Trithiocyanurate Complexes of Iron, Manganese and Nickel and Their Anticholinesterase Activity

Molecules 2014, 19, 4338-4354; doi:10.3390/molecules19044338 molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Article Trithiocyanurate Complexes of Iron, Manganese and Nickel and Their Anticholinesterase Activity Pavel Kopel 1,2,*, Karel Dolezal 3, Vratislav Langer 4, Daniel Jun 5,6, Vojtech Adam 1,2, Kamil Kuca 6 and Rene Kizek 1,2 1 Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic 2 Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00 Brno, Czech Republic 3 Centre of the Region Hana for Biotechnological and Agricultural Research, Faculty of Science, Palacky University & Institute of Experimental Botany, Academy of Sciences of Czech Republic, Slechtitelu 11, CZ-783 71 Olomouc, Czech Republic 4 Environmental Inorganic Chemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology, SE-412 96 Göteborg, Sweden 5 Faculty of Military Health Sciences, University of Defence, Trebesska 1575, CZ-50001 Hradec Kralove, Czech Republic 6 Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, CZ-50005 Hradec Kralove, Czech Republic * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +420-5-4513-3350; Fax: +420-5-4521-2044. Received: 19 December 2013; in revised form: 31 March 2014 / Accepted: 1 April 2014 / Published: 8 April 2014 Abstract: The complexes of Fe(II), Mn(II) and Ni(II) with a combination of a Schiff base, nitrogen-donor ligand or macrocyclic ligand and trithiocyanuric acid (ttcH3) were prepared and characterized by elemental analysis and spectroscopies. Crystal and molecular structures of the iron complex of composition [Fe(L1)](ttcH2)(ClO4)·EtOH·H2O (1), where L1 is Schiff base derived from tris(2-aminoethyl)amine and 2-pyridinecarboxaldehyde, were solved. It was found that the Schiff base is coordinated to the central iron atom by six nitrogens forming deformed octahedral arrangement, whereas trithiocyanurate(1-) anion, perchlorate and solvent molecules are not coordinated. The X-ray structure of the Schiff base sodium salt is also presented and compared with the iron complex. The anticholinesterase activity of the complexes was also studied. OPEN ACCESS Molecules 2014, 19 4339 Keywords: trithiocyanuric acid; trimercaptotriazine; crystal structure; complexes; acetylcholinesterase activity; Schiff base 1. Introduction The sodium salt of trithiocyanuric acid (ttcH3 = trithiocyanuric acid, also named as 2,4,6-trimercapto-1,3,5-triazine (TMT)) readily forms precipitates with heavy metal ions and that is why it is used for removal of heavy metal ions from industrial wastewater. The effectiveness of heavy metal removal was widely studied by Atwood et al. [1–3] and other groups [4]. Removal of residual palladium and its compounds from reaction mixtures in preparation of drugs, in which palladium is used as a catalyst, is also very important [5,6]. Biological activity of trithiocyanuric compound was also evaluated as it can serve as a ligand of Toxoplasma gondii orotate phosphoribosyltransferase [7–9]. This enzyme is necessary for replication of the parasitic protozoan Toxoplasma gondii, which causes the disease toxoplasmosis. It was proved that trithiocyanuric acid is a better ligand for the enzyme than 5-fluorouracil and emimycin, which are used for clinical treatment of toxoplasmosis. Kar et al. prepared a series of trinuclear Ru(II) complexes of a composition [{Ru(L)2}3(ttc)](ClO4)3, where L = 2,2'-bipyridine, 1,10-phenanthroline and arylazopyridine, which contain trithiocyanurate(3-) bridge bounding Ru(II) centers by chelating S,N donor sets of the anion [10,11]. In addition to the structural, electrochemical and spectral study, interaction of the complexes with the circular and linear forms of p-Bluescript DNA was reported. The Ru(II) complexes reduced the fluorescence intensity of both circular and linear DNA. Zn(II), Fe(II) and Mn(II) complexes with a combination of nitrogen-donor ligands and ttcH3 were prepared and their antitumor and antimicrobial activities were assayed [12]. The IC50 values of the Fe(II) and Mn(II) compounds turned out to be lower than those of cisplatin and oxaliplatin. Potentially six donor atoms can be used for coordination to metal centres. It is always difficult to avoid the formation of precipitates of unknown and probably polymeric structure with metal ions in the presence of deprotonated trithiocyanuric acid. Mostly blocking ligands on metal centres must be coordinated. Despite of that, bonding properties of trithiocyanuric acid complexes were proved by single crystal X-ray analysis. In some compounds, only deprotonated trithiocyanuric acid is present as anion not bonded to central atoms [13]. Mononuclear nickel and zinc complexes with nitrogen donor ligands and trithiocyanurate(2-) bonded by S and N have been structurally characterized [14–18]. Bridging, bischelating S,N mode was proved on cobalt complex [{Co(en)2}2(-ttc)](ClO4)3·2H2O (en = ethylenediamine) for the first time [19]. Metals preferring S donor atoms can form trinuclear species with coordination to S atoms only, for example in [{HgMe}3(-ttc)], [{SnMe3}3(-ttc)] and [{SnPh3}3(-ttc)] [20,21]. The hexanuclear [{AgPPh3}6(-ttc)2] complex with two parallel triazine rings held by six Cu-S bridges was characterized [22], as well as the Au(I) cluster [23] and Cu(I) polymer [24]. Trinuclear cyclopentadienyl complexes of rhodium and iridium were also reported [25,26]. Magnetic and structural studies on trinuclear copper complex with 1,3-bis(2-(4methylpyridyl)imino)isoindoline as blocking ligand and ttc were reported [27]. Pmdien (N,N,N',N'',N''- pentamethyldiethylenetriamine) was proven to be a very good terdentate ligand for complexes with ttc. Molecules 2014, 19 4340 Trinuclear complexes of compositions [M3(pmdien)3(-ttc)](ClO4)3, where M = Zn, Cu and Ni were prepared and structurally characterized [28–31]. The aim of this work was to prepare Fe(II), Mn(II) and Ni(II) complexes with nitrogen atom donors and trithiocyanurate anion. The complexes are of the following composition: [Fe(L1)](ttcH2)(ClO4)·EtOH·H2O (1), [Mn3(phen)6(ttc)](ClO4)3 (2), and Ni2(L2)(ttcH)(ClO4)2·6H2O·EtOH (3), where L1 = 2-[(E)-2-pyridylmethyleneamino]-N,N-bis[2-[(E)-2-pyridylmethyleneamino]ethyl]ethanamine, ttcH3 = trithiocyanuric acid, phen = 1,10-phenanthroline and L2 = 3-[2-(1,3,5,9,12-pentazacyclopentadec3-yl)ethyl]-1,3,5,9,12-pentazacyclopentadecane. The structures of the ligands are depicted in Figure 1. Figure 1. Structural formulas of the ligands used. L1 = 2-[(E)-2-pyridylmethyleneamino]- N,N-bis[2-[(E)-2-pyridylmethyleneamino]ethyl]ethanamine, phen = 1,10-phenanthroline, L2 = 3-[2-(1,3,5,9,12-pentazacyclopentadec-3-yl)ethyl]-1,3,5,9,12-pentazacyclopentadecane. We also attempted to prepare single crystals for X-ray analysis to confirm the stereochemistry of the compounds and characterize them by physico-chemical methods. Due to the presence of a positive charge in the molecule, prepared compounds can interact with the enzyme acetylcholinesterase (AChE; EC 3.1.1.7). Acetylcholine, the natural AChE substrate, contains a positively charged quaternary nitrogen, which is responsible for its interaction with the enzyme active site [32]. Therefore, the other goal of our study was to test the possible anticholinesterase activity of the synthesized complexes. Molecules 2014, 19 4341 2. Results and Discussion 2.1. Synthesis and Spectral Study [Fe(L1)](ttcH2)(ClO4)·EtOH·H2O (1) was prepared by the reaction of iron perchlorate, Schiff base (formed in situ), and ttcNa3 in an ethanol–water mixture. Although we expected the formation of a binuclear or polynuclear complex with a trithiocyanurate bridge, only a mononuclear Fe(II) complex was formed. Its composition was proposed on the base of elemental analysis and unambiguously confirmed by single crystal X-ray analysis. The deformed octahedral coordination of the central Fe(II) was also confirmed by Mössbauer spectroscopy (see Figure 2). The room temperature Mössbauer spectrum of 1 is composed of two doublets with the isomer shift values (0.28 and 0.14 mm s−1) typical of octahedral low-spin iron(II) complexes [33,34]. The doublet I with relative spectrum area A = 91.4% has a higher value of the quadrupole splitting parameter (q.s. = 0.28 mm s−1) than the doublet II (A = 8.6%, q.s. = 0.20 mm s−1). The two different values of quadrupole splitting show that there are two octahedrally coordinated iron centers with lower and higher distortion from the ideal octahedral arrangement, found in the polycrystalline material, but one arrangement is dominant. Similar spectra with two doublets were also found as a result of the octahedral arrangement distortion of the central atoms in Fe(II) complexes [12,13]. Our attempts to prepare Schiff base L1 in solid form were unsuccessful, but finally its sodium complex Na(L1)ClO4 (4) was obtained from the reaction mixture as light-yellow crystals, suitable for X-ray study. Complex 4 was also obtained by the reaction of L1 with sodium perchlorate. Its structure is discussed hereinafter. Figure 2. The room temperature Mössbauer spectrum of 1. The solid line results from least squares fitting of the data to the theoretical equation. Molecules 2014, 19 4342 The complex [Mn3(phen)6(ttc)](ClO4)3 (2) was prepared according to Cermakova [35]. The complex was characterized by FTIR and Raman spectroscopies, MALDI-TOF mass spectrometry, magnetic and conductivity measurements. On the basis of different techniques, the trinuclear structure of complex was proposed, where three central manganese atoms are connected by trithiocyanurate(3-) bridge. Complex Ni2(L2)(ttcH)(ClO4)2·6H2O·EtOH (3) was prepared from Ni(bapen)(ClO4)2 (bapen = N,N'- bis(3-aminopropyl)ethylenediamine) and in situ formation of macrocyclic ligand L2 by the condensation reaction of the terminal amino groups of bapen and ethylenediamine with formaldehyde. A similar preparation of macrocyclic complexes was for example published by Comba et al. [36]. Addition of ttcNa3 led to a formation of violet crystalline product. As our attempts to prepare crystals for X-ray analysis were unsuccessful we used mass spectroscopy to confirm the composition of 3. The ESI− mass spectra displays intense peaks at m/z = 947 and m/z = 848, corresponding to the binuclear molecular ion with ClO4− adducts of composition [Ni2(L2)(ttcH)(ClO4)2H−]− and [Ni2(L2)(ttcH)(ClO4)H−]−, respectively. The formation of perchlorate ion adducts is well known for such kinds of complex ions [31,37]. The peaks observed at lower m/z = 514, 455, 233 and 99, correspond to different fragments of the complex and its organic parts. The value of effective magnetic moment calculated per nickel(II) (μeff = 3.31 BM) for 3 is higher than that expected for the spin only value of octahedral or pentacoordinated nickel central atoms (μso = 2.83 BM). The higher value of the magnetic moment can be explained by a spin-orbital contribution to the spin only value. We can assume that the central nickel atoms are coordinated by four N atoms of macrocyclic ligand and by N or N, S set of donor atoms of ttcH− anion. 2.2. X-ray Structures of [Fe(L1)](ttcH2)(ClO4)·EtOH·H2O (1) and Na(L1)ClO4 (4) The molecular structure of [Fe(L1)](ttcH2)(ClO4)·EtOH·H2O (1) is depicted in Figure 3, while selected bond lengths and angles are listed in Table 1. The crystal structure is stabilized by hydrogen bonds (see Table 2, Figure 4). The molecular structure of 1 consists of an electroneutral iron(II) complex, ttcH2− and ClO4− anions [disordered at two orientations with occupancies 0.536(8)/0.464(8)] and crystal water and EtOH molecules (mathematically squeezed of due to a disorder which could not be properly modeled). The central iron atom is coordinated by six N atoms of Schiff base L1 in a deformed octahedral arrangement. The bond lengths of the azomethine nitrogens N3A, N3B and N3C to central atom are in the range of 1.9527(16)-1.9635(16) Å, whereas the bond lengths of the pyridine nitrogens N6A, N6B and N6C are significantly longer (1.9720(16)-1.9997(15) Å). The N1 atom is out the coordination sphere of Fe atom with distance 3.4576(18) Å. The molecular structure of Na(L1)ClO4 (4) is depicted in Figure 5, while selected bond lengths and angles are listed in Table 3. Again, the perchlorate was disordered with occupancies 0.48(2)/0.52(2). The bond lengths to azomethine nitrogens are again shorter [2.580(14)-2.5406(13) Å] than those to pyridine nitrogens [2.6224(13)-2.7353(14) Å]. Moreover, atom N1 is in the coordination sphere of sodium, so Na is coordinated by seven N atoms. Molecules 2014, 19 4343 Figure 3. Numbering scheme of 1 with atomic displacement ellipsoids drawn at 30% probability level. Hydrogen atoms are omitted for clarity. Note the disordered perchlorate anion. Table 1. Selected bond lengths [Å] and angles [°] for 1. Fe-N3B 1.9527(16) N3B-Fe-N3C 96.12(7) N3C-Fe-N6A 174.37(7) Fe-N3A 1.9569(16) N3A-Fe-N3C 96.15(7) N6C-Fe-N6A 94.01(7) Fe-N3C 1.9635(16) N3B-Fe-N6C 171.87(7) N3B-Fe-N6B 80.89(6) Fe-N6C 1.9720(16) N3A-Fe-N6C 91.45(7) N3A-Fe-N6B 175.87(7) Fe-N6A 1.9764(16) N3C-Fe-N6C 81.10(7) N3C-Fe-N6B 87.31(6) Fe-N6B 1.9997(15) N3B-Fe-N6A 89.10(7) N6C-Fe-N6B 91.32(6) N3B-Fe-N3A 96.45(7) N3A-Fe-N6A 81.11(7) N6A-Fe-N6B 95.64(6) Molecules 2014, 19 4344 Table 2. Hydrogen bonds for 1 [Å, °]. D-H...A d(D-H) d(H...A) d(D...A) <(DHA) O5-H52...O2B 0.931(18) 1.96(2) 2.825(7) 153 O5-H52...O4A 0.931(18) 2.35(2) 3.243(10) 160 O5-H52...O1B 0.931(18) 2.54(3) 3.334(9) 144 O5-H52...Cl 0.931(18) 2.84(2) 3.765(2) 171 N2-H2...S5i 0.88 2.52 3.3879(17) 169 N4-H4...S1ii 0.88 2.40 3.2418(17) 160 Symmetry transformations used to generate equivalent atoms: (i): −x+1,y +1/2,−z−1/2; (ii): −x+1,y−1/2,−z−1/2. Figure 4. Projection of the contents of the unit cell along b-axis (on left). Note the chains of ttc along the b-axis (on right). Molecules 2014, 19 4345 Figure 5. Numbering scheme of 4 with atomic displacement ellipsoids drawn at 30% probability level. Hydrogen atoms are omitted for clarity. Note the disordered perchlorate anion. Table 3. Selected bond lengths [Å] and angles [°] for 4. Na-N3A 2.5280(14) N3A-Na-N6C 115.01(5) N6C-Na-N6A 88.66(4) Na-N3C 2.5338(13) N3C-Na-N6C 64.88(4) N6B-Na-N6A 90.08(4) Na-N3B 2.5406(13) N3B-Na-N6C 141.07(5) N3A-Na-N1 65.01(4) Na-N6C 2.6224(13) N3A-Na-N6B 145.06(5) N3C-Na-N1 64.31(4) Na-N6B 2.6300(14) N3C-Na-N6B 110.99(5) N3B-Na-N1 65.04(4) Na-N6A 2.7353(14) N3B-Na-N6B 65.02(4) N6C-Na-N1 127.09(4) Na-N1 2.8431(12) N6C-Na-N6B 84.78(4) N6B-Na-N1 126.93(4) N3A-Na-N3C 103.63(4) N3A-Na-N6A 63.49(4) N6A-Na-N1 126.25(4) N3A-Na-N3B 103.60(4) N3C-Na-N6A 143.27(5) N6C-Na-N6A 88.66(4) N3C-Na-N3B 102.28(4) N3B-Na-N6A 114.01(4) The absolute configuration with Flack parameter −0.03(4) was determined. The crystal structure is stabilized by weak hydrogen bonds (see Table 4, Figure 6). Dihedral angles between the pyridine rings A, B and C are 89.70(10), 75.41(9) and 82.48(10) degrees for 1 and 53.78(8), 67.49(8) and 68.95(9) degrees for 4, respectively. Molecules 2014, 19 4346 Table 4. Hydrogen bonds for 4 [Å, °]. D-H...A d(D-H) d(H...A) d(D...A) <(DHA) C2B-H2B1...O3Bi 0.99 2.56 3.483(11) 154 C7A-H7A...O1B 0.95 2.59 3.264(10) 128 Symmetry transformations used to generate equivalent atoms: (i): x−1/2,y−1/2,z. Figure 6. Projection of the contents of the unit cell along b-axis for 4. 2.3. Anticholinesterase Activity The anticholinesterase activity of the complexes 1–3 and Fe(II), Mn(II) and Ni(II) salts were studied. The results of the study are presented in Table 5 and in Figure 7. As it is clearly seen, the newly prepared complexes of Fe(II) and Mn(II) were more than one hundred times and Ni(II) complex one thousand times stronger inhibitors if compared with corresponding standards (FeSO 4 , MnSO 4 , NiSO 4 ). All the complexes show low solubility in water and are well soluble in DMF and DMSO. From the composition of [Fe(L 1 )](ttcH 2 )(ClO 4 )·EtOH·H 2 O (1) proved by X-ray it is obvious that in solution, complex cation and ttcH 2 and ClO 4 anions are formed. The complex cation is very stable due to the chelating Shiff base on the iron(II) center as was demonstrated, for example, in a study of oxygen bridged [(salen)FeOFe(salen)] (H 2 salen = N,N'- bis(salicylidene)ethylene diamine) complex [38]. Also in complexes [Fe(bpy) 3 ](ttcH)·2bpy·7H 2 O and [Fe(phen) 3 ](ttcH 2 )(ClO 4 )·2CH 3 OH·2H 2 O, where bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, the strong N-N ligands prevent the coordination of ttc anion to the metal center [13]. 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Sample Availability: Samples of the prepared compounds are available from the authors. © 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).