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Article

Antitumor Activity and Physicochemical Properties of New Thiosemicarbazide Derivative and Its Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) Complexes

by
Bartłomiej Rogalewicz
1,*,
Alina Climova
1,
Ekaterina Pivovarova
1,
Jarosław Sukiennik
1,
Kamila Czarnecka
2,
Paweł Szymański
2,3,
Małgorzata Szczesio
1,
Katarzyna Gas
4,
Maciej Sawicki
4,
Monika Pitucha
5 and
Agnieszka Czylkowska
1,*
1
Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland
2
Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Lodz, Poland
3
Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163 Warsaw, Poland
4
Institute of Physics, Polish Academy of Sciences, Aleja Lotnikow 32/46, PL-02668 Warsaw, Poland
5
Independent Radiopharmacy Unit, Faculty of Pharmacy, Medical University of Lublin, PL-20093 Lublin, Poland
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(9), 2703; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27092703
Submission received: 28 March 2022 / Revised: 13 April 2022 / Accepted: 19 April 2022 / Published: 22 April 2022
(This article belongs to the Special Issue Synthesis of Organic Ligands and Their Metal Complexes in Medicinal Chemistry)
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Versions Notes

Abstract

:
A novel biologically active thiosemicarbazide derivative ligand L (N-[(phenylcarbamothioyl)amino]pyridine-3-carboxamide) and a series of its five metal(II) complexes, namely: [Co(L)Cl2], [Ni(L)Cl2(H2O)], [Cu(L)Cl2(H2O)], [Zn(L)Cl2] and [Cd(L)Cl2(H2O)] have been synthesized and thoroughly investigated. The physicochemical characterization of the newly obtained compounds has been performed using appropriate analytical techniques, such as 1H and l3C nuclear magnetic resonance (NMR), inductively coupled plasma (ICP), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR) and magnetic measurements. In order to study the pharmacokinetic profile of the compounds, ADMET analysis was performed. The in vitro studies revealed that the synthesized compounds exhibit potent biological activity against A549 human cancer cell line.

1. Introduction

The process of the search of new drugs is a challenge which involves the participation of different research laboratories and medical groups. Well-known and described diseases change their form and improve their endurance against medicines, which become less and less effective. In that continuous race for the new active compounds, or the increase in the activity of present structures, our research team contributes to the development of new effective drugs. Thiosemicarbazides (Figure 1a) are known to exhibit antitubercular [1,2] antibacterial [3,4] and herbicidal properties [5]. There are reported derivatives with tuberculostatic activity [6] and against large spectra DNA and RNA viruses [7,8,9]. They have promising anticancer properties [10]. Additionally, complexes of thiosemicarbazides with metals ions can increase their activity [11,12].
Based on the thiosemicarbazides, 1,2,4-triazol-3-thiones (Figure 1b) can be synthesized [12]. Their derivatives are promising compound agents against viruses and a few cancers [13,14]. The formation of complexes of active compounds using metal ions as coordinate centers is one of the methods which can increase their properties as active molecules. It is possible to manipulate the compound’s activity by changing the metal ion in the complex [15]. One of the most popular metal ion used in these kind of research is copper (II), which itself has biological activity [16] such as blood–brain barrier penetration. Excess of copper in the human organism can cause Alzheimer’s Disease [17]. Copper complexes have numerous properties including proteasome activity inhibitors [18], DNA intercalation [19] and anticancer chelators. They can also increase the activity of the ligand itself. For example, 4-Cyclohexyl-3-(4-nitrophenyl)methyl-1,2,4-triazolin-5-thione has no activity against selected bacteria, but after obtaining the metal(II) complex, the activity increases to a mild score [20]. A few of the subjects of our studies are the thiosemicarbazide derivatives, such as the one presented here, N-[(phenylcarbamothioyl)amino]pyridine-3-carboxamide (Figure 2). These kinds of organic compounds are known in the literature as substrates for the synthesis of heterocyclic compounds [21,22].
In recent years, scientists have become more interested in the biological activity of thiosemicarbazide derivatives. Some of them have an antiproliferative effect on the human breast adenocarcinoma and human hepatocellular carcinoma cell lines [23]. Compounds are known to significantly inhibit A549, HepG2 and MCF-7 cell division [24]. 1-(Pyridin-3-yl)-4-(phenyl)thiosemicarbazide was screened for urease inhibitory [25]. In our work we used the obtained compound for a series of the complexation reactions using Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) chloride salts. We present our study of the synthesis procedure and physicochemical properties, as well as biological activity investigations of the synthesized compounds. They were assessed as cytotoxic candidates against human lung carcinoma cells (A549).

2. Results and Discussion

2.1. Thermogravimetric Analysis (TGA) Analysis

Thermogravimetric analysis (TGA) is an alternative, fast and useful technique for determining composition of coordination compounds. Therefore, thermograms of the ligand and five complexes: [Co(L)Cl2], [Ni(L)Cl2(H2O)], [Cu(L)Cl2(H2O)], [Zn(L)Cl2] and [Cd(L)Cl2(H2O)] were prepared and analyzed (Figure 3). Table 1 demonstrates the decomposition stages of the complexes with the identified temperature ranges. All compounds decompose progressively. Hydrous complexes of Ni(II), Cu(II) and Zn(II) are stable up to 40 °C, while anhydrous Co(II) and Zn(II) is up to 280 °C. Thermolysis of free ligand starts at 180 °C. Based on the obtained results, we are able to distinguish general decomposition stages: two in Zn(II) complex; three in free ligand, Co(II), Cd(II) compounds; and four in the case of Ni(II) and Cu(II). The first stage of decomposition of the Cd(II), Cu(II) and Ni(II) complexes clearly proves the presence of H2O molecule in these compounds. The next stages are connected with partial and total decomposition of the organic ligand. As the temperature increases, the anhydrous Co(II) and Zn(II) complexes undergo gradual thermal decomposition combined with the destruction of the organic ligand. The last stage for all coordination compounds is the decomposition of the residual parts of the organic ligand, loss of chloride anions and the formation of pure metal oxides. Pyrolysis of free ligand stops around 700 °C with total decomposition.

2.2. Fourier-Transform Infrared Spectroscopy (FTIR) Analysis

Figure 4 and Figure 5 present the FTIR spectra of pure ligand and obtained coordination compounds. The spectrum of the pure ligand contains peaks in the region of 3200–2950 cm−1 which are assigned to the ν(NH) vibrations [26]. The spectra of [Co(L)Cl2], [Ni(L)Cl2(H2O)], [Cu(L)Cl2(H2O)] and [Zn(L)Cl2] also include slightly moved peaks at the same region. This indicates the presence of an amino group, which does not take part in the process of complex formation. All obtained coordination compounds have new-formed peaks in the range of 3600–3400 cm−1 which can be attributed to the ν(OH). In the spectrum of pure ligand, the strong peak at 1681 cm−1 is presented, which corresponds to the ν(C=O) presence [27]. In the case of [Co(L)Cl2], [Ni(L)Cl2(H2O)], [Cu(L)Cl2(H2O)] and [Zn(L)Cl2] this peak is very weak or completely absent, indicating the movement of the hydrogen atom to the nearest donor atom, which leads to the formation of the C–OH group.
The uncoordinated ligand shows bands at 1592 cm−1 due to ν(C=C), 1532 cm−1 due to ν(C=N) and 1021 cm−1 due to ν(N-N), respectively. In the case of all achieved complexes, the peak, which correspond to the ν(C=N), is shifted toward the higher and lower frequencies regions as a result of coordination between metals ions and organic ligand. This peak indicates that one nitrogen atom is involved in the complexes formation. The vibration modes of ν(C=N) and ν(N-N) for all coordination compounds are shifted as well. The absorption peaks are observed in the pure ligand at 1253 cm−1 and 802 cm−1 which can be related to the ν(C=S). For the following complexes: [Co(L)Cl2], [Ni(L)Cl2(H2O)], [Cu(L)Cl2(H2O)] and [Zn(L)Cl2], these modes are shifted to the higher wavenumber region. This shift indicates the coordination of the metal ions with sulfur atom. For pure ligand, there are also modes of β(CH) and γ(CH) in the ranges 1370–1300 cm−1 and 890–715 cm−1, respectively. In the complexes they appear in similar ranges.
Thus, from the obtained FTIR spectra we can say that the ligand acts in the bidentate manner for the most cases. The sulfur atom and nitrogen atom are involved in metal (II) coordination in the case of [Co(L)Cl2], [Ni(L)Cl2(H2O)], [Cu(L)Cl2(H2O)] and [Zn(L)Cl2]. For the [Cd(L)Cl2(H2O)], the metal is coordinated by one nitrogen atom from the pyridine ring, and ligand behaves as a monodentate one.

2.3. Magnetic Properties

The magnetic response of the coordination compounds synthesized here is determined by the spin state of the metal ion and by the diamagnetic response of the whole structure of the compound, i.e., the organic ligand, the metal and their coordinate bonds. Although the diamagnetic response of the organic ligand can be established by means of the direct measurements (we present the results in Figure 6), it is of a limited help here since the chemical structures of the final coordination compounds differ in a few key places. We therefore employ the measurements of [Zn(L)Cl2] and [Cd(L)Cl2(H2O)], that is, of the two compounds in which the coordinating metals (Zn and Cd) are expected to retain their closed d-shell configuration (3d10 and 4d10, respectively). The temperature T dependence of the magnetic susceptibility of these two compounds as well as of the organic ligand is presented in Figure 6. Clearly, with the experimental uncertainty, these three compounds exert nearly the same diamagnetic response. Interestingly, however, though the diamagnetism of the ligand is temperature-dependent, both d10 coordination compounds do not exhibit any temperature dependence of their magnetic susceptibility χ within the exercised here temperature range. Moreover, these susceptibilities are found to be nearly the same, or they can be regarded identical within the experimental uncertainty. The latter has been determined predominantly by the uncertainty of the mass of the investigated specimen (specified in the caption to Figure 6). We take, therefore, the value of χdia = −5 × 10−7 emu/g/Oe, the average of the two magnitudes of χ of Zn and Cd coordinated compounds, as the reference value of the diamagnetic susceptibility for the remaining three coordination compounds investigated in this study.
The remaining three coordination compounds [Co(L)Cl2], [Ni(L)Cl2(H2O)] and [Cu(L)Cl2(H2O)] contain transition metal group atoms with unfilled 3d shells: 3d7, 3d8 and 3d9 for Co, Ni and Cu, respectively. These metals ions very often experience a square planar ligand field. In such coordination, the d levels should split into four sets with the dxz and dyz orbitals forming the lowest levels and the dx2–y2 orbital as the highest energy one. The electron distribution among these orbitals, or the spin state of the ion, is determined by the ratio of the ligand field splitting Δsp ≅ 1.74Δ0 to the spin pairing energy. This last expression represents the fully symmetric square configuration. Δ0 denotes the magnitude of the eg to t2g splitting in the octahedral configuration. In order to gain quantitative information on the spin state of the metal ions in these complexes, we measured the magnetic response as the function of temperature T in a broad temperature range, from 2 to 330 K. All compounds exhibit a strong paramagnetic response. The magnetic signal is positive and increases strongly on lowering T. The results are presented in Figure 7 in the time honored manner of the Curie–Weiss plot, that is, we plot the inverse of the molar susceptibility χm of the all three metals as the function of T. To establish χm, the experimental data are corrected for the value of the χdia established previously for d10 complexes with the same organic ligand (Figure 6). The results form convincingly straight lines. The slopes of these lines yield the magnitudes of the inverse of the Curie constant Cmol−1 = 3 kB/μeff2/NA, from which the magnitude of the effective magnetic moment μeff2 ≅ 8/Cmol is readily obtained. In this notation μeff is given in units of Bohr magnetons μB, kB is the Boltzmann constant and NA is the Avogadro number. The magnitudes of μeff established upon this procedure are given in the Figure 7. We find that the μeff of Cu in [Cu(L)Cl2(H2O)] matches the expected values for a typical Cu2+ ion. For the 3d9 configuration with a fully quenched orbital momentum L the total angular orbital momentum J assumes the magnitude of spin moment S = ½ and so μeff should be 1.73 μB. Experimentally, a value of about 1.9 was found [28], and our measurements yielded μeffCu = 1.8 μB. This indicates that presence of water molecules in this coordination compound does not really alter the distribution of d orbitals in Cu, similarly to d10 ions in [Zn(L)Cl2] and [Cd(L)Cl2(H2O)]. The data collected for the [Co(L)Cl2] yield μeffCo = 4.5 μB. This value is somehow above the L-quenched theoretical value of 3.8 μB and very close to the experimental one of 4.8 μB. The latter appears to be a well-known exception of Co2+ ions across the whole 3d series, where an orbital contribution pushes μeff above the spin-only value [28]. This finding indicates that also in this case the ligands coordination does not alter the high spin state of Co2+ ions in [Co(L)Cl2]. In the case of [Ni(L)Cl2(H2O)], the magnitude of the experimental Curie constant yields μeffNi = 2.2 μB. This value lies significantly below both the theoretically expected and experimental magnitudes of 2.83 μB and 3.2 μB, respectively [28]. However, such anomalous magnetic behaviors of some nickel and other transition metal complexes have already been reported several times in the literature [29,30,31,32,33,34,35,36].

2.4. ADMET

ADME analysis enables the first selection of compounds for costly biological studies. The selected compounds should meet the basic properties that will suggest their usefulness in research on a specific organ. All tested complexes meet the rules of Lipinski [37], Ghose [38], Egan [39], Veber [40] and Muegge [41]. Bioavailability Radars (Figure 8) present six physicochemical properties such as lipophilicity, size, polarity, solubility, flexibility and saturation. All compounds have a good bioavailability score of 0.55, calculated from relying on total charge, TPSA, and violation to the Lipinski filter. All tested compounds are good drug candidates.
Figure 9 presents the BOILED-Egg diagram for the studied compounds. All of them are absorbed from the gastrointestinal tract (all compounds can be found in the white area of the diagram) and do not pass the blood–brain barrier (none of them can be found in the yellow area). Cadmium complex is not P-gp substrate that can be a candidate against multidrug-resistant cancer cells. The more negative the log Kp value, the less the molecule passes through the skin. All compounds displayed negative values ranging from −7.08 to −5.64 cm/s, meaning that they are not accessible through the skin. All compounds belong to the fourth class of toxicity (harmful if swallowed; 300 < LD50 ≤ 2000). Predicted LD50 doses: ligand—1700 mg/kg; [Co(L)Cl2]—1000 mg/kg; [Ni(L)Cl2(H2O)]—1000 mg/kg; [Cu(L)Cl2(H2O)]—1600 mg/kg; [Zn(L)Cl2]—1600 mg/kg; [Cd(L)Cl2(H2O)]—400 mg/kg.

2.5. Cytotoxicity Assay

The inhibitory potency of the newly prepared compounds was tested using the colorimetric MTT assay. The concentrations of the compounds that induced 50% inhibition of cell viability (IC50) are tabulated in Table 2.
Significantly, three of the tested derivatives displayed potent cytotoxic activity against A549 cell lines of IC50 range 410–599 μM (Figure 10). On the other hand, while comparing the resultant activities of the compounds with etoposide, compound [Cd(L)Cl2(H2O)] represented more potent activity than that of the reference drug against A549 cell lines (Figure 11). A mild decrease in the activity was determined by [Cu(L)Cl2] compound to be approximately equipotent to the free ligand.

3. Materials and Methods

3.1. Synthesis of the L Ligand

For the first time, this compound was obtained by our team by heating phenyl isocyanate and pyridin-3-carboxylic acid hydrazide in an oil bath at 100 °C for 8 h [42]. Here, we present the modified method of the synthesis—we used methanol as the solvent and reduced the heating time to 1 h. The structure and the purity of the compound were confirmed by determining the melting point and the 1H and 13NMR spectroscopy.
Pyridin-3-carboxylic acid hydrazide (1.37 g, 0.01 mole) was dissolved in methanol (40 mL), and phenyl isothiocyanate (1.35 g, 0.01 mole) was added. The mixture was heated at the reflux temperature of the solvent for 1 h. The mixture was then cooled, and the precipitate was crystallized from ethanol.
Ligand L (C13H12N4OS) (272.32 g/mol), (yield 93%), (m.p. 174–176 °C), 1H NMR (DMSO-d6) δ: 7.14–7.57 (m, 5H, CHphenyl), 8.26–8.30 (d, 1H, CHpyridin), 8.74 (s, 1H, CHpyridin), 8.76 (s, 1H, CHpyridin), 9.76 (s, 1H, NH), 9.87 (s, 1H, NH), 10.77 (s, 1H, NH); 13C NMR (DMSO-d6) δ: 122, 125, 126, 128, 130, 139, 140, 164, 181. FTIR spectra (KBr, cm−1): ν(NH) 3162, 2916; ν(C=O) 1682; ν(C=C) 1592; ν(C=N) 1532; δ(NH) 1494; β(CH) 1363, 1305; ν(C=S) 1253, 802; ν(N-N) 1021; γ(CH) 737, 693.

3.2. Synthesis of the Coordination Compounds

In each case, 162 mg (0.6 mmol) of the ligand was dissolved in the ethanol at 50 °C with constant stirring, until the clear ligand solutions were obtained. These solutions were then added to water/ethanol (v/v = 1/1) solutions of 0.6 mmol of Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) chlorides. Total volumes did not exceed 60 mL. Reaction mixtures were then stirred on a magnetic stirrer for 4 h. After that time, the obtained precipitates of complexes were filtered, washed several times with ethanol and water/ethanol (v/v = 1/1) and later dried in the open air, weighted and analyzed.
[Co(L)Cl2] (C13H12N4OSCoCl2) (402.16 g/mol), (yield 46%), anal. calculated (%): Co, 14.66; S, 7.97. Found (%): Co, 14.13; S, 8.10. FTIR spectra (KBr, cm−1): ν(NH) 3197, 3041; ν(C=C) 1581; ν(C=N) 1550; δ(NH) 1495; β(CH) 1373, 1322; ν(C=S) 1271, 810; ν(N-N) 1053; γ(CH) 752, 701.
[Ni(L)Cl2(H2O)] (C13H12N4OSNiCl2) (401.92 g/mol), (yield 38%), anal. calculated (%): Ni, 14.60; S, 7.98. Found (%): Ni, 14.83; S, 7.67. FTIR spectra (KBr, cm−1): ν(NH) 3280, 2975; ν(C=C) 1598; ν(C=N) 1522; δ(NH) 1460; β(CH) 1414, 1347; ν(C=S) 1261, 818; ν(N-N) 955; γ(CH) 753, 700.
[Cu(L)Cl2(H2O)] (C13H12N4OSCuCl2) (406.78 g/mol), (yield 36%), anal. calculated (%): Cu, 15.62; S, 7.88. Found (%): Cu, 15.95; S, 7.50. FTIR spectra (KBr, cm−1): ν(NH) 3210, 3060; ν(C=C) 1596; ν(C=N) 1537; δ(NH) 1497; β(CH) 1372, 1350; ν(C=S) 1258, 815; ν(N-N) 960; γ(CH) 756, 698.
[Zn(L)Cl2] (C13H12N4OSZnCl2) (408.64 g/mol), (yield 63%), anal. calculated (%): Zn, 16.01; S, 7.85. Found (%): Zn, 15.83; S, 8.00. FTIR spectra (KBr, cm−1): ν(NH) 3195, 3032; ν(C=C) 1612; ν(C=N) 1552; δ(NH) 1497; β(CH) 1377, 1321; ν(C=S) 1273, 825; ν(N-N) 957; γ(CH) 753, 702.
[Cd(L)Cl2(H2O)] (C13H14N4O2SCdCl2) (473.66 g/mol), (yield 46%), anal. calculated (%): Cd, 23.73; S, 6.77. Found (%): Cd, 23.21; S, 6.20. FTIR spectra (KBr, cm−1): ν(NH) 3241, 3155; ν(C=O) 1684; ν(C=C) 1600; ν(C=N) 1541; δ(NH) 1497; β(CH) 1363, 1313; ν(C=S) 1272, 826; ν(N-N) 1032; γ(CH) 767, 693.

3.3. Chemistry

All chemicals used for the synthesis were purchased from Sigma-Aldrich (St. Louis, MO, USA), AlfaAesar (Haverhill, MA, USA) and POCH (Gliwice, Poland) companies and used without further purification. Melting points were determined using Fisher–Johns block and presented without corrections. The 1H and l3C NMR spectra were recorded on a Bruker Avance 300 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) in d6-DMSO. Chemical shifts were reported in parts per million (ppm, δ scale) relative either to internal standard (TMS) or residual solvent peak. The contents of Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and S in solid complexes were determined by the ICP spectroscopy. Standard solutions from Merck (1000 mg/L, Darmstadt, Germany) were used for the preparation of diluted solutions used for calibration. For analysis, distilled water (electrical conductivity 0.05 µS) was used (obtained with Polwater system). Solid samples were decomposed using the Anton Paar Multiwave 3000 closed system instrument. Mineralization was carried out for 45 min at 240 °C under pressure 60 bar. Thermogravimetric analysis of formed complexes was investigated on a Netzsch TG 209 apparatus (NETZSCH GmbH, Selb, Germany) under air atmosphere, v = 20 mL·min−1, using ceramic crucibles. Thermograms represent TG-DTG curves in the range of temperature 25 to 800 °C at a heating rate of 10 °C min−1. FTIR spectra were performed using IR Tracer-100 Schimadzu Spectrometer (Schimadzu Corporation, Kyoto, Japan) (4000–600 cm−1) with an accuracy of recording of 1 cm−1, using KBr pellets.

3.4. ADMET

Compounds were analyzed by using SwissADME service (Swiss Institute of Bioinformatics 2021) [43,44] and ProTOX II service [45] to obtain computational pharmacokinetic and toxicologic profiles.

3.5. Cytotoxicity Assay

In order to survey the antilung cancer effects of the new synthesized compounds, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used on human lung carcinoma cell lines (A549) [46,47]. Cell lines were maintained in a Dulbecco modified eagle medium (DMEM) with 10% Fetal bovine serum (FBS) and 1% penicillin/streptomycin antibiotic. Cytotoxic activity screening was performed using MTT assay. Cells were placed in 104 cells/well for 24 h, and all cells were cultivated at 37 °C and 5% CO2. After incubation for 24 h, the cells were placed into 96 well plates, and different concentrations of sample (10, 50, 100, 200, 400 and 600 μM) were added; the incubation was continued for 24 h. The A549 cell lines were incubated with 50 μL of MTT at 37 °C for 2 h. After incubation, media were removed slowly, and we added 100 μL of dimethyl sulfoxide to each well to dissolve insoluble formazan crystals; they were then incubated for 10 min. The cytotoxicity was estimated by IC50 in (μM), and the concentration that inhibits 50% of growth of cancer cell from the absorbance values was recorded at 570 nm.

3.6. Magnetic Measurements

Magnetic measurements were performed in a superconducting quantum interference device (SQUID)-based magnetometer MPMS XL of a Quantum Design (San Diego, CA, USA). In order to facilitate accurate measurements of single-milligram-sized powder specimens, two experimental approaches were applied and compared. In the first one, the powders are mixed with a strongly ethanol-diluted GE-varnish, and such thick solutions are transferred onto small rectangular silicon 5 × 4 × 0.2 mm3 plates to provide a solid support and to ease the handling, as already exercised and validated [48,49]. The relatively weak magnetic signal of the Si base plate has been adequately removed from the results, yielding the magnetic response of the investigated substances. The need for the ex situ compensation of the signal exerted by the specimen carriers is alleviated by the second approach in which an in situ compensation method of the specimen carriers (polycarbonate capsules), recently elaborated by some of the present authors, is applied [50]. We confirm that within the uncertainty of the exact mass of the specimens used in each of the measurements (±0.1 mg), both methods yield the same results. Regardless to the approach to the measurement, the data reduction and the final magnetic moment determination were performed following the code elaborated for high sensitivity studies of minute magnetic signals [51].

4. Conclusions

In the current years, numerous thiosemicarbazide derivatives have been synthesized and investigated with regard to their biological activity. In this article, thiosemicarbazide-based organic ligand and five metal (II) complexes were synthesized, and their physicochemical and biological properties were investigated. All six compounds form solids stable under room temperature. When heated, they gradually decompose. The final solid products of decomposition of the studied coordination compounds are corresponding metal (II) oxides. The Fourier-transform infrared spectroscopy spectra revealed the presence of water molecules in Ni, Cu and Cd complexes. Furthermore, the FTIR results were corroborated by the magnetic measurements. The quantitative information on the spin state of the metal ions measured as the function of temperature (from 2 to 330 K) has shown that Co, Ni and Cu compounds exhibit strong paramagnetic response. The magnetic signal is positive and increases strongly on lowering temperature. Interestingly, the diamagnetism of the ligand is temperature-dependent, but both Zn and Cd compounds did not exhibit any temperature dependence of their magnetic susceptibility within the exercised temperature range. The ADME/Tox analysis of the new synthesized organic ligand and coordination compounds indicated that all compounds do not violate the Lipinski, Ghose, Egan, Veber and Muegge rules. Additionally, all compounds have good bioavailability score of 0.55, and all belong to the fourth class of toxicity. New compounds were evaluated as cytotoxic candidates against human lung carcinoma cells (A549), with etoposide serving as a reference material. The compounds we have developed show comparable anticancer properties to etoposide. Organic ligand exhibited potent anticancer activity (with IC50 = 589 ± 18 μM), and [Cu(L)Cl2] complex was equipotent to it (with IC50 = 599 ± 71 μM). There are several treatment options for small cell lung cancer involving etoposide as a topoisomerase inhibitor. We used etoposide as a reference due to its frequent use. The investigated compounds exhibit comparable antitumor properties to this reference, as outlined above. However, one of them, [Cd(L)Cl2(H2O)], has better biological properties (IC50 = 410 ± 31 μM). The antitumor activity may be related to the type of metabolism of the compound inside the cells. This may also apply to cellular pathways that are a therapeutic target [52]. The full mechanism of action of the complexes themselves remains unknown. In this regard, research in the field of molecular biology will be continued. It is, however, known that free cadmium affects several processes in cells. This includes: cells proliferation, cells differentiation, apoptosis, DNA repair and production reactive oxygen species [53,54]. Such studies are of a great importance, taking into consideration the search for new drugs and thus the possibility of developing new treatment possibilities. This gives hope for a more effective fight against one of the most dangerous types of cancer.

Author Contributions

Conceptualization, A.C. (Agnieszka Czylkowska); methodology, A.C. (Agnieszka Czylkowska), M.S. (Maciej Sawicki) and P.S.; formal analysis, B.R., A.C. (Alina Climova), E.P. and K.G.; investigation, B.R., A.C. (Alina Climova), E.P., K.G., K.C., M.S. (Małgorzata Szczesio), M.P. and J.S.; writing—original draft preparation, A.C. (Agnieszka Czylkowska), B.R., A.C. (Alina Climova), E.P., J.S., P.S. and M.S. (Maciej Sawicki); writing—review and editing, A.C. (Agnieszka Czylkowska), B.R., A.C. (Alina Climova), E.P., P.S. and M.S. (Maciej Sawicki); visualization, A.C. (Agnieszka Czylkowska) and B.R.; supervision, A.C. (Agnieszka Czylkowska). All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

This article has been completed while the first four authors were the Doctoral Candidates in the Interdisciplinary Doctoral School at the Lodz University of Technology, Poland. (B.R., A.C. (Alina Climova), E.P., J.S.).

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

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Molecules 27 02703 g001 550
Figure 1. Thiosemicarbazides (a) and 1,2,4-triazol-3-thiones (b).
Figure 1. Thiosemicarbazides (a) and 1,2,4-triazol-3-thiones (b).
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Molecules 27 02703 g002 550
Figure 2. Tautomers of the obtained ligand, N-[(phenylcarbamothioyl)amino]pyridine-3-carboxamide.
Figure 2. Tautomers of the obtained ligand, N-[(phenylcarbamothioyl)amino]pyridine-3-carboxamide.
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Molecules 27 02703 g003 550
Figure 3. TG (green)-DTG (blue) curves of the free ligand and five complexes.
Figure 3. TG (green)-DTG (blue) curves of the free ligand and five complexes.
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Molecules 27 02703 g004 550
Figure 4. FTIR spectra of pure ligand and obtained complexes of [Co(L)Cl2] and [Zn(L)Cl2].
Figure 4. FTIR spectra of pure ligand and obtained complexes of [Co(L)Cl2] and [Zn(L)Cl2].
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Molecules 27 02703 g005 550
Figure 5. FTIR spectra of pure ligand and obtained complex of [Cd(L)Cl2(H2O)], [Ni(L)Cl2(H2O)] and [Cu(L)Cl2(H2O)].
Figure 5. FTIR spectra of pure ligand and obtained complex of [Cd(L)Cl2(H2O)], [Ni(L)Cl2(H2O)] and [Cu(L)Cl2(H2O)].
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Molecules 27 02703 g006 550
Figure 6. Temperature dependence of the mass magnetic susceptibility χ of the coordination compounds [Cd(L)Cl2(H2O)] (orange) and [Zn(L)Cl2] (purple) and of the uncoordinated organic L ligand (gray). The color-matched bars indicate the magnitude of the experimental error bar determined predominantly by the uncertainty of the masses of the samples: 1.5(1), 4.3(1) and 2.5(1) mg for [Cd(L)Cl2(H2O)], [Zn(L)Cl2] and the uncoordinated organic L ligand, respectively.
Figure 6. Temperature dependence of the mass magnetic susceptibility χ of the coordination compounds [Cd(L)Cl2(H2O)] (orange) and [Zn(L)Cl2] (purple) and of the uncoordinated organic L ligand (gray). The color-matched bars indicate the magnitude of the experimental error bar determined predominantly by the uncertainty of the masses of the samples: 1.5(1), 4.3(1) and 2.5(1) mg for [Cd(L)Cl2(H2O)], [Zn(L)Cl2] and the uncoordinated organic L ligand, respectively.
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Figure 7. Temperature dependence of the inverse of the molar magnetic susceptibility. χm of the coordination compounds [Cu(L)Cl2(H2O)], [Ni(L)Cl2(H2O)] and [Co(L)Cl2] (blue, brown and navy markers, respectively). The slopes of dashed straight lines of corresponding hues define the magnitudes of the Curie constants and so of the effective magnetic moments μeff, which values are indicated in the figure.
Figure 7. Temperature dependence of the inverse of the molar magnetic susceptibility. χm of the coordination compounds [Cu(L)Cl2(H2O)], [Ni(L)Cl2(H2O)] and [Co(L)Cl2] (blue, brown and navy markers, respectively). The slopes of dashed straight lines of corresponding hues define the magnitudes of the Curie constants and so of the effective magnetic moments μeff, which values are indicated in the figure.
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Figure 8. Oral bioavailability graphs generated using the SwissADME service. The red–colored zone is physicochemically suitable for oral bioavailability. LIPO—lipophility (−0.7 < XlogP3 < +5.0); SIZE—molecular weight (150 g/mol < MW < 500 g/mol); POLAR—polarity (20 Å2 < TPSA < 130 Å2); INSOLU—insolubility (0 < logS < 6); INSATU—insaturation (0.25 < fraction Csp3 < 1); FLEX—flexibility (0 < num. of rotatable bonds < 9).
Figure 8. Oral bioavailability graphs generated using the SwissADME service. The red–colored zone is physicochemically suitable for oral bioavailability. LIPO—lipophility (−0.7 < XlogP3 < +5.0); SIZE—molecular weight (150 g/mol < MW < 500 g/mol); POLAR—polarity (20 Å2 < TPSA < 130 Å2); INSOLU—insolubility (0 < logS < 6); INSATU—insaturation (0.25 < fraction Csp3 < 1); FLEX—flexibility (0 < num. of rotatable bonds < 9).
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Figure 9. BOILED-Egg diagram for all studied compounds.
Figure 9. BOILED-Egg diagram for all studied compounds.
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Figure 10. In vitro cytotoxic activity of the three most potent compounds and etoposide as reference material. Statistical significance was assessed using one-way ANOVA analysis. p < 0.01 was considered as significantly different between cytotoxicity of etoposide and the best tested compounds.
Figure 10. In vitro cytotoxic activity of the three most potent compounds and etoposide as reference material. Statistical significance was assessed using one-way ANOVA analysis. p < 0.01 was considered as significantly different between cytotoxicity of etoposide and the best tested compounds.
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Figure 11. Antitumor effect of [Cd(L)Cl2(H2O)] compound on A549 cancer cells. Cells were cultured in the absence (left) or in the presence (right) of the tested compound. Representative phase-contrast cell images are shown after 24 h (100× magnification).
Figure 11. Antitumor effect of [Cd(L)Cl2(H2O)] compound on A549 cancer cells. Cells were cultured in the absence (left) or in the presence (right) of the tested compound. Representative phase-contrast cell images are shown after 24 h (100× magnification).
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Table
Table 1. Thermal decomposition data of the ligand and Co(II) Ni(II) Cu(II) Zn(II) and Cd(II) complexes.
Table 1. Thermal decomposition data of the ligand and Co(II) Ni(II) Cu(II) Zn(II) and Cd(II) complexes.
CompoundStagesTemperature RangeFinal Solid Product of the Thermal Decomposition
IIIIIIIV
Ligand3180–210210–400550–700--
[Co(L)Cl2]3275–460460–550550–640-CoO
[Ni(L)Cl2(H2O)]440–120120–250250–420420–600NiO
[Cu(L)Cl2(H2O)]440–150150–250250–380380–720CuO
[Zn(L)Cl2]2280–500500–800--ZnO
[Cd(L)Cl2(H2O)]340–200210–450450–760-CdO
Table
Table 2. In vitro cytotoxic efficiency of the new derivatives against A549 (IC50 values = mean ± SD of two independent determinations; IC50—50% inhibition of the cell viability, (μM)).
Table 2. In vitro cytotoxic efficiency of the new derivatives against A549 (IC50 values = mean ± SD of two independent determinations; IC50—50% inhibition of the cell viability, (μM)).
CompoundIC50 against A549 ± SD (μM)
Ligand589 ± 18
[Co(L)Cl2]>600
[Ni(L)Cl2(H2O)]>600
[Cu(L)Cl2(H2O)]599 ± 71
[Zn(L)Cl2]>600
[Cd(L)Cl2(H2O)]410 ± 31
Etoposide452 ± 18
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Rogalewicz, B.; Climova, A.; Pivovarova, E.; Sukiennik, J.; Czarnecka, K.; Szymański, P.; Szczesio, M.; Gas, K.; Sawicki, M.; Pitucha, M.; et al. Antitumor Activity and Physicochemical Properties of New Thiosemicarbazide Derivative and Its Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) Complexes. Molecules 2022, 27, 2703. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27092703

AMA Style

Rogalewicz B, Climova A, Pivovarova E, Sukiennik J, Czarnecka K, Szymański P, Szczesio M, Gas K, Sawicki M, Pitucha M, et al. Antitumor Activity and Physicochemical Properties of New Thiosemicarbazide Derivative and Its Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) Complexes. Molecules. 2022; 27(9):2703. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27092703

Chicago/Turabian Style

Rogalewicz, Bartłomiej, Alina Climova, Ekaterina Pivovarova, Jarosław Sukiennik, Kamila Czarnecka, Paweł Szymański, Małgorzata Szczesio, Katarzyna Gas, Maciej Sawicki, Monika Pitucha, and et al. 2022. "Antitumor Activity and Physicochemical Properties of New Thiosemicarbazide Derivative and Its Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) Complexes" Molecules 27, no. 9: 2703. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27092703

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