Elsevier

Inorganica Chimica Acta

Volume 404, 1 August 2013, Pages 5-12
Inorganica Chimica Acta

Synthesis, characterization, DFT calculations and biological activity of derivatives of 3-acetylpyridine and the zinc(II) complex with the condensation product of 3-acetylpyridine and semicarbazide

https://doi.org/10.1016/j.ica.2013.04.017Get rights and content

Highlights

  • Tetrahedral complex of Zn(II) with 3-acetylpyridine semicarbazone.

  • DFT calculations on stabilities of various structures.

  • Moderate antibacterial, antifungal and cytotoxic activities.

  • Induction of ROS in tumor cell lines by a complex with a non-redox active metal.

  • Effect on cell cycle progresion in tumor cell lines and induction of autophagy.

Abstract

A Schiff base of 3-acetylpyridine with semicarbazide as well as the corresponding tetrahedral Zn(II) complex were synthesized and characterized by X-ray crystal structure analysis and spectroscopic methods. It is interesting to note that the ligand coordinated as a monodentate although there are several donor atoms in it. Computational studies showed that such structure is more stable than the hypothetical structure with one ligand bound as a bidentate. The complex exibited moderate antibacterial, antifungal and cytotoxic activities while the ligand was mostly inactive. The complex strongly induced formation of reactive oxygen species in tumor cell lines. It also influenced cell cycle progression in tumor cell lines, and induced autophagy. The latter effect is, at least in part, a protective one.

Graphical abstract

Synthesis of tetrahedral Zn(II) complex with 3-acetylpyridine semicarbazone. The complex exibited moderate antibacterial, antifungal and cytotoxic activities, induced formation of ROS and autophagy and influenced cell cycle progression.

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Introduction

Condensation derivatives of 2-acetylpyridine with hydrazines, hydrazides and dihydrazides and their transition metal compexes have been extensively studied by our group [1], [2], [3]. These ligands have a large number of possible donor atoms and therefore display a diverse behavior in metal coordination. The central metal atom and the nature of the ligand determine the way of coordination.

There is a small number of papers concerning derivates of 3-acetylpyridine and their complexes in none of which biological activity was studied [4], [5], [6], [7], [8]. Bis hydrazone of hydrazine and 3-acetylpyridine was coordinated to Zn(II) via pyridine nitrogen and not via hydrazone nitrogen [4].

In the complexes of Pt(II), Co(II), Ni(II) and Cu(I) with condensation derivative of 3-acetylpyridine and thiosemicarbazide the ligand is coordinated as a bidentate via thione sulfur and azomethine nitrogen while the heteroaromatic nitrogen is not involved in coordination [5], [6], [7].

There is only one publication concerning complexes of the condensation derivative of 3-acetylpyridine with semicarbazide. Based on similarity of spectral properties of oxovanadium(IV) complexes with 3-acetylpyridine semicarbazone and 2-acetylpyridine semicarbazone and X-ray structure of the latter complex, it was assumed that the 3-acetylpyridine derivative was coordinated as a monodentate in neutral form via the carbonyl oxygen of the side chain [8].

Zinc is considered the most abundant trace intracellular element and a substantial amount of this element is incorporated in the nucleus [9]. As some other metal ions zinc has many positive physiological effects but changes in its metabolism or trafficking may be related to some diseases [10], [11].

Zinc(II) ions are present in zinc finger proteins that recognize and bind to DNA [12], [13]. In zinc fingers the zinc ion is usually tetrahedrally coordinated by cysteine and histidine residues [14]. Lippert has stressed that the role of zinc in nucleic acid chemistry is unique in many aspects [15]. For example, from all metal ions only zinc(II) ions are able to facilitate the rewinding of molten DNA [15].

In the present paper condensation products of 3-acetylpyridine with different hydrazide type compounds were studied for their coordination behavior and antitumor and antimicrobial activities. The present work describes synthesis, characterization and biological activity of derivatives of 3-acetylpyridine with semicarbazide, oxamic hydrazide, ethyl carbazate and zinc(II) complex with 3-acetylpyridine semicarbazone. Coordination behaviour of the ligands was investigated by DFT calculations.

Section snippets

Materials and methods

All solvents (reagent grade) were obtained from commercial suppliers and used without further purification. The elemental analyses (C, H, N) were performed by the standard micromethods using the ELEMENTAR Vario ELIII C, H, N analyser. IR spectra were recorded on Perkin-Elmer FT-IR 1725X spectrophotometer by the KBr technique in the region 4000–400 cm−1. Abbreviations used for IR spectra: vs very strong; s, strong; m, medium; w, weak. NMR spectral assignments and structural parameters were

General

The condensation reaction of 3-acetylpyridine and semicarbazide, oxamic hydrazide and ethyl carbazate in water was performed similary to the procedure by Wyrzykiewicz and Blaszczyk [33], affording three ligands: HL1, HL2 and HL3 (Scheme 1), respectively. Using these ligands and Zn(OAc)2·2H2O in molar ratio 2:1 in methanol solution only in the case of HL1 a defined product could be isolated. Zn(II) complex with the formula [ZnCl2(HL1)2] (1) was obtained with two ligands HL1 coordinated in a

Conclusion

A Zn(II) complex of the Schiff base of 3-acetylpyridine and semicarbazide, where two ligands were monodentately coordinated, was obtained. This behaviour is a consequence of a much higher stability of the structure of the complex with two ligands bound as monodentates than the hypothetical structure with one ligand bound as a bidentate, as calculated at SSB-D/ET-pVQZ level of theory.

Complex 1 showed moderate antibacterial, antifungal and cytotoxic activities. It is likely that the biological

Acknowledgment

This work was supported by the Ministry of Education and Science of the Republic of Serbia (Grant OI 172055 and III41025). We thank the Slovenian Research Agency (ARRS) thrugh program P-0175 for financial support and EN-FIST Centre of Excellence, Dunajska 156, 1000 Ljubljana, Slovenia, for using SuperNova diffractometer. The following organizations are thanked for financial support: the Ministerio de Ciencia e Innovación (MICINN, project number CTQ2011-25086/BQU), and the DIUE of the

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