Next Article in Journal
Ion Acceleration and D-D Nuclear Fusion in Laser-Generated Plasma from Advanced Deuterated Polyethylene
Next Article in Special Issue
Synthesis and Anti-Tumor Activity of Novel Aminomethylated Derivatives of Isoliquiritigenin
Previous Article in Journal
New Developments in Spin Labels for Pulsed Dipolar EPR
Previous Article in Special Issue
Stereoselective Synthesis and Cytoselective Toxicity of Monoterpene-Fused 2-Imino-1,3-thiazines
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 19
Issue 10
10.3390/molecules191017026
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Structural Diversity of Copper(II) Complexes with N-(2-Pyridyl)Imidazolidin-2-Ones(Thiones) and Their in Vitro Antitumor Activity

by
Łukasz Balewski
1,
Franciszek Sączewski
1,*,
Patrick J. Bednarski
2,
Maria Gdaniec
3,
Ewa Borys
1 and
Anna Makowska
1
1
Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdańsk, 80-416 Gdańsk, Poland
2
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, L.-F.-Jahn Str., D-17489 Greifswald, Germany
3
Faculty of Chemistry, A. Mickiewicz University, 60-780 Poznań, Poland
*
Author to whom correspondence should be addressed.
Molecules 2014, 19(10), 17026-17051; https://doi.org/10.3390/molecules191017026
Submission received: 29 August 2014 / Revised: 30 September 2014 / Accepted: 13 October 2014 / Published: 23 October 2014
(This article belongs to the Collection Efficient Pharmaceutical and Chemical Approaches for Anticancer Therapy: Design, Preliminary Evaluations, and Further Developments)
Browse Figures
Versions Notes

Abstract

:
Six series of structurally different mono- and binuclear copper(II) complexes 5–10 were obtained by reacting N-(2-pyridyl)imidazolidin-2-ones (1a–l), N,N'-bis(2-pyridyl)imidazolidin-2-ones (2a,b), N-acyl-N'(2-pyridyl)imidazolodin-2-ones (3a–j) and N-(2-pyridyl)imidazolidine-2-thiones (4a–g) with copper(II) chloride at an ambient temperature. The coordination modes of the complexes obtained were established by elemental analysis, IR spectroscopic data and single crystal X-ray diffraction studies. The in vitro cytotoxic activities of both the free ligands and copper(II) complexes were evaluated using a crystal violet microtiter plate assay on five human tumor cell lines: LCLC-103H, A-427, SISO, RT-4 and DAN-G. The free ligands 1–4 at concentration attainable in cancer cells of 20 μM showed no meaningful cytotoxic effect with cell viability in the range of 88%–100%. The most potent copper(II) complex of 1-(6-ethoxy-2-pyridyl)imidazolidin-2-one (6b) exhibited selective cytotoxicity against A-427 lung cancer cell line, while the complexes of 1-(5-methyl-2-pyridyl)imidazolidine-2-thione (5h) and 1-(4-tert-butyl-2-pyridyl)imidazolidine-2-thione (5j) showed cytostatic effect against a whole panel of five human tumor cell lines. In conclusion, the only complexes that showed remarkably increased activity in comparison to the free ligands were those obtained from N-(2-pyridyl)imidazolidine-2-thiones 4c and 4e substituted with alkyl group at position 4 or 5 of pyridine ring.

Graphical Abstract

1. Introduction

Among the transition metals copper occupies a unique position with respect to its biological role. Copper, which is found in living organisms, is an essential cofactor in a number of enzymes and is involved in the function of several proteins and physiological processes such as cell metabolism, mitochondrial respiration, antioxidation processes, synthesis of some active compounds [1,2]. Additionally, copper a redox-active metal may form stable complexes with chelate ligands containing donor atoms such as nitrogen, sulfur or oxygen [2].
In the field of medicinal chemistry it has been found that complexes of transient metals such as copper may possess a higher biological activity compared to the free ligands, with lower toxicity and improved physicochemical properties [3]. Moreover, coordination may lead to significant reduction of drug-resistance. Therefore a considerable research has been devoted to the synthesis of copper compounds which exhibit anticancer [3,4,5,6,7,8,9,10], SOD-mimicking [11,12,13], antimicrobial [14], anti-parasitic [15] and anti-inflammatory properties [16].
Recently, our attention has been focused on the cyclic analogues of N-aryl(heteroaryl)ureas and N-aryl(heteroaryl)thioureas of type I (Figure 1) with proved anticancer activity [17,18,19]. In this paper, we wish to report the results of our studies on the synthesis and reactions of cyclic ureas and thioureas of Type 2 (Figure 1) with copper(II) chloride, X-ray structure determination of the complexes obtained, as well as the results of evaluation of their in vitro cytotoxic activity against several human tumor cell lines.
Molecules 19 17026 g001 550
Figure 1. N-aryl(heteroaryl)ureas (I) and their cyclic analogues II.
Figure 1. N-aryl(heteroaryl)ureas (I) and their cyclic analogues II.
Molecules 19 17026 g001

2. Results and Discussion

2.1. Synthesis of Ligands

Two series of chelating ligands 1a–l and 2a–b with N, O or S donor atoms are shown in Scheme 1. The bidentate ligand 1a and tridentate ligand 2a were prepared by copper-catalyzed N-heteroarylation of 2-imidazolidinone, i.e., by reacting 2-imidazolidinone with 2-iodopyridine in the presence of CuI, N,N'-dimethylethylenediamine and K2CO3 in n-BuOH at 100 °C [20]. The substituted ligands 1b–l and 2b were obtained according to the previously described α-ureidation of corresponding pyridine-N-oxides with 2-chloroimidazoline [21,22].
Molecules 19 17026 g008 550
Scheme 1. Synthesis of bidentate ligands 1a–l and tridentate ligands 2a–b.
Scheme 1. Synthesis of bidentate ligands 1a–l and tridentate ligands 2a–b.
Molecules 19 17026 g008
Novel N-acyl-imidazolidin-2-one tridentate ligands 3a–j suitable for preparation of the coordination compounds were obtained by the treatment of 1 with acetyl or butyryl anhydride, as shown in Scheme 2. On the other hand, imidazolidin-2-ones 1 were also converted into the corresponding imidazolidine-2-thiones using standard method with Lawesson’s reagent in boiling toluene (Scheme 2).
Molecules 19 17026 g009 550
Scheme 2. Preparation of novel N-acyl-imidazolidin-2-ones 3a–j and imidazolidine-2-thiones 4a–g.
Scheme 2. Preparation of novel N-acyl-imidazolidin-2-ones 3a–j and imidazolidine-2-thiones 4a–g.
Molecules 19 17026 g009

2.2. Synthesis and Structure of Cu(II) Complexes

The reaction of N-(2-pyridyl)imidazolidin-2-one(thione) ligands 1, 2, 3 and 4 with CuCl2 were carried out at room temperature in either DMF or methanol solution containing 1% of water. Crystals suitable for the X-ray analysis were obtained by slow evaporation of the solvent. According to the X-ray data collected during the study, the following sequence of events is involved in this reaction yielding complexes with different geometries depending on the nature of ligand (Scheme 3):
(i)
Initial formation of the LCuCl2 complex of type 5 from bidentate ligands (2-alkyl-pyridines) with tetrahedral or square planar configuration, or five-coordinate 6 from tridentate ligands (2-alkoxy-pyridines) with square pyramidal or trigonal bipyramidal configuration.
(ii)
Four-coordinate complex 5 can then react with a molecule of water to give a five-coordinate complex 7.
(iii)
Complexes of type 5 can also form di-μ-chloro dinuclear five-coordinate [Cu2(L)2Cl4] complexes of type 8 or react with a second molecule of ligand to give octahedral [Cu(L)2Cl2] complexes of type 9.
(iv)
A geometrical change occurs upon dissociation of a weakly bonded axially coordinated chloride anion from 9, leading to square pyramidal complexes 10 with the same sp3d2 electronic geometry.
It should be pointed out, that the preferential formation of a particular complex type may depend on solubility of 5, i.e., precipitation of 5 prevents subsequent formation of 7, 8, 9 and 10. It is also possible that several species are in equilibrium in solution, and which are obtained in crystalline form depends on solubility, crystallization kinetics and other, medium dependent, properties. List of ligands 1–4 and corresponding complexes 5–10 obtained is presented in Table 1.
Table
Table 1. List of ligands and copper(II) complexes obtained.
Table 1. List of ligands and copper(II) complexes obtained.
LigandComplex †
NoXRR15678910
1aOHH5a
1bO6-CH3H5b
1cO5-CH3H 9
1dO4-CH3H5c
1eO4-C6H5H 10a, 10b
1fO6-OCH3H 6a
1gO4-OCH3H5d 10c
1hO6-OC2H5H 6b
1iO6-n-OC3H7H 6c
1jO6-i-OC3H7H 6d
1kO6-CH3, 4-OC2H5H5e
1lO6-n-OC4H9H 6e
2aOH2-pyridyl 8a
2bO4-CH32-pyridyl 7
3aO5-CH3COCH3 8b
3bO4-CH3COCH3 8c
3cO4-CH3COC3H7 8d
3dO4-C(CH3)3COCH3 8e
3eO4-C6H5COCH3 8f
3fO4-C6H5COC3H7 8g
3gO4-(CH2)3C6H5COCH3 8h
3hO4-OCH3COCH3 8i
3iO4-OCH3COC3H7 8j
3jO4-OCH2C6H5COCH3 8k
4aSHH5f
4bS6-CH3H5g
4cS5-CH3H5h
4d *S4-CH3H5i
4eS4-C(CH3)3H5j
4fS4-C6H5H5k
4gS6-OCH3H 6f
Notes: † Numbers in bold denote complexes whose structure was confirmed by X-ray analysis; * Ligand prepared according to ref. [21].
Copper(II) complexes exhibit a variety of irregular stereochemistries as a result of the lack of spherical symmetry of this d9 ion. Classification of coordination geometry of the obtained complexes was accomplished based on the equation described by D. Venkataraman and co-workers (Equation (1)), which determines the best fit of the observed structure of complex compound to the ideal coordination polyhedra [23]. The best fit shows minimum of deviation in ligand-copper-ligand bond angles (<L-Cu-L) between the observed coordination structure and the reference polyhedra with the same coordination number (CN). Such classification is unambiguous since a unique set of angles exists for each of the reference polyhedral. Hence, the coordination geometry is classified as polyhedron that gives the smallest value of the average angular displacement (ΔΘ) according to the following Equation (1):
ΔΘ = Σi=1(n/2) x (n−1))|Θi − Θ°i|/n/2 × (n − 1)
where: n—coordination number, Θi—the angle of the observed structure, Θ°i—corresponding valence angle of the reference polyhedron under consideration, ΔΘ—evaluation of the average angular displacement.
For example, in the case of a complex 5b with coordination number n = 4, the number of valence angles < L-Cu-L, according to the formula n = (n/2) × (n − 1), is 6. The geometry of this complex may be: square planar with ideal angles of 90, 90, 90, 90, 180, 180 (°) or tetrahedral with angles 109.5, 109.5, 109.5, 109.5, 109.5, 109.5 (°). Comparison of the observed angles in the structure of 5b (Figure 2, Table 2) with ideal values of each polyhedron geometry angles determined by the value of (X vs. Y vs. Z) indicates that the coordination geometry in CuNOCl2 core is intermediate between square-planar and tetrahedral, however, the copper ion adopts geometry that fit best to the square planar (ΔΘ = 17.79 for square planar vs ΔΘ = 18.72 for tetrahedral geometry).
Molecules 19 17026 g010 550
Scheme 3. Reaction of N-(2-pyridyl)imidazolidin-2-one(thione) ligands 1, 2, 3 and 4 with CuCl2.
Scheme 3. Reaction of N-(2-pyridyl)imidazolidin-2-one(thione) ligands 1, 2, 3 and 4 with CuCl2.
Molecules 19 17026 g010
A similar distorted square planar coordination geometries were found in crystals of imidazolidine-2-thiones 5h, 5i and 5j (Figure 2, Table 2).
Table
Table 2. Selected bond lengths and bond angles in copper complexes 5b, 5h, 5i and 5j.
Table 2. Selected bond lengths and bond angles in copper complexes 5b, 5h, 5i and 5j.
No.Bond Lengths (Å)Bond Angles (°)
5bCu1-Cl12.2239(5)Cl1-Cu1-N198.45(5)
Cu1-Cl22.2096(5)Cl1-Cu1-Cl2103.57(2)
Cu1-N11.977(2)Cl1-Cu1-O1135.46(4)
Cu1-O21.980(1)O1-Cu1-Cl293.53(4)
Cl2-Cu1-N1143.81(6)
O1-Cu1-N190.43(7)
5hCu1-Cl12.261(1)Cl1-Cu1-Cl2100.99(3)
Cu1-Cl22.2139(6)Cl1-Cu1-S1141.86(3)
Cu1-N71.977(1)Cl1-Cu1-N797.01(6)
Cu1-S12.2324(8)Cl2-Cu1-N7139.51(6)
Cl2-Cu1-S193.25(3)
S1-Cu1-N794.50(6)
5iCu1-Cl12.239(3)Cl1-Cu1-Cl297.44(2)
Cu1-Cl22.239(4)Cl1-Cu1-S191.17(2)
Cu1-N71.983(3)Cl2-Cu1-N794.33(4)
Cu1-S12.2708(8)Cl1-Cu1-N7149.94(4)
Cl2-Cu1-S1152.71(2)
N7-Cu1-S190.88(4)
5jCu1-Cl12.239(3)Cl1-Cu1-Cl296.92(1)
Cu1-Cl22.243(3)Cl2-Cu1-S190.85(9)
Cu1-N12.011(6)Cl1-Cu1-S1146.47(9)
Cu1-S12.245(2)Cl2-Cu1-N1143.0(2)
Cl1-Cu1-N196.94(1)
Cl2-Cu1-S190.87(9)
Molecules 19 17026 g002 550
Figure 2. ORTEP [24] representation of molecular structure of 5b, 5h, 5i and 5j.
Figure 2. ORTEP [24] representation of molecular structure of 5b, 5h, 5i and 5j.
Molecules 19 17026 g002
Ligands 1 and 4 containing alkoxy group at position 6 of pyridine ring form mononuclear five-coordinate (4 + 1) copper(II) complexes with the central atom chelated by neutral ligand and bound to two chloride ions and oxygen of alkoxy group. In the complex 6a both pyridine and imidazolidine rings are approximately planar with N1-C2-N7-C8 torsion angle of 14.4°. As exemplified by the crystal structure of 6a (Figure 3, Table 3), the geometry around Cu(II) is best described as distorted trigonal bipyramid. Atoms -Cu1-N1-C2-C8-N7-O12- form six-membered ring and atoms -Cu1-N1-C6-O13- form four-membered ring of considerable tension. The length of the bond between the atoms Cu1 and O13 of the methoxy group is longer (2.647 Å) than that between Cu1 atom and the oxygen atom O12 of the carbonyl group (1.994 Å).
Molecules 19 17026 g003 550
Figure 3. ORTEP representation of molecular structure of 6a.
Figure 3. ORTEP representation of molecular structure of 6a.
Molecules 19 17026 g003
Table
Table 3. Selected bond lengths and bond angles in copper complex 6a.
Table 3. Selected bond lengths and bond angles in copper complex 6a.
Bond Lengths (Å)Bond Angles (°)
Cu1-Cl12.2325(2)Cl1-Cu1-Cl2104.23
Cu1-Cl22.1848(2)N1-Cu1-Cl2147.16
Cu1-O121.9943(2)O12-Cu1-Cl294.11
Cu1-O132.6472(3)O13-Cu1-Cl2104.53
Cu1-N11.9754(2)N1-Cu1-O1288.06
O12-Cu1-O13134.79
O12-Cu1-Cl1130.17
O13-Cu1-N154.71
O13-Cu1-Cl184.85
N1-Cu1-Cl199.10
Interesting five-coordinated mononuclar complex 7 was prepared by reacting equimolar amount of 1,3-bis(4-methyl-2-pyridyl)imidazolidin-2-one (2b) with copper(II) chloride in methanol containing 1% of water. Elemental analysis data suggested the presence of water molecule in the complex compound, which was confirmed by IR spectrum revealing a broad absorption band with a maximum at 3372 cm−1. X-ray analysis (Figure 4, Table 4) indicate that the molecule 7 is not isostructural with 6a, but it does have a similar molecular structure. Thus, central atom chelated by neutral ligand 2b and bound to two chloride ions and oxygen of H2O. The coordination geometry around the central atom is best described as distorted trigonal bipyramid due to differences in the five Cu-donor bond lengths.
Table
Table 4. Selected bond lengths and bond angles in copper complex 7.
Table 4. Selected bond lengths and bond angles in copper complex 7.
Bond Lengths (Å)Bond Angles (°)
Cu1-Cl12.362(2)N14-Cu1-O187.58(7)
Cu1-Cl22.289(8)N14-Cu1-Cl189.40(6)
Cu1-N142.007(8)N14-Cu1-Cl295.83(6)
Cu1-O12.042(3)O1W-Cu1-Cl192.45(5)
Cu1-O1W1.974(4)O1W-Cu1-O184.87(7)
Cl2-Cu1-O1119.07(5)
O1W-Cu1-N14172.37(8)
Cl1-Cu1-O1111.82(4)
Cl1-Cu1-Cl2128.99(3)
Molecules 19 17026 g004 550
Figure 4. ORTEP representation of molecular structure of 7.
Figure 4. ORTEP representation of molecular structure of 7.
Molecules 19 17026 g004
1,3-Bis(2-pyridyl)imidazolidin-2-one (2b) and 1-acyl-3-(2-pyridyl)imidazolidin-2-ones (3a–j) subjected to the reaction with copper(II) chloride gave rise to the formation of the products 8a–k, which appear to be binuclear five-coordinate di-μ-chloro copper(II) complexes. The determination of the three-dimensional structure of the complexes 8a and 8c by X-ray diffraction (Figure 5, Table 5) indicates that symmetrical coordination polyhedra of these complexes are square-pyramidal with the central atom displaced from the plane of the four basal atoms towards the apical position. It is noteworthy, however, that the arrangement of ligands in both complexes is different. Thus, in 8c the apical position is occupied by non-bridging Cl atom which is basal to the other copper in the dimer, while complex 8a incorporates O atom in that position.
Molecules 19 17026 g005 550
Figure 5. ORTEP representation of molecular structure of 8a and 8c. Displacement ellipsoids are shown at the 50% probability level. Only the symmetry independent part of the molecule is labelled.
Figure 5. ORTEP representation of molecular structure of 8a and 8c. Displacement ellipsoids are shown at the 50% probability level. Only the symmetry independent part of the molecule is labelled.
Molecules 19 17026 g005
Table
Table 5. Selected bond lengths and bond angles in copper complexes 8a and 8c.
Table 5. Selected bond lengths and bond angles in copper complexes 8a and 8c.
No.Bond Lengths (Å)Bond Angles (°)
8aCl1-Cu12.3260(5)Cl1-Cu1-Cl185.06(2)
Cl1-Cu12.3064(6)Cl1-Cu1-Cl292.25(2)
Cl2-Cu12.2492(5)N7-Cu1-Cl291.17(5)
Cu1-N72.014(2)Cl1-Cu1-N791.72(5)
Cu1-O12.143(1)O1-Cu1-Cl192.84(4)
O1-Cu1-Cl1102.79(4)
O1-Cu1-N786.65(6)
O1-Cu1-Cl2106.24(4)
N7-Cu1-Cl1176.55(4)
Cl1-Cu1-Cl2150.94(2)
8cCl1-Cu12.2889(1)Cl1-Cu1-O185.15
Cl1-Cu12.6261(5)O1-Cu1-N786.80
Cl2-Cu12.2349(1)Cl2-Cu1-N797.38
Cu1-N72.0651(1)Cl1-Cu1-Cl292.09
Cu1-O11.9829(1)N7-Cu1-Cl1170.49
O1-Cu1-Cl2152.31
Cl1-Cu1-O194.23(1)
Cl1-Cu1-N785.37(1)
Cl1-Cu1-Cl2113.35(1)
Cl1-Cu1-Cl190.15(1)
N-(5-methyl-2-pyridyl)imidazolidin-2-one (1c) reacted with copper(II) chloride with the formation of mononuclear complex trans-CuCl2L2 (compound 9, Figure 6, Table 6). A similar structure was previously obtained using N,N'bis(2-pyridyl)urea [25]. The six-coordinate copper ion sits upon crystallographic inversion center, with ligand chelated through its oxygen atom and 2-pyridyl nitrogen atom. The axial positions are occupied by two chloride ligands. The bond angles around the copper ion are close to 90°, indicating a slight distortion of the octahedral coordination sphere.
Molecules 19 17026 g006 550
Figure 6. ORTEP representation of molecular structure of 9. Displacement ellipsoids are shown at the 50% probability level. Only symmetry independent part is labelled.
Figure 6. ORTEP representation of molecular structure of 9. Displacement ellipsoids are shown at the 50% probability level. Only symmetry independent part is labelled.
Molecules 19 17026 g006
Table
Table 6. Selected bond lengths and bond angles in copper(II) complex 9.
Table 6. Selected bond lengths and bond angles in copper(II) complex 9.
Bond Lengths (Å)Bond Angles (°)
Cu1-Cl12.8254(8)O1-Cu1-N788.31(8)
Cu1-N72.019(2)N7-Cu1-O191.69(8)
Cu1-O11.950(2)Cl1-Cu1-O192.31(6)
O1-Cu1-Cl187.69(6)
N7-Cu1-Cl190.71(6)
O1-Cu1-O1180.00(8)
N7-Cu1-N7180.00(9)
Cl1-Cu1-Cl1180.00(2)
As shown in Table 6 in octahedral complex Cu(II)L2Cl2 (9) the Cu(II)-Cl bonds are elongated (2.8254 Å), and therefore, are susceptible to dissociation. Indeed, in polar solvents ligands 1e (1-(4-phenyl-2-pyridyl)imidazolidin-2-one) and 1g (1-(4-methoxy-2-pyridyl)imidazolidin-2-one) subjected to the reaction with copper(II) chloride gave the monocationic complexes 10a/b and 10c of general structure [CuL2Cl]+ whose charge is neutralized by either the Cl− (10a and 10c) or CuCl3− (10b) ion. Their crystal structures show (Figure 7, Table 7) that two bidentate ligands arranged in trans fashion are coordinated to the copper(II) ion through N(pyridine) and O(imidazolidin-2-one) atoms. The fifth coordination comes from chloride ion, and the Cu-Cl bond lengths of 2.4910–2.4877 Å are shorter than those in the octahedral complex 9 discussed above. The geometries around the central atom are best described by square-pyramidal with trigonal-bipyramidal distortion. The counterions, i.e., Cl− in complexes 10a and 10c and CuCl3− in complex 10b, remain uncoordinated, however were found to engage in several weak hydrogen-bonding interactions.
Molecules 19 17026 g007 550
Figure 7. ORTEP representation of molecular structure of 10a (Cl− counterion), 10b (CuCl3− counterion) and 10c (Cl− counterion). Hydrogen bonds are shown with dashed lines.
Figure 7. ORTEP representation of molecular structure of 10a (Cl− counterion), 10b (CuCl3− counterion) and 10c (Cl− counterion). Hydrogen bonds are shown with dashed lines.
Molecules 19 17026 g007
Table
Table 7. Selected bond lengths and bond angles in copper(II) complexes 10a, 10b and 10c.
Table 7. Selected bond lengths and bond angles in copper(II) complexes 10a, 10b and 10c.
No.Bond Lengths (Å)Bond Angles (°)
10aCu1-Cl12.4274(5)Cl1-Cu1-O1A101.91(4)
Cu1-N1A2.053(2)Cl1-Cu1-O1B107.23(4)
Cu1-N1B2.041(2)O1A-Cu1-O1B150.84(6)
Cu1-O1A1.967(1)N1A-Cu1-O1A87.52(6)
Cu1-O1B1.922(1)N1A-Cu1-Cl194.08(5)
N1A-Cu1-N1B171.28(6)
N1A-Cu1-O1B89.42(6)
N1B-Cu1-Cl194.58(5)
N1B-Cu1-O1A89.74(6)
N1B-Cu1-O1B88.95(6)
10bCu1-Cl12.4877(6)Cl1-Cu1-O1A111.06(5)
Cu1-N1A2.019(2)Cl1-Cu1-O1B92.85(5)
Cu1-N1B2.015(2)O1A-Cu1-O1B156.09(7)
Cu1-O1A1.946(2)N1A-Cu1-O1A86.87(7)
Cu1-O1B1.964(2)N1A-Cu1-Cl197.44(6)
Cu2-Cl22.195(1)N1A-Cu1-N1B172.10(8)
Cu2-Cl32.3018(8)N1A-Cu1-O1B89.79(7)
N1B-Cu1-Cl190.45(6)
N1B-Cu1-O1A89.95(7)
N1B-Cu1-O1B90.19(7)
Cl2-Cu2-Cl3120.59(4)
Cl3-Cu2-Cl3118.81(3)
10cCu1A-Cl1A2.4910(5)N1B-Cu1A-Cl1A90.04(5)
Cu1A-N1A2.031(1)O2A-Cu1A-Cl1A105.98(5)
Cu1A-N1B2.044(2)N1A-Cu1A-Cl1A97.78(5)
Cu1A-O2A1.928(2)O2B-Cu1A-Cl1A94.12(5)
Cu1A-O2B1.948(2)O2B-Cu1A-N1A88.03(7)
N1A-Cu1A-O2A89.02(7)
O2A-Cu1A-N1B89.78(7)
O2B-Cu1A-N1B88.65(7)
O2-Cu1A-O2B159.90(6)
N1B-Cu1A-N1A166.96(7)

2.3. In Vitro Antitumor Activity

The in vitro antitumor potential of the free ligands 1–4 and copper(II) complexes 5–10 against human lung cancer (either LCLC-103H or A-427), human bladder cancer (either 5637 or RT-4), human cervical cancer (SISO), and human esophagus cancer (KYSE-520) cell lines was evaluated using a crystal violet microtiter plate assay as described earlier [26]. Primary screening of the new compounds was performed to indicate whether a substance possesses enough activity to inhibit cell growth by 50% at a concentration attainable in cancer cells, i.e., 20 µM.
The free ligands 1–4 were inactive, while the complexes of type 5 and 6 obtained from imidazolidin-2-ones, including these substituted with acyl group at the nitrogen atom, showed a remarkable inhibitory activity against lung cancer A-427 cell line (Table 8). It should be pointed out, however, that some copper(II) complexes, although fairly soluble in aprotic polar solvents such as DMF or DMSO, showed rather poor solubility in water and precipitated out of culture media. Therefore, Table 8 incorporates the results of primary screening obtained for the complexes that remained in solution at the test concentration of 20 μM.
Table
Table 8. Percent of cell growth relative to untreated control at a concentration of 20 µM (values are averages of three independent determinations with standard deviations, otherwise averages of two determinations without SD. Values were calculated according to Equation (2)).
Table 8. Percent of cell growth relative to untreated control at a concentration of 20 µM (values are averages of three independent determinations with standard deviations, otherwise averages of two determinations without SD. Values were calculated according to Equation (2)).
Cell LineLCLC-103H5637A-427SISOKYSE-520RT-4
No.
5a38.74nd †35.5796.68ndnd
5bnd101.05nd113.6595.75nd
5e88.2 ± 17.4135.9 ± 43.634.9 ± 9.8ndndnd
5f91.78nd79.8285.30ndnd
5g63.1796.6744.69ndndnd
5h36.52nd45.11ndnd31.67
5i89.3833.48ndndnd71.86
5j38.28nd29.18ndnd41.65
6a101.2 ± 13.1106.2 ± 31.148.30 ± 11.13ndndnd
6b91.5 ± 8.887.4 ± 20.6−40.6 ± 31.8ndndnd
6c75.9 ± 21.7104.05 ± 40.5430.4 ± 10.1ndndnd
6d78.4 ± 21.2145.6 ± 30.826.6 ± 11.3ndndnd
766.9393.78ndndnd94.21
8a27.45nd18.3089.69ndnd
969.23 ± 23.21135.88 ± 10.6675.12 ± 13.31ndndnd
10c216.63 ± 14.43105.96 ± 24.0679.4 ± 6.26ndndnd
Note: † nd: = not determined.
For secondary screening aimed at determining cytotoxic potencies (IC50) we selected imidazolidine-2-thione complexes 5h and 5j which exhibited a pronounced activity against at least three cancer cell lines. The results of secondary screenings are presented in Table 9. Thus, for complexes 5h and 5j, both of which exhibited growth inhibitory effects against LCLC-103H, A-427, SISO, RT-4 and DAN-G cell lines, the calculated IC50 values were in the range of 8–25 µM. It is worth noting that most active (IC50 in the range of 8.55–12.80 µM) was compound 5j containing tert-butyl substituent at the position 4 of pyridine ring. This observation is in line with recent findings that an electron-donating tert-butyl group may stabilize a copper(II) complexes by increasing the electron density at the central ion which, in turn, elicits a “self-activating” mechanism of DNA strand scission through the generation of reactive oxygen species (ROS) that are possibly responsible for the DNA cleavage [27,28,29]. Further work will be needed to confirm this, however.
Table
Table 9. IC50 (µM) values in five human cancer cell lines obtained after 96 h exposure †.
Table 9. IC50 (µM) values in five human cancer cell lines obtained after 96 h exposure †.
Cell LineLCLC-103HA-427SISORT-4DAN-G
No.
5h11.16 ± 3.2024.38 ± 14.2824.81 ± 13.788.25 ± 3.7924.88 ± 3.04
5j11.71 ± 5.068.55 ± 3.1010.83 ± 3.059.64 ± 4.9512.80 ± 0.64
cisplatin *0.90 ± 0.191.96 ± 0.540.24 ± 0.061.61 ± 0.160.73 ± 0.34
Notes: † Values are average of three independent determinations with standard deviations; * Ref. [26].

3. Experimental Section

Melting points both the ligands and copper(II) complexes were determined on a Boetius apparatus and are uncorrected. FT-IR spectra were measured by Nicolet-380 spectrophotometer and 1H-NMR and 13C-NMR spectra were recorded on a Varian Gemini instrument operating at 200 MHz and 50 MHz, respectively, in CDCl3 or DMSO-d6 as a solvent. Chemical shifts are shown in parts per million (ppm) on the δ scale. Coupling constants are shown in hertz (Hz).
Chromatographic separations were performed on silica gel 60 PF254 containing gypsum (Merck) by use of chromatotron or flash column chromatography (silica gel 0.040–0.063 mm). Thin-layer chromatography (TLC) was performed with Merck silica gel plates and spots were visualized with UV light at 254 nm.
The diffraction data for single crystals were collected with KM4CCD, Oxford Diffraction Xcalibur or Oxford Diffraction SuperNova diffractometers. The intensity data were processed using the CrysAlis software [30]. The structures were solved by direct methods with the program SHELXS-97 [31] and refined by full-matrix least-squares method on F2 with SHELXL-97 [31].
Crystallographic data for compounds have been deposited with the Cambridge Crystallographic Data Centre, with the deposition Nos CCDC 986094, 986095, 986193–986202. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.
Elemental analyses of C, H and N were within ±0.4% of the theoretical values.
All cell culture reagents were purchased from Sigma (Deisenhofen, FRG). Cancer cell lines: human large cell lung carcinoma LCLC-103H, human urinary bladder carcinoma 5637, human lung carcinoma A-427, human uterine cervical adenocarcinoma SISO, esophageal squamous cell carcinoma KYSE-520, human bladder cell carcinoma RT-4 and human pancreas cell adenocarcinoma DAN-G were obtained from the German Collection of Microorganisms and Cell Cultures (DSMZ, Brauschweig, FRG). The culture medium for cell lines was RPMI-1640 medium containing 2 g/L HCO3, and 10% FCS. Cells were grown in 75 cm2 plastic culture flasks (Sarstedt, Nümbrecht, FRG) in a humid atmosphere of 5% CO2 at 37 °C and were passaged shortly before becoming confluent.
For the cytotoxicity studies, 100 μL of a cell suspension were seeded into 96-well microtiter plates (Sarstedt) at a density of 1000 cell per well except for the LCLC-103H cell line, which was plated out at 250 cells per well. One day after plating, the cells were treated with test substance at five concentrations per compound. The 1000-fold concentrated stock solutions in DMF or DMSO were serially diluted by 50% in DMF or DMSO to give the feed solutions, which were diluted 500-fold into culture medium. The controls received just DMF or DMSO. Each concentration was tested in eight wells, with each well receiving 100 μL of the medium containing the substance. The concentration ranges were chosen to bracket the expected IC50 values as best as possible. Cells were then incubated for 96 h, after which time the medium was removed and replaced with 1% glutaraldehyde/PBS. Staining with crystal violet was done as previously described [26]. O.D. was measured at λ = 570 nm with an Anthos 2010 plate reader (Salzburg, Austria).
Corrected T/C values were calculated using MS Excel 2007 program by the equation:
(T/C)corr(%) = (O.D.T − O.D.c.0)/(O.D.C − O.D.c.0) × 100
where O.D.T is the mean absorbance of the treated cells; O.D.C the mean absorbance of the controls and O.D.c.0 the mean absorbance at the time drug was added. The IC50 values were estimated by a linear least-square regression of the T/Ccorr values versus the logarithm of the substance concentration; only concentrations that yielded T/Ccorr values between 10% and 90% were used in the calculation. The reported IC50 values are the averages of 3 independent experiments.

3.1. Synthesis of 1-Acyl-3-(2-pyridyl)imidazolidin-2-ones 3a–j (General Procedure)

Imidazolidin-2-one (0.001 mol) was refluxed in 5 mL of acetic anhydride or butyric anhydride for 6 h. The reaction mixture was concentrated under reduced pressure and basified with 20% solution of K2CO3. Precipitated was collected by suction, washed with water and dried. In case when oily residue was formed after addition of K2CO3 the product was extracted with chloroform (3 × 15 mL), dried with anhydrous MgSO4, filtrated and concentrated under reduced pressure. Product was purified by use of chromatotron, flash column chromatography or crystallization. According to described general procedure were obtained following compounds:
1-Acetyl-3-(5-methyl-2-pyridyl)imidazolidin-2-one (3a). Compound 3a was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 7:3, v/v); yield 60%; mp. 179–181 °C; IR (KBr) ν [cm−1]: 2999, 2953, 2922, 2853, 1731, 1680, 1484, 1403, 1375, 1291, 1246, 1023; 1H-NMR (500 MHz, CDCl3): δ 2.30 (s, 3H, CH3), 2.57 (s, 3H, CH3), 3.93 (t, 2H, CH2), 4.10 (t, 2H, CH2), 7.54 (d, J = 8.3 Hz, 1H, Ar-H), 8.13 (d, J = 8.3 Hz, 1H, Ar-H), 8.16 (s, 1H, Ar-H); Anal. Calcd. for C11H13N3O2: C, 60.26; H, 5.98; N, 19.17; Found: C, 60.11; H, 5.78; N, 19.08.
1-Acetyl-3-(4-methyl-2-pyridyl)imidazolidin-2-one (3b). Compound 3b was purified by use of chromatotron (eluent: dichloromethane/acetone, 95:5, v/v); yield 70%; mp. 152–154 °C; IR (KBr) ν [cm−1]: 3017, 2920, 1732, 1679, 1605, 1485, 1426, 1373, 1296, 1249, 1195; 1H-NMR (200 MHz, (CD3)2SO): δ 2.33 (s, 3H, CH3), 2.43 (s, 3H, OCH3), 3.76 (t, 2H, CH2), 3.96 (t, 2H, CH2), 6.97 (d, J = 4.5 Hz, 1H, Ar-H), 8.02 (s, 1H, Ar-H), 8.22 (d, J = 4.5 Hz, 1H, Ar-H); Anal. Calcd. for C11H13N3O2: C, 60.26; H, 5.98; N, 19.17; Found: C, 60.08; H, 5.81; N, 18.96.
1-Butyryl-3-(4-methyl-2-pyridyl)imidazolidin-2-one (3c). Compound 3c was purified by use of chromatotron (eluent: chloroform); yield 54%; mp. 82–83 °C; IR (KBr) ν [cm−1]: 3058, 2967, 2915, 2878, 1734, 1677, 1603, 1560, 1374, 1323, 1246, 1190; 1H-NMR (500 MHz, CDCl3): δ 1.00 (t, 3H, CH3), 1.73 (sextet, 2H, CH2), 2.38 (s, 3H, CH3), 2.97 (t, 2H, CH2), 3.93 (t, 2H, CH2), 4.10 (t, 2H, CH2), 6.87 (d, J = 5.4 Hz, 1H, Ar-H), 8.08 (s, 1H, Ar-H), 8.19 (d, J = 5.4 Hz, 1H, Ar-H); Anal. Calcd. for C13H17N3O2: C, 63.14; H, 6.93; N, 16.99; Found: C, 62.99; H, 6.81; N, 16.89.
1-Acetyl-3-(4-tert-butyl-2-pyridyl)imidazolidin-2-one (3d). Compound 3d was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 4:1, v/v); yield 59%; mp. 163–166 °C; IR (KBr) ν [cm−1]: 2970, 2919, 2870, 1726, 1685, 1598, 1547, 1484, 1420, 1374, 1293, 1252, 1120; 1H-NMR (200 MHz, CDCl3): δ 1.35 (s, 9H, C(CH3)3), 2.60 (s, 3H, CH3), 3.94–3.98 (m, 2H, CH2), 4.10–4.14 (m, 2H, CH2), 7.08 (dd, J1 = 1.3 Hz, J2 = 5.4 Hz, 1H, Ar-H), 8.26 (d, J = 5.4 Hz, 1H, Ar-H), 8.30 (s, 1H, Ar-H); Anal. Calcd. for C14H19N3O2: C, 64.35; H, 7.33; N, 16.08; Found: C, 64.17; H, 7.19; N, 15.86.
1-Acetyl-3-(4-phenyl-2-pyridyl)imidazolidin-2-one (3e). Compound 3e was purified by use of flash column chromatography (eluent: chloroform/ethyl acetate:methanol, 5:2:1, v/v/v); yield 76%; mp. 156–157 °C; IR (KBr) ν [cm−1]: 3067, 3021, 2960, 2918, 1747, 1685, 1594, 1545, 1474, 1420, 1377, 1368, 1308, 1251; 1H-NMR (200 MHz, (CD3)2SO): δ 2.45 (s, 3H, CH3), 3.77–3.85 (m, 2H, CH2), 3.99–4.07 (m, 2H, CH2), 7.45–7.58 (m, 4H, Ar-H), 7.72–7.77 (m, 2H, Ar-H), 8.43–8.48 (m, 2H, Ar-H), 13C-NMR (50 MHz, (CD3)2SO): δ 23.98, 38.55, 41.05, 110.29, 117.28, 127.07 (two overlapping signals), 129.58 (two overlapping signals), 129.66, 137.72, 148.68, 149.18, 152.32, 153.02, 170.09; Anal. Calcd. for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94; Found: C, 68.22; H, 5.23; N, 14.78.
1-Butyryl-3-(4-phenyl-2-pyridyl)imidazolidin-2-one (3f). Compound 3f was purified by use of chromatotron (eluent: chloroform); yield 70%; mp. 155–156 °C; IR (KBr) ν [cm−1]: 3110, 3069, 2962, 2918, 2872, 1735, 1682, 1593, 1474, 1374, 1248, 1224; 1H-NMR (500 MHz, CDCl3): δ 1.02 (t, 3H, CH3), 1.75 (sextet, 2H, CH2), 3.00 (t, 2H, CH2), 3.97 (t, 2H, CH2), 4.16 (t, 2H, CH2), 7.28 (d, J = 5.4 Hz, 1H, Ar-H), 7.43–7.50 (m, 3H, Ar-H), 7.70 (d, J = 7.8 Hz, 2H, Ar-H), 8.39 (d, J = 5.4 Hz, 1H, Ar-H), 8.53 (s, 1H, Ar-H); Anal. Calcd. for C18H19N3O2: C, 69.88; H, 6.19; N, 13.58; Found: C, 69.79; H, 6.02; N, 13.50.
1-Acetyl-3-[4-(3-phenylpropyl)-2-pyridyl]imidazolidin-2-one (3g). Compound 3g was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 4:1, v/v); yield 64%; mp. 89–90 °C; IR (KBr) ν [cm−1]: 3060, 3024, 2943, 2925, 2858, 1722, 1683, 1601, 1560, 1483, 1438, 1402, 1379, 1305, 1278, 1254; 1H-NMR (500 MHz, (CD3)2SO): δ 1.90 (q, 2H, CH2), 2.45 (s, 3H, CH3), 2.60–2.64 (m, 4H, 2×CH2), 3.79 (t, 2H, CH2), 3.98 (t, 2H, CH2), 7.02 (d, J = 4.9 Hz, 1H, Ar-H), 7.16–7.29 (m, 5H, Ar-H), 8.07 (s, 1H, Ar-H), 8.27 (d, J = 4.9 Hz, 1H, Ar-H); Anal. Calcd. for C19H21N3O2: C, 70.57; H, 6.55; N, 12.99; Found: C, 70.43; H, 6.51; N, 13.20.
1-Acetyl-3-(4-methoxy-2-pyridyl)imidazolidin-2-one (3h). Compound 3h was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 4:1, v/v); yield 87%; mp. 139–140 °C; IR (KBr) ν [cm−1]: 3023, 2983, 2920, 1731, 1687, 1594, 1566, 1455, 1406, 1382, 1309, 1257, 1223, 1179; 1H-NMR (500 MHz, (CD3)2SO): δ 2.44 (s, 3H, CH3), 3.78 (t, 2H, CH2), 3.84 (s, 3H, OCH3), 3.97 (t, 2H, CH2), 6.77 (dd, J1 = 1.9 Hz, J2 = 5.9 Hz, 1H, Ar-H), 7.77 (d, J = 1.9 Hz, 1H, Ar-H), 8.19 (d, J = 5.9 Hz, 1H, Ar-H); Anal. Calcd. for C11H13N3O3: C, 56.16; H, 5.57; N, 17.86; Found: C, 55.99; H, 5.51; N, 17.80.
1-Butyryl-3-(4-methoxy-2-pyridyl)imidazolidin-2-one (3i). Compound 3i was purified by use of chromatotron (eluent: chloroform); yield 66%; mp. 112–113 °C; IR (KBr) ν [cm−1]: 3112, 3016, 2964, 2921, 2875, 1736, 1691, 1595, 1564, 1482, 1398, 1375, 1255, 1216, 1178; 1H-NMR (200 MHz, CDCl3): δ 1.01 (t, 3H, CH3), 1.72 (sextet, 2H, CH2), 2.98 (t, 2H, CH2), 3.89 (s, 3H, OCH3), 3.92–4.00 (m, 2H, CH2), 4.07–4.16 (m, 2H, CH2), 6.61 (dd, J1 = 2.2 Hz, J2 = 5.9 Hz, 1H, Ar-H), 7.86 (d, J = 2.2 Hz, 1H, Ar-H), 8.14 (d, J = 5.9 Hz, 1H, Ar-H); Anal. Calcd. for C13H17N3O3: C, 59.30; H, 6.51; N, 15.96; Found: C, 59.21; H, 6.46; N, 16.00.
1-Acetyl-3-(4-benzyloxy-2-pyridyl)imidazolidin-2-one (3j). Compound 3j was purified by use of chromatotron (eluent: chloroform/ethyl acetate, 4:1, v/v); yield 70%; mp. 151–153 °C; IR (KBr) ν [cm−1]: 3101, 3069, 3027, 2916, 1743, 1737, 1673, 1596, 1563, 1481, 1452, 1386, 1318, 1255, 1215, 1011, 868; 1H-NMR (500 MHz, (CD3)2SO): δ 2.45 (s, 3H, OCH3), 3.78 (t, 2H, CH2), 3.98 (t, 2H, CH2), 5.21 (s, 2H, OCH2), 6.86 (dd, J1 = 1.9 Hz, J2 = 5.9 Hz, 1H, Ar-H), 7.36–7.49 (m, 5H, Ar-H), 7.87 (d, J = 1.9 Hz, 1H, Ar-H), 8.21 (d, J = 5.9 Hz, 1H, Ar-H); Anal. Calcd. for C17H17N3O3: C, 65.58; H, 5.50; N, 13.50; Found: C, 65.42; H, 5.28; N, 13.71.

3.2. Synthesis of N-(2-Pyridyl)imidazolidine-2-thiones 4a–c, e–g (General Procedure)

Appropriate N-(2-pyridyl)imidazolidin-2-one (0.001 mol) was refluxed with Lawesson’s reagent (0.00075 mol) in anhydrous toluene (8 mL) for 12 h and concentrated under reduced pressure. The residue was extracted with chloroform (2 × 20 mL), dried with anhydrous MgSO4, filtrated and concentrated under reduced pressure. Product was separated from oily residue by use of chromatotron. According above given procedure were obtained following compounds:
1-(2-Pyridyl)imidazolidine-2-thione (4a). Compound 4a was purified by use of chromatotron (eluent: chloroform/ethyl acetate/acetone, 8:1:1, v/v/v); yield 50%; mp. 99–102 °C; IR (KBr) ν [cm−1]: 3196, 3036, 2993, 1591, 1567, 1533, 1466, 1438, 1413, 1347, 1228; 1H-NMR (200 MHz, CDCl3): δ 3.68 (t, 2H, CH2); 4.44 (t, 2H, CH2); 6.96 (bs, 1H, NH); 7.01–7.07 (m, 1H, Ar-H); 7.64–7.73 (m, 1H, Ar-H); 8.33–8.36 (m, 1H, Ar-H); 8.93 (d, J = 8.0 Hz, 1H, Ar-H); 13C-NMR (50 MHz, CDCl3): δ 40.93, 49.43, 116.33, 119.62, 136.69, 147.32, 152.32, 181.27; Anal. Calcd. for C8H9N3S: C, 53.61; H, 5.06; N, 23.44; Found: C, 53.54; H, 4.92; N, 23.37.
1-(6-Methyl-2-pyridyl)imidazolidine-2-thione (4b). Compound 4b was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 1:1, v/v); yield 31%; mp. 133–135 °C; IR (KBr) ν [cm−1]: 3222, 3101, 3029, 2974, 1588, 1519, 1456, 1428, 1397, 1346, 1254, 1231; 1H-NMR (200 MHz, (CD3)2SO): δ 2.41 (s, 3H, CH3), 3.53 (t, 2H, CH2), 4.26 (t, 2H, CH2), 6.97 (d, J = 7.3 Hz, 1H, Ar-H), 7.64 (t, 1H, Ar-H), 8.60 (d, J = 8.4 Hz, 1H, Ar-H), 9.00 (s, 1H, NH); 13C-NMR (50 MHz, (CD3)2SO): δ 24.25, 41.05, 49.09, 113.18, 118.54, 137.04, 152.14, 156.09, 180.19; Anal. Calcd. for C9H11N3S: C, 55.93; H, 5.74; N, 21.74; Found: C, 55.86; H, 5.64; N, 21.48.
1-(5-Methyl-2-pyridyl)imidazolidine-2-thione (4c). Compound 4c was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 7:3, v/v); yield 51%; mp. 200–203 °C; IR (KBr) ν [cm−1]: 3271, 2969, 2904, 1608, 1570, 1514, 1479, 1388, 1341, 1239, 1217; 1H-NMR (200 MHz, (CD3)2SO): δ 2.26 (s, 3H, CH3); 3.53 (t, 2H, CH2); 4.24 (t, 2H, CH2); 7.59 (dd, J1 = 2.1 Hz, J2 = 8.5 Hz, 1H, Ar-H), 8.18 (s, 1H, Ar-H), 8.67 (d, J = 8.5 Hz, 1H, Ar-H), 8.96 (s, 1H, NH); 13C-NMR (50 MHz, (CD3)2SO): δ 17.52, 40.65, 49.12, 115.84, 128.49, 137.28, 147.28, 150.70, 180.15; Anal. Calcd. for C9H11N3S: C, 55.93; H, 5.74; N, 21.74; Found: C, 55.81; H, 5.63; N, 21.68.
1-(4-Tert-butyl-2-pyridyl)imidazolidine-2-thione (4e). Compound 4e was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 7:3, v/v); yield 50%; mp. 160–163 °C; IR (KBr) ν [cm−1]: 3197, 3018, 2962, 2927, 2859, 1602, 1548, 1521, 1482, 1412, 1311, 1236, 1119, 830, 553; 1H-NMR (200 MHz, CDCl3): δ 1.34 (s, 9H, 3×CH3), 3.68 (t, 2H, CH2), 4.46 (t, 2H, CH2), 6.76 (br.s, 1H, NH), 7.06 (dd, J1 = 1.6 Hz, J2 = 5.5 Hz, 1H, Ar-H), 8.25 (d, J = 5.5 Hz, 1H, Ar-H), 9.01 (d, J = 1.6 Hz, 1H, Ar-H); 13C-NMR (50 MHz, CDCl3): δ 31.02 (three overlapping signals), 35.73, 41.52, 50.06, 114.33, 117.67, 147.21, 152.85, 161.89, 181.86; Anal. Calcd. for C12H17N3S: C, 61.24; H, 7.28; N, 17.85; Found C, 61.02; H, 6.18; N, 17.78.
1-(4-Phenyl-2-pyridyl)imidazolidine-2-thione (4f). Compound 4f was purified by use of chromatotron (eluent: dichloromethane/ethyl acetate, 4:1, v/v); yield 51%; mp. 201–202 °C; IR (KBr) ν [cm−1]: 3204, 3026, 2969, 2924, 1597, 1532, 1466, 1412, 1230; 1H-NMR (200 MHz, (CD3)2SO): δ 3.58 (t, 2H, CH2), 4.33 (t, 2H, CH2), 7.44–7.60 (m, 4H, Ar-H), 7.73–7.77 (m, 2H, Ar-H), 8.43 (d, J = 5.2 Hz, 1H, Ar-H), 9.16 (s, 1H, NH), 9.25 (s, 1H, Ar-H); 13C-NMR (50 MHz, (CD3)2SO): δ 41.06, 49.12, 113.36, 117.10, 127.01 (two overlapping signals), 129,58 (three overlapping signals), 137.82, 147.69, 148.29, 153.54, 180.19; Anal. Calcd. for C14H13N3S: C, 65.85; H, 5.13; N, 16.46; Found: C, 65.78; H, 5.04; N, 16.24.
1-(6-Methoxy-2-pyridyl)imidazolidine-2-thione (4g). Compound 4g was purified by use of chromatotron (eluent: chloroform); yield 43%; mp. 186–190 °C; IR (KBr) ν [cm−1]: 3365, 3008, 2947, 1594, 1584, 1431, 1397, 1361, 1247; 1H-NMR (500 MHz, (CD3)2SO): δ 3.56 (t, 2H, CH2), 3.84 (s, 3H, OCH3), 4.32 (t, 2H, CH2), 6.53 (d, J = 7.8 Hz, 1H, Ar-H), 7.68 (t, 1H, Ar-H), 8.47 (d, J = 7.8 Hz, 1H, Ar-H), 9.05 (s, 1H, NH); 13C-NMR [50 MHz, (CD3)2SO]: δ 39.40, 48.88, 53.20, 104.42, 107.59, 139.81, 150.72, 162.09, 179.98; Anal. Calcd. for C9H11N3OS: C, 51.65; H, 5.30; N, 20.08; Found: C, 51.52; H, 5.24; N, 19.79.

3.3. Synthesis of Copper(II) Complexes 5a–8k (General Procedure)

To a solution of appropriate ligand in 5 mL of ethanol or methanol was added dropwise at ambient temperature, copper(II) chloride dissolved in 1 mL of ethanol or methanol (in 1:1 molar ratio). The solution was left at room temperature and then the solvent was slowly evaporated. The resulting precipitate (a few minutes to 48 h) was filtered and washed with ethanol or methanol and dried in a desiccator. The following complexes were prepared according to above given procedure:
Dichloro[1-(2-pyridyl)imidazolidin-2-one]copper(II) (5a). Solvent: ethanol, dark green crystals, yield 55%; mp. 241–245 °C; IR (KBr) ν [cm−1]: 3251, 3126, 2923, 1675, 1606, 1474, 1451, 1436, 1317, 1284, 1170, 769; Anal. Calcd. for C8H9Cl2CuN3O (297.63): C, 32.28; H, 3.05; N, 14.12; Found: C, 32.14; H, 2.91; N, 13.79.
Dichloro[1-(6-methyl-2-pyridyl)imidazolidin-2-one]copper(II) (5b). Solvent: methanol, dark brown crystals; mp. 211–215 °C; IR (KBr) ν [cm−1]: 3316, 3069, 2920, 1662, 1604, 1494, 1443, 1351, 1285, 1087; Anal. Calcd. for C9H11Cl2CuN3O (311.65): C, 34.68; H, 3.56; N, 13.48; Found: C, 34.42; H, 3.50; N, 13.28.
Crystal data for 5b CCDC no. 986196: C9H11Cl2CuN3O, M = 311.65, monoclinic, space group P21/n (no. 14), Z = 4, a = 6.7379(2) Å, b = 16.9634(3) Å, c = 9.9351(2) Å, β = 105.290(2), V = 1095.36(4) Å3, T = 100 K, μ(MoKα) = 2.460 mm−1, 12880 reflections measured, 2816 unique (Rint = 0.0200) which were used in all calculations. The final wR2 was 0.0630 (all data) and R1 was 0.0217 [I > 2σ (I)].
Dichloro[1-(4-methyl-2-pyridyl)imidazolidin-2-one]copper(II) (5c). Solvent: methanol, light green crystals, yield 65%; mp. 237–238 °C; IR (KBr) ν [cm−1]: 3202, 1658, 1625, 1508, 1480, 1461, 1317, 1290, 1249, 1024, 828, 818, 742; Anal. Calcd. for C9H11Cl2CuN3O (311.66): C, 34.68; H, 3.56; N, 13.48; Found: C, 34.42; H, 3.46; N, 13.17.
Dichloro[1-(4-methoxy-2-pyridyl)imidazolidin-2-one]copper(II) (5d). Solvent: ethanol, green crystals, yield 47%; mp. 223–227 °C; IR (KBr) ν [cm−1]: 3185, 2975, 1678, 1619, 1561, 1485, 1474, 1455, 1294, 1062, 1029, 833, 751, 737; Anal. Calcd. for C9H11Cl2CuN3O2 (327.65): C, 32.99; H, 3.38; N, 12.82; Found: C, 32.86; H, 3.32; N, 12.48.
Dichloro[1-(4-ethoxy-6-methyl-2-pyridyl)imidazolidin-2-one]copper(II) (5e). Solvent: ethanol, brown crystals, yield 87%; mp. 189–193 °C; IR (KBr) ν [cm−1]: 3336, 2985, 1673, 1612, 1459, 1430, 1300, 1205, 1154, 1047, 851, 837, 744, 715, 636; Anal. Calcd. for C11H15Cl2CuN3O2 (355.71): C, 37.14; H, 4.25; N, 11.81; Found: C, 37.02; H, 4.17; N, 11.68.
Dichloro[1-(2-pyridyl)imidazolidine-2-thione]copper(II) (5f). Solvent: ethanol, dark green crystals, yield 74%; mp. 195–198 °C; IR (KBr) ν [cm−1]: 3198, 1601, 1575, 1540, 1466, 1440, 1419, 1353, 1323, 1238, 777, 670, 543; Anal. Calcd. for C8H9Cl2CuN3S (313.69): C, 30.63; H, 2.89; N, 13.40; Found: C, 30.52; H, 2.86; N, 13.76.
Dichloro[1-(6-methyl-2-pyridyl)imidazolidine-2-thione]copper(II) (5g). Solvent: ethanol, dark green crystals, yield 65%; mp. 230–233 °C; IR (KBr) ν [cm−1]: 3322, 3064, 1662, 1604, 1462, 1444, 1351, 1286, 1087, 801, 747, 734; Anal. Calcd. for C9H11Cl2CuN3S (327.72): C, 32.98; H, 3.38; N, 12.82; Found: C, 32.88; H, 3.30; N, 12.58.
Dichloro[1-(5-methyl-2-pyridyl)imidazolidine-2-thione]copper(II) (5h). Solvent: ethanol, dark green crystals, yield 59%; mp. 186–190 °C; IR (KBr) ν [cm−1]: 3202, 3058, 2962, 2912, 1613, 1539, 1504, 1429, 1385, 1321, 1232, 1053, 821; Anal. Calcd. for C9H11Cl2CuN3S (327.71): C, 32.98; H, 3.38; N, 12.82; Found: C, 32.84; H, 3.27; N, 12.61.
Crystal data for 5h CCDC no. 986201: C9H11Cl2CuN3S, M = 327.71, triclinic, space group P-1 (no. 2), Z = 2, a = 8.1363(3) Å, b = 9.0505(4) Å, c = 9.9441(3) Å, α = 63.452(4), β = 77.213(3), γ = 69.989(4), V = 613.46(4) Å3, T = 296 K, μ(CuKα) = 7.908 mm−1, 12399 reflections measured, 2531 unique (Rint = 0.0378) which were used in all calculations. The final wR2 was 0.0942 (all data) and R1 was 0.0318 [I > 2σ (I)].
Dichloro[1-(4-methyl-2-pyridyl)imidazolidine-2-thione]copper(II) (5i). Solvent: methanol, dark green crystals; mp. 179–181 °C; IR (KBr) ν [cm−1]: 3174, 3070, 1618, 1566, 1547, 1440, 1347, 1239; Anal. Calcd. for C9H11Cl2CuN3S (327.71): C, 32.98; H, 3.38; N, 12.82; Found: C, 32.84; H, 3.32; N, 12.78.
Crystal data for 5i CCDC no. 986193: C9H11Cl2CuN3S, M = 327.71, monoclinic, space group P21/c (no. 14), Z = 4, a = 8.4124(4) Å, b = 13.8054(6) Å, c = 11.4288(5) Å, β = 110.782(4), V = 1240.94(1) Å3, T = 140 K, μ(MoKα) = 2.333 mm−1, 10224 reflections measured, 2538 unique (Rint = 0.0189) which were used in all calculations. The final wR2 was 0.0545 (all data) and R1 was 0.0201 [I > 2σ (I)].
Dichloro[1-(4-tert-butyl-2-pyridyl)imidazolidine-2-thione]copper(II) (5j). Solvent: methanol, dark green crystals, yield 76%; mp. 165–168 °C; IR (KBr) ν [cm−1]: 3163, 3054, 2957, 2923, 1615, 1554, 1536, 1442, 1294, 1247, 1020, 863, 843; Anal. Calcd. for C12H17Cl2CuN3S (369.79): C, 38.97; H, 4.63; N, 11.36; Found: C, 38.92; H, 4.58; N, 11.21.
Crystal data for 5j CCDC no. 986094: C12H17Cl2CuN3S, M = 369.79, orthorhombic, space group Pbca (no. 61), Z = 8, a = 14.6475(9) Å, b = 11.3493(8) Å, c = 18.1891(13) Å, V = 3023.7(4) Å3, T = 130 K, μ(CuKα) = 6.490 mm−1, 16551 reflections measured, 3117 unique (Rint = 0.0944) which were used in all calculations. The final wR2 was 0.1678 (all data) and R1 was 0.0583 (I > 2σ (I)). In the diffraction pattern reflections with l = 2n + 1 were weak. The structure is strongly disordered with the complex molecule adopting three different overlapping orientations. The main orientation has an occupancy of 0.689(4) and the remaining ones 0.153(4) and 0.158(4). The atoms forming the minor orientation of the molecule were refined with a common isotropic temperature factor, except Cu, Cl and S atoms which were refined anisotropically. The geometry of the molecules in minor orientation was restricted to be the same as for the major orientation. Some restraints were also imposed on the planar fragments of the molecules.
Dichloro[1-(4-phenyl-2-pyridyl)imidazolidine-2-thione]copper(II) (5k). Solvent: ethanol, dark green, yield 59%; mp. 165–170 °C; IR (KBr) ν [cm−1]: 3207, 3052, 3004, 2960, 1613, 1552, 1466, 1437, 1276, 1236, 763, 696, 556; Anal. Calcd. for C14H13Cl2CuN3S (389.79): C, 43.14; H, 3.36; N, 10.78; Found: C, 42.99; H, 3.26; N, 10.43.
Dichloro[1-(6-methoxy-2-pyridyl)imidazolidin-2-one]copper(II) (6a). Solvent: ethanol, brown crystals, yield 91%; mp. 207–209 °C; IR (KBr) ν [cm−1]: 3316, 3293, 3082, 3030, 2905, 1673, 1606, 1474, 1440, 1295, 1267, 1168, 1117, 1030, 796, 746, 736; Anal. Calcd. for C9H11Cl2CuN3O2 (327.65): C, 32.99; H, 3.38; N, 12.82; Found: C, 32.83; H, 3.34; N, 13.16.
Crystal data for 6a CCDC no. 986200: C9H11Cl2CuN3O2, M = 327.65, triclinic, space group P-1 (no. 2), Z = 2, a = 7.3569(8) Å, b = 8.7648(8) Å, c = 9.7086(10) Å, α = 86.242(8), β = 86.557(9), γ = 77.925(9), V = 610.17(11) Å3, T = 293 K, μ(CuKα) = 6.521 mm−1, 7294 reflections measured, 2226 unique (Rint = 0.0366) which were used in all calculations. The final wR2 was 0.1024 (all data) and R1 was 0.0342 (I >2 σ (I)).
Dichloro[1-(6-ethoxy-2-pyridyl)imidazolidin-2-one]copper(II) (6b). Solvent: ethanol, brown crystals, yield 23%; mp. 199–202 °C; IR (KBr) ν [cm−1]: 3329, 3079, 2982, 2925, 1670, 1605, 1480, 1466, 1451, 1429, 1294, 1264, 1164, 1118, 1034, 1017, 786; Anal. Calcd. for C10H13Cl2CuN3O2 (341.68): C, 35.15; H, 3.83; N, 12.30; Found: C, 35.02; H, 3.79; N, 12.63.
Dichloro[1-(6-n-propoxy-2-pyridyl)imidazolidin-2-one]copper(II) (6c). Solvent: ethanol, brown crystals, yield 68%; mp. 185–187 °C; IR (KBr) ν [cm−1]: 3249, 3094, 2958, 2925, 2877, 1712, 1676, 1605, 1474, 1445, 1425, 1294, 1266, 1165, 1113, 1091, 993, 962, 792, 735; Anal. Calcd. for C11H15Cl2CuN3O2 (355.71): C, 37.14; H, 4.25; N, 11.81; Found: C, 37.10; H, 4.08; N, 12.08.
Dichloro[1-(6-isopropoxy-2-pyridyl)imidazolidin-2-one]copper(II) (6d). Solvent: ethanol, brown crystals, yield 56%; mp. 211–212 °C; IR (KBr) ν [cm−1]: 3303, 3112, 3056, 2983, 2931, 1672, 1603, 1469, 1441, 1425, 1372, 1293, 1266, 1166, 1115, 1092, 987, 952, 798, 734; Anal. Calcd. for C11H15Cl2CuN3O2 (355.71): C, 37.14; H, 4.25; N, 11.81; Found: C, 36.98; H, 4.18; N, 11.80.
Dichloro[1-(6-n-butoxy-2-pyridyl)imidazolidin-2-one]copper(II) (6e). Solvent: ethanol, golden crystals, yield 48%; mp. 187–189 °C; IR (KBr) ν [cm−1]: 3229, 3104, 2956, 2871, 1678, 1607, 1467, 1444, 1428, 1294, 1294, 1265, 1166, 1094, 790, 735; Anal. Calcd. for C12H17Cl2CuN3O2 (369.73): C, 38.98; H, 4.63; N, 11.36; Found: C, 38.91; H, 4.56; N, 11.62.
Dichloro[1-(6-methoxy-2-pyridyl)imidazolidine-2-thione]copper(II) (6f). Solvent: ethanol, brown crystals, yield 49%; mp. 149–154 °C; IR (KBr) ν [cm−1]: 3159, 3066, 2953, 2923, 1604, 1543, 1468, 1435, 1418, 1286, 1232, 1129, 787; Anal. Calcd. for C9H11Cl2CuN3OS (343.72): C, 31.45; H, 3.23; N, 12.23; Found: C: 31.38; H, 3.19; N, 11.88.
Dichloro[1,3-bis(4-methyl-2-pyridyl)imidazolidin-2-one]copper(II).H2O (7). Solvent: methanol, green crystals; mp. 170–172°C; IR (KBr) ν [cm−1]: 3372, 1635, 1506, 1472, 1436, 1335, 1261, 1195.
Crystal data for 7 CCDC no. 986194: C15H18Cl2CuN4O2, M = 420.77, triclinic, space group P-1 (no. 2), Z = 2, a = 8.9310(7) Å, b = 10.6693(7) Å, c = 10.9789(9) Å, α = 112.749(7), β = 95.298(7), γ = 111.370(7), V = 864.67(11) Å3, T = 293 K, μ(MoKα) = 1.587 mm−1, 7039 reflections measured, 3517 unique (Rint = 0.0181) which were used in all calculations. The final wR2 was 0.0742 (all data) and R1 was 0.0287 (I > 2σ (I)).
Dichloro[1,3-bis(2-pyridyl)imidazolidin-2-one]copper(II) (8a). Solvent: ethanol, yellow-green crystals, yield 77%; mp. 265–267 °C; IR (KBr) ν [cm−1]: 3074, 2901, 1679, 1604, 1587, 1463, 1438, 1412, 1351, 1312, 1245, 1138, 781, 752, 740; Anal. Calcd. for C13H12Cl2CuN4O (374.71): C, 41.67; H, 3.23; N, 14.95; Found: C, 41.64; H, 3.19; N, 14.92.
Crystal data for 8a CCDC no. 986095: C26H24Cl4Cu2N8O2, M = 749.43, monoclinic, space group P21/n (no. 14), Z = 2, a = 7.83450(10) Å, b = 16.3329(2) Å, c = 10.8358(2) Å, β = 90.7160(10), V = 1386.44(4) Å3, T = 130 K, μ(MoKα) = 1.963 mm−1, 22938 reflections measured, 3444 unique (Rint = 0.0379) which were used in all calculations. The final wR2 was 0.0665 (all data) and R1 was 0.0293 [I > 2σ (I)].
Dichloro[1-acetyl-3-(5-methyl-2-pyridyl)imidazolidin-2-one]copper(II) (8b). Solvent: ethanol, green crystals, yield 50%; mp. 233–235 °C; IR (KBr) ν [cm−1]: 3091, 2984, 2927, 1698, 1655, 1468, 1434, 1401, 1323, 1291, 1256, 1042, 962, 839, 740, 617; Anal. Calcd. for C11H13Cl2CuN3O2 (353.69): C, 37.35; H, 3.70; N, 11.88; Found: C, 37.28; H, 3.64; N, 12.18.
Dichloro[1-acetyl-3-(4-methyl-2-pyridyl)imidazolidin-2-one]copper(II) (8c). Solvent: ethanol, green crystals, yield 62%; mp. 222–225 °C; IR (KBr) ν [cm−1]: 3091, 3060, 2986, 1708, 1683, 1622, 1455, 1412, 1372, 1321, 1271, 1192, 1150, 1038, 971, 841, 749, 742, 619, 456; Anal. Calcd. for C11H13Cl2CuN3O2 (353.69): C, 37.35; H, 3.70; N, 11.88; Found: C, 37.27; H, 3.63; N, 12.22.
Crystal data for 8c CCDC no. 986202: C22H26Cl4Cu2N6O4, M = 707.39, triclinic, space group P-1 (no. 2), Z = 1, a = 8.6259(2) Å, b = 9.2649(3) Å, c = 10.4228(3) Å, α = 102.178(3), β = 98.752(2), γ = 116.880(3), V = 696.37(3) Å3, T = 293 K, μ(Cu Kα) = 5.765 mm−1, 7991 reflections measured, 2869 unique (Rint = 0.0137) which were used in all calculations. The final wR2 was 0.0738 (all data) and R1 was 0.0268 (I > 2σ (I)).
Dichloro[1-butyryl-3-(4-methyl-2-pyridyl)imidazolidin-2-one]copper(II) (8d). Solvent: ethanol, green crystals, yield 93%; mp. 236–240 °C; IR (KBr) ν [cm−1]: 3123, 3089, 3054, 2960, 2936, 2877, 1705, 1681, 1622, 1455, 1413, 1384, 1322, 1272, 1227, 1211, 1180, 907, 840, 743, 709, 663, 458; Anal. Calcd. for C13H17Cl2CuN3O2 (381.74): C, 40.90; H, 4.49; N, 11.01; Found: C, 40.82; H, 4.42; N, 10.98.
Dichloro[1-acetyl-3-(4-tert-butyl-2-pyridyl)imidazolidin-2-one]copper(II) (8e). Solvent: ethanol, green crystals, yield 53%; mp. 150–155 °C; IR (KBr) ν [cm−1]: 2966, 1662, 1619, 1478, 1445, 1377, 1283, 1063, 734, 617; Anal. Calcd. for C14H19Cl2CuN3O2 (395.77): C, 42.49; H, 4.84; N, 10.62; Found: C, 42.38; H, 4.82; N, 10.31.
Dichloro[1-acetyl-3-(4-phenyl-2-pyridyl)imidazolidin-2-one]copper(II) (8f). Solvent: ethanol, green crystals, yield 95%; mp. 227–233 °C; IR (KBr) ν [cm−1]: 3055, 2962, 2926, 1718, 1673, 1615, 1473, 1436, 1410, 1372, 1278, 1237, 965, 771, 740, 630, 615; Anal. Calcd. for C16H15Cl2CuN3O2 (415.76): C, 46.22; H, 3.64; N, 10.11; Found: C, 46.01; H, 3.61; N, 10.02.
Dichloro[1-butyryl-3-(4-phenyl-2-pyridyl)imidazolidin-2-one]copper(II) (8g). Solvent: ethanol, dark green crystals, yield 77%; mp. 178–184 °C; IR (KBr) ν [cm−1]: 3051, 2963, 2873, 1671, 1616, 1474, 1437, 1409, 1372, 1284, 1222, 1178, 768, 629; Anal. Calcd. for C18H19Cl2CuN3O2 (443.81): C, 48.71; H, 4.32; N, 9.47; Found: C, 48.68; H, 4.26; N, 9.45.
Dichloro{1-acetyl-3-[4-(3-phenylpropyl)-2-pyridyl]imidazolidin-2-one}copper(II) (8h). Solvent: ethanol, dark green crystals, yield 56%; mp. 160–164 °C; IR (KBr) ν [cm−1]: 3078, 2920, 2860, 1713, 1671, 1649, 1623, 1476, 1451, 1420, 1375, 1282, 1245, 966, 735, 701, 615; Anal. Calcd. for C19H21Cl2CuN3O2 (457.84): C, 49.84; H, 4.62; N, 9.18; Found: C, 49.79; H, 4.58; N, 9.46.
Dichloro[1-acetyl-3-(4-methoxy-2-pyridyl)imidazolidin-2-one]copper(II) (8i). Solvent: ethanol, light green crystals, yield 69%; mp. 190–194 °C; IR (KBr) ν [cm−1]: 3143, 3117, 3085, 3030, 2993, 2929, 1709, 1667, 1617, 1477, 146, 1377, 1281, 1232, 1037, 968, 845, 741, 616; Anal. Calcd. for C11H13Cl2CuN3O3 (369.69): C, 35.74; H, 3.54; N, 11.37; Found: C, 35.69; H, 3.46; N, 11.38.
Dichloro[1-butyryl-3-(4-methoxy-2-pyridyl)imidazolidin-2-one]copper(II) (8j). Solvent: ethanol, green crystals, yield 66%; mp. 210–213 °C; IR (KBr): 3104, 2967, 2930, 2873, 1671, 1618, 1468, 1419, 1382, 1285, 1220, 1176, 1048, 842, 738, 708; Anal. Calcd. for C13H17Cl2CuN3O3 (397.74): C, 39.26; H, 4.31; N, 10.56; Found: C, 39.11; H, 4.26; N, 10.35.
Dichloro[1-acetyl-3-(4-benzyloxy-2-pyridyl)imidazolidin-2-one]copper(II) (8k). Solvent: ethanol, green crystals, yield 49%; mp. 195–199 °C; IR (KBr) ν [cm−1]: 3086, 2990, 2923, 1683, 1613, 1480, 1448, 1415, 1378, 1278, 1245, 1036, 1022, 834, 738, 622; Anal. Calcd. for C17H17Cl2CuN3O3 (445.79): C, 45.80; H, 3.84; N, 9.43; Found: C, 45.71; H, 3.76; N, 9.76.
Dichloro{bis[1-(5-methyl-2-pyridyl)imidazolidin-2-one]}copper(II).2H2O (9). 1-(5-Methyl-2-pyridyl)imidazolidin-2-one (0.1 g; 0.00056 mol) was dissolved in 7 mL of N,N-dimethylformamide and copper(II) chloride (0.144 g, 0.00085 mol) was added. After week of slow evaporation at room temperature green crystals suitable for the X-ray analysis were collected, washed with small amount of solvent and dried. Obtained 0.06 g of complex compound 9, yield 43%: C18H22Cl2CuN6O2.2H2O (524.89); mp. 224–229 °C; IR (KBr) ν [cm−1]: 3169, 3068, 2915, 1657, 1618, 1576, 1483, 1453, 1319, 1287, 1170, 824, 742.
Crystal data for 9 CCDC no. 986199: (C18H22CuN6O2)Cl2·2(H2O) , M = 524.89, monoclinic, space group C2/c (no. 15), Z = 4, a = 12.3708(7) Å, b = 13.6659(5) Å, c = 13.1220(16) Å, β = 109.417(1), V = 2092.2(3) Å3, T = 130 K, μ(MoKα) = 1.340 mm−1, 7717 reflections measured, 1832 unique (Rint = 0.0450) which were used in all calculations. The final wR2 was 0.0803 (all data) and R1 was 0.0321 (I > 2σ (I)).
Dichloro{bis[1-(4-phenyl-2-pyridyl)imidazolidin-2-one]}copper(II) (10a, 10b). 1-(4-Phenyl-2-pyridyl)imidazolidin-2-one (0.1 g, 0.00042 mol) was dissolved in 7 mL of N,N-dimethylformamide and copper(II) chloride (0.107 g, 0.00063 mol) was added. After two weeks of slow evaporation at room temperature green crystals suitable for the X-ray analysis were collected, washed with small amount of solvent and dried. Obtained 0.06 g of a mixture of complex compounds 10a and 10b, mp. 208–211 °C; IR (KBr) ν [cm−1]: 3447, 3056, 1669, 1616, 1473, 1446, 1319, 1296, 1070, 1014, 855, 763, 740.
Crystal data for 10a CCDC no. 986198: (C28H26ClCuN6O2)Cl·2(H2O), M = 649.02, triclinic, space group P-1 (no. 2), Z = 2, a = 10.5234(4) Å, b = 11.7728(5) Å, c = 12.5141(4) Å, α = 97.231(3), β = 106.598(3), γ = 108.593(4), V = 1367.46(9) Å3, T = 100 K, μ(MoKα) = 1.042 mm−1, 14433 reflections measured, 5552 unique (Rint = 0.0169) which were used in all calculations. The final wR2 was 0.0695 (all data) and R1 was 0.0263 (I > 2σ (I)).
Crystal data for 10b CCDC no. 986197: (C28H26ClCuN6O2)2[CuCl3]0.75[Cl]0.5P· 2.15(H2O)·C3H7NO, M = 1413.85, monoclinic, space group I2/a (no. 15), Z = 4, a = 13.8269(3) Å, b = 16.8610(3) Å, c = 25.7704(5) Å, β = 93.988(2), V = 5993.4(2) Å3, T = 100 K, μ(MoKα) = 1.246 mm−1, 34078 reflections measured, 6096 unique (Rint = 0.0240) which were used in all calculations. The final wR2 was 0.0827 (all data) and R1 was 0.0297 (I > 2σ (I)).The [CuCl3]2− anion and one of the water molecules are located on a twofold axis. The CuI and the Cl atom of the anion in special position occupy their positions in 75% whereas the water molecule in 25%. The remaining Cl atoms fully occupy their positions.
Dichloro{bis[1-(4-methoxy-2-pyridyl)imidazolidin-2-one]}copper(II).H2O (10c). 1-(4-Methoxy-2-pyridyl)imidazolidin-2-one (0.1 g; 0.00052 mol) was dissolved in 7 mL of N,N-dimethylformamide and copper(II) chloride (0.132 g, 0.00078 mol) was added. After two weeks of slow evaporation at room temperature blue crystals suitable for the X-ray analysis were collected, washed with small amount of solvent and dried. Obtained 0.05 g of complex compound 10c, yield 36%: C18H22Cl2CuN6O4.H2O (538.87); mp. 214–216 °C; IR (KBr) ν [cm−1]: 3431, 3176, 2985, 1670, 1615, 1472, 1452, 1428, 1291, 1248, 1064, 1030.
Crystal data for 10c CCDC no. 986195: (C18H22ClCuN6O4)Cl.H2O, M = 538.87, monoclinic, space group P21 (no. 4), Z = 4, a = 10.9160(1) Å, b = 13.4955(2) Å, c = 15.1544(2) Å, β = 107.429(2), V = 2130.00(5) Å3, T = 120 K, μ(MoKα) = 1.322 mm−1, 36883 reflections measured, 9877 unique (Rint = 0.0225) which were used in all calculations. The final wR2 was 0.0576 (all data) and R1 was 0.0227 (I > 2σ (I)).

4. Conclusions

The X-ray crystallography revealed that the 1-(2-pyridyl)imidazolidin-2-ones 1–3 and 1-(2-pyridyl)imidazolidine-2-thiones 4 behaved as neutral bidentate ligands, bonding to the copper(II) ion through the nitrogen atom of pyridine ring and oxygen or sulfur atom of imidazolidin-2-one(thione) moiety. Analysis of the structure–activity relationships of anticancer activities of the diverse complexes 5-10 revealed that the most active against a panel of 5 human tumor cell lines was dichloro[1-(4-tert-butyl-2-pyridyl)imidazolidine-2-thione]copper(II) (5j), which may act as a “self-activating” chemical nuclease, and therefore, may serve as a lead structure for further development of novel anticancer agents.

Author Contributions

Conceived and designed the project: Franciszek Sączewski and Łukasz Balewski. Performed chemical experiments: Łukasz Balewski and Ewa Borys. Performed X-ray crystal structure analysis: Maria Gdaniec. Designed the biological tests: Patrick J. Bednarski. Performed biological tests: Ewa Borys, Anna Makowska. Wrote the paper: Franciszek Sączewski, Łukasz Balewski, Patrick J. Bednarski. All authors read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Tapiero, H.; Townsend, D.M.; Tew, K.D. Trace elements in human physiology and pathology. Copper. Biomed. Pharmacother. 2003, 57, 386–398. [Google Scholar] [PubMed]
  2. Tisato, F.; Marzano, C.; Porchia, M.; Pellei, M.; Santini, C. Copper in diseases and treatments, and copper-based anticancer strategies. Med. Res. Rev. 2010, 30, 708–749. [Google Scholar] [PubMed]
  3. Chen, J.; Huang, Y.; Liu, G.; Afrasiabi, Z.; Sinn, E.; Padhye, S.; Ma, Y. The cytotoxicity and mechanism of 1,2-naphthoquinone thiosemicarbazone and its metal derivatives against MCF-7 human breast cancer cells. Toxicol. Appl. Pharmacol. 2004, 197, 40–48. [Google Scholar] [PubMed]
  4. Easmon, J.; Pürstinger, G.; Heinisch, G.; Roth, T.; Fiebig, T.R.; Holzer, W.; Jäger, W.; Jenny, M.; Hofmann, J. Synthesis, cytotoxicity, and antitumor activity of copper(II) and iron(II) complexes of 4N-azabicyclo[3.2.2]nonane thiosemicarbazones derived from acyl diazines. J. Med. Chem. 2001, 44, 2164–2171. [Google Scholar] [CrossRef] [PubMed]
  5. Adsule, S.; Barve, V.; Chen, D.; Ahmed, F.; Dou, Q.P.; Padhye, S.; Sarkar, F.H. Novel Schiff base copper complexes of quinoline-2 carboxaldehyde as proteasome inhibitors in human prostate cancer cells. J. Med. Chem. 2006, 49, 7242–7246. [Google Scholar] [CrossRef] [PubMed]
  6. Marzano, C.; Pellei, M.; Colavito, D.; Alidori, S.; Lobbia, G.G.; Gandin, V.; Tisato, F.; Santini, C. Synthesis, characterization, and in vitro antitumor properties of tris(hydroxymethyl)phosphine copper(I) complexes containing the new bis(1,2,4-triazol-1-yl)acetate ligand. J. Med. Chem. 2006, 49, 7317–7324. [Google Scholar] [CrossRef] [PubMed]
  7. Tardito, S.; Bussolati, O.; Maffini, M.; Tegoni, M.; Giannetto, M.; Dall’Asta, V.; Franchi-Gazzola, R.; Lanfranchi, M.; Pellinghelli, M.A.; Mucchino, C.; et al. Thioamido coordination in a thioxo-1,2,4-triazole copper(II) complex enhances nonapoptotic programmed cell death associated with copper accumulation and oxidative stress in human cancer cells. J. Med. Chem. 2007, 50, 1916–1924. [Google Scholar] [CrossRef] [PubMed]
  8. Sączewski, F.; Dziemidowicz-Borys, E.; Bednarski, P.J.; Gdaniec, M. Synthesis, crystal structure, cytotoxic and superoxide dismutase activities of copper(II) complexes of N-(4,5-dihydroimidazol-2-yl)azoles. Arch. Pharm. Chem. Life Sci. 2007, 340, 333–338. [Google Scholar] [CrossRef]
  9. Marzano, C.; Pellei, M.; Tisato, F.; Santini, C. Copper complexes as anticancer agents. Anticancer Agents Med. Chem. 2009, 9, 185–211. [Google Scholar] [CrossRef] [PubMed]
  10. Santini, C.; Pellei, M.; Gandin, V.; Porchia, M.; Tisato, F. Advances in copper complexes as anticancer agents. Chem. Rev. 2014, 114, 815–862. [Google Scholar] [PubMed]
  11. Sączewski, F.; Dziemidowicz-Borys, E.; Bednarski, P.J.; Grünert, R.; Gdaniec, M.; Tabin, P. Synthesis, crystal structure and biological activities of copper(II) complexes with chelating bidentate 2-substituted benzimidazole ligands. J. Inorg. Biochem. 2006, 100, 1389–1398. [Google Scholar] [PubMed]
  12. Szilágyi, I.; Labádi, I.; Hernadi, K.; Pálinko, I.; Kiss, T. Synthesis and IR spectroscopic characterization of immobilized superoxide dismutase (SOD) mimicking complexes. J. Mol. Struct. 2005, 744–747, 495–500. [Google Scholar] [CrossRef]
  13. Devereux, M.; O’Shea, D.; O’Connor, M.; Grehan, H.; Connor, G.; McCann, M.; Rosair, G.; Lyng, F.; Kellet, A.; Walsh, M.; et al. Synthesis, catalase, superoxide dismuthase and antitumour activities of copper(II) carboxylate complexes incorporating benzimidazole, 1,10-phenanthroline and bipyridine ligands: X-ray crystal structures of [Cu(BZA)2(bipy)(H2O)], [Cu(SalH)2(BZDH)2] and [Cu(CH3COO)2(5,6-DMBZDH)2] (SalH2 = salicylic acid; BZAH = benzoic acid; BZDH = benzimidazole and 5,6-DMBZDH = 5,6-dimethylbenzimidazole). Polyhedron 2007, 26, 4073–4084. [Google Scholar] [CrossRef]
  14. Mendes, I.C.; Moreira, J.P.; Mangrich, A.S.; Balena, S.P.; Rodrigues, B.L.; Beraldo, H. Coordination to copper(II) strongly enhances the in vitro antimicrobial activity of pyridine-derived N(4)-tolyl thiosemicarbazones. Polyhedron 2007, 26, 3263–3270. [Google Scholar] [CrossRef]
  15. Sharma, S.; Athar, F.; Maurya, M.R.; Naqvi, F.; Azam, A. Novel bidentate complexes of Cu(II) derived from 5-nitrofuran-2-carboxaldehyde thiosemicarbazones with antiamoebic activity against E. histolytica. Eur. J. Med. Chem. 2005, 40, 557–562. [Google Scholar] [CrossRef] [PubMed]
  16. Weder, J.E.; Dillon, C.T.; Hambley, T.W.; Kennedy, B.J.; Lay, P.A.; Biffin, J.R.; Regtop, H.L.; Davies, N.M. Copper complexes of non-steroidal anti-inflammatory drugs: An opportunity yet to be realized. Coord. Chem. Rev. 2002, 232, 95–126. [Google Scholar]
  17. Gennäs, G.B.; Mologni, L.; Ahmed, S.; Rajaratnam, M.; Marin, O.; Lindholm, N.; Viltadi, M.; Gambacorti-Passerini, C.; Scapozza, L.; Yli-Kauhaluoma, J. Design, synthesis, and biological activity of urea derivatives as anaplastic lymphoma kinase inhibitors. Chem. Med. Chem. 2011, 6, 1680–1692. [Google Scholar] [PubMed]
  18. Koca, I.; Özgür, A.; Coşkun, K.A.; Tutar, Y. Synthesis and anticancer activity of acyl thioureas bearing pyrazole moiety. Bioorg. Med. Chem. 2013, 21, 3859–3865. [Google Scholar] [PubMed]
  19. Petitclerc, É.; Deschesnes, R.G.; Côté, M.F.; Marquis, C.; Janvier, R.; Lacroix, J.; Miot-Noirault, É.; Legault, J.; Mounetou, E.; Madelmont, J.C. Antiangiogenic and antitumoral activity of phenyl-3-(2-chloroethyl)ureas: A class of soft alkylating agents disrupting microtubules that are unaffected by cell adhesion-mediated drug resistance. Cancer Res. 2004, 64, 4654–4663. [Google Scholar] [CrossRef] [PubMed]
  20. Stabile, P.; Lamonica, A.; Ribecai, A.; Castoldi, D.; Guercio, G.; Curcuruto, O. Mild, convenient and versatile Cu-mediated synthesis of N-aryl-2-imidazolidinones. Tetrahedron Lett. 2010, 51, 3232–3235. [Google Scholar] [CrossRef]
  21. Sączewski, F.; Bułakowska, A.; Gdaniec, M. 2-Chloro-4,5-dihydroimidazole, Part X. revisiting route to N-heteroarylimidazolidin-2-ones. J. Heterocycl. Chem. 2002, 39, 911–915. [Google Scholar]
  22. Balewski, Ł.; Sączewski, F.; Gdaniec, M.; Bednarski, P.J.; Jara, I. Synthesis of N-(2-pyridyl)imidazolidin-2-ones and 1-(2-pyridyl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b][1,3,5]-triazepin-5(6H)-ones with potential biological activity. Heterocycl. Commun. 2013, 19, 331–341. [Google Scholar]
  23. Venkataraman, D.; Du, Y.; Wilson, S.R.; Hirsch, K.A.; Zhang, P.; Moore, J.S. A coordination geometry table of the d-block elements and their ions. J. Chem. Educ. 1997, 74, 915–918. [Google Scholar] [CrossRef]
  24. Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.K.; Puschmann, H. OLEX2: A complete structure solution, refinement and analysis program. J. Appl. Cryst. 2009, 42, 339–341. [Google Scholar] [CrossRef]
  25. Tiliakos, M.; Cordopatis, P.; Terzis, A.; Raptopoulou, C.P.; Perlepes, S.P.; Manessi-Zoupa, E. Reactions of 3d-metal nitrates with N,N'-bis(2-pyridyl)urea (LH2): preparation, X-ray crystal structures and spectroscopic studies of the products trans-[M(II)(ONO2)2(LH2)2] (M = Mn, Fe, Co, Ni, Cu, Zn) and mer-[Co(III)(LH)2](NO3).MeOH. Polyhedron 2001, 20, 2203–2214. [Google Scholar]
  26. Bracht, K.; Boubakari; Grünert, R.; Bednarski, J.P. Correlations between the activities of 19 antitumor agents and the intracellular glutatione concentrations in a panel of 14 human cancer cell lines: comparisons with the National Cancer Institute data. Anticancer Drugs 2006, 11, 257–261. [Google Scholar]
  27. Ghosh, K.; Kumar, P.; Mohan, V.; Singh, U.P.; Kasiri, S. Nuclease activity via self-activation and anticancer activity of a mononuclear copper(II) complex: Novel role of the tertiary butyl group in the ligand frame. Inorg. Chem. 2012, 51, 3343–3345. [Google Scholar] [PubMed]
  28. Li, L.; Du, K.; Wang, Y.; Jia, H.; Hou, X.; Chao, H.; Ji, L. Self-activating nuclease and anticancer activities of copper(II) complexes with aryl-modified 2,6-di(thiazol-2-yl)pyridine. Dalton Trans. 2013, 42, 11576–11588. [Google Scholar] [CrossRef] [PubMed]
  29. Li, K.; Zhou, L.-H.; Zhang, J.; Chen, S.-Y.; Zhang, Z.-W.; Zhang, J.-J.; Lin, H.-H.; Yu, X.-Q. “Self-activating” chemical nuclease: Ferrocenyl cyclen Cu(II) complexes act as efficient DNA cleavage reagents in the absence of reductant. Eur. J. Med. Chem. 2009, 44, 1768–1772. [Google Scholar] [CrossRef] [PubMed]
  30. CrysAlis Software, Oxford Diffraction Ltd.: Yamton, Oxfordshire, UK, 2009.
  31. Sheldrick, G.M. A short history of SHELX. Acta Crystallogr. 2008, A64, 112–122. [Google Scholar]
  • Sample Availability: Samples of the compounds 1–10 are available from the authors.

Share and Cite

MDPI and ACS Style

Balewski, Ł.; Sączewski, F.; Bednarski, P.J.; Gdaniec, M.; Borys, E.; Makowska, A. Structural Diversity of Copper(II) Complexes with N-(2-Pyridyl)Imidazolidin-2-Ones(Thiones) and Their in Vitro Antitumor Activity. Molecules 2014, 19, 17026-17051. https://doi.org/10.3390/molecules191017026

AMA Style

Balewski Ł, Sączewski F, Bednarski PJ, Gdaniec M, Borys E, Makowska A. Structural Diversity of Copper(II) Complexes with N-(2-Pyridyl)Imidazolidin-2-Ones(Thiones) and Their in Vitro Antitumor Activity. Molecules. 2014; 19(10):17026-17051. https://doi.org/10.3390/molecules191017026

Chicago/Turabian Style

Balewski, Łukasz, Franciszek Sączewski, Patrick J. Bednarski, Maria Gdaniec, Ewa Borys, and Anna Makowska. 2014. "Structural Diversity of Copper(II) Complexes with N-(2-Pyridyl)Imidazolidin-2-Ones(Thiones) and Their in Vitro Antitumor Activity" Molecules 19, no. 10: 17026-17051. https://doi.org/10.3390/molecules191017026

Article Metrics

Back to TopTop