Synthesis and biological evaluation of thiosemicarbazone derivatives

Abstract

In this study, firstly, 22 thiosemicarbazone derivatives (3a-y) were synthesized. Then, ADME parameters, pharmacokinetic properties, drug-like structures, and suitability for medicinal chemistry of these molecules were studied theoretically by using SwissADME and admetSAR programs. According to the results of these theoretical studies, it can be said that the bioavailability and bioactivity of these compounds may be high. In silico molecular docking between ligands (thiosemicarbazone derivatives) and targeted proteins (protein-78 (GRP78) for C6 and quinone reductase-2 (4ZVM for MCF 7) was analyzed using Hex 8.0.0 docking software. According to the docking data, almost all molecules had higher negative E values than Imatinib (already used as a drug). For this, in vitro anticancer studies of these molecules were done. The cytotoxic activities of thiosemicarbazone derivatives (3a-y) were evaluated on C6 glioma and MCF7 breast cancer cell lines at 24 h, and Imatinib was used as the positive control. According to the results of the cytotoxicity assay, it can be said that the five compounds (3b, c, f, g, and m with IC50 = 10.59–9.08 μg/mL; Imatinib IC50 = 11.68 μg/mL) showed more potent cytotoxic activity than Imatinib on C6 cell line. Together with to these results ten compounds (3b, d, f, g, I, k, l, m, n, and r with IC50 = 7.02–9.08 μg/mL; Imatinib IC50 = 9.24 μg/mL) had a more effective cytotoxic activity against MCF7 cell line than Imatinib. Compound 3 m showed the highest antiproliferative effect against C6 and MCF7 cell lines.

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Medical Oncology (2022) 39:157
https://doi.org/10.1007/s12032-022-01784-y
ORIGINAL PAPER
Synthesis andbiological evaluation ofthiosemicarbazone derivatives
MuratDoğan1· ÜmitM.Koçyiğit2· MelihaBurcuGürdere3 · MustafaCeylan3· YakupBudak3
Received: 8 June 2022 / Accepted: 22 June 2022 / Published online: 21 July 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
In this study, firstly, 22 thiosemicarbazone derivatives (3a-y) were synthesized. Then, ADME parameters, pharmacokinetic
properties, drug-like structures, and suitability for medicinal chemistry of these molecules were studied theoretically by
using SwissADME and admetSAR programs. According to the results of these theoretical studies, it can be said that the
bioavailability and bioactivity of these compounds may be high. In silico molecular docking between ligands (thiosemi-
carbazone derivatives) and targeted proteins (protein-78 (GRP78) for C6 and quinone reductase-2 (4ZVM for MCF 7) was
analyzed using Hex 8.0.0 docking software. According to the docking data, almost all molecules had higher negative E val-
ues than Imatinib (already used as a drug). For this, invitro anticancer studies of these molecules were done. The cytotoxic
activities of thiosemicarbazone derivatives (3a-y) were evaluated on C6 glioma and MCF7 breast cancer cell lines at 24h,
and Imatinib was used as the positive control. According to the results of the cytotoxicity assay, it can be said that the five
compounds (3b, c, f, g, and m with IC50 = 10.59–9.08μg/mL; Imatinib IC50 = 11.68μg/mL) showed more potent cytotoxic
activity than Imatinib on C6 cell line. Together with to these results ten compounds (3b, d, f, g, I, k, l, m, n, and r with
IC50 = 7.02–9.08μg/mL; Imatinib IC50 = 9.24μg/mL) had a more effective cytotoxic activity against MCF7 cell line than
Imatinib. Compound 3m showed the highest antiproliferative effect against C6 and MCF7 cell lines.
Keywords Thiosemicarbazone· C6· MCF 7· SwissADME· Anticancer· Molecular docking
Introductıon
Thiosemicarbazones are compounds obtained by the reac-
tion of thiosemicarbazide with aldehydes and ketones. Due
to their biological activities and pharmacological proper-
ties, they have been the subject of many studies in recent
years. Thiosemicarbazones have important pharmacological
properties such as anti-cancer [1, 2], anti-microbial [3], anti-
bacterial [4, 5], anti-fungal [6], enzyme inhibition [7]. Thio-
semicarbazones, many of whose compounds have medicinal
features, show activity against tuberculosis, leprosy, cancer,
bacterial and viral infections, psoriasis, rheumatoid arthritis
[8, 9], and malaria. Also, the functional groups and aromatic
rings in their structures are very effective in showing the
pharmacological effects of thiosemicarbazones [10]. In addi-
tion, they have a wide range of physical and electrochemi-
cal properties such as potentiometric sensor against many
metals. [11–14] Cancer is one of the most difficult diseases
in the world and in our country in terms of response to treat-
ment [15]. Cancer is defined as the uncontrolled division,
proliferation, and spread of cells in an organism. It can affect
a single organ as well as spread to distant organs. Due to
the problems experienced in the effectiveness of existing
drugs and treatment methods used in cancer treatment and
the side-effect profiles that may arise, studies on the synthe-
sis of new molecules that can be effective in treatment have
intensified [16, 17].
The aim of this study includes the synthesis, theoreti-
cal, and invitro studies of thiosemicarbazone derivatives
that we think have anticancer activity potential in the litera-
ture studies. For this purpose, firstly, 22 thiosemicarbazone
derivatives were synthesized. Then, ADME parameters,
pharmacokinetic properties, drug-like structure, and suit-
ability for medicinal chemistry of these compounds were
tried to be explained theoretically by using SwissADME
* Meliha Burcu Gürdere
burcugurdere@gmail.com
1 Department ofBasic Pharmaceutical Sciences, Cumhuriyet
University, Sivas, Turkey
2 Department ofPharmaceutical Biotechnology, Cumhuriyet
University, Sivas, Turkey
3 Faculty ofScience andArts, Department ofChemistry, Tokat
Gaziosmanpaşa University, 60250Tokat, Turkey

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and admetSAR programs. Also, Hex 8.0.0 docking software
was used to examine in silico molecular docking between
ligands (thiosemicarbazone derivatives) and targeted pro-
teins (protein-78 (GRP78) for C6 and quinone reductase-2
(4ZVM for MCF 7). Finally, the cytotoxicity of thiosemicar-
bazone derivatives (3a-y) was tested on C6 and MCF 7 cell
lines for 24h, with Imatinib serving as a positive control.
The purpose of cytotoxicity tests is to evaluate and calcu-
late the antiproliferative effects of the synthesized deriva-
tives against cancer cells and compare their effectiveness
compared to Imatinib. In addition, it is aimed to determine
thiosemicarbazone derivatives that show higher cytotoxic
activity than Imatinib in cancer cell lines with cell viability
test, and to be beneficial for more comprehensive studies
and scientific literature that can be performed in the future.
According to the results obtained, compounds with high
cytotoxic effects against cancer cells will benefit scientific
resources and will be instrumental in the development of
new ideas and projects.
Material andmethods
General synthetic procedure forthiosemicarbazones
(3a‑y)
To a solution of benzaldehyde derivatives (1a–y) (0.01mol)
in warm ethanol (30mL) was added two drops of acetic
acid and thiosemicarbazide (2) (0.01mol) in warm water
(30mL). The reaction mixture was stirred at room tempera-
ture for 4h and monitored by TLC. The precipitate was fil-
tered off and recrystallized from ethanol to afford the target
compounds 3a-y.
Determination ofdrug similarity properties
ofcompounds using Swiss ADME andAdmet SAR
programs
Today, computer-based calculation methods are used to
reduce or eliminate the harm and undesirable effects of
chemicals. Before starting preclinical studies, it is possible
to make predictions about the pharmacokinetic properties,
bioactivity, and drug similarity of the compounds by con-
ducting theoretical studies. While designing a drug mol-
ecule, preliminary information about many properties such
as water solubility, water carrying capacity, absorption in
the gastrointestinal tract, protein affinity, and toxicity can
be obtained. As a result of many years of studies on drugs,
various drug similarity rules such as Lipinski, MDDR-like,
Veber, Ghose filter, BBB, CMC-50-like rules, and Quanti-
fication of Drug Similarity (QED) have been established.
In this study, the properties of the compounds synthesized
using the Swiss ADME and Admet SAR programs will be
evaluated by investigating their similarities and superiorities
with the standard drug [18–21].
Molecular docking
Hexe 8.0.0 Docking program was used in the calculations
[19–22]. The molecular formulas of each of the 22 thiosemi-
carbazone derivatives (3a-y) selected as Ligands in the pro-
gram were drawn with the MarvinSketch 21.20 program and
stored as a pdb (Protein Date Bank/PDB) file. The pdb file
of the receptor proteins (carbonic anhydrase I–II isoenzymes
and acetylcholinesterase) was obtained from RCSB PDB
(http:// www. rscb. org/ pdb). To compare the data obtained,
standards currently used as market drugs were used ligands
(thiosemicarbazone derivatives) and targeted proteins (pro-
tein-78 (GRP78) for C6 and quinone reductase-2 (4ZVM for
MCF 7). Receptor and Ligand files were imported in the Hex
8.0 software. Energy of docking (E value) was calculated
using Hex 8.0. [22–26].
Cell culture studies
The C6 glioma (ATCC® CCL-107) cell line and the MCF
7 breast cancer (ATCC® HTB-22) cell lines were obtained
from ATCC. Penicillin/streptomycin (10,000 U/mL),
DMEM, Fetal Bovine Serum (FBS), Trypsin–EDTA solu-
tion, and various consumables required for cell culture were
used.
Cell culture study andconsumables
Cells proliferated in DMEM cell culture medium containing
1% l-glutamine, 1% penicillin–streptomycin, and 10% fetal
bovine serum in 25 cm2 flasks in an oven at 37°C and 5%
CO2. Cells were passaged when they reached 80% density
and studies were started after a certain passage.
XTT cell viability assay
The effects of the synthesized compounds on the cell via-
bility of C6 and MCF 7 cells were evaluated by applying
the XTT (2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-
[(phenylamino)carbonyl]-2H-tetrazolium hydroxide) test.
This study was carried out by using the method applied by
Wolf etal. [27]. Synthesized (thiosemicarbazone deriva-
tives) compounds (3a-y) at determined concentrations
were treated in each cell line, and the XTT cell viability
test was performed for each cell line. Imatinib was con-
sidered a positive control group. XTT method is based on
the principle that metabolically active cells convert XTT,
a tetrazolium salt, into orange-colored formazan crystals.
The resulting dye is water-soluble, and the dye density can
be read at certain wavelengths (450nm) using an ELISA

Medical Oncology (2022) 39:157
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reading device. The dye intensity in orange is proportional
to the number of metabolically active cells. For cytotoxicity
experiments, cells were seeded into a 96-well microplate
with 10 × 103 cells per well in 100 µL of DMEM (contain-
ing 10% FBS + 1% antibiotic) medium and incubated over-
night for cells to attach. The following day, after removing
the medium on the cells and washing the wells with PBS,
fresh medium was added to the cells. Samples of compounds
(3a-y) at concentrations of 2, 5, 10, 25, and 50µg/mL were
treated with cells and incubated for 24h. At the end of this
period, the medium was removed, and the cells were washed
three times with PBS.
Then, 100µL of colorless DMEM and 50µL of XTT
solution were added to each well and incubated for 4h in
a CO2 incubator. After the incubation, the optical density
value was read at 450nm in the microplate reader, the cell
viability rate of the control group was accepted as 100% and
it was calculated using the formula:
According to the results obtained, IC50 values of com-
pounds (3a-y) and imatinib were calculated.
Result anddiscussion
Synthesis thiosemicarbazone derivatives (3a‑y)
A series of thiosemicarbazones (3a-y) was reprepared from
the reaction of benzaldehydes (1a-y) with thiosemicar-
bazide (2) in ethanol/water, as a solvent, and a few drops
of CH3COOH at room temperature within 4h, according
to literature, [28–30] as shown in the Scheme1 (Table1).
Evaluation ofdrug similarity properties
ofcompounds
Selected compounds (3a-y) have high gastrointestinal
absorption values. Compounds with high absorption
also have high bioavailability. According to the results
%Cell viability =(Concentration O.D.∕Control O.D.)×100
obtained, it was observed that the mentioned compounds
cannot cross the blood–brain barrier. In our hypothesis
and application, which we determined within the scope of
our study, a feature such as the compounds' crossing the
blood–brain barrier was not sought. The compounds are
therefore suitable in this respect. In addition, the fact that
the compounds do not cross the blood–brain barrier would
prevent possible neurotoxicity. PGP substrate properties
were not observed in almost any compound (except 3d).
The absence of the PGP substrate feature is a feature that
increases the absorption and bioavailability of the com-
pounds. Compounds (3a-y) synthesized according to drug
similarity tests have drug similarity characteristics (Lipin-
ski, Weber, Egan). The H bond of the compounds (3a-y)
is similar to imatinib in terms of acceptor–donor prop-
erty and number. Although LogP values are lower than
imatinib, they are within the range of Lipinski rules and a
lower LogP value is desired compared to the target. This
is present in our compounds. Solubility in water is very
important in terms of absorption, distribution in body flu-
ids and tissues, metabolism, and elimination, respectively.
A chemical with poor water solubility has low bioavail-
ability. Thanks to the generally good water-soluble proper-
ties of the compounds, their dissolution, absorption, and
distribution in tissue fluids and blood will be more effec-
tive and higher. Thus, it can be said that the bioavailability
and bioactivity of the compounds may be high (Scheme2).
Evaluation ofmolecular docking results
ofthiosemicarbazone derivatives (3a‑y)
Table2 shows the binding affinity between the molecules and
targeted proteins using Hex 8.0.0 docking software. When
the data are examined, it is seen that many molecules have
higher negative E values against MCF7 and C6 than stand-
ard substance. Also, the highest negative E value against
MCF 7 is − 339.46kcal mol−1 with 3i and (E = − 308.16
kcalmol−1 for standard substance Imatinib). The high-
est negative E value against C6 was -352.52kcal mol−1
Scheme1 Synthesis of thiosemicarbazones (3a-y)

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Table 1 Synthesized thiosemicarbazone derivatives (3a-y)
Scheme2 Radar views of bioactivity for selected molecules

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with 3g (E = − 349.86kcal mol−1 for standard substance
Imatinib)(Table2).
Evaluation ofantiproliferative activity results
ofthiosemicarbazone derivatives (3a‑y)
The cytotoxic activities of thiosemicarbazone derivatives
(3a-y) were evaluated on C6 and MCF 7 cell lines at 24h
and Imatinib was used as a positive control. Antiprolifera-
tive activities and IC50 values of compounds (3a-y) differ
depending on the functional groups they contain and the
differences in ring structures. The results clearly show that
some compounds show more potent cytotoxic activity than
Imatinib in both C6 and MCF 7 cell lines in Table3. The
IC50 values of the positive control Imatinib against C6
and MCF 7 cell lines were calculated as 11.68 ± 0.18µg/
mL and 9.24 ± 0.21µg/mL, respectively. The IC50 values
of the compounds (3a-y) on the C6 cell line ranged from
10.59 ± 0.15 µg/mL to 17.65 ± 0.22 µg/mL. When the
results were evaluated, we can say that the IC50 values of
five compounds were lower than Imatinib, so they showed
a more effective antiproliferative effect than Imatinib.
In addition, the IC50 values of the compounds (3a-y) on
the MCF 7 cell line were between 7.02 ± 0.14µg/mL
and 11.38 ± 0.08µg/mL. It was clearly seen that nine
compounds show more potent cytotoxic activity against
MCF 7 cell line than Imatinib. Compounds with the high-
est antiproliferative effect against C6 cell line were 3m
(IC50: 10.59 ± 0.15µg/mL) and 3b (IC50: 10.76 ± 0.32µg/
mL), respectively. In a study performed by Yakan etal.
cytotoxic activity of thiosemicarbazone‐based enzyme
inhibitors was evaluated on MCF 7 and MDA-MB-231
cell lines. Results showed that some of these compounds
have a significant antiproliferative effect and cell culture
study results were consistent with the docking study [31].
In another study performed by Koçyiğit etal. it was con-
cluded that many of the isatin thiosemicarbazone compo-
nents showed antiproliferative activity in both cancer cells
[32]. Similarly, in our study, thiosemicarbazone deriva-
tives were observed to have significant cytotoxic activity
in C6 and MCF 7 cells. Thiophene ring in the structure of
3m and the methoxy group attached to the aromatic ring in
the structure of 3b were effective in the high antiprolifera-
tive effect of these derivatives. Also, the compounds with
the greatest cytotoxic activity in the MCF 7 cell line were
3m (IC50: 7.02 ± 0.14µg/mL) and 3r (IC50: 7.08 ± 0.28µg/
mL), respectively. The thiophene ring in the structure of
3m and the pyridine aromatic ring in the structure of 3r
ensured that these derivatives showed significant antipro-
liferative effects. It was observed that the antiprolifera-
tive activity of the mentioned derivatives on cell lines was
significantly higher than Imatinib. When the results were
evaluated in detail, the IC50 values of thiosemicarbazone
derivatives (3a-y) in the MCF 7 cell line were gener-
ally calculated to be lower than the IC50 values in the C6
cell line. In this case, it can be said that the synthesized
Table 2 Molecular docking results of thiosemicarbazone derivatives
(3a-y)
Com-
pounds E total (kcal mol−1) Compounds E total (kcal mol−1)
MCF 7 C6 MCF 7 C6
3a − 308.15 − 311.94 3m − 331.13 − 308.97
3b − 322.48 − 341.84 3n − 329.22 − 294.47
3c − 262.91 − 308.16 3o − 275.51 − 258.07
3d − 277.99 − 247.89 3p − 305.38 − 246.84
3e − 302.69 − 209.03 3r − 226.39 − 249.58
3f − 295.73 − 211.96 3s − 254.09 − 221.86
3g − 333.88 − 352.52 3t − 190.78 − 180.71
3h − 323.76 − 242.40 3u − 314.89 − 258.07
3i − 339.46 − 303.51 3v − 252.43 − 242.89
3j − 254.15 − 221.78 3y − 231.01 − 238.97
3k − 235.80 − 233.37 Drug
(Imatinib)
− 308.16 − 349.86
3l − 279.34 − 252.74
Table 3 IC50 values of thiosemicarbazone-derived compounds on C6
and MCF 7 cell lines (mean ± SD, n = 3)
Samples C6 IC50 (µg/mL) MCF 7 IC50 (µg/mL)
3a 12.02 ± 0.21 9.34 ± 0.16
3b 10.76 ± 0.32 8.88 ± 0.19
3c 11.62 ± 0.21 9.76 ± 0.09
3d 12.84 ± 0.16 9.08 ± 0.24
3e 13.05 ± 0.07 10.22 ± 0.19
3f 11.68 ± 0.17 8.64 ± 0.24
3g 10.98 ± 0.13 8.28 ± 0.14
3h 13.65 ± 0.22 9.94 ± 0.27
3i 11.73 ± 0.14 7.96 ± 0.09
3j 13.56 ± 0.21 9.32 ± 0.15
3k 12.25 ± 0.12 8.64 ± 0.24
3l 14.84 ± 0.32 7.78 ± 0.18
3m 10.59 ± 0.15 7.02 ± 0.14
3n 12.22 ± 0.19 7.32 ± 0.31
3o 14.36 ± 0.13 10.57 ± 0.14
3p 14.78 ± 0.27 10.75 ± 0.44
3r 15.65 ± 0.23 7.08 ± 0.28
3s 12.65 ± 0.13 9.75 ± 0.21
3t 17.65 ± 0.22 10.76 ± 0.26
3u 13.65 ± 0.22 10.22 ± 0.25
3v 13.65 ± 0.22 11.38 ± 0.08
3y 12.64 ± 0.18 9.96 ± 0.15
Imatinib 11.68 ± 0.18 9.24 ± 0.21

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compounds (3a-y) are more effective in MCF 7 cells and
show better cytotoxic activity, and inhibit the proliferation
of the cells more.
Conclusions
In this study, firstly, 22 thiosemicarbazone derivatives (3a-
y) were synthesized. It was observed that the compounds fit
Lipinski, Ghose, Veber, Egan, Muagge quarals in the calcu-
lations made with the SwissADME program. Thanks to the
generally good water-soluble properties of the compounds,
their dissolution, absorption, and distribution in tissue flu-
ids and blood will be more effective and higher. Thus, it
can be said that the bioavailability and bioactivity of the
compounds may be high. In the invitro culture study, the
effects of derivatives and imatinib synthesized in C6 and
MCF 7 cell lines on cell proliferation were investigated and
calculated. When the results were evaluated, it was observed
that the synthesized derivatives showed a cytotoxic effect on
cancer cells and decreased cell viability as desired. Espe-
cially 3m, 3b and 3r thiosemicarbazone derivatives showed
the highest cytotoxic activity in C6 and MCF 7 cells. It can
be said that the chemical groups or rings in the structures
of these synthesized derivatives have positive effects on
their antiproliferative effects. As a result, it can be said that
thiosemicarbazone derivatives can be effective compounds
in terms of their stated properties, according to the data
obtained from both SwissADME evaluations and invitro
cell culture studies.
Supplementary Information The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s12032- 022- 01784-y.
Acknowledgements This work is supported by the Scientific Research
Project Fund of Sivas Cumhuriyet University under the project number
SHMYO-013 and Scientific Research Projects Commission of Tokat
Gaziosmanpasa University (Project Number: 2019/54).
Declarations
Conflict of interest The authors declare that there are no conflicts of
interest.
References
1. Hu K, Yang Z, Pan S-S, etal. Synthesis and antitumor activity of
liquiritigenin thiosemicarbazone derivatives. Eur J Med Chem.
2010;45:3453–8.
2. Gürdere MB, Kamo E, Budak Y, etal. Synthesis and anticancer
and cytotoxic effects of novel 1,4-phenylene-bis-N-thiocarba-
moylpyrazole and 1,4-phenylene-bis-pyrazolylthiazole deriva-
tives. Turk J Chem. 2017;41:179–89.
3. Joseph M, Kuriakose M, Kurup MRP, etal. Structural, antimi-
crobial, and spectral studies of copper (II) complexes of 2-ben-
zoylpyridine N (4)-phenyl thiosemicarbazone. Polyhedron.
2006;25:61–70.
4. Gupta RP, Narayana NL. Synthesis of some Mannich bases of
1-cyclohexylidene-N(1,2-dihydro-2-oxo-3H-indol-3- ylidene)
thiosemicarbazones and their antibacterial activity. Pharm Acta
Helv. 1997;72:43–5.
5. Budak Y, Koçyiğit UM, Gürdere MB, etal. Synthesis and inves-
tigation of antibacterial activities and carbonic anhydrase and
acetyl cholinesterase inhibition profiles of novel 4,5-dihydro-
pyrazol and pyrazolyl-thiazole derivatives containing metha-
noisoindol-1,3-dion unit. Synth Commun. 2017;47:2313–23.
6. Khan SA, Asiri AMAA, Khan KA, etal. Synthesis of novel
schiff bases by microwave irradiation and their invitro antibac-
terial activity. Asian J Chem. 2013;25:8643–6.
7. Hashmi S, Khan S, Shafiq Z, etal. Probing 4-(diethylamino)-
salicylaldehyde-based thiosemicarbazones as multi-target
directed ligands against cholinesterases, carbonic anhydrases
and α-glycosidase enzymes. Bioorg Chem. 2021;107:104554.
8. Zambre AP, Kulkarni VM, Padhye S, etal. Novel curcumin
analogs targeting TNF-induced NF-jB activation and prolif-
eration in human leukemic KBM-5 cells. Bioorg Med Chem.
2006;14:7196–204.
9. Pavan FR, da Maia SP, Leite SRA, etal. Thiosemicarbazones,
semicarbazones, dithiocarbazates and hydrazide/hydrazones:
anti—mycobacterium tuberculosis activity and cytotoxicity.
Eur J Med Chem. 2010;45:1898–905.
10. Denny WA. Prodrug strategies in cancer therapy. Eur J Med
Chem. 2001;36:577–95.
11. Huseynova M, Taslimi P, Medjidov A, etal. Synthesis, charac-
terization, crystal structure, electrochemical studies and biologi-
cal evaluation of metal complexes with thiosemicarbazone of
glyoxylic acid. Polyhedron. 2018;2018(155):25–33.
12. Ozbek O, Isildak O, Gürdere MB, etal. Cadmium (II)-selective
potentiometric sensor based on synthesised (E)-2-benzylidene-
hydrazinecarbothioamide for the determination of Cd2+ in dif-
ferent environmental samples. Int J Environ Anal Chem. 2020.
https:// doi. org/ 10. 1080/ 03067 319. 2020. 18174 27.
13. Isildak Ö, Özbek O, Gürdere MB. Development of
chromium(III)-selective potentiometric sensor by using syn-
thesized pyrazole derivative as an ionophore in PVC matrix
and its applications. J Anal Test. 2020;4:273–80.
14. Özbek O. A novel potentiometric sensor for the determination of
Pb(II) Ions based on a carbothioamide derivative in PVC matrix.
J Turk Chem Soc Sect A. 2022;9(3):651–62.
15. DeSantis CE, Lin CC, Mariotto AB, etal. Cancer treatment and
survivorship statistics. CA Cancer J Clin. 2014;64:252–71.
16. Fitzmaurice C, Dicker D, Pain A, etal. The global burden of
cancer 2013. JAMA Oncol. 2015;1(4):505–27.
17. Pavlopoulou A, Spandidos DA, Michalopoulos I. Human cancer
databases (review). Oncol Rep. 2015;33(1):3–18.
18. Ritchie DW. Evaluation of protein docking predictions using
Hex 3.1 in CAPRI Rounds 1 and 2. Proteins Struct Funct Genet.
2003;52(1):98–106.
19. Ghoorah AW, Smail-Tabbone M, Devignes MD, etal. Protein
docking using case-based reasoning. Proteins Struct Funct
Genet. 2013;81:2150–8.
20. Ritchie DW. Recent progress and future directions in protein-
protein docking. Curr Prot Pep Sci. 2008;9(1):1–15.
21. Macindoe G, Mavridis L, Venkatraman V, etal. HexServer: an
FFT-based protein docking server powered by graphics proces-
sors. Nucleic Acids Res. 2010;38:W445–9.
22. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to
evaluate pharmacokinetics, drug-likeness and medicinal chem-
istry friendliness of small molecules. Sci Rep. 2017;7:42717.

Medical Oncology (2022) 39:157
1 3
Page 7 of 7 157
23. Yang H, Lou C, Sun L, etal. AdmetSAR 2.0: web-service for
prediction and optimization of chemical ADMET properties.
Bioinformatics. 2018;35(6):1067–9.
24. Yang H, Lou C, Sun L, etal. AdmetSAR 2.0: web-service for
prediction and optimization of chemical ADMET properties.
Bioinformatics. 2019;35(6):1067–9.
25. Cheng F, Li W, Zhou Y, etal. AdmetSAR: a comprehensive
source and free tool for assessment of chemical ADMET prop-
erties. J Chem Inf Model. 2012;52(11):3099–105.
26. Lipinski CA, Lombardo F, Dominy BW, etal. Experimental and
computational approaches to estimate solubility and permeability
in drug discovery and development settings. Adv Drug Deliv Rev.
1997;23(1–3):3–25.
27. Wolf NB, Kuchler S, Radowski MR, etal. Influences of opioids
and nanoparticles on invitro wound healing models. Eur J Pharm
Biopharm. 2009;73:34–42.
28. da Silva SJ, de Melos LRJ, Lima GS, etal. Synthesis, anti-
Trypanosoma cruzi activity and quantitative structure relation-
ships of some fluorinated thiosemicarbazones. J Fluor Chem.
2017;195:31–6.
29. Matsaa R, Makamb P, Kaushikc M, etal. Thiosemicarbazone
derivatives: Design, synthesis and in vitro antimalarial activity
studies. Eur J Pharm Sci. 2019;137:104986.
30. Sardari S, Feizi S, Rezayan AH, etal. Synthesis and biologi-
cal evaluation of thiosemicarbazide derivatives endowed with
high activity toward Mycobacterium Bovis. Iran J Pharm Sci.
2017;16(3):1128–40.
31. Yakan H, Koçyiğit ÜM, Muğlu H, etal. Potential thiosemicar-
bazone-based enzyme inhibitors: assessment of antiproliferative
activity, metabolic enzyme inhibition properties, and molecular
docking calculations. J Biochem Mol Toxicol. 2022;36(5):e23018.
32. Koçyiğit ÜM, Doğan M, Muğlu H, etal. Determination of biologi-
cal studies and molecular docking calculations of isatin-thiosemi-
carbazone hybrid compounds. J Mol Struct. 2022;1264:133249.
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