Design and synthesis of two new thiosemicarbazide based Schiff base metal complexes of nickel (II): DNA binding study and cytotoxicity profile analysis

doi:10.1016/j.ica.2024.122337

Inorganica Chimica Acta

Volume 574, 1 January 2025, 122337

https://doi.org/10.1016/j.ica.2024.122337 Get rights and content

Highlights

•
Two nickel(II) complexes with substituted 4-methyl 3-thiosemicarbazide Schiff base ligands were studied.
•
Both the nickel (II) complexes were mononuclear.
•
Both the complexes show interaction with CT-DNA.
•
Both the complexes are active against MDA-MB-231 and A375 cancer cell lines.
•
All the results indicate good anti cancer activity of both the complexes.

Abstract

Two new nickel (II) substituted thiosemicarbazone Schiff base complexes [Ni(meph)₂] (1) [where H₂meph = (2E)-N-methyl-2-[1-(pyridin-2-yl)ethylidene]hydrazine-1-carbothioamide] and [Ni(hmm)₂](NO₃)₂·2H₂O (2) [where H₂hmm = (2E)-2-[(2-hydroxyphenyl)methylidene]-N-methylhydrazine-1-carbothioamide] have been designed and synthesized by the condensation of 4-methyl-3-thiosemicarbazide with 2-acetylpyridine and salicylaldehyde respectively. Both the metal complexes 1 and 2 are characterized using different available spectroscopic techniques like FT-IR, UV–Vis spectroscopy, elemental analysis, and single crystal X-ray structure analysis. X-ray crystal structure analysis reveal that complex 1 and 2 are octahedral Ni(II) complexes. The calf-thymus CT-DNA-binding property of 1 and 2 has been evaluated by employing UV–Vis and fluorescence spectral titration. All the results show that CT-DNA binds with both nickel(II) complexes 1 and 2. In vitro cytotoxicity activity of complexes 1 and 2 toward A375 and MDA-MB-231 was evaluated using MTT assay and other methods which confirm that both complexes 1 and 2 behave as promising anti-cancer agents.

Graphical abstract

Introduction

In the recent years the interests of the coordination chemists have been shifted from the structural diversity to the functional diversity of synthesized compounds. Therefore, rational synthesis of the ligands as well as the coordination compounds along with the enhanced strategies to produce such molecules are required to meet the need of materials in a variety of fields like environment, renewable energy, chemical biology etc [1]. Sometimes such compounds are lacking in their pharmaco-kinetic and pharmaco-dynamic properties and therefore are not considered as drug candidates still they are important in the field of medicinal chemistry [2]. These small molecules may act as ‘chemical probes’ [3] to study the mechanism in biological systems which are an important step in drug discovery. The requirement for a small molecule to act as an efficient chemical probe is its selectivity to bind to a molecular target [4]. These molecular targets may be a cell surface receptor, an enzyme, ion channel, and transporter or may be nucleic acid. In this respect DNA and proteins are considered as potential target molecules which would control the action of the drug molecules by means of molecular imaging [5]. Thus, synthesis of metal complexes and to study their interaction with DNA or protein molecules has become an interesting field of research [6]. Proteins have the high affinity to bind either endogenously or extraneously with the small drug-like molecules and thereafter by studying the structural changes and conformational signalling of the target protein is a way for rational drugs designing [7]. On the other hand, the DNA and metal-complexes can interact in a diverse binding mode which finds its application in the field of anti-cancer therapeutics [8].

Recent study of metal(II) complexes with thiosemicarbazone-derived ligands have proved their ability as effective antiviral [9], antimicrobial [10], anti-inflammatory [11], antimalarial [12], antileukemic [13], antidiabetic [14] and anticancer [15] agents. Antioxidant activities as well as DNA-binding activity of such type of compounds are also investigated extensively [16], [17]. These thiosemicarbazone metal(II) complexes are also found to be very effective to induce apoptosis in the cancerous cell lines [18]. Some of the copper(II) and nickel(II) complexes with substituted thiosemicarbazone ligands were capable to exhibit in vitro anticancer activity against cancer cell line by inducing apoptosis [19], [14]. In recent time, researchers are interested to synthesize such metal complexes not only because of their mode of action in different fields but also because of a wide variety of their chemical structures [16]. Thiosemicarbazones are very interesting ligands having sulphur donor atoms into it which can form heteroatomic rings while making complex with transition metal ions and can manipulate the activity of these complex compounds [20]. Usually these transition metal complexes containing thiosemicarbazone ligands are found to possess more effective pharmacological properties than the ligand itself [21] and therefore their properties can be improved and customized by chelation with transition metal ions [22]. A great amount of attention has been committed to study the “Structure Activity Relationships” (SARs) of metal thiosemicarbazone complexes [23]. Substituted thiosemicarbazones are very much interesting in this regard because, variation of substituents may provide variation in the mode of biological activity [24] and also additional specificity to inhibit the growth of human and animal tumours, fungi or bacteria [25]. In our previous paper we reported biological activity of two such substituted thiosemicarbazone copper(II) complexes. In some of our previous papers [26] we described the synthesis of two different thiosemicarbazone ligands derived from 2- acetylpyridine and 4-methyl or 4-ethyl-3-thiosemicarbazides and their corresponding thiocyanato-bridged Cu(II) complexes and DNA/albumin binding, biological profile analysis, and molecular docking study have been studied for the complexes.

In this paper, two new ligands [H₂meph = (2E)-N-methyl-2-[1-(pyridin-2- yl)ethylidene]hydrazine-1-carbothioamide]and [H₂hmm = (2E)-2-[(2-hydroxyphenyl)methylidene]-N-methylhydrazine-1-carbothioamide] and their nickel(II) complexes [Ni(meph)₂] (1) and [Ni(hmm)₂](NO₃)₂·2H₂O (2) were synthesized and characterized by different physico-chemical techniques, single crystal X-ray diffraction (XRD) analysis. The binding with CT-DNA was evaluated by UV–Vis and fluorescence titrations technique. Moreover, both complexes 1 and 2 were examined for anti-cancer activity on A375 (malignant melanoma) and MDA-MB-231 (human breast adenocarcinoma) cell lines by in vitro MTT assay. The results show that both the complexes are effective as anti-cancer agents (See Scheme 1A and Scheme 1B).

Access through your organization

Check access to the full text by signing in through your organization.

Access through your organization

Section snippets

Materials

All materials were of reagent grade. Ni(NO₃)₂·6H₂O, 4-methyl 3-thisemicarbazide (Sigma Aldrich), Salicylaldehyde (Sigma Aldrich), 2-acetylepyridine (E-Merck) were used as received.

Physical measurements

Fourier Transform Infrared spectra (4000–400 cm⁻¹) of metal complexes were recorded on a Perkin-Elmer SPECTRUM - 2 FT-IR spectrophotometer in solid KBr matrices. Electronic spectra of complexes 1 and 2 were recorded at 300 K on a Perkin-Elmer λ-35 UV-vis spectrophotometer in DMSO medium using 1 cm path length. C, H, N

Infrared spectral study

Fig. S3A and B represent FT-IR spectra of complexes 1 and 2 show characteristic azomethine stretching vibrations at 1606 cm⁻¹ and 1592 cm⁻¹ respectively [39]. Moderate sharp peaks at 3336 cm⁻¹ and 3448 cm⁻¹, for the complexes 1 and 2, are due to the presence of ν(O

H) group in both complexes [39], [40]. Formation of M

N bond gives the peaks at 576 cm⁻¹ and 565 cm⁻¹ for complexes 1 and 2 respectively. Peaks at 805 cm⁻¹ and 821 cm⁻¹ for complexes 1 and 2 can be correlated to sulphur coordination to

Conclusion

The present work focuses on the design, synthesis and X-ray single structure analysis of two new nickel (II) substituted thiosemicarbazone Schiff base metal complexes. Both the complexes 1 and 2 are mononuclear in nature. The significant binding capability of 1 and 2 with CT-DNA proves both the complexes bind with CT-DNA moderately. In vitro cytotoxic activity of complexes 1 and 2 against human melanoma cell line (A375) and human breast carcinoma cell lines (MDA-MB-231) has been evaluated with

CRediT authorship contribution statement

Manas Chowdhury: Conceptualization, Methodology. Niladri Biswas: Methodology, Writing – original draft. Sandeepta Saha: Methodology, Visualization, Investigation. Barun Kumar Biswas: Methodology. Ashikur Rahaman: Investigation. Deba Prasad Mandal: Investigation, Writing – original draft. Shamee Bhattacharjee: Investigation, Writing – original draft. Corrado Rizzoli: Software, Supervision. Ruma Roy Choudhury: Writing – original draft. Chirantan Roy Choudhury: Writing – review & editing,

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

N. Biswas acknowledges CSIR, New Delhi, Govt. of India, for awarding junior research fellowship (Project No: 01/2537/11- EMR - II). M. Chowdhury acknowledges UGC, New Delhi, Government of India, for awarding Senior Research Fellowship (sr. no. 2121410140, ref. no. 21/12/2014 (II) EU-V). C. Roy Choudhury acknowledges DST- FIST (Project No. SR/FST/CSI-246/2012) New Delhi, Govt. of India for instrumental support under capital heads.

Research data for this article

Cambridge Crystallographic Data Center

Crystallographic data

Data associated with the article:

CCDC 2342810: Experimental Crystal Structure Determination

CCDC 2342809: Experimental Crystal Structure Determination

Further information on research data

References (60)

E.J. Anthony et al.
Chem. Sci.
(2020)
A. Frei et al.
Chem. Sci.
(2020)
V.M. Miranda
Rev. Inorg. Chem.
(2022)
S.V. Frye
Nat. Chem. Biol.
(2010)
F. Bisceglie et al.
J. Inorg. Biol. Chem.
(2014)
P.P. Netalkar et al.
Polyhedron
(2015)
K. Kumar et al.
Eur. J. Med. Chem.
(2014)
E. Pahontu et al.
J. Cell. Mol. Med.
(2015)
R. Yanardag et al.
Eur. J. Med. Chem.
(2009)
B.-D. Wang et al.
J. Organomet. Chem.
(2009)
D.-C. Ilies et al.
Polyhedron
(2015)
M.A. Bhat et al.
Bioorg. Med. Chem. Lett.
(2015)

S. Adsule et al.

J. Med. Chem.

(2006)

D.S. Kalinowski et al.

J. Med. Chem.

(2007)

Cited by (4)

A combined experimental and theoretical study on synthesis, characterization and anti-cancer activities of oxidovanadium-hydrazone complexes containing VO3+, V2O34+ and V2O33+ motifs
2026, Journal of Molecular Structure
(E)-2‑hydroxy-N'-(1-(2‑hydroxy-5-methylphenyl)ethylidene)benzohydrazide (H₃L) on reaction with equimolar amount of bis-2,4-pentane-dionatooxidovanadium(IV) [V^IVO(acac)₂] under refluxing condition in methanol, followed by slow evaporation respectively at 298 K and 283 K afforded complexes [V^VO(HL)(OCH₃)] (1) and [V^VO(HL)(OCH₃)]₂ (2) in excellent yields. However, on replacing methanol by CH₂Cl₂, the above reaction mixture yielded a different complex namely [V^V₂O₃(HL²)₂] (3) in good yield. Both complexes 1 and 2 quantitatively transformed to complex 3 on dissolution in non-hydroxylic solvents (e.g., CH₂Cl₂, CHCl₃, CH₃CN, C₆H₆) followed by slow evaporation at room temperature for 2 days. The formation of complexes 1–3 and the conversion of complexes 1 and 2 to complex 3 are supported by DFT study. Complexes were characterized by elemental analyses, IR, ¹H NMR, ⁵¹V NMR, Uv-vis spectroscopy and mass spectrometry. The distorted square pyramidal geometry for the metal in both 1 and 3 complexes has been established by single crystal X-ray studies. Complexes 1–3 are electro-active displaying one electron reduction peak near +0.20 V vs. Ag/AgCl in CH₂Cl₂ solution. Upon one-electron reduction of complex 3 (selectively at one V-centre) at +0.10 V, a mixed-valence complex (NBuⁿ₄)⁺[(HL)V^IVO-(μ-O)-OV^V(HL)]^- (4) was obtained, which showed valence delocalization at 298 K and localization at 77 K. During delocalization of odd electron, the twist-angular configuration of 3 changes to anti-angular configuration in 4 which is supported by DFT study. Complexes 1–3 exhibited potential anti-cancer activity on SiHa cervical cancer cell-line through apoptosis with IC₅₀ values of 67.6 ± 7.8, 43.8 ± 3.6, 14.9 ± 4.0 μM respectively. Docking studies have been carried out for theoretical interpretation of experimental results.
Investigating the binding properties of DNA/BSA with novel indole carboxylic acid complexes (M = Ni (II), Cd (II)) – A comparative analysis
2026, Inorganica Chimica Acta
Two novel complexes {[Ni(AIH)₂(H₂O)₂]·2(CH₃CH₂OH)}_n (1) and {[Cd(AIH)₂]·(CH₃CH₂OH)·2(H₂O)}_n (2), (AIH = 7-Azaindole-3-carboxylic acid), were determined by a single-crystal diffractometer, infrared spectra, elemental analysis, nuclear magnetic resonance and thermogravimetric analysis. Determination of the molecular structures of complexes by single-crystal X-ray diffraction studies revealed a slightly distorted octahedral geometry for 1 and a pentagonal-bipyramidal geometry for 2. These complexes show 2D and 3D networks with relatively large channels filled with solvent molecules. The lipophilic properties of both complexes were assessed by measuring their log P, which are 0.17 and 0.21, indicating favorable lipophilicity. The interactions between complexes 1 and 2 with bovine serum albumin (BSA) and calf thymus DNA (CT-DNA) were examined using various techniques, such as ultraviolet-visible spectroscopy (UV–vis), fluorescence spectroscopy (FS), circular dichroism spectroscopy (CD), molecular docking and viscosity measurements. The binding constants of BSA for complexes 1 and 2 were determined to be 2.03 × 10⁶ and 1.45 × 10⁴ L·mol⁻¹, respectively. These complexes exhibit static quenching mechanisms and show a higher affinity than the ligand, as evidenced by significant hyperchromism. Both complexes were associated with CT-DNA via intercalation, exhibiting binding constants (K_sv) of 5.56 × 10³ and 4.74 × 10³ L·mol⁻¹, respectively. These complexes exhibit higher affinity than the ligand (3.40 × 10³ L·mol⁻¹). Temperature-dependent studies on the interactions between the complexes and BSA reveal thermodynamic parameters (ΔG, ΔH and ΔS) with negative values. These findings demonstrate that the binding interactions between complexes 1 and 2 and BSA are thermodynamically spontaneous and predominantly governed by hydrogen bonding and van der Waals forces. The aforementioned studies demonstrate that complexes 1 and 2 exhibit stronger binding affinity for biomolecules than free ligands, owing to synergistic interactions between the metal center and ligands. This highlights complexes 1 and 2 significant importance in the fields of bioinorganic chemistry and medicinal chemistry.
Copper(II) binuclear complexes with 3-aminopyridine-2-carboxaldehyde N(4)-methylthiosemicarbazone: Synthesis, crystal structure, biological evaluation
2025, Journal of Molecular Structure
Platinum drugs have achieved good results in the treatment of malignant tumors. However, severe neutropenia caused by platinum drugs would lead to pathogenic infections. We proposed a new Copper(II) metal complex to effectively inhibit tumor growth and avoid unexpected bacterial infection. This paper reported the synthesis, structural elucidation, and biological evaluation of the Copper(II) binuclear complexes. 3-aminopyridine-2-carbaldehyde N(4)-methylthiosemicarbazone (HL) was used as a ligand for the synthesis of new copper(II) complexe, [CuLCl]₂ (1). Single crystal X-ray diffraction, ¹H NMR titration, and FT-IR XRD were performed to identify the molecular structure of 1. Results demonstrated that 1 contained one binuclear [CuLCl]₂ unit, where a five-coordinated Cu(II) ion adopts a distorted square-pyramidal geometry with an N₂S₂Cl coordination environment. The free radical scavenging ability assay, agar punch method, MTT assay, and tumor transplantation model in mice were performed to evaluate the pharmacological action of 1. Results showed that 1 had significant antibacterial and radical scavenging activity. The mechanism study showed that 1 could destroy bacterial cell membranes and lead to bacterial death. At the same time, 1 significantly inhibited the proliferation of hepatocellular carcinoma cells HepG2, and evidently inhibited H22 xenograft tumor growth in mice (10 mg/kg; inhibitory rate = 51.11 %). Network pharmacology analysis suggested that the anti-tumor mechanism of 1 was that 1 targeted CCNB1 and AURKAB to regulate the tumor cell cycle. This study can provide a research basis for the development of anti-tumor drugs and provide a new strategy for the clinical treatment of tumors.
Green Synthesis of Nanoscale Mixed-Ligand Complexes: DNA Interaction, Biomedical Applications, and Computational Studies
2025, Applied Organometallic Chemistry

View full text

Research paperDesign and synthesis of two new thiosemicarbazide based Schiff base metal complexes of nickel (II): DNA binding study and cytotoxicity profile analysis

Highlights

Abstract

Graphical abstract

Introduction

Access through your organization

Section snippets

Materials

Physical measurements

Infrared spectral study

Conclusion

CRediT authorship contribution statement

Declaration of competing interest

Acknowledgements

Research data for this article

Chem. Sci.

Chem. Sci.

Rev. Inorg. Chem.

Nat. Chem. Biol.

J. Inorg. Biol. Chem.

Polyhedron

Eur. J. Med. Chem.

J. Cell. Mol. Med.

Eur. J. Med. Chem.

J. Organomet. Chem.

Polyhedron

Bioorg. Med. Chem. Lett.

Metallomics

Polyhedron

J. Inorg. Biochem.

Metallomics

Eur. J. Med. Chem.

New J. Chem.

New J. Chem.

New J. Chem.

Dalton Trans.

Coord. Chem. Rev.

Cardiovasc. Imaging

New J. Chem.

Nat. Rev. Drug Discov.

Bentham Science Publisher

J. Photochem. Photobiol.

Nat. Chem.

Antiviral Res.

Eur. J. Med. Chem.

Chem. Commun.

J. Med. Chem.

J. Med. Chem.

Research paper
Design and synthesis of two new thiosemicarbazide based Schiff base metal complexes of nickel (II): DNA binding study and cytotoxicity profile analysis