Novel Antioxidants Based on Selected 3d Metal Coordination Compounds with 2-Hydroxybenzaldehyde 4,S-Diallylisothiosemicarbazone.

2-Hydroxybenzaldehyde 4,S-diallylisothiosemicarbazone (HL) was synthesized and characterized by 1H, 13C NMR and FTIR spectroscopies. It exists in solution in two isomeric forms: cis (~25%) and trans (~75%). Six stable complexes were obtained by interaction of HL with copper(II), nickel(II), cobalt(III) and iron(III) salts: [Cu(L)Cl] (1), [Cu(L)NO3] (2), [Cu(3,4-Lut)(L)NO3] (3), [Ni(L)OAc] (4), [Co(L)2]Cl (5), [Fe(L)2]NO3 (6). The synthesized complexes have been studied by elemental analysis, FTIR, molar electrical conductivity and single crystal X-ray diffraction (6). For all compounds the antioxidant activity against cation radicals ABTS•+ was studied. All complexes and free ligand are more active than trolox that is used in medicine practice. Complex 4 (IC50=7.20µM) is the most active one. The introduction of heterocyclic amine did not improve the antioxidant activity. The introduction of S-allyl group into isothiosemicarbazone affected the activity of the synthesized substances, and in some cases the resulting complexes exhibit greater activity than complexes with isothiosemicarbazones with other S-radicals.

Introducing N-Heteroaromatic Bases into Copper(II) Thiosemicarbazon Complexes: A Way to Change their Biological Activity.

Three new copper(II) complexes, [Cu(1,10-Phen)(L)] (1), [Cu(2,2'-Bpy)(L)] (2) and [Cu(3,4-Lut)(L)] (3), where H2 L=2-[(2,4-dihydroxyphenyl)methylidene]-N-(prop-2-en-1-yl)hydrazine-1-carbothioamide, 1,10-Phen=1,10-phenanthroline, 2,2'-Bpy=2,2'-bipyridine, 3,4-Lut=3,4-lutidine, have been synthesized and characterized by elemental analysis, FTIR spectroscopy and single crystal X-ray crystallography (1, 2). All compounds are mononuclear. The introduction of a monodentate N-heteroaromatic base (3,4-dimethylpyridine) has led to a significant increase of antimicrobial activity against Gram-negative Escherichia coli and antifungal activity against Candida albicans compared to the pro-ligand and the precursor complex [Cu(L)H2 O]. The introduction of bidentate N-heteroaromatic bases did not lead to such increase of antimicrobial and antifungal activities. Moreover, complex 3 surpasses the inhibitory activity of tetracycline toward Enterobacter cloacae and the inhibitory activity of fluconazole toward Candida parapsilosis and Cryptococcus neoformans. The study of antioxidant activity against cation radicals ABTS⋅+ showed that complexes 1-3 are more active than Trolox, but only introduction of the monodentate N-heteroaromatic base (3,4-dimethylpyridine) led to the increase of antioxidant properties compared to the precursor complex.

Synthesis, Structure, and Biologic Activity of Some Copper, Nickel, Cobalt, and Zinc Complexes with 2-Formylpyridine N 4-Allylthiosemicarbazone.

A series of zinc(II) ([Zn(H2O)(L)Cl] (1)), copper (II) ([Cu(L)Cl] (2), [Cu(L)Br] (3), [Cu2(L)2(CH3COO)2]·4H2O (4)), nickel(II) ([Ni(HL)2]Cl2·H2O (5)), and cobalt(III) ([Co(L)2]Cl (6)) complexes were obtained with 2-formylpyridine N 4-allylthiosemicarbazone (HL). In addition another two thiosemicarbazones (3-formylpyridine N 4-allylthiosemicarbazone (HL a) and 4-formylpyridine N 4-allylthiosemicarbazone (HL b)) have been obtained. The synthesized thiosemicarbazones have been studied using 1H and 13C NMR spectroscopy, IR spectroscopy, and X-ray diffraction analysis. The composition and structure of complexes were studied using elemental analysis, IR and UV-Vis spectroscopies, molar conductivity, and magnetic susceptibility measurements. Single crystal X-ray diffraction analysis elucidated the structure of thiosemicarbazones HL, HL a, and HL b, as well as complexes 4 and 5. The antiproliferative properties of these compounds toward a series of cancer cell lines (HL-60, HeLa, BxPC-3, RD) and a normal cell line (MDCK) have been investigated. The nickel complex shows high selectivity (SI > 1000) toward HL-60 cell line and is the least toxic. The zinc complex shows the highest selectivity toward RD cell line (SI = 640). The copper complexes (2-4) are the most active molecular inhibitors of proliferation of cancer cells, but exhibit not such a high selectivity and are significantly more toxic. Zinc and copper complexes manifest high antibacterial activity. It was found that calculated at B3LYP level of theory different reactivity descriptors of studied compounds strongly correlate with their biological activity.

Biological Evaluation of a Series of Amine-Containing Mixed-Ligand Copper(II) Coordination Compounds with 2-(2-hydroxybenzylidene)-N-(prop-2-en-1-yl)hydrazinecarbothioamide.

Five compounds 2-(2-hydroxybenzylidene)-N-(prop-2-en-1-yl)hydrazinecarbothioamide (H2L), bis[µ2-2-({2-[(prop-2-en-1-yl)carbamothioyl]hydrazinylidene}methyl)phenolato-S,N,O:O]diaquadicopper(II) nitrate (1), bis[µ2-2-({2-[(prop-2-en-1-yl)carbamothioyl]hydrazinylidene}methyl)phenolato-S,N,O:O]diimidazoldicopper(II) nitrate (2), bis[µ2-2-({2-[(prop-2-en-1-yl)carbamothioyl]-hydrazinylidene}methyl)phenolato-S,N,O:O]bis-(3,5-dibromopyridine)dicopper(II) nitrate (3), bis[µ2-2-({2-[(prop-2-en-1-yl)carbamothioyl]-hydrazinylidene}methyl)phenolato-S,N,O:O]bis(4-methylpyridine)dicopper(II) nitrate hexahydrate (4) were synthesized. The antiproliferative properties of these compounds toward cancer cell lines RD, HeLa, and normal cell line MDCK have been investigated. The tested complexes surpass Doxorubicin (DOXO) in the efficiency of anticancer activity as their IC50 values toward cancer cells are lower than the corresponding values of DOXO and the selectivity indexes exceed the corresponding SI value of DOXO. The tested compounds demonstrated a high antioxidant effect against ABTS•+ radical cations as well as low toxicity on Daphnia magna.