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Abstract

2-[1-Oxo-1-(piperidin-1-yl)propan-2-ylidene]-N-(prop-2-en-1-yl)hydrazinecarbothioamide (HL) and its six coordination compounds [Cu(L)X] (X = Cl⁻ (1), NO₃⁻ (2)), [Cu(A)(L)NO₃](A = 1,10-Phen (3), 2,2′-Bpy (4)), [Ni(HL)₂](NO₃)₂ (5), and [Fe(L)₂]Cl (6) are synthesized and characterized by elemental analysis, Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and single-crystal X-ray crystallography. Uncoordinated thiosemicarbazone HL shows higher antioxidant activity against 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS^+•) cation radicals compared with most of the other complexes. Complex 5 is the most active and its activity exceeds that of HL and is close to that of trolox, which is used in medicine as an antioxidant. The introduction of N-heteroaromatic bases (1,10-phenanthroline and 2,2′-bipyridine) into the inner sphere of the complex [Cu(L)NO₃] did not lead to an increase in antioxidant activity.

Keywords

3d metal complex amide antioxidants pyruvic acid thiosemicarbazone

Introduction

Thiosemicarbazones are the subject of constant and multidisciplinary interest, not only because of their structural features and extremely rich coordination chemistry, but also due to their versatile pharmacological properties such as antimicrobial,^1,2 antiviral,^3,4 anticonvulsant,^5,6 and carcinostatic activity.⁷ Particular attention has been paid to thiosemicarbazones derived from N-heterocycles with α-carbonyl groups. This class of thiosemicarbazones and the corresponding metal complexes exhibit pronounced biological activity. Metals bonded to atoms such as N, O, and S can form a chelate ring, similar to the interactions between metal ions and many important biological molecules such as proteins, enzymes, and DNA.

In this context, pyruvic acid is one of the α-keto acids of the Krebs cycle and plays a critical role in important biochemical processes such as the metabolism of proteins, fats, carbohydrates, and amino acids in humans and animals.^8,9 Pyruvic acid is a natural product found in Populus tremula, Macrobrachium nipponense, and other organisms. Pyruvic acid thiosemicarbazone and its complexes exhibit various types of biological activity: antimicrobial,^10,11 antifungal,^12,13 cytotoxic,¹⁴ and antitumor.¹⁵ The complexes were more active than the uncoordinated thiosemicarbazone and even exceeded the activity of medicinal compounds used as standards. Also, it was found that this thiosemicarbazone inhibits soluble ornithine carbamoyltransferase in vitro and the enzyme in a mitochondria-rich cell fraction.¹⁶

The α-ketoamide moiety is a key structural unit present in many natural and non-natural products with a wide range of interesting biological activities. For example, they are effective as a reversible covalent inhibitors against cysteine proteases. Pyruvamides are representative of this class of substances. They also manifest different types of biological activity, which have been studied in vitro and in vivo. For example, N,N-diethyl-2-oxopropanamide has anti-inflammatory and antiexcitotoxic effects. It effectively blocks neutrophils that accumulate around damaged brain tissue and exacerbate tissue damage during a stroke.¹⁷ N,N-Diisopropyl-2-oxopropanamide manifests anti-inflammatory and neuroprotective activity and is a potential therapeutic agent for improving ischemic brain injury and other pathologies associated with inflammation.¹⁸

Thus, it is of interest to study thiosemicarbazones of pyruvamides and their coordination compounds, which are limited to only a few reports.^19–21

Recent developments in the medicinal field report a number of diseases associated with free radicals.²² Such free radicals are normally neutralized by efficient systems in the body that include antioxidant enzymes and nutrient-derived antioxidant small molecules. In healthy individuals, a delicate balance exists between free radicals and antioxidants. In some pathologic conditions, oxidative stress causes the levels of antioxidants to fall below normal. Antioxidant supplements for such conditions are expected to be of benefit.²³ Thiosemicarbazones and their coordination compounds manifest antioxidant activity, often exhibiting values that exceed the activity of medicines used as antioxidants.^24–27 Studies of the antioxidant activity of pyruvic acid have shown that it has potential for controlling inflammation and preventing diseases caused by oxidative stress.²⁸

The aim of the present investigation is the synthesis of 2-[1-oxo-1-(piperidin-1-yl)propan-2-ylidene]-N-(prop-2-en-1-yl)hydrazinecarbothioamide (1-(piperidin-1-yl)propane-1,2-dione N⁴-allylthiosemicarbazone) (Figure 1) and its 3d metal coordination compounds, which include bidentate N-heteroaromatic bases such as 1,10-phenanthroline (1,10-Phen) and 2,2′-bipyridine (2,2′-Bpy), along with studies of the antioxidant activities.

Figure 1.

Structure of 2-[1-oxo-1-(piperidin-1-yl)propan-2-ylidene]-N-(prop-2-en-1-yl)hydrazinecarbothioamide (HL).

Results and discussion

Synthesis and characterization

The new N⁴-allylthiosemicarbazone (HL) was synthesized in two stages (Scheme 1). In the first step, 1-(piperidin-1-yl)propane-1,2-dione was obtained by the reaction between pyruvic acid, oxalyl chloride, and piperidine in CH₂Cl₂ in the presence of a catalytic amount of dimethylformamide (DMF). Next, the reaction between the obtained 1-(piperidin-1-yl)propane-1,2-dione and N-(prop-2-en-1-yl)hydrazinecarbothioamide was performed in ethanol in a 1:1 molar ratio to give the desired product HL.

Scheme 1.

Synthesis of 2-[1-oxo-1-(piperidin-1-yl)propan-2-ylidene]-N-(prop-2-en-1-yl)hydrazinecarbothioamide (HL).

Complex 1 was prepared by the reaction of pro-ligand HL with copper(II) chloride dihydrate in ethanol in a 1:1 molar ratio (Scheme 2). Complex 2 was prepared by a similar method to complex 1, but copper(II) chloride dihydrate was replaced with copper(II) nitrate trihydrate. Complexes 3 and 4 were obtained by reactions between pro-ligand HL, copper(II) nitrate trihydrate, and corresponding N-heteroaromatic base (1,10-phenanthroline for complex 3 and 2,2′-bipyridine for complex 4) in ethanol. Complexes 5 and 6 were obtained by reactions of HL with nickel(II) nitrate hexahydrate and iron(III) chloride hexahydrate, respectively. In the cases of complexes 5 and 6, the reaction took place in a molar ratio of 1:2. Single crystals of the thiosemicarbazone HL and complex 1 were obtained by recrystallization of the solid products from methanol and ethanol. Elemental analyses of the complexes suggest the general formulas [Cu(L)X] (X = Cl⁻ (1); NO₃⁻ (2)), [Cu(A)(L)NO₃] (A = 1,10-Phen (3), 2,2′-Bpy (4)), [Ni(HL)₂](NO₃)₂ (5), and [FeL₂]Cl (6). The formula of complex 1 is in accordance with its molecular structure determined by single-crystal X-ray analysis. The molar conductivity values of the synthesized complexes 1–4 and 6 are in the range 72–114 Ω⁻¹ cm² mol⁻¹, indicating that they behave as 1:1 electrolytes in solution. Complex 5 is a 1:2 electrolyte (158 Ω⁻¹ cm² mol⁻¹).²⁹

Scheme 2.

The synthesis of coordination compounds 1–6.

Spectroscopic studies

The FTIR spectra of HL pro-ligand contain absorption bands at 3315 and 3288 cm⁻¹ that correspond to the two NH groups, a ν(С=O) absorption band at 1632 cm⁻¹, a ν(C=N) absorption band at 1620 cm⁻¹, and a ν(С=S) absorption band at 1362 cm⁻¹ (Table 1, see Supplemental Figures S3–S9 in the supporting information). The spectra of the synthesized coordination compounds contain ν(N-H) absorption band in the regions of 3219–3225 cm⁻¹, one ν(С=O) absorption band in the regions of 1613–1623 cm⁻¹ and a ν(C=N) absorption band in the regions of 1570–1583 cm⁻¹, which characterize the stretching vibrations of the coordinated molecules of HL.³⁰ One of the ν(N–H) absorption bands disappears from the FTIR spectra of complexes 1–4 and 6, which points to deprotonation of HL. However, the position of the absorption band of the second NH group shifts to the low-frequency region by 63–69 cm⁻¹. In the case of complex 5, two ν(N–H) absorption bands remain in the FTIR spectra indicating that the HL ligand in this complex is nondeprotonated. In addition, the spectra show shifts to the low-frequency region by 9–19 cm⁻¹ of the ν(С=O) absorption band and 37–46 cm⁻¹ for the ν(С=N) absorption band. Also, we observed the disappearance of the ν(С=S) band and the appearance of a ν(С–S) absorption band in the region of 780–791 cm⁻¹.

Table 1.

Selected FTIR absorption bands of HL and complexes 1–6.

Compound	ν(N–H)	ν(C=O)	ν(C=N¹)	ν(C=S)	ν(C–S)
HL	3315, 3288	1632	1620	1362	—
1	3219	1621	1574	—	791
2	3225	1618	1583	—	787
3	3225	1623	1583	—	780
4	3225	1621	1574	—	785
5	3333, 3311	1615	1570	1342	—
6	3223	1613	1574	—	791

The disappearance of the ν(С=S) group indicates that the HL ligand has transformed from the thione form into a thiol tautomeric form followed by deprotonation. In the FTIR spectra of complex 5, the ν(С=S) absorption band does not disappear, which indicates that the HL ligand in this complex is in the thione form.

On these bases, it can be proved that the HL coordinates to the metal ions in a mono deprotonated thiol form by means of the oxygen atom of the amide group, the nitrogen atom of azomethine group, and the deprotonated sulfur atom forming five- and six-membered metallacycles.³¹

Structure description of HL and complex 1

X-ray single-crystal structure analysis revealed that N⁴-allylthiosemicarbazone HL crystallizes in the centrosymmetric orthorhombic space group Pbca (Table 2, Figure 2). In the crystal, the thiosemicarbazide fragment of the molecule HL adopts an E configuration. The N2–N3–C1–S1 torsion angle is 175.1(1)°. The C1–S1, C1–N3, and C1–N4 bonds equal 1.681(2), 1.359(3), and 1.317(3) Å, respectively (Table 3). The azomethine C2=N2 bond distance of 1.271(3) Å corresponds to a double bond, thereby confirming its imino form.

Table 2.

Crystal and structure refinement data for HL and 1.

Compound	HL	1
Empirical formula	C₁₂H₂₀N₄O₁S₁	C₁₂H₁₉Cl₁Cu₁N₄O₁S₁
Formula weight	268.38	366.36
Crystal system	Orthorhombic	Monoclinic
Space group	Pbca	P2₁/c
a (Å)	9.5100(3)	8.3801(3)
b (Å)	16.2201(6)	15.1794(4)
c (Å)	18.9439(8)	12.7248(4)
α (°)	90	90
β (°)	90	104.007(4)
γ (°)	90	90
V (Å³)	2922.2(2)	1570.51(9)
Z	8	4
ρ_calc (g cm⁻³)	1.220	1.549
µ_Mo (mm⁻¹)	0.217	1.694
F(000)	1152	756
Crystal size (mm)	0.6 × 0.5 × 0.4	0.25 × 0.20 × 0.10
θ range (°)	3.035–25.05	2.966–25.042
Index range	−10 ⩽ h ⩽ 11 −19 ⩽ k ⩽ 18 −15 ⩽ l ⩽ 22	−9 ⩽ h ⩽ 5 −18 ⩽ k ⩽ 14 −14 ⩽ l ⩽ 15
Reflections collected/unique	6552/2576	5423/2761
Completeness (%)	99.5 (θ = 25.05°)	99.8 (θ = 25.042°)
Reflections with I > 2σ(I)	2090	2264
Number of refined parameters	164	182
Goodness of fit	1.002	1.003
R (for I > 2σ(I))	R₁ = 0.0501 wR₂ = 0.1413	R₁ = 0.0337 wR₂ = 0.0841
R (for all reflections)	R₁ = 0.0637 wR₂ = 0.1533	R₁ = 0.0458 wR₂ = 0.0895
Δρ_max/Δρ_min (e·Å⁻³)	0.382/−0.289	0.566/−0.299

Figure 2.

X-ray crystal structure of HL with atom numbering. Thermal ellipsoids are drawn at the 50% probability level.

Table 3.

Selected bond lengths and angles in HL and 1.

Bond	Bond length (Å)
Bond	HL	1
S(1)–C(1)	1.681(2)	1.738(3)
O(1)–C(3)	1.218(3)	1.263(3)
N(1)–C(3)	1.334(3)	1.325(3)
N(1)–C(8)	1.459(3)	1.475(4)
N(1)–C(4)	1.469(3)	1.470(3)
N(2)–C(2)	1.271(3)	1.300(3)
N(2)–N(3)	1.374(2)	1.357(3)
N(3)–C(1)	1.358(3)	1.330(4)
N(4)–C(1)	1.317(3)	1.336(4)
N(4)–C(10)	1.438(3)	1.455(4)
Cu(1)–N(2)	—	1.949(2)
Cu(1)–O(1)	—	1.991(2)
Cu(1)–Cl(1)	—	2.2022(8)
Cu(1)–S(1)	—	2.2309(8)
Angle	Bond angle (°)
C(3)–N(1)–C(8)	120.0(2)	120.0(2)
C(3)–N(1)–C(4)	126.2(2)	127.0(2)
C(2)–N(2)–N(3)	120.6(2)	118.9(2)
C(1)–N(3)–N(2)	117.5(2)	111.1(2)
C(1)–N(4)–C(10)	125.1(2)	124.6(3)
N(4)–C(1)–N(3)	116.3(2)	117.1(3)
N(4)–C(1)–S(1)	124.3(2)	117.4(2)
N(3)–C(1)–S(1)	119.4(2)	125.5(2)
N(2)–C(2)–C(9)	128.2(2)	120.8(3)
N(2)–C(2)–C(3)	114.8(2)	110.6(2)
C(9)–C(2)–C(3)	116.8(2)	128.2(2)
O(1)–C(3)–N(1)	123.1(2)	119.9(3)
O(1)–C(3)–C(2)	117.6(2)	116.5(2)
N(2)–Cu(1)–O(1)	—	79.97(9)
N(2)–Cu(1)–Cl(1)	—	175.13(7)
O(1)–Cu(1)–Cl(1)	—	96.48(6)
N(2)–Cu(1)–S(1)	—	85.05(7)
O(1)–Cu(1)–S(1)	—	161.92(7)
Cl(1)–Cu(1)–S(1)	—	99.01(3)
C(1)–S(1)–Cu(1)	—	94.71(10)

Intermolecular N–H···S and N–H···O hydrogen bonds occur between molecules in supramolecular corrugated layers parallel to the ac crystallographic plane (Table 4, Figure 3).

Table 4.

Hydrogen bond distances (Å) and angles (°) in HL and 1.

	d(H···A)	d(D···A)	∠(DHA)	Symmetry transformation for acceptor
HL
N(3)–H(3N)···S(1)	2.62	3.475(2)	174.7	−x+2, −y+1, −z+1
N(4)–H(4N)···O(1)	2.15	2.864(2)	140.8	2x−1/2, y, −z+3/2
1
N(4)–H(1N)···Cl(1)	2.66	3.395(3)	144.8	−x+2, y−1/2, −z+3/2
C(8)–H(8B)···S(1)	2.99	3.835(3)	146.2	−x+2, y+1/2, −z+3/2

Figure 3.

Fragment of the crystal packing of the corrugated layers parallel to ac crystallographic plane of HL. All hydrogen atoms, except for those involved in hydrogen bonds, have been omitted for clarity.

Complex 1 crystallizes in the monoclinic space group P2₁/c (Table 2). Structural studies revealed that the formula of complex 1 is [Cu(L)Cl]. Upon complexation with Cu(II), the ligand undergoes a configurational change of the thiosemicarbazone moiety from E to Z form and rotation around the C2–C3 bond bending to a cis–cis configuration of the donor O, N, and S atoms that favors the tridentate chelating form of coordination. Such a mode of coordination was also established in previously studied Cu(II) compounds with different substituted thiosemicarbazones.^11,25,32

The Cu₁ atom in complex 1 is tetracoordinated and the copper centre exhibits a square planar coordination. The tridentate thiosemicarbazone ligand is coordinated to the central atom in the monodeprotonated form (L)⁻ using an ONS set of donor atoms (Figure 4) and forms two fused metallacycles. Four donor atoms O(1), N(2), S(1), and Cl(1), are coplanar within ±0.113 Å, and copper center exhibits a distorted square planar environment with descriptor parameter τ₄ = 0.163.³³ The coordination of (L)⁻ with Cu(II) shortened the bond length of C1–N3 to 1.330(4) Å and increased the bond lengths S1–C1 and C1–N4 to 1.738(3) and 1.336(4) Å, respectively. The allyl substituent on the N4 atom adopts an orthogonal orientation with respect to this plane. The C1–N4–C10–C11 and N1–C10–C11–C12 torsion angles are 102.5(4)° and 120.8(5)°, respectively.

Figure 4.

X-ray crystal structure of complex 1 with atom numbering. Thermal ellipsoids are drawn at the 50% probability level.

The complexes are linked via N–H···Cl and C–H···S1 hydrogen bonds in supramolecular chains running along the crystallographic b-axis (Table 4, Figure 5). The antiparallel complexes from neighboring chains reveal stacking interactions of the metallacycles.³⁴ These π-π stacking interactions unite chains in supramolecular layers parallel to the (bc) plane. The interplanar separation between mean planes of overlapping fragments equals 3.421 Å, while the centroid···centroid distance is 3.547 Å and the Cu···Cu distance within stacked complexes is 4.690 Å.

Figure 5.

The supramolecular architecture in the crystal structure of complex 1.

Antioxidant activity

The antioxidant activity of the compounds was determined by the ABTS^+• method (Table 5). The uncoordinated thiosemicarbazone HL exhibited antioxidant activity with an IC₅₀ value of 56.4 μM, which makes it more active than most of its 3d metal coordination compounds 1–6 described in this article and also more active than copper(II) mixed ligand compounds with bidentate N-heteroaromatic bases.

Table 5.

Antioxidant activity of HL and compounds 1–6 against cationic ABTS^+• radicals.

Compound	IC₅₀ (μM)
HL	56.4 ± 1.5
1	106.0 ± 4.5
2	77.8 ± 14.2
3	89.6 ± 4.5
4	102.8 ± 3.3
5	38.6 ± 2.1
6	137.4 ± 3.4
Trolox	33.0 ± 0.2

Among all the coordination compounds, complex 5 showed the highest activity. It is more active than the uncoordinated thiosemicarbazone HL. Also, its IC₅₀ value is close to that of trolox, which was used as a standard. Trolox is a hydrophilic and cell-permeable analog of vitamin E. It is a potent antioxidative used in biochemical applications to reduce oxidative stress and is the standard antioxidant used in antioxidant capacity assays. Mixed-ligand copper(II) coordination compounds with 1,10-phenanthroline and 2,2′-bipyridine showed moderate activity. For comparison, a complex with 1,10-phenanthroline located in the inner sphere is more active than that with 2,2′-bipyridine. In the literature, cases of similar systems with thiosemicarbazones are described, in which introducing a bidentate N-heteroaromatic base into the inner sphere of copper(II) complexes also did not lead to an increase in antioxidant activity.²⁷ The antioxidant activity of coordination compounds is influenced by the nature of the central atom, and the activity decreases in the following order: Fe³⁺ > Cu²⁺ > Ni²⁺. In the literature, there are numerous cases where copper complexes are identified as the most active antioxidants toward ABTS^+• cation radicals.^35–37 However, there are several sources in which nickel coordination compounds manifest higher antioxidant activity.^38,39

Conclusion

The new 1-(piperidin-1-yl)propane-1,2-dione N⁴-allylthiosemicarbazone and its six complexes have been prepared and characterized. The structures of the initial ligand HL and complex 1 are confirmed by single-crystal X-ray diffraction.

The studied complexes and ligand show antioxidant activity against ABTS^+• cation radicals. The uncoordinated ligand HL was more active than most of its complexes. The nickel compound 5 is the most active with its activity exceeding that of the uncoordinated ligand HL and is close to the activity of trolox, which is used in medicine. Thus, the nature of the central atom has a significant effect on the antioxidant activity of coordination compounds, and it is worth continuing the search for new antioxidants among nickel complexes with thiosemicarbazones. The introduction of N-heteroaromatic bases (1,10-phenanthroline and 2,2′-bipyridine) into the inner sphere of complex 2 did not lead to an increase in activity.

Experimental

Materials and methods

3-Isothiocyanatoprop-1-ene, hydrazine hydrate, pyruvic acid, oxalyl chloride, sodium carbonate, dichloromethane, dimethylformamide, piperidine, copper(II) chloride dihydrate, copper(II) nitrate trihydrate, nickel(II) nitrate hexahydrate, iron(III) chloride hexahydrate, 1,10-phenanthroline, and 2,2′-bipyridine were obtained from Sigma-Aldrich. The ¹H and ¹³C NMR spectra were recorded on a Bruker DRX-400. Chemical shifts are measured in ppm relative to tetramethylsilane, as solvents were used CDCl₃. FTIR spectra were obtained for powders on a Bruker ALPHA FTIR spectrophotometer at room temperature in the range of 4000–400 cm⁻¹. Elemental analysis was performed similar to the literature procedure.⁴⁰ The resistance of solutions of complexes in methanol (20 °C, c 0.001 M) was measured using an R-38 rheochord bridge.

N-(Prop-2-en-1-yl)hydrazinecarbothioamide (N⁴-allyl-3-thiosemicarbazide) was synthesized by the reaction between 3-isothiocyanatoprop-1-ene (allyl isothiocyanate) and hydrazine hydrate.⁴¹

1-(Piperidin-1-yl)propane-1,2-dione was synthesized by the method described in the literature,⁴² with some modifications. Pyruvic acid (8.80 g and 0.100 mmol) was dissolved in CH₂Cl₂ (5 mL) and placed in a flat-bottomed flask. Oxalyl chloride (15.24 g and 0.120 mmol) was dissolved in CH₂Cl₂ (10 mL) and was added dropwise to the reaction mixture with stirring at 0 °C. Next, 3 drops of dimethylformamide were added as a catalyst, and a condenser fitted with a drying tube containing calcium chloride was attached to the flask. The reaction mixture was stirred and heated for 1.5 h to afford a yellow oil. A suspension of piperidine (8.50 g and 0.100 mmol), sodium carbonate (10.60 g and 0.100 mmol), and CH₂Cl₂ (10 mL) was stirred at 0 °C. 2-Oxopropanoyl chloride was added dropwise to the obtained cooled suspension, and the mixture was stirred at room temperature for 1 h. The mixture was filtered, washed with water (3 × 100 cm³), and dried in the air to afford the crude product as a mobile yellow oil.

2-[1-Oxo-1-(piperidin-1-yl)propan-2-ylidene]-N-(prop-2-en-1-yl)hydrazinecarbothioamide (1-(piperidin-1-yl)propane-1,2-dione 4-allylthiosemi-carbazone) (HL).

The product was synthesized by the reaction between 1-(piperidin-1-yl)propane-1,2-dione (3.10 g and 20.0 mmol) and N-(prop-2-en-1-yl)hydrazinecarbothioamide (2.62 g and 20.0 mmol) in ethanol with stirring and heating. The obtained pale-yellow precipitate was filtered, washed with a small amount of ethanol, and dried in air. The solid product was crystallized from ethanol to give pale-yellow single crystals that were suitable for X-ray diffraction. The crystals were isolated by filtration. Yield: 83%; m.p. 137–139 °C. ¹H NMR (Supplemental Figure S1) (400 MHz, CDCl₃): δ = 8.71 (br. s, 1H, NH), 7.46 (br. s, 1H, NH), 5.89 (m, 1H, СH), 5.20 (m, 2H, СH₂), 4.30 (m, 2H, NH-CH₂), 3.50 (m, 2 × 2H, CH_2piperidine), 2.11 (s, 3H, CH₃), and 1.62 (m, 3 × 2H, CH_2piperidine); ¹³C NMR (Supplemental Figure S2) (100 MHz, CDCl₃): δ = 178.20 (C=S), 165.33 (C=O), 143.47 (C=N), 132.88 (CH=CH₂), 117.37 (CH₂=), 46.93 (C_allyl), 45.54, 45.51, 26.02, 24.44, 20.35 (C_piperidine), and 14.19 (CH₃); FTIR: 3315, 3288 (NH), 1632 (C=O), 1620 (C=N), and 1362 (C=S) cm⁻¹. Elemental analysis calcd (%) for C₁₂H₂₀N₄OS: C, 53.70; H, 7.51; N, 20.88; and S, 11.95. Found: C, 53.65; H, 7.47; N, 20.80; and S, 12.00.

Synthesis of the complexes

[Cu(L)Cl] (1)

An ethanolic solution of N⁴-allylthiosemicarbazone HL (0.268 g and 1.00 mmol) was mixed with an ethanolic solution of copper(II) chloride dihydrate (0.171 g and 1.00 mmol). A green precipitate formed during stirring which was filtered off, washed with a small amount of ethanol, and dried. The solid product was recrystallized from methanol to give green single crystals suitable for X-ray diffraction. The crystals were isolated by filtration. Yield: 82%. FTIR: 3219, 1642, 1621, 1574, and 791 cm⁻¹; λ (MeOH, Ω⁻¹ cm² mol⁻¹): 95. Elemental analysis calcd (%) for C₁₂H₁₉ClCuN₄OS: Cu, 17.34; C, 39.34; H, 5.23; N, 15.29; S, 8.75; and Cl, 9.68. Found: Cu, 17.28; C, 39.25; H, 5.17; N, 15.15; S, 8.66; and Cl, 9.54.

[Cu(L)NO₃] (2)

An ethanolic solution of N⁴-allylthiosemicarbazone HL (0.268 g and 1.00 mmol) was mixed with an ethanolic solution of copper(II) nitrate trihydrate (0.242 g and 1.00 mmol). A green precipitate formed during stirring which was filtered off, washed with a small amount of ethanol, and dried. Yield: 87%. FTIR: 3225, 1618, 1583, and 797 cm⁻¹; λ (MeOH, Ω⁻¹ cm² mol⁻¹): 82. Elemental analysis calcd (%) for C₁₂H₁₉CuN₅O₄S: Cu, 16.17; C, 36.68; H, 4.87; N, 17.82; and S, 8.16. Found: Cu, 16.09; C, 36.54; H, 4.95; N, 17.73; and S, 8.03.

[Cu(1,10-Phen)(L)]NO₃ (3)

An ethanolic solution of N⁴-allylthiosemicarbazone HL (0.268 g and 1.00 mmol) was mixed with an ethanolic solution of copper(II) nitrate trihydrate (0.242 g and 1.00 mmol). The resulting mixture was stirred for 30 min with heating (60 °C), and then, 1,10-phenanthroline (0.180 g and 1.00 mmol) was added to the reaction mixture. A green precipitate formed during stirring which was filtered off, washed with a small amount of ethanol, and dried. Yield: 86%. FTIR: 3225, 1623, 1583, and 780 cm⁻¹; λ (MeOH, Ω⁻¹ cm² mol⁻¹): 80. Elemental analysis calcd (%) for C₂₄H₂₇CuN₇O₄S: Cu,11.09; C, 50.30; H, 4.75; N, 17.11; and S, 5.59. Found: Cu, 11.00; C, 50.21; H, 4.67; N, 17.02; and S, 5.43.

[Cu(2,2′-BPy)(L)]NO₃ (4)

An ethanolic solution of N⁴-allylthiosemicarbazone HL (0.268 g and 1.00 mmol) was mixed with an ethanolic solution of copper(II) nitrate trihydrate (0.242 g and 1.00 mmol). The resulting mixture was stirred for 30 min with heating (60 °C), and then, 2,2′-bipyridine (0.156 g and 1.00 mmol) was added to the reaction mixture. A green precipitate formed during stirring which was filtered off, washed with a small amount of ethanol, and dried. Yield: 84%. FTIR: 3225, 1621, 1574, and 785 cm⁻¹. λ (MeOH, Ω⁻¹ cm² mol⁻¹): 72. Elemental analysis calcd (%) for C₂₂H₂₇CuN₇O₄S: Cu,11.57; C, 48.12; H, 4.96; N, 17.86; and S, 5.84. Found: Cu, 11.42; C, 48.21; H, 4.84; N, 17.98; and S, 5.73.

[Ni(HL)₂](NO₃)₂ (5)

An ethanolic solution of N⁴-allylthiosemicarbazone HL (0.268 g and 1.00 mmol) was mixed with an ethanolic solution of nickel(II) nitrate hexahydrate (0.146 g and 0.50 mmol). A green precipitate formed during stirring which was filtered off, washed with a small amount of ethanol, and dried. Yield: 85%. FTIR: 3333, 3311, 1615, 1570, and 1342 cm⁻¹. λ (MeOH, Ω⁻¹ cm² mol⁻¹): 158. Elemental analysis calcd (%) for C₂₄H₄₀N₁₀NiO₈S₂: Ni, 8.16; C, 40.07; H, 5.60; N, 19.47; and S, 8.91. Found: Ni, 8.03; C, 40.17; H, 5.49; N, 19.39; and S, 9.02.

[Fe(L)₂]Cl (6)

An ethanolic solution of N⁴-allylthiosemicarbazone HL (0.268 g and 1.00 mmol) was mixed with an ethanolic solution of iron(III) chloride hexahydrate (0.135 g and 0.50 mmol). A brown precipitate formed during stirring which was filtered off, washed with a small amount of ethanol, and dried. Yield: 88%. FTIR: 3223, 1613, 1574, and 791 cm⁻¹. λ (MeOH, Ω⁻¹ cm² mol⁻¹): 114. Elemental analysis calcd (%) for C₂₄H₃₈ClFeN₈O₂S₂: Fe, 8.92; C, 46.04; H, 6.12; N, 17.90; and S, 10.24. Found: Fe, 8.85; C, 46.14; H, 5.99; N, 17.86; and S, 10.18.

X-ray crystallography

The diffraction data of crystals of HL and complex 1 were obtained using an Xcalibur E diffractometer equipped with a charge-coupled device (CCD) area detector and a graphite monochromator (MoKα radiation) (0.71073 Å), at room temperature (293 K). Data collection and reduction, unit cell determination were performed using CrysAlis PRO CCD (Oxford Diffraction). The SHELXS97 and SHELXL2014 program packages^43,44 were used to solve and refine the structures. The structure was solved by direct methods and refined by full-matrix least-squares on F² with anisotropic displacement parameters for all nonhydrogen atoms. The C-bound H-atoms were positioned geometrically and treated as riding atoms using SHELXL default parameters with U_iso(H) = 1.2U_eq(C) and U_iso(H) = 1.5U_eq(CH₃); the N-bound H-atoms were found from the difference Fourier maps. The X-ray data and details of the refinement for HL and complex 1 are summarized in Table 2. The selected bond distances and angles in HL and complex 1 have common values and are summarized in Table 2. The figures were produced using MERCURY.⁴⁵ The crystallographic data were deposited with the Cambridge Crystallographic Data Centre, CCDC 2255382 (HL) and 2255383 (1). Copies of this information may be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge CHB2 1EZ, UK (Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.ukor www.ccdc.cam.ac.uk).

Biological activity

The ABTS^+• radical cation decolorization assay is a method for screening of antioxidant activity applicable to both lipophilic and hydrophilic antioxidants.⁴⁶ Standard solutions of ABTS^+• radical cations and the tested substances, and the conditions for the spectrophotometric measurements and calculations of inhibition were made as described.⁴⁷ The 10 mM stock solutions of the studied compounds and trolox that was used as the reference compound were prepared by dissolving 10 μmol of the corresponding compound in dimethylsulfoxide (DMSO) 1 mL. The 1, 10, 100, and 1000 μM solutions were prepared by the dilution of stock solutions with DMSO. After that, 20 μL of each solution was transferred to a 96-well microtiter plate, and 180 μL of ABTS^+• working solution was added to give solutions with final concentrations of the tested compounds of 0.1, 1, 10, and 100 μM, respectively. All tested samples were dispensed with a dispense module hybrid reader (BioTek). The decrease in absorbance at 734 nm was measured exactly after 30 min of incubation at 25 °C. DMSO was used as negative control. Blank samples were run by solvent without ABTS^+•. The measurement was made by hybrid reader (Synergy H1, BioTek). All tests were performed in triplicate, and the obtained results were averaged.

Supplemental Material

sj-docx-1-chl-10.1177_17475198231216422 – Supplemental material for A new thiosemicarbazone and its 3d metal complexes: Synthetic, structural, and antioxidant studies

Supplemental material, sj-docx-1-chl-10.1177_17475198231216422 for A new thiosemicarbazone and its 3d metal complexes: Synthetic, structural, and antioxidant studies by Ianina Graur, Tatiana Bespalova, Vasilii Graur, Victor Tsapkov, Olga Garbuz, Elena Melnic, Pavlina Bourosh and Aurelian Gulea in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was fulfilled with financial support from the National Agency for Research and Development projects 20.80009.5007.10 and 20.80009.5007.15.

ORCID iD

Ianina Graur

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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A new thiosemicarbazone and its 3d metal complexes: Synthetic,structural,and antioxidant studies

Abstract

Keywords

Introduction

Results and discussion

Synthesis and characterization

Spectroscopic studies

Structure description of HL and complex 1

Antioxidant activity

Conclusion

Experimental

Materials and methods

Synthesis of the complexes

[Cu(L)Cl] (1)

[Cu(L)NO3] (2)

[Cu(1,10-Phen)(L)]NO3 (3)

[Cu(2,2′-BPy)(L)]NO3 (4)

[Ni(HL)2](NO3)2 (5)

[Fe(L)2]Cl (6)

X-ray crystallography

Biological activity

Supplemental Material

sj-docx-1-chl-10.1177_17475198231216422 – Supplemental material for A new thiosemicarbazone and its 3d metal complexes: Synthetic, structural, and antioxidant studies

Footnotes

Declaration of conflicting interests

Funding

ORCID iD

Supplemental material

References

Supplementary Material

[Cu(L)NO₃] (2)

[Cu(1,10-Phen)(L)]NO₃ (3)

[Cu(2,2′-BPy)(L)]NO₃ (4)

[Ni(HL)₂](NO₃)₂ (5)

[Fe(L)₂]Cl (6)