Synthesis of novel chiral metal complexes derived from chiral thiosemicarbazide ligands as potential antioxidant agents

Article abstract of DOI:10.1002/chir.23069

Two new chiral thiosemicarbazide ligands and their Cu (II), Ni (II), Pd (II), and Zn (II) complexes were synthesized and characterized by nuclear magnetic resonance (NMR) (only for ligand), Fourier transform infrared (FT-IR), ultraviolet visible (UV-Vis), mass, and elemental analysis. The antioxidant activity of ligands and their metal complexes was examined. It was found that the antioxidant activity of metal complexes was better than their ligands. In addition, the antioxidant activity, as reflected by free radical scavenging, was evaluated. Besides, Pd (II) complexes exhibited better antioxidant activity than Ni (II), Cu (II), and Zn (II) complexes. Therefore, complexes (3a-Pd and 3b-Pd) can be used as an antioxidant agent or antioxidant test standard.

Full text of DOI:10.1002/chir.23069

Received: 12 November 2018
DOI: 10.1002/chir.23069
Revised: 11 March 2019
Accepted: 14 March 2019
R E G U L A R A R T I C L E
Synthesis of novel chiral metal complexes derived from
chiral thiosemicarbazide ligands as potential antioxidant
agents
Eyüp Başaran1
| Yusuf Sıcak2
| Hatice Gamze Sogukomerogullari3
|
Ayşegül Karaküçük‐Iyidoğan1
| Emine Elçin Oruç‐Emre1
| Mehmet Sönmez1
|
Mehmet Öztürk4
1 Faculty of Science and Arts, Department
of Chemistry, Gaziantep University,
Gaziantep, Turkey
2 Köyceğiz Vocational School, Muğla Sıtkı
Koçman University, Muğla, Turkey
3 Medical Services and Techniques
Department, Health Services Vocational
School, Gaziantep University, Gaziantep,
Turkey
4 Faculty of Science, Department of
Chemistry, Muğla Sıtkı Koçman
University, Muğla, Turkey
Abstract
Two new chiral thiosemicarbazide ligands and their Cu (II), Ni (II), Pd (II),
and Zn (II) complexes were synthesized and characterized by nuclear magnetic
resonance (NMR) (only for ligand), Fourier transform infrared (FT‐IR),
ultraviolet visible (UV‐Vis), mass, and elemental analysis. The antioxidant
activity of ligands and their metal complexes was examined. It was found that
the antioxidant activity of metal complexes was better than their ligands.
In addition, the antioxidant activity, as reflected by free radical scavenging,
was evaluated. Besides, Pd (II) complexes exhibited better antioxidant activity
than Ni (II), Cu (II), and Zn (II) complexes. Therefore, complexes (3a‐Pd and
3b‐Pd) can be used as an antioxidant agent or antioxidant test standard.
Correspondence
Hatice Gamze Sogukomerogullari,
Gaziantep University, Medical Services
and Techniques Department, Health
Services Vocational School, 27310
Gaziantep, Turkey.
KEYWORDS
antioxidant activity, characterization, chiral complex, thiosemicarbazide
Email: hgcelikel@gantep.edu.tr
1 | INTRODUCTION
included in the cofactor of many oxidative enzymes and
vitamins including hydrogenase, tyrosinase, vitamin
Stereochemistry plays a significant role in drugs' structure
because of changing their activities. Thiosemicarbazides
and their derivatives are important organic compounds
due to their biological and pharmacological activities such
as antibacterial, anticancer, anti‐HIV, antifungal, and
antiviral.1-3 Thiosemicarbazides are good intermediate
compounds for the synthesis of bioactive and pharmaceu-
tical materials in this way. These compounds are especially
used in medicinal chemistry. In recent years, most studies
have demonstrated that some thiosemicarbazides and
their metal complexes were evaluated as semiconduc-
tors,4,5 and they are used to prevent the corrosion of steel.6
In addition, the metal complexes are significant for both
plants and animals. Especially, these compounds are
B12, and lactase.7 Metal complexes are generally found
to be more active and stable than ligands.8-11 Metal
complexes of thiosemicarbazides are formed by the coordi-
nation of metal with N, O, and/or S donor atoms.12 When
the metal complexes are compared with thiosemicarbazide
ligands, the metal complexes increased biological activity
such as antifungal, anticancer, antioxidant, and antiviral.
This is due to the higher lipophilicity of metal complexes
than their ligands.13 Although there are many biological
activity studies of chiral thiosemicarbazides in the
literature, the antioxidant studies of these compounds
and metal complexes are quite small.14
In the present work, antioxidant activity studies of
Cu (II), Ni (II), Pd (II), and Zn (II) complexes derived
Chirality. 2019;1–11.
wileyonlinelibrary.com/journal/chir
© 2019 Wiley Periodicals, Inc.
1

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BAŞARAN ET AL.
from new chiral thiosemicarbazide ligands were used
for the treatment of various diseases and the development
of new drugs.
the solid product and extracted with 2 N HCl (aqua).
The organic phase was dried over anhydrous Na2SO4
and then the solvent evaporated. The crude product
was recrystallized from ethanol.
2 | MATERIALS AND METHODS
2.1 | Chemicals and instruments
2.2.1 | (−)‐(R)‐methyl 3‐phenyl‐2‐(4‐
nitrobenzenesulfonamido) propanoate (1a)
All chemicals and solvents used in the experiments were
obtained from Turkey's representative of Sigma Aldrich
(St. Louis, MO) and Fluka (Buchs, Switzerland)
Yellow solid; yield 83%; mp. 146°C to 147°C; [α]D = −22.6
(c: 0.67, THF); UV‐Vis (DMF, λmax, nm (Abs)): 367
(0.045), 279 (1.451), 275 (1.530); IR (νmax, cm−1): 3264
(N―H), 1720 (C═O), 1522 (NO2, asymmetric), 1345
(SO2, asymmetric), 1289 (NO2, symmetric), 1168 (SO2,
symmetric); EI‐MS (m/z): 364.3 [M]+; 1H NMR
(400 MHz, DMSO‐d6): δ 2.74 (dd, 1H, J1 = J2 = 9.6 Hz,
―CH2―, Hb), 2.91 (dd, 1H, J1 = J2 = 5.4 Hz, ―CH2―,
Ha), 3.42 (t, 3H, ―CH3), 4.04 to 4.08 (m, 1H, ―CH―),
7.08 to 7.16 (m, 5H, aromatic protons), 7.41 (d, 2H,
J = 9.0 Hz, aromatic protons), 8.21 (d, 2H, J = 9.0 Hz,
aromatic protons), 8.89 (d, 1H, J = 9.0 Hz, ―NHSO2―);
13C NMR (100 MHz, DMSO‐d6): δ37.86 (―CH2―),
52.39 (―CH3), 57.90 (―CH―), 124.65, 126.97, 128.06,
128.60, 129.59, 136.60, 146.76, 149.65 (aromatic carbons),
171.50 (C═O); anal. calcd. for C16H16N2O6S: C, 52.74;
H, 4.43; N, 7.69; S, 8.80%. Found: C, 52.99; H, 4.49;
N, 7.90; S, 8.52%.
All reactions were monitored by thin layer chromatog-
raphy (TLC). TLC plates were based on silica gel 60F254
aluminum plates with a 0.2‐mm layer thickness (Merck
Co., Darmstadt, Germany). The spots in TLC were
determined by UV lamp. Stuart (UK), a SMP30 melting
point apparatus, was used to measure the melting
points of the synthesized compounds. The specific
rotation [α] values of ligands were determined by an
automatic polarimeter P8000 (A.KRÜSS Optronic GmbH,
Germany) in 20°C of solutions of tetrahydrofuran. Ultra-
violet visible (UV‐Vis) spectrums of compounds in DMF
were recorded by a PG Instrument (UK) T80 + UV‐visible
spectrophotometer. The Fourier transform infrared (FT‐
IR) spectra of compounds were measured in the range
of 4000 to 400 cm−1 using a Perkin Elmer Spectrum
100 FT‐IR Spectrometer (universal ATR sampling acces-
sory). The 1H and 13C nuclear magnetic resonance
(NMR) spectra of compounds were measured in
DMSO‐d6 by using a Bruker (Billerica, MA) AVANC‐
DPX‐400 MHz spectrometer at 400 and 100 MHz,
respectively. Tetramethylsilane (TMS) was used as the
internal reference The mass spectra (MS) of compounds
were recorded using an ABSciex (Framingham, MA)
3200 QTrap system liquid chromatography with tandem
mass spectroscopy (LC/MS/MS) in the electrospray
mode. CHNS elemental analyses were determined
using a Thermo Scientific (Pittsburgh, PA) Flash 2000
elemental analyzer. Bioactivity assays were realized
by using a 96‐well microplate reader, SpectraMax
340PC384, Molecular Devices (USA).
2.2.2 | (+)‐(S)‐ethyl 3‐phenyl‐2‐(4‐
nitrobenzenesulfonamido) propanoate (1b)
Yellow solid; yield 85%; mp. 107°C to 108°C; [α]D = +27.8
(c: 0.67, THF); UV‐Vis (DMF, λmax, nm (Abs)): 346
(0.074), 276 (1.714), 270 (1.764); IR (νmax, cm−1): 3280
(N―H), 1736 (C═O), 1526 (NO2, asymmetric), 1348
(SO2, asymmetric), 1308 (NO2, symmetric),1162 (SO2,
symmetric); EI‐MS (m/z): 378.4 [M]+; 1H NMR
(400 MHz, DMSO‐d6): δ 0.98 (t,3H, ―OCH2CH3), 2.75
(dd, 1H, J1 = J2 = 9.6 Hz, ―CH2―, Hb), 2.93 (dd, 1H,
J1 = J2 = 6.0 Hz, ―CH2―, Ha), 3.85 (q, 2H,
―OCH2CH3), 4.01 to 4.05 (m, 1H, ―CH―), 7.08 to 7.14
(m, 5H, aromatic protons), 7.77 (d, 2H, J = 8.4 Hz,
aromatic protons), 8.22 (d, 2H, J = 8.4 Hz, aromatic
protons), 8.88 (d, 1H, J = 9.6 Hz, ―NHSO2―);
13C NMR (100 MHz, DMSO‐d6): δ 14.6 (―OCH2CH3),
38.01 (―CH2―), 57.92 (―CH―), 61.22 (―OCH2CH3),
124.66, 126.9, 128.13, 128.59, 129.62, 136.56, 146.85,
149.67 (aromatic carbons), 171.01 (C═O); anal. calcd.
for C17H18N2O6S: C, 53.36; H, 4.61; N, 7.54; S, 8.63%.
Found: C, 53.41; H, 4.34; N, 7.44; S, 8.58% at 0°C.
2.2 | Synthesis of benzenesulfonamide
compounds (1a‐1b)
To the solution of 4‐nitrobenzenesulfonyl chloride
(1.89 mmol) in dichloromethane (3 mL), D‐phenylalanine
methyl ester (1.26 mmol) or L‐phenylalanine ethyl ester
(1.26 mmol) was added and triethylamine (3.78 mmol)
as catalyst. The reaction mixture was stirred at 0°C for
30 minutes. Then, the mixture was refluxed for 3 hours.
The solvent evaporated, and ethyl acetate was added to

BAŞARAN ET AL.
3
δ 38.79 (―CH2―), 57.12 (―CH―), 124.46, 126.67,
128.01, 128.44, 129.63, 137.38, 147.02, 149.51 (aromatic
carbons), 169.55 (C═O); anal. calcd. for C15H16N4O5S:
C, 49.44; H, 4.43; N, 15.38; S, 8.80%. Found: C, 50.90;
H, 4.55; N, 14.93; S, 8.72%
2.3 | Synthesis of hydrazide derivatives
(2a‐2b)
To a solution of homochiral ester derivatives 1a
(0.78 mmol) in MeOH (10 mL) or 1b (0.78 mmol) in
EtOH (10 mL), hydrazine monohydrate (3.12 mmol)
dropwise was added, and the mixture was refluxed for
6 hours. Solid product was obtained after cooling the
mixture filtering, washing with water, and recrystallizing
from ethanol.
2.4 | Synthesis of thiosemicarbazide
derivatives (3a‐3b)
A mixture of the homochiral hydrazide compounds 2a‐2b
(0.32 mmol) in 10 mL of MeOH, followed by the addition
of 4‐nitrophenylisothiocyanate (0.32 mmol) in methanol
(10 mL). The reaction mixture was refluxed at 80°C
for 10 hours. After cooling, the precipitate was separated
by filtration and recrystallized from ethanol.
2.3.1 | (−)‐(R)‐2‐(4‐
nitrobenzenesulfonamido)‐3‐phenyl
propanylhydrazide (2a)
Yellow solid; yield 87%; mp. 187°C to 188°C; [α]
= −48.9 (c: 0.67, THF); UV‐Vis (DMF, λmax, nm
D
2.4.1 | (+)‐(R)‐1‐[2‐(4‐
(Abs)): 361 (0.025), 331 (0.057), 279 (0.552), 270
(0.620); IR (νmax, cm−1): 3326 and 3262 (N―H), 1665
(C═O), 1520 (NO2, asymmetric), 1338 (SO2, asymmetric),
1288 (NO2, symmetric), 1159 (SO2, symmetric); EI‐MS
(m/z): 365.1 [M]+; 1H NMR (400 MHz, DMSO‐d6): δ
2.60 (dd, 1H, J1 = 10.2 Hz, J2 = 9.6 Hz, ―CH2―, Hb),
2.78 (dd, 1H, J1 = J2 = 4.8 Hz, ―CH2―, Ha), 3.93
(brs, 1H, ―CH―), 4.05 (brs, 2H, ―NHNH2), 7.05 to
7.12 (m, 5H, aromatic protons), 7.71 (d, 2H,
J = 8.4 Hz, aromatic protons), 8.18 (d, 2H, J = 8.4 Hz,
aromatic protons), 8.61 (brs, 1H, ―NHSO2―), 9.19
(s, 1H, ―NHNH2); 13C NMR (100 MHz, DMSO‐d6): δ
38.79 (―CH2―), 57.12 (―CH―), 124.46, 126.67,
128.01, 128.44, 129.63, 137.38, 147.02, 149.51 (aromatic
carbons), 169.55 (C═O); anal. calcd. for C15H16N4O5S:
C, 49.44; H, 4.43; N, 15.38; S, 8.80%. Found: C, 49.96;
H, 4.67; N, 15.20; S, 8.57%.
nitrobenzenesulfonamido)‐3‐phenyl
propanoyl]‐4‐[(4‐nitro)phenyl]
thiosemicarbazide (3a)
Yellow solid; yield 74%; mp. 196°C to 197°C; [α]
= +59.4 (c: 0.67, THF); UV‐Vis (DMF, λmax, nm
D
(Abs)): 405 (0.981), 354 (0.819), 273 (1.325); IR (νmax
,
cm−1): 3292 (N―H), 1711 (C═O), 1596 (C═N), 1537
(NO2, asymmetric), 1332 (SO2, asymmetric), 1307
(C═S), 1278 (NO2, symmetric), 1159 (SO2, symmetric);
EI‐MS (m/z): 545.0 [M + H]+; 1H NMR (400 MHz,
DMSO‐d6): δ 2.67 (t, 1H, ―CH2―, Hb), 3.09 (brs, 1H,
―CH2―, Ha), 4.20 (brs, 1H, ―CH―), 7.06 to 7.15
(m, 5H, aromatic protons), 7.71 (d, 2H, J = 8.4 Hz,
aromatic protons) 7.87 (d, 2H, J = 8.4 Hz, aromatic
protons), 8.10 (brs, 2H, aromatic protons), 8.19 (d, 2H,
J
= 8.4 Hz, aromatic protons), 8.79 (brs, 1H,
―NHSO2―), 10.18 (brs, 1H, N3―H), 10.41 (brs, 1H,
N1―H), 10.60 (s, 1H, N2―H); 13C NMR (100 MHz,
DMSO‐d6): δ 38.71 (―CH2―); 56.99 (―CH―); 121.53,
124.49, 124.65, 125.09, 126.73, 128.05, 128.46, 129.70,
137.28, 143.43, 146.76, 149.46 (aromatic carbons),
2.3.2 | (+)‐(S)‐2‐(4‐
nitrobenzenesulfonamido)‐3‐phenyl
propanylhydrazide (2b)
Yellow solid; yield 82%; mp. 187°C to 188°C; [α]D = +48.5
(c: 0.67, THF); UV‐Vis (DMF, λmax, nm (Abs)): 353
(0.034), 280 (0.703), 270 (0.783); IR (νmax, cm−1): 3326
and 3262 (N―H), 1665 (C═O), 1520 (NO2, asymmetric),
1338 (SO2, asymmetric), 1288 (NO2, symmetric), 1159
(SO2, symmetric); EI‐MS (m/z): 365.2 [M]+; 1H NMR
(400 MHz, DMSO‐d6): δ 2.64 (dd, 1H, J1 = J2 = 10.2 Hz,
―CH2―, Hb), 2.77 (dd, 1H, J1 = 6.0 Hz, J2 = 5.4 Hz,
―CH2―, Ha), 3.93 (brs, 1H, ―CH―), 4.04 (brs, 2H,
―NHNH2), 7.05 to 7.13 (m, 5H, aromatic protons), 7.71
(d, 2H, J = 8.4 Hz, aromatic protons), 8.18 (d, 2H,
J = 8.4 Hz, aromatic protons), 8.60 (brs, 1H, ―NHSO2―),
9.19 (s, 1H, ―NHNH2); 13C NMR (100 MHz, DMSO‐d6):
169.48
(C═O),
180.96
(C═S);
anal.
calcd.
for C22H20N6O7S2: C, 48.52; H, 3.70; N, 15.43; S,
11.78%. Found: C, 48.25; H, 3.71; N, 15.29; S, 11.30%
2.4.2 | (−)‐(S)‐1‐[2‐(4‐
nitrobenzenesulfonamido)‐3‐phenyl
propanoyl]‐4‐[(4‐nitro)phenyl]
thiosemicarbazide (3b)
Yellow solid; yield 72%; mp. 196°C to 197°C; [α]D = −59.7
(c: 0.67, THF); UV‐Vis (DMF, λmax, nm (Abs)):405
(0.976), 354 (0.799), 273 (1.308); IR (νmax, cm−1):

4
BAŞARAN ET AL.
3293 (N―H), 1712 (C═O), 1596 (C═N), 1538 (NO2,
asymmetric), 1332 (SO2, asymmetric), 1307 (C═S), 1278
(NO2, symmetric), 1159 (SO2, symmetric); EI‐MS (m/z):
544.6 [M]+;1H NMR (400 MHz, DMSO‐d6): δ 2.66 (t, 1H,
―CH2―, Hb), 3.09 (brs, 1H, ―CH2―, Ha), 4.20
(brs, 1H, ―CH―), 7.06 to 7.15 (m, 5H, aromatic protons),
7.71 (d, 2H, J = 8.4 Hz, aromatic protons) 7.87 (d, 2H,
J = 8.4 Hz, aromatic protons), 8.10 (brs, 2H, aromatic
protons), 8.19 (d, 2H, J = 8.4 Hz, aromatic protons),
8.78 (brs, 1H, ―NHSO2―), 10.15 (brs, 1H, N3―H),
10.47 (brs, 1H, N1―H), 10.60 (s, 1H, N2―H); 13C NMR
2.5.2 | Synthesis of [Ni(3a)(OAc)2] 2C4H8O
(3a‐Ni)
The 3a‐Ni complex was synthesized following the
analogous procedure as given above using Ni
(CH3COO)2.4H2O (0.124 g, 0.5 mmol) and 3a ligand
(0.273 g, 0.5 mmol). The compound was purified by
crystallization from a mixture of THF/MeOH. The
3a‐Ni complex was obtained as a green solid. Yield:
80%. mp. 193°C decomp.; μeff: 0.67 B.M. UV‐Vis (DMF,
λmax, nm (Abs)):520 (0.051), 442 (0.391), 405 (0.586),
(100 MHz, DMSO‐d6):
δ
38.72 (―CH2―), 56.98
357 (0.427), 287 (0.617), 270 (0.721); IR (νmax, cm−1):
3292 (N―H), 1712 (C═O), 1597 (C═N), 1538 (NO2,
asymmetric), 1327 (SO2, asymmetric), 1302 (C═S),
1159 (SO2, symmetric), 567 (M―N), 491 (M―O); EI‐MS
(m/z): 863.2 [M + H]+; anal. calcd. for C34H40N6NiO13S2:
C, 47.29; H, 4.67; N, 9.73; S, 7.43%. Found: C, 46.90;
H, 4.26; N, 9.50; S, 7.38%.
(―CH―), 121.53, 124.50, 124.70, 125.10, 126.73, 128.05,
128.46, 129.70, 137.22, 145.96, 146.87, 149.46 (aromatic
carbons), 169.48 (C═O), 180.97 (C═S); anal. calcd.
for C22H20N6O7S2: C, 48.52; H, 3.70; N, 15.43; S, 11.78%.
Found: C, 48.68; H, 3.97; N, 15.01; S, 11.75%.
2.5.3 | Synthesis of [Pd(3a)(OAc)2] 2C4H8O
(3a‐Pd)
2.5 | Synthesis of chiral
thiosemicarbazides metal complexes
(3a‐Cu/Ni/Pd/Zn and 3b‐Cu/Ni/Pd/Zn)
The 3a‐Pd complex was synthesized following the
analogous procedure as given above using Pd (CH3COO)2
(0.112 g, 0.5 mmol) and 3a ligand (0.273 g, 0.5 mmol).
The compound was purified by crystallization from a
mixture of THF/MeOH. The 3a‐Pd complex was obtained
as a brown solid. Yield: 50%. mp. 133°C decomp.; μeff: dia.
UV‐Vis (DMF, λmax, nm (Abs)):518 (0.104), 445 (0.449),
400 (0.676,), 354 (0.552), 274 (0.905), 270 (0.978); IR
(νmax, cm−1): 3287 (N―H), 1708 (C═O), 1596 (C═N),
1524 (NO2, asymmetric), 1327 (SO2, asymmetric), 1303
(C═S), 1158 (SO2, symmetric), 563 (M―N), 487 (M―O);
A solution of the corresponding ligand (0.5 mmol) in
20 mL of THF/MeOH (4:1) was added by continuous
stirring to a M (AcO)2.nH2O (0.5 mmol) in methanol
(10 mL) solution. The reaction mixture was stirred at
70°C. After 30 minutes, the obtained solid was filtered
and washed with methanol and diethylether, and
dried in a vacuum. The compound was purified by
crystallization from a mixture of THF/MeOH.
EI‐MS (m/z): 911.2 [M
+
H]+; anal. calcd. for
C34H40N6O13PdS2: C, 44.81; H, 4.42; N, 9.22; S, 7.04%.
Found: C, 45.09; H, 4.01; N, 9.18; S, 7.11%
2.5.1 | Synthesis of [Cu(3a)(OAc)2] 5H2O
(3a‐Cu)
The 3a‐Cu complex was synthesized following the
analogous procedure as given above using Cu
(CH3COO)2.H2O (0.100 g, 0.5 mmol) and 3a ligand
(0.273 g, 0.5 mmol). The compound was purified by
crystallization from a mixture of THF/MeOH. The
3a‐Cu complex was obtained as a dark green solid. Yield:
62%. mp. 203°C decomp.; μeff: 1.63 B.M. UV‐Vis (DMF,
2.5.4 | Synthesis of [Zn(3a)(OAc)2] 2C4H8O
(3a‐Zn)
The 3a‐Zn complex was synthesized following the
analogous procedure as given above using Zn
(CH3COO)2.2H2O (0.109 g, 0.5 mmol) and 3a ligand
(0.273 g, 0.5 mmol). The compound was purified by
crystallization from a mixture of THF/MeOH. The
3a‐Zn complex was obtained as a yellow solid. Yield:
λmax, nm (Abs)): 519 (0.056), 445 (0.160), 345 (0.414),
285 (0.385), 270 (0.442); IR (νmax, cm−1): 3587 (O―H),
3300 (N―H), 1703 (C═O), 1598 (C═N), 1527 (NO2,
asymmetric), 1330 (SO2, asymmetric), 1304 (C═S), 1273
(NO2, symmetric),1155 (SO2, symmetric), 577 (M―N),
492 (M―O); EI‐MS (m/z): 814.2 [M + H]+; anal. calcd.
for C26H34CuN6O16S2: C, 38.35; H, 4.21; N, 10.32; S,
7.88%. Found: C, 38.77; H, 3.91; N, 9.75; S, 7.21%.
72%. mp. 200°C decomp.; μeff: dia UV‐Vis (DMF, λmax
,
nm (Abs)):517 (0.045), 483 (0.119), 442 (0.383), 400
(0.665), 284 (0.719), 270 (0.762); IR (νmax, cm−1):
3292 (N―H), 1712 (C═O), 1596 (C═N), 1531 (NO2,
asymmetric), 1326 (SO2, asymmetric), 1290 (C═S),
1158 (SO2, symmetric), 554 (M―N), 491 (M―O); EI‐MS

BAŞARAN ET AL.
5
(m/z): 870.5 [M + H]+; anal. calcd. for C34H40N6O13S2Zn:
C, 46.93; H, 4.63; N, 9.66; S, 7.37%. Found: C, 46.84;
H, 4.51; N, 9.65; S, 7.24%.
(0.699), 355 (0.603), 270 (0.963); IR (νmax, cm−1): 3236
(N―H), 1698 (C═O), 1596 (C═N), 1524 (NO2, asymmet-
ric), 1327 (SO2, asymmetric), 1306 (C═S), 1159 (SO2,
symmetric), 554 (M―N), 491 (M―O); EI‐MS (m/z):
911.6 [M + H]+; anal. calcd. for C34H40N6O13PdS2:
C, 44.81; H, 4.42; N, 9.22; S, 7.04%. Found: C, 45.37;
H, 4.10; N, 9.39; S, 7.35%.
2.5.5 | Synthesis of [Cu(3b)(OAc)2] 2C4H8O
(3b‐Cu)
The 3b‐Cu complex was synthesized following an
analogous procedure as given above using Cu
(CH3COO)2.H2O (0.100 g, 0.5 mmol) and 3b ligand
(0.273 g, 0.5 mmol). The compound was purified by
crystallization from a mixture of THF/MeOH. The
3b‐Cu complex was obtained as a dark green solid. Yield:
2.5.8 | Synthesis of [Zn(3b)(OAc)2] 2C4H8O
(3b‐Zn)
The 3b‐Zn complex was synthesized following the
analogous procedure as given above using Zn
(CH3COO)2.2H2O (0.109 g, 0.5 mmol) and 3b ligand
(0.273 g, 0.5 mmol). The compound was purified by crys-
tallization from a mixture of THF/MeOH. The 3b‐Zn
complex was obtained as a yellow solid. Yield: 78%. mp.
166°C decomp.; UV‐Vis (DMF, λmax, nm (Abs)): 502
(0.082), 400 (0.691), 354 (0.596), 285 (0.780), 270 (0.831);
IR (νmax, cm−1): 3292 (N―H), 1713 (C═O), 1596 (C═N),
1531 (NO2, asymmetric), 1326 (SO2, asymmetric), 1290
(C═S), 1158 (SO2, symmetric), 555 (M―N), 491 (M―O);
70%. mp. 130°C dec.; μeff: 1.82 B.M. UV‐Vis (DMF, λmax
,
nm (Abs)):504 (0.140), 350 (1.727), 398 (1.339), 273;
(1.871). IR (νmax, cm−1): 3297 (N―H), 1704 (C═O), 1595
(C═N), 1526 (NO2, asymmetric), 1327 (SO2, asymmetric),
1305 (C═S), 1156 (SO2, symmetric), 553 (M―N), 491
(M―O); EI‐MS (m/z): 868.1 [M + H]+; anal. calcd. for
C34H40CuN6O13S2: C, 47.03; H, 4.64; N, 9.68; S, 7.38%.
Found: C, 47.34; H, 4.45; N, 9.16; S, 7.22%.
EI‐MS (m/z): 869.7 [M
+
H]+; anal. calcd. for
2.5.6 | Synthesis of [Ni(3b)(OAc)2] 2C4H8O
(3b‐Ni)
C34H40N6O13S2Zn: C, 46.93; H, 4.63; N, 9.66; S, 7.37%.
Found: C, 46.96; H, 4.36; N, 9.75; S, 7.25%
The 3b‐Ni complex was synthesized following an
analogous procedure as given above using Ni
(CH3COO)2.4H2O (0.124 g, 0.5 mmol) and 3b ligand
(0.273 g, 0.5 mmol). The compound was purified by
crystallization from a mixture of THF/MeOH. The 3b‐
Ni complex was obtained as a green solid. Yield: 75%.
2.6 | Determination of antioxidant
activity
Solutions in dimethylsulfoxide (DMSO) of synthesized
compounds were prepared at 200‐100‐50‐25 μM concen-
trations. DMSO was used as a control, while α‐tocopherol
(α‐TOC) and butylated hydroxytoluene (BHT) were used
as antioxidant standards for comparison of the activity.
The results were given as a 50% concentration (IC50) of
β‐carotene‐linoleic acid, DPPH. scavenging, superoxide
anion radical scavenging, and ABTS.+ scavenging activity
assays. The sample concentration was calculated from the
graph of antioxidant activity percentage against sample
concentration, while results of the CUPRAC capacity
activity assay were given as absorbance (A0.5).
mp. 174°C decomp.; μeff: 0.89 B.M. UV‐Vis (DMF, λmax
,
nm (Abs)): 520 (0.037), 444 (0.332), 405 (0.508), 354
(0.391), 281 (0.596), 270 (0.662); IR (νmax, cm−1):
3293 (N―H), 1712 (C═O), 1597 (C═N), 1538 (NO2,
asymmetric), 1327 (SO2, asymmetric), 1308 (C═S),
1159 (SO2, symmetric), 567 (M―N), 491 (M―O); EI‐MS
(m/z): 863.5 [M + H]+; anal. calcd. for C34H40N6NiO13S2:
C, 47.29; H, 4.67; N, 9.73; S, 7.43%. Found: C, 47.66;
H, 4.32; N, 9.84; S, 7.40%
The total antioxidant activity was determined using
the β‐carotene‐linoleic acid assay.15,16 The DPPH free
radical scavenging method and ABTS.+ scavenging
method described by Blois17 and Re et al,18 respectively,
with slight modifications16 were used to determine
antioxidant activity. In addition, the superoxide anion
radical scavenging activity (O2•−) was evaluated accord-
ing to the method described by Liu et al19 with slight
modification. The CUPRAC capacity was tested accord-
ing to the methods of Apak et al20 and Öztürk et al.16
2.5.7 | Synthesis of [Pd(3b)(OAc)2] 2C4H8O
(3b‐Pd)
The 3b‐Pd complex was synthesized following the
analogous procedure as given above using Pd (CH3COO)2
(0.112 g, 0.5 mmol) and 3b ligand (0.273 g, 0.5 mmol).
The compound was purified by crystallization from a
mixture of THF/MeOH. The complex 3b‐Pd was obtained
as a brown solid. Yield: 65%. mp. 141°C decomp.; UV‐Vis
(DMF, λmax, nm (Abs)): 518 (0.104), 444 (0.442), 400

6
BAŞARAN ET AL.
Metal complexes were synthesized from the reaction of
ligands 3a or 3b with Cu (II), Ni (II), Pd (II), and Zn (II)
metal salts in THF/MeOH, respectively. Compounds 3a
and 3b are the R and S forms of the same compound.
Eight different metal compounds were synthesized from
the reaction of the ligand compounds in R and S form
with four different metal salts. The colors, melting points,
and magnetic moment values of these complexes are
different from each other. The general formula of the
complexes is [ML (OAc)2] xH2O/C4H8O. These complexes
are generally soluble in DMF, acetonitrile, and THF.
The complexes are colored and air stable. The complex
compounds were purified by crystallization, but not a
single crystal was obtained for the X‐ray. NMR spectra
could not be obtained because the diamagnetic complexes
could not be fully dissolved in the active solvents by
NMR. The IR spectra of the thiosemicarbazide ligands
3a and 3b displaying a sharp band around 1711 cm−1
and 1712 cm−1 were assigned to carbonyl group
stretching, respectively. However, this band in the
complexes was shifted to higher or lower (1‐8 cm−1 for
3a, 1‐14 cm−1 for 3b) wavenumbers, indicating the
participation of carbonyl oxygen in coordination with
the metal ion.23 Moreover, a new band in the complexes
at 577 to 553 cm−1 and 492 to 487 cm−1 is attributed
to the v(M―N) and v(M―O) vibrations, respectively
(Figure 1).23,24
3 | RESULTS AND DISCUSSION
3.1 | Chemistry
The target compounds were synthesized and carried out as
indicated in Scheme 1. (R)‐1‐[2‐(4‐nitrobenzenesul
fonamido)‐3‐phenylpropanoyl] ‐4‐[(4‐nitro)phenyl]thiose
micarbazide (3a) and (S)‐1‐[2‐(4‐nitrobenzenesulfona
mido)‐3‐phenylpropanoyl]‐4‐[(4‐nitro)phenyl]thiosemica
rbazide (3b) were synthesized by condensing acid hydra-
zide with 4‐nitrophenylisothiocyanate in methanol.21 The
elucidation of the chemical structures of all compounds
were determined by UV‐Vis, IR, 1H NMR, 13C NMR, mass
spectral data, and elemental analysis. The IR spectra of
novel chiral thiosemicarbazide ligands (3a‐3b) showed a
shift in the C═O stretching bands of hydrazides in a range
of 1665 to 1712 cm−1. An absorption band of the
thiocarbonyl group ν(C═S) was detected at 1307 cm−1
and the absorption band of ν(N―H) was attributed to
,
1
3292 to 3293 cm−1 21,22
In the H NMR spectra of com-
.
pound 3a and 3b, three singlet peaks were observed due
to three different ―NH groups (N3―H, N1―H, N2―H)
around δ 10.15 to 10.18, δ 10.41 to 10.47, and δ
10.60 ppm, respectively (Figures S1, S3). Also, a broad
singlet peak at δ 3.93 ppm belonging to hydrazides
(―NH2) disappeared. In the 13C NMR spectra of
thiosemicarbazide derivatives (3a‐3b), the signal for car-
bonyl (C═O) carbons at δ 169.48 ppm and the thiocarbonyl
(C═S) carbons at δ 180.96 to 180.97 ppm was seen
(Figures S2‐S4) The chiral carbon atom of novel
thiosemicarbazides (3a‐3b) was present at δ 56.98 to
56.99 ppm in the 13C NMR spectra, and the proton at the
chiral center was observed at δ 4.20 ppm as a broad singlet
in the 1H NMR spectra.
The mass spectra of the thiosemicarbazide ligands 3a
and 3b revealed the molecular ion peak at m/e 545.0 and
544.6, respectively, which is compatible with the formula
weight after adding approximately one proton (544.08)
and supporting of the identity of the structures (Figure 2).
Molecular ion peaks of metal complexes were associated
with their formula weights at m/z 814.2 [[Cu(3a)(OAc)2]
SCHEME 1 Synthesis of chiral
compounds in (R)‐enantiomeric form.
Reagents and condition: (i) 4‐
nitrobenzensulfonyl chloride, DCM,TEA,
pyridine, 0°C 30 min, reflux 3 h; (ii)
NH2NH2.H2O (%98), MeOH, reflux, 6 h;
(iii) 4‐nitrophenylisothiocyanate, MeOH,
reflux, 8 to 10 h; (iv)THF‐MeOH 70°C,
30 min

BAŞARAN ET AL.
7
FIGURE 1 FT‐IR spectra of compounds 3a‐Pd and 3a
FIGURE 2 ESI‐mass spectra of compound 3a
5H2O]+, 863.2 [[Ni(3a)(OAc)2] 2C4H8O]+, 911.2 [[Pd(3a)
(OAc)2] 2C4H8O]+, 870.5 [[Zn(3a)(OAc)2] 2C4H8O]+,
868.1 [[Cu(3b)(OAc)2] 2C4H8O]+, 863.5 [[Ni(3b)(OAc)2]
2C4H8O]+, 911.6 [[Pd(3b)(OAc)2] 2C4H8O]+, and 869.7
[[Zn(3b)(OAc)2] 2C4H8O]+ (Figure 3).
The electronic absorption spectra of the complexes
were recorded at 25°C. When the UV‐Vis spectrum of
thiosemicarbazide ligands and their complexes were
examined, bands at 270 to 287 and 345 to 405 nm
were observed (Figure 4). These bands indicate π‐π* and

8
BAŞARAN ET AL.
FIGURE 3 ESI‐mass spectra of compound 3a‐Pd
FIGURE 4 UV‐vis spectra of
compounds 3a‐Pd and 3a
n‐π* transitions. The bands seen in the range of 398 to
483 nm indicate the presence of charge transfer transi-
tions. The bands seen in the range of 502 to 520 nm
indicate the presence of d‐d transitions. When the
magnetic moment value of the compounds was exam-
ined, it was seen that the Zn (II) and Pd (II) complexes
are diamagnetic. When the Ni (II) complexes were
examined, it was seen that μeff value was 0.67 BM for
3a‐Ni and 0.89 BM for 3b‐Ni. It was thought that the
3a‐Ni and 3b‐Ni complexes were close to the diamagnetic
value and had a square planar structure.25 When the Cu
(II) complexes were examined, the μeff value of 1.63 BM
for 3a‐Cu and 1.82 BM for 3b‐Cu were observed.
The 3b‐Cu and 3a‐Cu complexes are thought to be in
the square planar structure. Square planar complexes
show lower magnetic moment values in the range of
1.8 to 1.9 BM.26
3.2 | Antioxidant activities of synthesized
compounds
The antioxidant activity of synthesized complex com-
pounds was screened by using five different assays
(Table 1). α‐tocopherol (α‐TOC) and butylated hydroxyl
toluene (BHT) were used as the positive standards

BAŞARAN ET AL.
9
TABLE 1 Antioxidant activity results of compoundsa
•−
Sample
Code
β‐Carotene/Linoleic
Acid Assay IC50, μM
DPPH.. Assay
IC50, μM
ABTS.+ Assay
IC50, μM
O2 Assay
CUPRAC
A0.50, μM
IC50, μM
1a
14.37 0.42
19.32 0.11
22.60 0.68
25.45 0.94
26.88 0.17
28.09 0.33
20.55 0.69
24.10 0.92
18.01 0.15
18.96 0.68
15.73 0.44
17.30 0.56
21.64 0.38
25.70 0.23
2.31 0.11
4.48 0.17
20.18 0.64
21.74 0.50
24.41 0.58
26.03 0.07
26.56 0.34
27.35 0.29
26.25 0.47
28.08 0.18
24.27 0.24
25.06 0.85
22.08 0.49
23.11 0.20
26.40 0.72
29.71 0.96
54.80 0.78
12.21 0.06
8.20 0.61
12.74 0.32
14.66 0.37
19.50 0.33
21.93 0.54
24.07 0.15
26.90 0.44
31.06 0.12
21.49 0.36
23.93 0.18
19.01 0.77
19.68 0.21
29.33 0.29
35.61 0.52
2.97 0.50
4.95 0.30
11.26 0.60
15.09 0.43
19.25 0.60
26.48 0.22
23.11 0.13
30.08 0.52
29.49 0.30
36.16 0.84
23.83 0.41
26.39 0.65
18.68 0.35
20.37 0.24
31.97 0.36
40.81 0.74
22.81 0.84
8.61 0.29
16.95 0.01
20.04 0.04
21.44 0.00
26.15 0.02
25.73 0.02
27.18 0.02
26.70 0.03
31.03 0.01
20.13 0.03
23.45 0.00
19.81 0.01
21.07 0.01
35.80 0.03
40.22 0.04
3.92 0.04
40.44 0.03
1b
2a
2b
3a
3b
3a‐Cu
3b‐Cu
3a‐Ni
3b‐Ni
3a‐Pd
3b‐Pd
3a‐Zn
3b‐Zn
b
BHT
α‐TOCb
aValues expressed are means SD of three parallel measurements. P < 0.05, significantly different with Student's t‐test.
bReference compounds.
of assays. According to the antioxidant activity
assay results, compounds 3a‐Pd (IC50 = 15.73 0.44 μM),
as the standard. Also, compounds 3a‐Pd (A0.5
=
19.81 0.01 μM) and 3a‐Ni (A0.5 = 20.13 0.03 μM) were
determined to be the most active compounds
for CUPRAC capacity activity.
3b‐Pd (IC50 = 17.30
0.56 μM), 3a‐Ni (IC50 =
18.01 0.15 μM), and 3b‐Ni (IC50 = 18.96 0.68 μM)
within synthesized products exhibited the most
activity for the lipid peroxidation inhibitory activity.
In the DPPH free scavenging activity, all synthesis
products were found to be more active than BHT
(IC50 = 54.80 0.78 μM) as a standard, while the IC50
values of compounds 3a‐Pd, 3b‐Pd, and 3a‐Ni were
lower than 25 μM, which showed more active compounds
Chelation has a key role in the enhanced biological
activity of the complexes over the ligands.27 Especially,
the presence of electron‐donating N‐terminal groups in
the thiosemicarbazone ligands increased antioxidant
activity.27 Antioxidants are reducing agents. The ability
to give off electrons for an antioxidant compound deter-
mines its antioxidant power. In this study, among the
complexes, the Pd complex exhibited the highest antioxi-
dant activity in five complementary assays, followed by
nickel complex, copper complex, and zinc complex,
respectively. The electro‐negativity of the central atom is
the main reason for the activity. The electronegativity of
Pd, Ni, Cu, and Zn are 2.20, 1.91, 1,90, and 1.65, respec-
tively. In the same order, the antioxidant activity decreases
(Table 1). In other words, the electronegativity of Pd is the
highest, and the antioxidant activity was the highest.
Because of the large diameter of Pd among complex
formed metals, antioxidant activity is active.28 Accord-
ingly, the electronegativity of Zn is the lowest, and the
antioxidant activity was the lowest. An electronegative
metal ion attracts the electrons of the coordination bond,
inductively. Therefore, in case of more electronegative
central atom, the nitrogen atom having coordination bond
with IC50 value of 22.08
0.49, 23.11
0.20, and
24.27 0.24 μM, respectively. Among the tested
compounds, the compound 3a‐Pd (IC50 = 19.01 0.77 μM)
was found to be more active in the cation
radical scavenging activity in ABTS.+ activity, while
compounds 3b‐Pd (IC50 = 19.68
0.21 μM), 3a‐
Ni (IC50 21.49 0.36 μM), and 3b‐Ni
=
(IC50 = 23.93 0.18 μM) showed the best cation radical
scavenging activity in ABTS.+ activity. In the superoxide
anion radical scavenging activity assay, compounds
3a‐Pd and 3b‐Pd indicated more active compounds with
the IC50 value of 18.68
0.35 and 20.37
0.24 μM,
respectively, than BHT (IC50 = 22.81
0.84 μM) as
the standard. In the CUPRAC reduced power assay,
all of the complexes exhibited excellent activity than
α‐TOC (A0.5 = 40.44
0.03 μM) using pharmaceutical

10
BAŞARAN ET AL.
in the ligand becomes more electropositive—the electro-
negativity of the carbon atom between two nitrogen atoms
decreases. Therefore, the electron‐donating ability or gen-
erating hydrogen radical of sulfur increases. This affects
antioxidant activity results. Moreover, the antioxidant
activity of complex compounds is related to various factors
such as involving donor atom type present in ligand, the
type of metal ion and metal salt anion, the overall charge
on the complex ion, and coordination geometry.29
Emine Elçin Oruç‐Emre https://orcid.org/0000-0001-6840-
9660
Mehmet Sönmez https://orcid.org/0000-0003-3127-666X
Mehmet Öztürk https://orcid.org/0000-0001-8932-4535
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How to cite this article: Başaran E, Sıcak Y,
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