ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 5, pp. 953–964. © Pleiades Publishing, Ltd., 2019. Russian Text © The Authors(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 5, pp. 766–778. 953 Synthesis, Structure, and Biological Activity of Copper and Cobalt Coordination Compounds with Substituted 2-(2-Hydroxybenzylidene)-N-(prop-2-en-1-yl)hydrazine- carbothioamides A. P. Guleaa, V. O. Graura, Yu. M. Chumakovb, c, P. A. Petrenkob, G. G. Baland, O. S. Burduniucd, e, V. I. Tsapkova*, and V. F. Rudicf a State University of Moldova, ul. Mateevicha 60, Kishinev, Moldova *e-mail: vtsapkov@gmail.com b Institute of Applied Physics, Kishinev, Moldova c Gebze Institute of Technology, Gebze/Kocaeli, Ҫayirova, Turkey d Testemitanu State University of Medicine and Pharmacy, Kishinev, Moldova e National Agency of Public Health, Kishinev, Moldova f Institute of Microbiology and Biotechnology, Academy of Sciences of Moldova, Kishinev, Moldova Received November 29, 2018; revised November 29, 2018; accepted February 22, 2019 Abstract—The reaction of N-(prop-2-en-1-yl)hydrazinecarbothioamide with substituted 2-hydroxybenzalde- hydes afforded the corresponding Schiff bases which were used as ligands to obtain copper and cobalt coordination compounds Cu(NL1–6)X · n H2O (X = Cl–, NO3 –; n = 0–3), Co(HL2)2NO3, and Co(NL6)2Cl. The structure of the isolated complexes was determined by NMR spectroscopy and X-ray analysis. The complexes were tested for antimicrobial and antifungal activity against S. aureus, E. coli, and yeast-like fungi. Inhibitory effect of the initial thioamides and their complexes against human myeloid leukemia HL-60 cancer cell line was also studied. Keywords: coordination compounds, 2-hydroxybenzaldehyde, allylthiosemicarbazones, antimicrobial activity, anticancer activity 2-(2-Hydroxybenzylidene)-N-(prop-2-en-1-yl)hyd- razinecarbothioamide possesses a number of donor atoms and is capable of forming structurally diverse coordination compounds with transition metals [1–6]; such complexes showed selective anticancer activity [7, 8]. It was found that their biological activity correlates with their structure. Therefore, synthesis and study of new metal complexes with 2-(2-hydroxy- benzylidene)-N-(prop-2-en-1-yl)hydrazinecarbothioamide and its derivatives attract interest from both theoretical and practical viewpoints. The present work was aimed at synthesizing copper and cobalt coordination compounds with 2-(5-bromo-2- hydroxybenzilidene)- (H2L 1), 2-(3,5-dibromo-2-hydroxy- benzylidene)- (H2L 2), 2-(2,3-dihydroxybenzylidene)- (H2L 3), 2-(2,4-dihydroxybenzylidene)- (H2L 4), 2-(2-hyd- roxy-3-nitrobenzylidene)- (H2L 5), and 2-(2-hydroxy-3- methoxybenzylidene)-N-(prop-2-en-1-yl)hydrazinecarbo- thioamides (H2L 6) (Scheme 1) and studying their struc- ture, physicochemical properties, and biological activity. Thioamides H2L 1–H2L 6 were synthesized by condensation of equimolar amounts of N-(prop-2-en-1- yl)hydrazinecarbothioamide (4-allylthiosemicarbazide) and substituted 2-hydroxybenzaldehydes in ethanol. The yields, melting points, and elemental analyses of ligands H2L 1–H2L 6 are given in Table 1, and their NMR spectral data are collected in Table 2. We suc- ceeded in obtaining single crystals of H2L 4–H2L 6 suitable for X-ray analysis (Table 3) by recrystal- lization from ethanol. DOI: 10.1134/S1070363219050153 Figures 1 and 2 show the structures of hydrazine- carbothioamides H2L 4–H2L 6 in crystal according to the X-ray diffraction data (arbitrary atom numbering). Unlike previously described thiosemicarbazides and thiosemicarbazones [12–15], the N1–C1 bond has Z configuration. However, the N3=C5 bond has E configuration, which is consistent with published data. The C1N1N2N3S1C5 fragment (A) in thioamides H2L 4– H2L 6 is almost planar; the maximum deviations of atoms from the corresponding mean-square planes are 0.053, 0.07, and 0.062 Å, respectively. On the other hand, the entire molecules H2L 4–H2L 6 are non-planar. The mean-square planes of the benzene rings (C6–C11) are turned through angles of 17.3°, 11.2°, and 10.7° with respect to the A planes, and the torsion angles C1N1C2C3 and C1C2C3C4 are 92.2, –134.7°, 109.6, 2.9°, and 142.1, 128.8°, respectively. The S1–C1 and N1–C1 distances in H2L 6 are shorter than those in H2L 4 and H2L 5 by 0.021, 0.026 Å and 0.024, 0.035 Å, respectively (Table 4). Molecules H2L 4 in crystal are linked through inter- molecular hydrogen bonds O1–H···S1 i C2–H···O1 to form chains along the b axis due to double screw molecular axis (Fig. 3, Table. 5). Owing to the symmetry center, the chains are linked to each other through hydrogen bonds N2–H···S1. Molecules H2L 5 and H2L 6 in crystal form centrosymmetric dimers through hydrogen bonds N2–H···S1, N2–H···O1, and O1–H···S1 (Figs. 4, 5; Table 5). The dimers interact with each other mainly through van der Waals forces. In keeping with the criterion proposed in [16] (CgI···CgJ < 6.0 Å, β < 60.0°, where β is the angle formed by the CgICgJ vector and normal to the aromatic ring CgI), the crystal structure of thioamides H2L 4–H2L 6 is also characterized by π–π stacking between the benzene rings (C6–C11) related to each other through the symmetry center in H2L 4 and H2L 5 or through the double screw axis in H2L 6. The distances between the centroids of these fragments are 5.334, 5.613, and 4.46 Å, and the angles β are 53.5°, 57.0°, and 12.2°, respectively. Apart from the above π–π interactions, ligand H2L 5 features Y–X···Cg (π-ring) interaction (X···Cg < 4.0 Å, γ < 30.0°, where γ is the angle between the XCg vector and normal to the aromatic ring), and X–H···Cg (π-ring) interaction (H···Cg < 3.0 Å, γ < 30.0°, where γ is the angle between the HCg vector and normal to the aromatic ring [16, 17]) is observed in the crystal structure of H2L 6. For the C1–S1···Cg (C6–C11) interaction (–x, –y, 1 – z), the distance between the S1 atom and centroid of the benzene ring is 3.489 Å, and the angle γ is 2.7°. The C9–H···Cg (C6–C11) (–x, 0.5 + y, 0.5 – z) interaction in H2L 6 is characterized by H···Cg 2.83 Å and γ 7.6°. OH R2 R3 R1 N NH NH S H2L1−6 Scheme 1. R1 = R2 =H, R3 = Br (H2L 1); R1 = R3 = Br, R2 = H (H2L 2); R1 = OH, R2 = R3 = H (H2L 3); R1 = R3 = H, R2 = OH (H2L 4); R1 = NO2, R2 = R3 = H (H2L 5); R1 = OCH3, R2 = R3 = H (H2L 6). Thioamide Yield, % mp, °C Found, % Formula Calculated, % C H N C H N H2L 1 87 172–174 41.82 3.73 13.21 C11H12BrN3OS 42.05 3.85 13.37 H2L 2 90 210–212 33.72 2.65 10.93 C11H11Br2N3OS 33.61 2.82 10.69 H2L 3 75 198–200 52.76 5.35 16.44 C11H13N3O2S 52.57 5.21 16.72 H2L 4 78 186–188 52.36 5.18 16.56 C11H13N3O2S 52.57 5.21 16.72 H2L 5 85 151–153 47.00 4.02 20.24 C11H12N4O3S 47.13 4.32 19.99 H2L 6 92 225–227 54.14 5.54 15.77 C12H15N3O2S 54.32 5.70 15.84 Table 1. Yields, melting points, and elemental analyses of substituted 2-(2-hydroxybenzylidene)-N-(prop-2-en-1-yl)hydra- zinecarbothioamides H2L 1–H2L 6 a a Some characteristics of thioamides H2L 1, H2L 4, and H2L 6 were given in [9–11]. RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019 GULEA et al. 954 By mixing hot (50–55°C) ethanolic solutions of copper and cobalt chlorides or nitrates and thioamides H2L 1–H2L 6 at a molar ratio of 1 : 1 or 1 : 2 and subsequent heating for 50–60 min we obtained coordination compounds 1–10 whose elemental compositions (Table 6) corresponded to the formulas Cu(HL1–6)X · n H2O (1, 3–9) [X = Cl– (1, 5, 7, 8), NO3 – (3, 4, 6, 9); n = 0 (1, 5, 7, 8), 1 (3, 4, 6), 3 (9)], Co(HL2)2NO3 (2), and Co(HL6)2Cl (10). Complexes 1–10 are insoluble in diethyl ether, poorly soluble in Thioamide δ, ppm δC, ppm H2L 1 10.56 br.s ( 1H, OH), 9.41 br.s (1H, NH), 8.47 br.s (1H, NH), 8.45 s (1H, CH=N), 7.90 d (1H, Harom, J = 2.5 Hz), 7.38 m (1H, Harom), 6.91 d (1H, Harom, J = 8.8 Hz), 5.97 m (1H, CH=CH2), 5.15 m (2H, CH2=), 4.35 m (2H, CH2N) 177.42 (C=S); 155.74, 133.52, 129.87, 122.24, 118.30, 111.44 (Carom); 139.48 (CH=N), 134.73 (CH=CH2), 115.24 (CH2=), 46.37 (CH2N) H2L 2 10.71 br.s (1H, OH), 9.88 br.s (1H, NH), 8.45 br.s (1H, NH), 8.40 s (1H, CH=N), 7.77 d (1H, Harom, J = 2.4 Hz), 7.73 d (1H, Harom, J = 2.4 Hz), 5.98 m (1H, CH=CH2), 5.16 m (2H, CH2=), 4.37 m (2H, CH2N) 177.43 (C=S); 152.49, 135.66, 131.14, 122.35, 111.49, 111.35 (Carom); 141.38 (CH=N), 134.51 (CH=CH2), 115.41 (CH2=), 46.58 (CH2N) H2L 3 10.48 br.s (1H, OH), 8.73 br.s (1H, OH), 8.47 s (1H, CH=N), 8.27 br.s (2H, NH), 7.15 d (1H, Harom, J = 7.9 Hz), 6.91 d (1H, Harom, J = 7.9 Hz), 6.76 t (1H, Harom, J = 7.9 Hz), 5.99 m (1H, CH=CH2), 5.17 m (2H, CH2=), 4.36 m (2H, CH2N) 178.32 (C=S); 145.31, 145.06, 142.92, 119.66, 119.61, 116.79 (Carom); 142.96 (CH=N), 134.75 (CH=CH2), 115.26 (CH2=), 46.40 (CH2N) H2L 4 10.29 br.s (1H, OH), 9.44 br.s (1H, OH), 8.92 br.s (1H, NH), 8.35 s (1H, CH=N), 8.11 br.s (1H, NH), 7.38 d (1H, Harom, J = 8.5 Hz), 6.45 d (1H, Harom, J = 8.5 Hz), 6.41 s (1H, Harom), 5.98 m (1H, CH=CH2), 5.15 m (2H, CH2=), 4.35 m (2H, CH2N) 177.85 (C=S); 160.84, 158.84, 131.50, 111.22, 108.10, 102.71 (Carom); 145.01 (CH=N), 134.86 (CH=CH2), 115.15 (CH2=), 46.41 (CH2N) H2L 5 10.80 br.s (1H, OH), 10.69 br.s (1H, NH), 8.52 br.s (1H, NH), 8.58 s (1H, CH=N); 8.37 m, 8.16 m, 7.13 m (3H, Harom); 5.98 m (1H, CH=CH2), 5.16 m (2H, CH2=), 4.36 m (2H, CH2N) 178.56 (C=S); 161.61, 135.83, 133.55, 126.21, 119.85, 116.74 (Carom); 152.76 (CH=N), 134.63 (CH=CH2), 115.33 (CH2=), 46.31 (CH2N) H2L 6 b 11.52 br.s (1H, OH), 9.23 br.s (1H, NH), 8.62 br.s (1H, NH), 8.42 s (1H, CH=N), 7.58 d (1H, Harom, J = 7.9 Hz), 6.97 d (1H, Harom, J = 7.9 Hz), 6.79 t (1H, Harom, J = 7.9 Hz), 5.92 m (1H, CH=CH2), 5.13 m (2H, CH2=), 4.22 m (2H, CH2N), 3.82 s (3H, CH3) 177.46 (C=S); 148.39, 139.62, 121.30, 119.40, 118.57, 113.23 (Carom); 146.42 (CH=N), 135.66 (CH=CH2), 115.94 (CH2=), 56.35 (CH3), 46.22 (CH2N) Table 2. 1H and 13C NMR spectra (acetone-d6) of thioamides H2L 1–H2L 6 a a Some characteristics of thioamides H2L 1, H2L 4, and H2L 6 were given in [9–11]. b In DMSO-d6. Fig. 1. Structure of the molecule of 2-(2,4-dihydroxybenzyl- idene)-N-(prop-2-en-1-yl)hydrazinecarbothioamide (H2L 4) in crystal according to the X-ray diffraction data. Fig. 2. Structure of the molecule of 2-(2-hydroxy-3-methoxy- benzyl-idene)-N-(prop-2-en-1-yl)hydrazinecarbothioamide (H2L 6) in crystal according to the X-ray diffraction data. SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF COPPER AND COBALT RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019 955 water, better soluble in alcohols, and readily soluble in DMF, DMSO, and acetonitrile. Their yields and some physicochemical characteristics are given in Table 6. The structure of copper complex 9 was determined by X-ray analysis of its single crystal which was obtained by recrystallization from ethanol (Table 3). A unit cell of 9 contains two nonequivalent [Cu(HL6)H2O]+ cations, two nitrate ions, and four water molecules. The copper atom in each cation coordinates singly deprotonated H2L 6 molecule acting as a tridentate ligand to form two chelate rings, as well Parameter H2L 4 H2L 5 H2L 6 9 Formula C11H13N3O2.75S C11H12N4O3S C12H15N3O2S C12H20N4O8SCu M 263.30 280.31 265.33 443.92 Crystal system Monoclinic Monoclinic Monoclinic Triclinic Space group P21/c P21/c P21/c P-1 Z 4 4 4 4 a, Å 15.236(4) 8.9728(5) 13.661(14) 6.8720(7) b, Å 4.5098(13) 16.6764(7) 5.978(4) 14.0564(18) c, Å 20.553(5) 8.8395(5) 16.834(6) 18.901(2) α, deg 90 90 90 79.178(10) β, deg 95.65(2) 104.396(6) 108.17(6) 89.523(9) γ, deg 90 90 90 87.640(10) V, Å 3 1405.4(6) 1281.16(12) 1306.2(17) 1791.8(4) dcalc, g/cm3 1.244 1.453 1.349 1.646 λ, Å 0.71073 0.71073 0.71073 0.71073 μ, cm–1 0.232 0.263 0.246 1.384 Temperature, K 293(2) 293(2) 293(2) 293(2) Crystal dimensions, mm 0.80×0.05×0.02 0.20×0.18×0.30 0.40×0.03×0.01 0.50×0.27×0.04 θmax, deg 25.05 25.04 28.96 25.05 h, k, l –16 ≤ h ≤ 18 –3 ≤ k ≤ 5 –24 ≤ l ≤ 15 –7 ≤ h ≤ 10 –17 ≤ k ≤ 19 –9 ≤ l ≤ 10 –18 ≤ h ≤ 18 –7 ≤ k ≤ 7 –22 ≤ l ≤ 22 –8 ≤ h ≤ 8 –16 ≤ k ≤ 15 –22 ≤ l ≤ 14 Number of independent reflections (Rint) Number of reflections with I > 2σ(I) 4482/ 2409 0.0699 2785/1926 0.0186 4767/4915 0.00 9835/6197 0.0507 Number of refined parameters 156 172 150 485 R1/wR2 (independent reflections) 0.0739/0.1345 0.0425/0.0851 0.0736/0.1064 0.0866/0.1625 R1/wR2 (reflections with I > 2σ(I)] 0.1822/0.1703 0.0657/0.0960 0.2974/0.2091 0.1751/0.2013 Goodness of fit S 0.883 1.004 0.828 0.962 Δρmax/Δρmin, ē/A 3 0.291/–0.224 0.144/–0.201 0.310/–0.304 1.776/–0.473 Table 3. Crystallographic data and parameters of X-ray diffraction experiments and structure refinement for compounds H2L 4– H2L 6 and 9 RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019 GULEA et al. 956 as a water molecule (Fig. 6). The lengths of the coordination bonds are as follows: Cu1–O1 1.9152(2) [1.9112(2)], Cu1–S1 2.2636(3) [2.2591(3)], Cu1–N3 1.9270(2) [1.9331(2)], and Cu1–OW 1.9430(2) Å [1.9605(3) Å] (Table 7). The six- and five-membered chelate rings lie virtually in one plane; the corresponding dihedral angles are 3.83 and 3.79°. Molecules 9 in crystal are linked to each other through the nitrate anions and water molecules to form a three- dimensional intermolecular hydrogen bond system (Fig. 7). In keeping with the above noted criterion (CgI···CgJ < 6.0 Å, β < 60.0°, where β is the angle between the CgICgJ vector and normal to the aromatic ring CgI) [16], there exists π–π-stacking interaction between the Cu2O1AC11AC6AC5AN3A metallacycles related through a symmetry center. The distance Cg1···Cg1 (1 – x, 1 – y, –z) between the centroids of these fragments is 3.513 Å, and the angle β is equal to 13.8°. Apart from the π–π stacking, metal–Cg (π-ring) interaction (Cu···Cg < 4.0 Å) is observed in the crystal structure of complex 9. The Cu···Cg distances for the Cu1···Cg (C6C7C8C9C10C11) (–x, 1 – y, 1 – z) and Cu2···Cg (C6AC7AC8AC9AC10AC11A) (1 – x, 1 – y, –z) interactions are 3.517 and 3.487 Å, respectively. Complexes 1–10 were characterized by elemental analyses, molar electrical conductivities, magneto- chemical data, and IR spectra (Table 6). According to the molar conductivity measurements, compounds 1, 5, 7, and 8 in DMF solution are nonelectrolytes (æ = 2– 4 Ω–1 cm2 mol–1), and complexes 2–4, 6, 9, and 10 are binary electrolytes (æ = 54–70 Ω–1 cm2 mol–1). Cobalt complexes 2 and 10 are diamagnetic at room Bond d, Å H2L 4 H2L 5 H2L 6 S1–C1 1.687(5) 1.683(3) 1.662(7) C5–N3 1.283(5) 1.276(3) 1.264(7) C5–C6 1.460(6) 1.461(3) 1.448(8) N3–N2 1.397(5) 1.374(3) 1.399(6) N1–C1 1.330(5) 1.325(3) 1.295(8) N1–C2 1.437(5) 1.455(3) 1.476(9) N2–C1 1.355(5) 1.354(3) 1.356(8) C2–C3 1.463(7) 1.478(4) 1.462(10) Angle ω, deg N3C5C6 122.0(4) 121.4(2) 121.0(6) C5N3N2 115.9(4) 115.4(2) 115.9(5) C1N1C2 125.3(4) 123.9(2) 124.2(7) C1N2N3 120.1(4) 121.1(2) 122.4(5) N1C1N2 117.0(4) 115.7(2) 115.5(6) N1C1S1 123.9(4) 125.43(19) 125.0(6) N2C1S1 119.1(4) 118.87(18) 119.5(5) C9C8C7 119.3(5) 119.6(2) 119.8(6) N1C2C3 115.6(5) 112.3(2) 112.3(7) C4C3C2 127.2(5) 126.0(3) 125.7(10) Table 4. Selected bond lengths and bond angles in molecules H2L 4–H2L 6 in crystal Fig. 3. A fragment of crystal packing of 2-(2,4-dihydroxy- benzylidene)-N-(prop-2-en-1-yl)hydrazinecarbothioamide (H2L 4). Fig. 4. H-Bonded chains in the crystal structure of 2-(2-hyd- roxy-3-nitrobenzylidene)-N-(prop-2-en-1-yl)hydrazinecarbo- thioamide (H2L 5). SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF COPPER AND COBALT RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019 957 Bond D–H···A Distance, Å ∠DHA, deg Coordinates of A D–H H···A D···A H2L 4 O1–H···N3 0.82 1.95 2.672 147 x, y, z N2···H···S1 0.86 2.60 3.448 171 1–x, 2–y, 1–z N1···H···N3 0.86 2.26 2.659 108 x, y, z C2···H···S1 0.97 2.61 3.109 112 x, y, z H2L 5 O1···H···O3 0.82 1.90 2.594 142 x, y, z O1···H···S1 0.82 2.82 3.367 126 –x, –1/2+y, 1/2–z N1···H···N3 0.86 2.25 2.638 107 x, y, z N2···H···S1 0.86 2.72 3.479 148 –x, –y, –z C2···H···O1 0.97 2.46 3.349 153 –x, 1/2+y, 1/2–z H2L 6 N2···H···O1 0.86 2.19 2.978 151 –x, 2–y, –z O1···H···O2 0.82 2.18 2.637 116 x, y, z O1···H···S1 0.82 2.52 3.184 139 –x, 2–y, –z N1···H···N3 0.86 2.26 2.664 109 x, y, z C5···H···O1 0.93 2.43 2.754 100 x, y, z C2···H···S1 0.97 2.64 3.081 108 x, y, z 9 N1···H···O2N2 0.86 2.04 2.897 174 x, y, z N1A···H···O2N1 0.86 2.02 2.870 169 1–x, 1–y, –z N2···H···O1N2 0.86 1.93 2.783 169 x, y, z N2A···H···O1N1 0.86 1.96 2.815 170 1–x, 1–y, –z O1W···H···O4W 0.85 2.21 2.685 115 –x, 1–y, 1–z O1W···H···O4W 0.85 2.41 2.685 100 –x, 1–y, 1–z O1WA···H···O2W 0.87 1.88 2.743 171 x, y, z O1WA···H···O5W 0.87 190 2.655 144 x, y, z O2W···H···O1N1 0.85 2.34 3.090 148 x, y, z O2W···H···O1A 0.85 2.22 2.926 141 x, y, z O2W···H···O2A 0.85 2.27 3.022 147 x, y, z O3W···H···O5W 0.85 2.51 3.343 167 –1+x, y, z O4W···H···O1A 0.85 2.23 2.977 146 x, y, z O4W···H···O2A 0.85 2.48 3.233 147 x, y, z O5W···H···O1N2 0.85 206 2.893 167 x, y, z O5W···H···O1 0.85 2.18 3.005 163 1–x, 1–y, 1–z C2A···H···S1A 0.97 2.62 3.089 110 x, y, z C2···H···S1 0.97 2.60 3.112 113 x, y, z Table 5. Geometric parameters of hydrogen bonds in the crystal structures of compounds H2L 4–H2L 6 and 9 RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019 GULEA et al. 958 temperature (294 K), and the central metal atom therein has a degree of oxidation of 3+ and a pseudo- octahedral ligand environment (Table 6). The effective magnetic moments of the copper complexes correspond to spin values for one unpaired electron. These findings suggest monomeric structure of the complexes. The mode of ligand coordination to the central metal ion in complexes 1–10 was determined by comparing their IR spectra with the spectra of initial thioamides H2L 1–H2L 6 with account taken of the X-ray diffraction data for compound 9. The IR spectra of initial ligands H2L 1–H2L 6 contained absorption bands Fig. 5. A fragment of crystal packing of 2-(2-hydroxy-3- methoxybenzylidene)-N-(prop-2-en-1-yl)hydrazinecarbothio- amide (H2L 6). Fig. 6. Structure of the molecule of complex 9 in crystal according to the X-ray diffraction data. Bond d, Å Bond d, Å Angle ω, deg Angle ω, deg Cu1–O1 1.915(5) S1–C1 1.705(8) O1Cu1N3 93.6(3) O1WACu2S1A 92.68(18) Cu1–N3 1.927(6) C5–N3 1.277(9) O1Cu1O1W 86.6(2) N3C5C6 126.1(8) Cu1–S1 2.264(2) C5–C6 1.458(10) N3Cu1O1W 175.4(3) C5N3N2 116.5(6) Cu1–O1W 1.943(5) N3–N2 1.393(8) O1Cu1S1 173.98(19) C1N1C2 125.6(8) Cu2–O1A 1.911(5) N1–C1 1.325(9) N3Cu1S1 86.7(2) C1N2N3 118.7(7) Cu2–N3A 1.933(6) N1–C2 1.472(10) O1WCu1S1 93.54(17) N1C1N2 116.1(8) Cu2–S1A 2.259(2) N2–C1 1.325(9) O1ACu2N3A 93.8(2) N1C1S1 122.6(7) Cu2–O1WA 1.961(6) C2–C3 1.389(14) O1ACu2O1WA 86.8(2) N2C1S1 121.3(6) N3ACu2O1WA 176.8(3) C9C8C7 120.7(8) O1ACu2S1A 174.74(17) N1C2C3 113.2(9) N3ACu2S1A 86.99(19) C4C3C2 125.7(13) Table 6. Selected bond lengths and bond angles in molecule 9 SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF COPPER AND COBALT RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019 959 at 3450–3100, 1660–1580, and 1400–1100 cm–1. The IR spectra of all complexes lacked absorption in the region 3450–3100 cm–1, which is typical of phenolic O–H stretchings of the free ligands. This indicates deprotonation of the OH group upon coordination. The same conclusion follows from the 40–50 cm–1 low- frequency shift of the ν(C–O) band observed at 1260– 1190 cm–1 in the spectra of H2L 1–H2L 6. In addition, the complexation is accompanied by low-frequency shift of the ν(C=N) band (by 20–30 cm–1) and high- frequency shift of the ν(C=C) band (by 25–40 cm–1). These data suggest coordination of deprotonated ligands HL1–HL6 to the metal ion through phenolic oxygen atom, nitrogen atom of the azomethine group, and thionic sulfur atom. This coordination mode is also supported by the appearance in the IR spectra of all Yield, % μef, a B.M. æ,a Ω–1 cm2 mol–1 Found, % Formula Calculated, % Cl M N S Cl M N S 1 80 1.75 4 8.47 15.19 9.90 7.48 C11H11BrClCuN3OS 8.60 15.42 10.19 7.78 2 75 б 70 – 6.25 10.57 6.94 С22H20Br4CoN7O5S2 – 6.51 10.83 7.09 3 82 1.82 57 – 11.60 10.17 5.70 C11H12Br2CuN4O5S – 11.86 10.46 5.99 4 67 1.81 65 – 15.87 13.98 7.91 C11H14CuN4O6S – 16.13 14.22 8.14 5 78 1.92 4 9.88 17.93 11.94 8.89 C11H12ClCuN3O2S 10.15 18.19 12.03 9.18 6 69 1.83 67 – 15.87 14.01 7.99 C11H14CuN4O6S – 16.13 14.22 8.14 7 77 1.79 2 9.14 16.59 14.60 8.31 C11H11ClCuN4O3S 9.37 16.80 14.81 8.48 8 73 1.78 3 9.55 17.32 11.39 8.74 C12H14ClCuN3O2S 9.76 17.49 11.57 8.83 9 69 1.87 61 – 14.17 12.47 6.98 C12H20CuN4O6S – 14.31 12.62 7.22 10 72 b 54 5.47 9.17 13.32 10.07 C24H28ClCoN6O4S2 5.69 9.46 13.49 10.29 Table 7. Yields, effective magnetic moments, electrical conductivities, and elemental analyses of copper and cobalt coordination compounds 1–10 a At 294 K. b Diamagnetic. Fig. 7. A fragment of crystal packing of complex 9. C om p. n o. RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019 GULEA et al. 960 complexes of new bands in the region 530–405 cm–1, in particular ν(M–N) bands at 525–505 and 430– 405 cm–1 and ν(M–S) bands at 450–440 cm–1. The other functional groups of thioamides H2L 1–H2L 6 are not involved in the complexation since the corresponding characteristic bands of the complexes are observed in the same regions as in the spectra of the initial thiosemicarbazones. On the basis of the obtained data, the synthesized complexes were assigned structures A (1, 5, 7, 8), B (3, 4, 6, 9), and C (2, 10) (Scheme 2). As shown in [7, 8] complexes of biometals with 2- (2-hydroxybenzylidene)-N-(prop-2-en-1-yl)hydrazine- carbothioamide selectively inhibit the growth and proliferation of some cancer cell lines and some microorganisms. In this work we tested initial metal salts and ligands and coordination compounds 1–10 for in vitro antimicrobial and antifungal activities against standard strains of gram-positive (Staphylococcus aureus, Bacillus cereus) and gram-negative bacteria (Escherichia coli, Salmonella abony) and yeast-like fungi (Candida albicans). The results are summarized in Table 8. It is seen that all initial copper and cobalt salts showed no activity against the above listed microorganisms and that ligands H2L 1, H2L 2, and H2L 4 were active only against gram-positive bacteria and fungi and low active against gram-negative bacteria. Complexes 1–10 showed selective bacteriostatic and and bactericidal activities against S. aureus and C. albicans in the concentration range 1.5–120 μg/mL and against E. coli in the concentration range 15–500 μg/mL. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the complexes depended on the nature of the central metal ion and substituents in thiosemicarbazones H2L 1–H2L 6. Complex 3 turned out to be the most active against gram-positive bacteria, and complex 8, against gram- negative bacteria. Furthermore, similarity of the MIC Compound Staphylococcus aureus ATCC 25923 Bacillus cereus GISK 8035 Escherichia coli ATCC 25922 Salmonella abony GISK 03/03 Candida albicans ATCC 90028 MIC MBC MIC MBC MIC MBC MIC MBC MIC MBC Initial saltsa ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 H2L 1 15 60 1.5 15 ˃1000 ˃1000 ˃1000 ˃1000 3 3 1 3 15 1.5 3 ˃1000 ˃1000 ˃1000 ˃1000 3 30 H2L 2 1.5 3 1.5 3 >1000 >1000 >1000 >1000 1.5 3 2 3 7 ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 1.5 3 3 1.5 1.5 1.5 3 >1000 >1000 >1000 >1000 1.5 3 H2L 3 15 30 30 60 120 250 250 500 30 120 4 7 15 7 15 30 60 60 120 7 7 H2L 4 3 15 30 60 ˃1000 ˃1000 ˃1000 ˃1000 3 15 5 7 15 7 15 500 500 250 500 3 7 6 3 7 3 7 12 250 12 60 3 7 H2L 5 60 250 15 120 120 500 120 500 3 30 7 15 120 1.5 15 15 120 120 120 3 15 H2L 6 ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 ˃1000 8 7 60 7 30 30 120 15 60 15 60 9 7 7 120 120 500 500 500 500 7 7 Table 8. Minimum inhibitory concentrations (MIC, μg/mL) and minimum bactericidal concentrations (MBC, μg/mL) of ligands H2L 1–H2L 6 and coordination compounds 1–10 a CuCl2·2H2O; Cu(NO3)2·3H2O; CoCl2·6H2O; Co(NO3)2·6H2O. SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF COPPER AND COBALT RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019 961 and MBC values for many compounds indicated bactericidal character of their action. As reported previously for 3d metal complexes with 2-(2-hydroxybenzylidene)-N-(prop-2-en-1-yl)hydrazine- carbothioamide, complexes 1–10 at a concentration of 0.1–10 μM showed antiproliferative activity against HL-60 human myeloid leukemia cancer cell line and model MDCK (Madin–Darby canine kidney) normal cell line (Table 9). The activity of both ligands and complexes derived therefrom strongly depended on the substituent in the salicylidene fragment. For example, introduction of two bromine atoms into the benzene ring (H2L 2) led to complete loss of activity. The highest activity was observed for the ligands containing a bromine atom in the 5-position and a methoxy group in the 3-position, which inhibited cancer cell proliferation by more than 50% at a concentration of 10 μM. Copper complexes with these ligands showed the highest activity in the examined series. The activity of the copper complexes was higher than that of the corresponding ligand, whereas the cobalt complexes were low active. The highest Scheme 2. Compound IC50 , μM HL-60 MDCK H2L 1 8.0 ˃100 1 1.8 18 H2L 2 >10 ˃ 100 2 >10 >100 3 3.8 92 H2L 3 >10 >100 4 3.8 4.8 H2L 4 >10 ˃100 6 >10 50 H2L 5 >10 >100 7 0.6 ˃100 H2L 6 7.2 ˃100 8 0.4 ˃100 10 >10 ˃100 Table 9. Antiproliferation activity of ligands H2L 1–H2L 6 and coordination compounds 1–10 against cancer (HL-60) and healthy cells (MDCK) N Cu O N H S R1R2 R3 N H Cl N Cu O N H S R1R2 R3 N H OH2 NO3 nH2O. S N SN Co O O NH HN HN NH R1 R2 R3 R1 R2R3 X А B C RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019 GULEA et al. 962 cytostatic activity was found for complex 8 which completely inhibited proliferation of cancer cells at concentrations of 10 and 1 μM; however, it showed almost no activity at lower concentrations. The selectivity of action of thioamides H2L 1–H2L 6 and complexes 1–10 was assayed by estimating their antiproliferative activity healthy MDCK cells. Table 9 contains IC50 values characterizing the cytostatic effect of these compounds with respect to HL-60 and MDCK cells. It is seen that in most cases the antiproliferative activity against healthy cells is lower by a factor of 10 and more than their effect on HL-60 cancer cells. Thus, the synthesized compounds selectively inhibit proliferation of HL-60 cancer cells without appreciable negative effect on healthy cells. Our results indicate promise of further search for antimicrobial, antifungal, and anticancer agents among coordination compounds of biometals with thioamide- based ligands. EXPERIMENTAL The X-ray diffraction data for compounds H2L 4– H2L 6 and 9 were obtained with an Oxford Diffraction Xcalibur diffractometer [18]. The structures were solved by the direct method and were refined by the least-squares method in anisotropic approximation for non-hydrogen atoms using SHELX-97 software [19]; the crystal structure of H2L 4 was refined as racemic twin. Hydrogen atoms were placed in geometrically calculated positions, and their temperature factors UH were assumed to be higher by a factor of 1.2 than those of the corresponding carbon and oxygen atoms. The principal crystallographic data and parameters of X-ray diffraction experiments and structure refinement are given in Table 1, and selected interatomic distances and bond angles are given in Table 2. The coordinates of atoms in structures H2L 4–H2L 6 and 9 were deposited to the Cambridge Crystallographic Data Centre (CCDC entry nos. 929 459–929 461, 1 872 426). The geometry calculations and were performed, and the molecular structures were plotted, using PLATON [16]; only those hydrogen atoms which are involved in hydrogen bonds are shown in the crystal packing images. The structures were analyzed using the CCDC data (versiin 5.39) [20, 21]. The electrical conductivity of solutions of com- plexes 1–10 in DMF with a concentration of 0.001 M were measured at 20°C with an R-38 rheochord bridge. The IR spectra (4000–400 cm–1) were recorded on an Bruker ALPHA spectrometer. The effective magnetic moments were measured by the Gouy method. The molar magnetic susceptibilities were calculated with a correction for diamagnetism on the basis of theoretical magnetic susceptibilities of organic compounds. The antimicrobial, antifungal, and anticancer activities were assessed according to standard procedures [22]. 2-(5-Bromo-2-hydroxybenzylidene)-N-(prop-2-en- 1-yl)hydrazinecarbothioamide (H2L 1) was synthesized as described in [9]. 2-(3,5-Dibromo-2-hydroxybenzylidene)-N-(prop- 2-en-1-yl)hydrazinecarbothioamide (H2L 2). A solu- tion of 10 mmol of N-(prop-2-en-1-yl)hydrazine- carbothioamide in 35 mL of ethanol was added to a hot (55–60°C) solution of 10 mmol of 3,5-dibromo-2- hydroxybenzaldehyde in 15 mL of ethanol. After cooling, light yellow solid precipitated and was filtered off on a glass filter, washed with a small amount of ethanol, and dried in air. Ligands H2L 3 i H2L 5 were synthesized in a similar way from N-(prop-2-en-1-yl)hydrazinecarbothioamide and 2,3-dihydroxy- or 2-hydroxy-3-nitrobenzaldehyde, respectively, at a molar ratio of 1 : 1. Compounds H2L 4 and H2L 6 were prepared according to the procedures described in [10, 11]. Some characteristics of thioamides H2L 1–H2L 6 are given in Tables 1 and 2. Thioamides H2L 1–H2L 6 are readily soluble in DMF and DMSO, as well as in alcohols on heating. [2-(5-Bromo-2-hydroxybenzylidene)-N-(prop-2- en-1-yl)hydrazinecarbothioamido]chlorocopper(II) (1). A solution of 10 mmol of ligand H2L 1 in 50 mL of ethanol was heated to 50–55°C, and a solution of 10 mmol of copper(II) chloride dihydrate in 20 mL of ethanol was added with continuous stirring. The mixture was refluxed for 50–60 min. After cooling to room temperature, the precipitate was filtered on a glass filter, washed with small amounts of alcohol and diethyl ether, and dried in air until constant weight. Complexes 2–10 were synthesized in a similar way from thioamides H2L 2–H2L 6 and the corresponding cobalt(II) and copper(II) salts taken at a ratio of 2 : 1 or 1 : 1. ACKNOWLEDGMENTS The authors thank Prof. D. Poirier (Laval University, Quebec, Canada) and O.S. Garbuz for their help in performing biological testing. SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF COPPER AND COBALT RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 5 2019 963 CONFLICT OF INTERESTS No conflict of interest was declared by the authors. REFERENCES 1. Bal-Demirci, T., Polyhedron, 2008, vol. 27, p. 440. doi 10.1016/j.poly.2007.10.001 2. Orysyk, S.I., Bon, V.V., Zholob, O.O., Pekhnyo, V.I., Orysyk, V.V., Zborovskii, Yu.L., and Vovk, M.V., Polyhedron, 2013, vol. 51, p. 211. doi 10.1016/ j.poly.2012.12.021 3. Bon, V.V., Orysyk, S.I., and Pekhnyo, V.I., Russ. J. Coord. Chem., 2011, vol. 37, no. 2, p. 149. doi 10.1134/ s1070328411010027 4. Bon, V.V., Acta Crystallogr., Sect. C, 2010, vol. 66, p. 300. doi 10.1107/S0108270110035754 5. Orysyk, S.I., Bon, V.V., Obolentseva. O.O., Zborovskii, Yu.L., Orysyk, V.V., Pekhnyo, V.I., Staninets, V.I., and Vovk, M.V., Inorg. Chim. Acta, 2012, vol. 382, p. 127. doi 10.1016/ j.ica.2011.10.027 6. 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