to the respective
fve-membered rings containing the metal atom with angles
of 79.689(2)° and 78.162(2)° (1a, 86.022(1)° and 79.890(8)°
3a). It was observed that these angles are closer for other
compounds with values of 60.904(9)° and 83.365(9)° (1b)
and from 64.940(1)°–72.314(1)° (4b). The orientation of the
phenyl rings attached to C7a or C7b atoms seems to generate
less steric efect, once both R-Ph group and NH–Ph are in
opposite sites. Concerning the NH–Ph moiety, the phenyl
ring is coplanar to the C16–N2–N1–C7 skeleton (a and b
ligands) in all compounds and this is attributed to the estab-
lishment of intramolecular hydrogen bonds N–H···H–Csp2,
as exemplifed in Fig. 3a for 1a.
intermolecular S···S bond (θ and ϕ) of 130°. These geom-
etry parameters lie on the typical ranges found in the lit-
erature (S···S = 3.4–4.3 Å and θ, ϕ = 90°–140°) [31]. The
R-substituent plays a key role in the crystal packing of the
compounds due to intermolecular short contacts between the
main molecular units and the crystallization solvents. For
1b, 3a and 4b, the face-to-face molecular synthons involv-
ing azomethine hydrogen atom and the neighboring sulfur
atom lead to supramolecular dimers, which interact with
each other through Csp2–H···Cl (1a), Csp2–H···S (3a) weak
contacts or NH···Ncyano hydrogen bonds (4b) (Fig. 3b, c).
Biological assays
The toxicity of the ligands HL1, HL3 and HL4 and the
complexes 1a, 3a, 4a, 1b, 3b and 4b was evaluated toward
S. cerevisiae cells (control strain—BY4741) after 4-h incu-
bation at 100 μM (Table 4). HL2, 2a and 2b were not tested
due to low solubility.
The results have shown that HL4 was the most damaging
compound, resulting in a cell viability of 53.53 14.21%,
while HL1 and HL3 showed lower toxicity. It has been
reported in the literature that thiosemicarbazone derivatives
exhibit toxicity against microorganisms such as S. cerevisiae
A short intermolecular S1b···S1bi (i=−x,y,1/2−z) con-
tact was observed only in 1a with distance of 3.358(1) Å
and the angles between the axes that pass through the
middle of the C–S–Cu moiety of each fragment and the
1 3

Transition Metal Chemistry
Fig. 3 Details of the crystal packing of compounds 1a, 1b and 4b. Only hydrogen atoms involved in intramolecular and intermolecular contacts
are shown
1 3

Transition Metal Chemistry
Table 4 Cell viability (%)
HL1 showed similar toxicity to the positive control
(H2O2), proving to be more damaging than HL3 and HL4.
This result revealed a diferent profle to that observed in
cell viability (Table 4). Both assays have indicated that HL1
and HL4 cause damage to yeast cells; however, HL4 inter-
feres in cell proliferation by preventing formation of viable
daughter cells, whereas HL1 causes lipid peroxidation in
the plasma membrane. In this case, it appears that the dif-
ference in substituents resulted in diferent actions on S. cer-
evisiae cells. Other studies have reported thiosemicarbazone
derivatives acting in diferent ways on cellular structures
and metabolism, such as antiproliferative activity [34] and
redox homeostasis [35]. One of the features of cancer cells
is presenting sustained proliferative capacity, which favors
tumorigenesis. Thus, therapies that interfere and limit this
capacity are desirable, to which compound HL4 might be a
potential alternative to be further evaluated against human
cancer cells.
Compound Cell viability (%)
after 4-h incubation with the
compounds at 0.100 mmol L−1
cells (control strain—BY4741)
Control
H2O*2
HL1
HL3
HL4
1a
100 0.00a
0.0 0.00
81.33 11.66a
72.83 8.97a
53.53 14.21b
97.37 20.86c
81.14 7.95c
66.11 27.66c
92.72 0.00c
80.77 10.44c
77.09 3.49c
3a
4a
1b
3b
4b
Statistical analysis was per-
formed with one-way ANOVA
plus Tukey’s posttest, with p
values<0.05 considered signif-
cant
a,b,cDiferent letters mean statis-
tically diferent results
In order to investigate whether coordination interferes in
the ability of the proligand to induce plasma membrane dam-
age, 1a and 1b—derived from HL1—were also evaluated
(Fig. 5). The result shows that the Zn(II) complex 1b has
not caused membrane damage, but the Cu(II) complex 1a
revealed a twofold increase in the lipid peroxidation when
compared to the control and 1b, yet induced less damage
than HL1.
*Tested at 1 mM
and Candida albicans fungi [32]. Also, some studies have
shown that Zn(II) and Cu(II) thiosemicarbazone complexes
produce damage in yeast and other cell types [33]. In our
case, the complexes exhibited lower toxicity toward S. cer-
evisiae, compared to the free proligands. In addition, no
signifcant diference was observed between the Cu(II) and
Zn(II) complexes. Thus, our results indicate that complexa-
tion was not efective in increasing the toxicity of the chal-
cone–thiosemicarbazones against S. cerevisiae.
Coordination to Cu(II) and Zn(II) atoms has not led to an
increase in membrane damage toward S. cerevisiae, when
compared to HL1, even though 1a has exhibited some
level of lipid peroxidation. According to our results, chal-
cone–thiosemicarbazones were more toxic to yeast cells than
the complexes, with emphasis on HL4. On the other hand,
the metal complexes caused little toxicity in this cellular
model. Considering the potential applicability of Cu(II) and
Zn(II) complexes also as antimicrobials, this result may be
In order to further investigate the proligands, lipid per-
oxidation assay was performed in the BY4741 strain. HL1,
HL3 and HL4 showed increase in MDA levels (Fig. 4).
200
Control
H2O2
Control
**
200
150
HL1
**
H2O2
HL1
***
HL3
HL4
**
150
100
50
100
50
0
**
1a
1b
****
***
*
*
*
Fig. 4 Efect on lipid peroxidation after 4-h incubation with H2O2
and the ligands HL1, HL3 and HL4 at 0.100 mmol L−1. Lipid per-
oxidation was measured as pmol of MDA (malondialdehyde) by the
method of TBARS (thiobarbituric acid-reactive species). Data repre-
sent the means SDs of at least three independent experiments (dif-
ferent numbers of asterisks mean statistically diferent results in each
group; p<0.05)
0
Fig. 5 Lipid peroxidation assay with hydrogen peroxide, HL1, 1a
and 1b. Data represent the means SDs of at least three independent
experiments (diferent numbers of asterisks mean statistically difer-
ent results in each group; p<0.05)
1 3

Transition Metal Chemistry
that are more than just ribonucleotide reductase inhibitors. J Med
Chem 52:5271–5294
particularly interesting, since this application requires low
toxicity to human living cells.
3. Mendes IC, Moreira JP, Mangrich AS, Balena SP, Rodrigues BL,
Beraldo H (2007) Coordination to copper(II) strongly enhances
the in vitro antimicrobial activity of pyridine-derived N(4)-tolyl
thiosemicarbazones. Polyhedron 26:3263–3270
Conclusions
4. Kovala-Demertzi D, Yadav PN, Wiecek J, Skoulika S, Varadi-
nova T, Demertzis MA (2006) Zinc(II) complexes derived from
pyridine-2-carbaldehyde thiosemicarbazone and (1E)-1-pyridin-
2-ylethan-1-one thiosemicarbazone: synthesis, crystal structures
and antiproliferative activity of zinc(II) complexes. J Inorg Bio-
chem 100:1558–1567
A series of new chalcone–thiosemicarbazone hybrids as well
as their Cu(II) and Zn(II) complexes have been obtained
and characterized. Spectroscopic analyses revealed that the
proligands exist in two tautomeric forms in solution (E and
Z isomers), and upon coordination, the Z form is preferential
for the complexes. The crystalline structures of two Cu(II)
(1a and 3a) and two Zn(II) complexes (1b and 4b) were
determined by X-ray difraction. As expected, the chalcone-
TSCs ligands coordinate in the anionic form, through the
azomethine nitrogen (N1a and N1b) and the S-thiolate, in
a 2:1 ligand:metal proportion, with the metal atom exhibit-
ing a seesaw geometry. Yeast activity demonstrated that the
chalcone-TSCs were the most active compounds, especially
that containing the cyano substituent, HL4. On the other
hand, HL1 (R = Cl) was found to better induce lipid per-
oxidation among the tested compounds. Coordination with
Cu(II) and Zn(II) did not enhance toxicity of the ligands
against S. cerevisiae. Also, complexes 1a and 1b did not
induce great levels of membrane damage, even though the
Cu(II) complex showed a twofold increase compared to
Zn(II). Additional biological investigations are under way
in order to evaluate the applicability of the complexes as
antimicrobials.
5. Singh P, Anand A, Kumar V (2014) Recent developments in bio-
logical activities of chalcones: a mini review. Eur J Med Chem
85:758–777
6. Verma CP, Kumar KS, Aravindhakshan KK (2017) Synthesis,
characterization and pharmacological activity of complexes
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methyl(phenyl)thiosemicarbazone. J Pharm Sci Res 9:1444–1449
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Supplementary data
The CCDC 1835513–1835516 contain the supplementary
crystallography data for 1a, 3a, 1b and 4b. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/conts
/retrieving.html, or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
(+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
13. Pahontu E, Julea F, Rosu T, Purcarea V, Chumakov Y, Petrenco P,
Gulea A (2015) Antibacterial, antifungal and in vitro antileukae-
mia activity of metal complexes with thiosemicarbazones. J Cell
Mol Med 19:865–878
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thiosemicarbazones derived from 6-nitropiperonal: antimicrobial
and biophysical properties. Spectrochim Acta A 183:158–171
15. Peycheva E, Alexandrova R, Miloshev G (2014) Application of
the yeast comet assay in testing of food additives for genotoxicity.
LWT Food Sci Technol 59:510–517
Acknowledgements The authors thank the Brazilian agencies CAPES,
CNPQ and FAPERJ (Grant: Sediadas E-26/010.002894/2014) for
fnancial support, LDRX-UFF (www.ldrx.uf.br/) for the X-ray dif-
fraction analysis and PPGQ-UFRRJ (http://cursos.ufrrj.br/posgraduac
ao/ppgq/) for the facilities.
16. Chandel A, Das KK, Bachhawat AK (2016) Glutathione depletion
activates the yeast vacuolar transient receptor potential channel,
Yvc1p, by reversible glutathionylation of specifc cysteines. Mol
Biol Cell 27:3913–3925
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