Pd(II) complexes bearing chromone based Schiff bases: Synthesis, characterisation and biological activity studies

P. Kavitha; K. Laxma Reddy

doi:10.1016/j.arabjc.2013.06.018

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Original article

9 (

); 640-648

doi:

10.1016/j.arabjc.2013.06.018

Pd(II) complexes bearing chromone based Schiff bases: Synthesis, characterisation and biological activity studies

P. Kavitha, K. Laxma Reddy^⁎

Department of Chemistry, National Institute of Technology, Warangal 506 004, India

⁎Corresponding author. Tel.: +91 870 2462663; fax: +91 870 2459547. laxmareddychem12@gmail.com (K. Laxma Reddy)

Received: 2013-3-4, Accepted: 2013-6-17, Published: 2013-09-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Pd(II) complexes of 3-formyl chromone Schiff bases such as 3-((2-hydroxyphenylimino) methyl)-4H-chromen-4-one (HL₁), 2-((4-oxo-4H-chromen-3-yl)methylneamino)benzoic acid (HL₂), 3-((3-hydroxypyridin-2-ylimino)methyl)-4H-chromen-4-one (HL₃), 3-((2-mercaptophenylimino) methyl)-4H-chromen-4-one (HL₄) and 3-((pyridine-2-ylimino)methyl)-4H-chromen-4-one (L₅) have been synthesised and characterised by elemental analysis, molar conductivity, IR, electronic, magnetic, TG–DTA, powder XRD and fluorescence spectral data. From the analytical, electronic and magnetic data square-planar geometry has been proposed for all the Pd(II) complexes. Powder XRD studies indicate the crystalline state of the Pd(II) complexes. The antimicrobial activity of Pd(II) complexes was performed against two Gram(−ve), two Gram(+ve) and fungal microorganisms and the results indicate that, complexes show better microbial inhibition activity than the ligands. Pd(II) complex of HL₁ displayed comparable antioxidant activity with reference to the standard drug (BHT). Agarose gel electrophoresis assay demonstrates the ability of complexes to cleave the pUC19 plasmid DNA. The cytotoxicity was tested by the MTT assay. The results indicate that the complexes exert cytotoxic effects against tested cell lines but their cytotoxicity is less than that of cisplatin.

Keywords

Antioxidant

Cytotoxicity

DNA cleavage

Formyl chromone

Palladium(II)

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1 Introduction

Formyl chromone Schiff bases have been the centre of attraction for many workers in the current research due to their miscellaneous activities. Chromones are naturally occurring compounds which are able to cause cytotoxic effect in various types of cells. They are widely known to have anticancer, antioxidant, antiproliferative, antiHIV, antiinflammatory, and many other activities (Martens and Mithofer, 2005; Di Braccio et al., 2003; Middleton et al., 2000 ). Since the last decade, metal coordination chemistry has been one of the most efficient strategies in the design of drugs (Jones and Thornbak, 2007). Many literature reports revealed that chromone and its derivatives are able to form stable and coloured complexes with various metal ions (Anitha et al., 2012; Li and Yang, 2010). According to literature reports, metal complexes of the chromone moiety possess various biological activities in some cases comparable with cisplatin (which is an effective anticancer drug) (Grazul and Budzisz, 2009) and some metal complexes which are connected with reactions generating free radicals, may in some cases obtain additional antioxidant ability (Kostyuk et al., 2001; Grazul et al., 2012). These metal complexes are also used in various fields (Nijhawan and Kakkar, 1998).

A large number of platinum and palladium complexes containing amine based ligands have become the subject of intensive research, since they are structurally related to cisplatin. The success of cisplatin and other Pt(II) complexes in the treatment of ovarian, testicular, neck and head, oesophageal and non-small cell lung cancers (Todd and Lippard, 2009; Eastman, 1999; Montana and Batalla, 2009; Abu-Surrah and Kettunen, 2006; Łakomska, 2009 ) and similar properties of Pt(II) and its congener Pd(II), have led to a large effort in the search to find Pd(II) antitumour drugs that are effective against Pt(II) resistant therapies and that have fewer side effects (Garoufis et al., 2009; Abu-Surrah et al., 2008; Gao et al., 2009; Štarha et al., 2009 ). The main target of chemotherapy is the destruction of tumour cells without any undue influence on proper cells. Compared to palladium and platinum complexes, palladium complexes are hydrolyzed 10⁵ times faster than their corresponding platinum analogues, which could lead to the hydrolysis of Pd(II) complexes before they reach their target DNA (Polyanskaya et al., 2010). Pd(II) complexes also posses antimicrobial and antioxidant activity etc. (Spera et al., 2011; Ramachandran et al., 2012). This has provoked interest in the design of Pd(II) complexes.

As part of our on-going research work on the synthesis of metal complexes with Schiff bases derived from formyl chromone and aromatic amines i.e. 3-((2hydroxyphenylimino) methyl)-4H-chromen-4-one (HL₁), 2-((4-oxo-4H-chromen-3-yl)methylneamino)benzoic acid (HL₂), 3-((3-hydroxypyridin-2-ylimino)methyl)-4H-chromen-4-one (HL₃), 3-((2-mercaptophenylimino) methyl)-4H-chromen-4-one (HL₄) and 3-((pyridine-2-ylimino)methyl)-4H-chromen-4-one (L₅) (Kavitha and Laxma Reddy, 2016; Kavitha et al., 2013a,b ), we present here the preparation, characterisation and evolution of biological activities (antimicrobial, antioxidant, cytotoxicity and DNA cleavage) of Pd(II) complexes with the 3-formyl chromone Schiff base ligands (HL₁, HL₂, HL₃, HL₄ and L₅).

2 Experimental

2.1

2.1 Reagents and equipments

All chemicals and solvents used were of AR grade. Palladium dichloride was obtained from Jhonson Matthew Chemicals (England).

The UV–Vis spectra of the ligands and their metal complexes were recorded on an Analytikzena Specord 205 UV–Vis spectrophotometer. Molar conductance of the complexes was measured in DMF at 1 × 10⁻³ M using a Digisun conductivity meter. Elemental analysis (C, H, and N) was performed using Perkin Elmer CHN analyser. The chloride ion was estimated by the Volhard’s method (Vogel, 1961). The IR spectra (4000–400 cm⁻¹) in KBr discs were recorded on TENSOR 2 spectrophotometer. Thermal studies of the complexes were carried out on a Perkin Elmer diamond TGA instrument at a heating rate of 10 °C and a nitrogen flow rate of 20 mL/min. The magnetic susceptibilities of Pd(II) complexes were measured with a Sherwood scientific balance. Fluorescence spectra were recorded using Perkin Elmer LS 55 fluorescence spectrometer. The X-ray powder diffraction analysis was carried out by using Xpert-Pro X-ray diffractometer using Cu-Kα (1.5360 Å) radiation.

2.2

2.2 Synthesis of ligands

Schiff base ligands HL₁, HL₂, HL₃, HL₄ and L₅ (Fig. 1) were synthesised and characterised according to the literature (Sigg et al., 1982; Khan et al., 2010; Kavitha et al., 2012, 2013b; Kavitha and Laxma Reddy, 2016).

2.3

2.3 Synthesis of Pd(II) complexes

All the palladium(II) complexes were prepared using the general procedure as given below. PdCl₂ solution in 0.1 M HCl (1 mM) was taken and treated with an equal volume of water. The hot methanolic ligand solution (2 mM) was added drop wise to the hot metal salt solution. The reaction mixture was stirred at room temperature for 30 min. The coloured complex thus separated out was filtered, washed several times with hot water and methanol until the washings were free from excess ligand and palladium chloride and dried in vacuo.

2.4

2.4 Pharmacology studies

2.4.1

2.4.1 Antimicrobial activity

In vitro antimicrobial activity of the Pd(II) complexes was evaluated against Proteus vulgaris, Klebsiella pnuemoniae as gram-negative, Staphylococcus aureus, Bacillus subtili as gram-positive bacteria cultures where as Candida albicans fungi culture using antibiotics kanamycin and clotrimazole are the standards. The disc diffusion method was adopted for activity measurements. Standard inoculums, 1–2 × 10⁷ cfu/mL 0.5 Mc Farland standards (Stemper and Matsen, 1970) were introduced onto the surface of the sterile nutrient agar plate and evenly spread by using a sterile glass spreader. Sterile antibiotic discs (6 mm in diameter, prepared using Whatmann No. 1 paper) were placed over the nutrient agar medium. Each disc was spread by 100 μg of the compounds (initially dissolved in DMSO). The plates were incubated with bacterial cultures for 24 h at 37 °C and fungal cultures at 25 °C for 48 h. The activity of the compounds was determined by measuring the diameter of inhibition zone in ‘millimetres’ and compared with standard antibiotics. DMSO (which has no activity) and standard antibiotics were used as negative and positive controls for antimicrobial activity studies. The activity results are calculated as a mean of triplicates.

Minimum inhibitory concentrations (MIC) of the complexes which showed antimicrobial activity were determined using the literature method (Shankar et al., 2009). All the compounds diluted within the range of 100–10 μg/mL were mixed in nutrient broth and 0.1 mL of active inoculums was added to each tube. The tubes were incubated aerobically at 37 °C for bacteria and 25 °C for fungi for 24 h. The lowest concentration of the compound that completely inhibited bacterial growth (no turbidity) in comparison to control was regarded as MIC.

2.4.2

2.4.2 Free radical scavenging activity

The antioxidant activity of Pd(II) complexes was evaluated in DPPH free radical scavenging method.

Test samples were applied on a TLC plate as a spot using mobile phase methanol:acetonitrile (7:1). It was allowed to develop the chromatogram for 30 min. After the completion of the chromatogram, the plate was sprayed with DPPH (0.2% w/v). The colour change (yellow spot on purple background on TLC plate) is an indication of the presence of antioxidant activity.

2.4.2.1

2.4.2.1 Quantitative analysis

0.004% solution of the DPPH radical in methanol was prepared, and 3 mL of this solution was added to 1 mL of the compounds (stock solution is 10 mg/10 mL). The mixture was shaken vigorously and allowed to stand at room temperature for 30 min. Then, the absorbance was measured at 517 nm using a spectrophotometer. DPPH solution was used as the control without the test compounds, whereas methanol was used as the blank. Lowering of the absorbance of the test compounds indicates higher free radical scavenging activity. BHT is used as the standard. The capability to scavenge the DPPH radical was calculated using the following equation: $Scavenging activity (%) = [\frac{(A_{0} - A_{i})}{A_{0}}] \times 100$ where A₀ is the absorbance of the control solution, and A_i is the absorbance in the presence of sample solutions or standards for positive control. IC₅₀ values were calculated, which exhibited significant activity.

2.4.3

2.4.3 Cytotoxicity

2.4.3.1

2.4.3.1 Solutions

The complexes were dissolved in DMSO at a concentration of 5 mg/100 mL as stock solution, and diluted in a culture medium at concentrations of 1, 10 and 100 μg/mL as working solution.

2.4.3.2

2.4.3.2 Cell culture and drug treatment

Raw 264.7 cell line (murine macrophage cell line), MCF-7 (human breast carcinoma cell line) and COLO 205 (human colon carcinoma cell line) were obtained from NCCS Pune. Cell lines were maintained in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, amphotericin (3 μg/mL), gentamycin (400 μg/mL), streptomycin (250 μg/mL) and penicillin (250 Units/mL) in a carbon dioxide incubator at 5% CO₂. About 700 cells per well were seeded in 96 well plates using a culture medium. The cell viability was tested using trypan blue dye with the help of a haemocytometer and 95% of the viability was confirmed. After 24 h, the new medium with compounds in the concentration of 1, 10 and 100 μg /mL was added at respective wells and kept in incubation for 48 h. After incubation, MTT assay was performed. Later than, 48 h of the drug treatment, the medium was changed again for all groups and 10 μL of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) (5 mg/mL stock solution) was added and the plates were incubated for an additional 4 h. The medium was discarded and formazan blue, which was formed in the cells, was dissolved in 50 μL of DMSO. The optical density was measured at 570 nm. The percentage toxicity was calculated by using the following formula (Sathiyaraj et al., 2012). $% Toxicity = 1 - (treated cells / untreated cells) \times 100$ IC₅₀ of compounds were calculated using Graphpad PRISM software tool.

2.4.4

2.4.4 DNA cleavage activity

Agarose gel electrophoresis was used to study the DNA cleavage activity of the Pd(II) complexes. pUC19 plasmid was cultured, isolated and used as DNA for the experiment. Test samples (1 mg/mL) were prepared in DMF. 25 μg of the test samples were added to the isolated plasmid and incubated for 2 h at 37 °C. After incubation, 30 μL of plasmid DNA sample mixed with bromophenol blue dye was loaded into the electrophoresis chamber wells along with control (plasmid DNA in DMF without test sample) and standard DNA markers. Finally, it was loaded onto an agarose gel and electrophoresed at a constant voltage of 50 V for 30 min. After the run, gel was removed and stained with 10.01 μg/mL ethidium bromide and image was taken in Versadoc (Bio-Rad) imaging system. The results were compared with the standard DNA marker. The same procedure was followed in the presence of oxidising agent H₂O₂ (5 μL, 500 μM) also.

3 Results and discussion

All Pd(II) complexes are coloured, non-hygroscopic, stable in air, insoluble in water and many common organic solvents but soluble in DMF and DMSO. The analytical, physical and molar conductivity data of the metal complexes are given in Table 1. The analytical data revealed that the metal to ligand molar ratio is 1:1 for all the complexes except the complex 5. However, 1:2 M ratio was found in the case of complex 5. The molar conductance values of all Pd(II) complexes except the complex 5 in DMF at 1 × 10⁻³ M are found to be in the range 10–20 Ω⁻¹ cm² mol⁻¹ indicating their non-electrolytic nature. However, molar conductance value for the complex 5 in DMF is 128 Ω⁻¹ cm² mol⁻¹ which indicates its 1:2 electrolytic nature (Geary, 1971).

Table 1 Physical, analytical and molar conductivity data of Pd(II) complexes.

Complex no.	Molecular formula	Colour	%Yield	% Found (calcd.)					Molar conductivity (ohm⁻¹ mol⁻¹ cm²)
Complex no.	Molecular formula	Colour	%Yield	C	H	N	S	Cl	Molar conductivity (ohm⁻¹ mol⁻¹ cm²)
(1)	[Pd(L₁)Cl]	Orange red	71	47.45	2.21	3.10		8.85	11
(1)	[Pd(L₁)Cl]	Orange red	71	(47.30)	(2.46)	(3.44)		(8.74)
(2)	[Pd(L₂)Cl]	Yellow	65	47.55	2.19	3.18		8.01	20
(2)	[Pd(L₂)Cl]	Yellow	65	(47.01)	(2.30)	(3.22)		(8.18)
(3)	[Pd(L₃)Cl]	Dark red	90	43.47	2.28	6.79		8.98	15
(3)	[Pd(L₃)Cl]	Dark red	90	(44.23)	(2.21)	(6.88)		(8.72)
(4)	[Pd(L₄)Cl]	Brick red	82	45.59	2.09	3.15	7.68	8.38	13
(4)	[Pd(L₄)Cl]	Brick red	82	(45.50)	(2.37)	(3.31)	(7.58)	(8.41)
(5)	[Pd(L₅)₂]·Cl₂	Green	78	52.98	2.25	8.62		10.78	128
(5)	[Pd(L₅)₂]·Cl₂	Green	78	(53.14)	(2.95)	(8.26)		(10.48)

3.1

3.1 Electronic spectra

The absorption spectra of ligands and their Pd(II) complexes were recorded in DMF solution in the wavelength range of 200–1100 nm. The bands in the UV–visible spectra of all the complexes were assigned upon comparison with the spectra of their corresponding ligands (HL₁–L₅). The absorption spectrum of HL₃ and its Pd(II) complex is shown in Fig. 2. Free ligands showed the absorption bands between 25,000 to 27,000 cm⁻¹ and 31,000 to 34,000 cm⁻¹ and are assigned to n → π^∗ and π → π^∗ transitions, respectively. These bands are shifted to the lower energy region upon complexation with the metal ion. All Pd(II) complexes exhibit one band in the visible region at around 20,000 to 25,000 cm⁻¹ and are assigned to $^{1} A_{1 g} \to^{1} E_{g}$ transition characteristic of square-planar geometry (Al-Noaimi et al., 2012). All the palladium complexes are also found to be diamagnetic which also supports the square-planar geometry of the complexes.

Electronic spectra of (a) HL3, and (b) Pd(II) complex.

3.2

3.2 IR spectra

The infrared spectra provide important information about the skeleton of the complexes. The main stretching frequencies of the Pd(II) complexes are presented in Table 2. The υ(C⚌O) of carbonyl group of the ligands appear in the range of 1650–1620 cm⁻¹, while in their Pd(II) complexes the band is shifted to lower wavenumber by 6–40 cm⁻¹ (Wang et al., 2008). It shows that the oxygen of the carbonyl group takes part in coordination in all the complexes. The υ(C⚌N) of azomethine group of ligands show a band in the region of 1600–1550 cm⁻¹ and it is shifted to 16–39 cm⁻¹ in Pd(II) complexes towards lower wave number region, indicating that the nitrogen of azomethine group is involved in the coordination (Li and Yang, 2010). The bands at 3241 and 3246 cm⁻¹ are due to υ(OH) group of HL₁ and HL₃ ligands. It disappeared in their corresponding Pd(II) complexes, indicating the participation of oxygen atom of the OH group in coordination with deprotination. A band at 1365 cm⁻¹ in HL₂ ligand is due to the υ(C–O) of carboxylic group, in its complex it was shifted by 16 cm⁻¹ suggesting the oxygen atom of carboxylic group participated in the coordination (Olczak-Kobza and Mrozek, 2009). The SH stretching vibration, υ(SH), is not useful in ascertaining its coordination in the complexes, since it displayed very weak bands in HL₄ ligand spectra. However, the participation of the SH group in chelation is ascertained from the shift of the υ(C–S) by 59 cm⁻¹ to lower wavenumber region in the spectra of its corresponding Pd(II) complex (Mohamed et al., 2006). Further the confirmation of N, O and Cl in coordination is demonstrated by new bands in the range of 500–300 cm⁻¹ (Patel et al., 2012).

Table 2 Infrared spectral data and their assignments of ligands and their Pd(II) complexes.

Compound	υ(C⚌O) (γ pyrone)	υ(C⚌N)	υ(CO) (carboxylate)	υ(C–S)	υ(M–N)	υ(M–O)	υ(M–Cl)
HL₁	1643	1605
HL₂	1651	1605	1365
HL₃	1647	1591
HL₄	1622	1597		790
L₅	1654	1596
[Pd(L₁)Cl] (1)
	1637	1571			489	390	348
[Pd(L₂)Cl] (2)	1611	1566	1349		470	360	346
[Pd(L₃)Cl] (3)	1634	1575			490	375	332
[Pd(L₄)Cl] (4)	1614	1566		731	485	399	314
[Pd(L₅)₂]·Cl₂ (5)	1611	1575			458	357	–

3.3

3.3 Thermogravimetric analysis

The thermal decomposition studies of the Pd(II) complexes were carried out in nitrogen atmosphere in the temperature range of 30–1000 °C. The TG graphs of complexes 1 and 5 are given in Fig. 3. In the case of complex 1 there is no weight loss up to 185 °C. However, all other complexes (2–5) undergo first step decomposition with a weight loss of 7.58–16.55% (calcd. 8.18–15.72%) in between 30 and 284 °C due to the removal of chloride ions (lattice and coordinated). All the complexes (1–5) show the second decomposition step 61.94–66.89% (calcd. 61.10–66.21%) in the temperature range of 196–710 °C due to the decomposition of organic part of the complexes. The final amount of residue of all complexes is close to calculated mass of palladium oxide.

TG graphs of (a) [Pd(L1)Cl], and (b) [Pd(L5)2]·Cl2.

On the basis of the above studies (elemental, conductivity, electronic and infrared data) the following structure (Fig. 4) may be proposed for all the Pd(II) complexes.

Structures of Pd(II) complexes, (a) Complexes 1–4, and (b) Complex 5.

3.4

3.4 Fluorescence

The solid state emission spectra of Pd(II) complexes were studied at room temperature. The emission spectra of complexes 1–5 are illustrated in Fig. 5 and the excitation and emission data are listed in Table 3. All Pd(II) complexes exhibit weak fluorescence except complex 4 compared to their corresponding ligands when excited at the absorption wavelengths in the range of 307–453 nm. However formyl chromone Schiff base ligands are highly emissive excitation upon different wavelengths (Kavitha et al., 2013a). It was observed that the emission spectra of metal complexes that are originated may be from the formyl chromone moiety. The emission intensity of the complexes significantly decreases compared to that of the corresponding ligands, but the emission intensity of complex 4 is much higher than those of other four complexes. This enhancement in the emission intensity may be due to low-lying excited state orbital of complex 4 (Guney et al., 2010). Literature reports revealed that, blue/red shift of emission maxima was observed, when ligands are coordinated with the metal ions (Jin et al., 2012; Guney et al., 2011).

Fluorescence spectra of all Pd(II) complexes, (a) [Pd(L1)Cl] (b) [Pd(L2)Cl] (c) [Pd(L3)Cl] (d) [Pd(L4)Cl], and (e) [Pd(L5)2]·Cl2.

Table 3 Excitation and emission wavelengths of Pd(II) complexes.

Compound	Excitation wavelength (nm)	Emission wavelength (nm)
[Pd(L₁)Cl] (1)	453	551, 621sh, 747sh
[Pd(L₂)Cl] (2)	381	481(sh), 558
[Pd(L₃)Cl] (3)	451	549 sh, 618, 743sh
[Pd(L₄)Cl] (4)	307	469
[Pd(L₅)₂]·Cl₂ (5)	384	484, 526sh, 634sh

3.5

3.5 X-ray powder diffraction

Single crystals of the studied complexes could not be obtained, because the complexes are insoluble in most common organic solvents except DMF and DMSO. The X-ray powder diffraction patterns of the Pd(II) complexes were recorded over 2θ = 10–80°. The diffractograms of the complexes are displayed in Fig. 6. The diffraction data like angle (2θ), interplanar spacing (d), and relative intensity (%) have been summarized in Table 4. From the data, all Pd(II) complexes show sharp crystalline peaks except complex 2 and 4, indicating their crystalline nature. However complex 2 and 4 show amorphous nature. The XRD patterns of all complexes are very similar and suggest that the complexes have similar structure. The average crystallite sizes of the complexes d_xrd were calculated using the Sherrers formula (Warren, 1990). Complexes 1, 3 and 5 have a crystallite size of 41, 46 and 20 nm respectively, suggesting that the complexes are in a nano crystalline phase.

PXRD patterns of (a) [Pd(L2)Cl], and (b) [Pd(L5)2]·Cl2.

Table 4 PXRD spectral data of Pd(II) complexes.

Complexes	2θ	d	Relative intensity	Full width at half maximum
[Pd(L₁)Cl] (1)	28.83	3.094	100	0.205
[Pd(L₃)Cl] (3)	30.45	2.933	100	0.183
[Pd(L₅)₂]·Cl₂ (5)	46.44	1.953	100	0.438

3.6

3.6 Pharmacology

3.6.1

3.6.1 Antimicrobial activity

The minimum inhibitory concentration (MIC) values of Pd(II) complexes are given in Table 5. In vitro antimicrobial screening results (Table 5), Pd(II) complexes are potent than their corresponding ligands and compared to the antibiotics, moderately active against tested microorganisms. The activity of the ligands has enhanced on complexation, which can be explained on the basis of Tweedy’s chelation theory and Overtones concept (Bahaffi et al., 2012; Mahalakshmi and Rajavel, 2014).

Table 5 MIC values of antimicrobial activity of Pd(II) complexes.

Compound	Bacillus subtilis	Staphylococcus aureus	Proteus vulgaris	Klebsiella pneumoniae	Candida albicans
HL₁	–	–	–	–	–
HL₂	80	80	80	80	80
HL₃	–	–	–	–	–
HL₄	–	–	–	–	–
L₅	53	53	53	53	53
[Pd(L₁)Cl] (1)	50	60	55	75	60
[Pd(L₂)Cl] (2)	55	55	55	55	55
[Pd(L₃)Cl] (3)	–	–	–	–	–
[Pd(L₄)Cl] (4)	–	–	–	–	–
[Pd(L₅)₂]·Cl₂ (5)	80	80	–	–	–
Kanamycin	4	10	8	11	–
Clotrimazole	–	–	–	–	10

Among all the Pd(II) complexes, complex 2 showed better activity against all microorganisms. Complex 3 and 4 exhibit very low activity against all bacteria and fungi strains. Complex 5 is active against only B. subtili and S. aureus.

3.6.2

3.6.2 Free radical scavenging activity

The stable DPPH radical scavenging is a widely used method to evaluate antioxidant activities, in a relatively short time compared with other methods. The DPPH radical contains an odd electron responsible for absorbance at 517 nm. When the reaction between antioxidant molecules and DPPH radical results in the scavenging of the radical by hydrogen or electron donation, the antioxidants cause to a decrease of the absorbance of the DPPH radical. This is visually noticeable as a discoloration from purple to yellow. Hence, DPPH is usually used as a substrate to evaluate the activity of antioxidants (Ceyhan et al., 2011). IC₅₀ values of antioxidant activity of Pd(II) complexes were reported in Table 6. These results indicate that the complexes 1 and 3 have a noticeable activity compared to the remaining Pd(II) complexes. The complexes 2, 4 and 5 do not show antioxidant activity. Among all the complexes, complex 1 showed activity comparable to BHT (standard).

Table 6 IC₅₀ values of antioxidant activity of Pd(II) complexes.

Compound	IC₅₀ (μg/mL)
[Pd(L₁)Cl] (1)	0.90
[Pd(L₃)Cl] (3)	1.31
BHT	0.67

3.6.3

3.6.3 Cytotoxicity

The cytotoxicity of complexes 1–5 was tested on three cell lines, that is murine macrophage cell line Raw 264.7, human breast cancer cell line MCF-7 and human colon carcinoma cell line COLO 205. Cisplatin was used as a positive reference. The activity is expressed as the concentration of the complexes required to inhibit the cellular survival fraction to 50% (IC₅₀) after exposure to the compounds for 48 h. The results are presented in Table 7.

Table 7 IC₅₀(μg/mL) values of cytotoxicity of Pd(II) complexes.

Compound	Raw	MCF-7	COLO 205
[Pd(L₁)Cl] (1)	44.0	62.3	63.9
[Pd(L₂)Cl] (2)	76.0	60.1	63.1
[Pd(L₃)Cl] (3)	51.0	49.9	56.2
[Pd(L₄)Cl] (4)	102.4	72.2	59.9
[Pd(L₅)₂]·Cl₂ (5)	45.2	25.5	51.0
Cisplatin	1.2	1.7	5.6

As shown in Table 7, Pd(II) complexes are found to be much less active when compared to cisplatin against three cell lines. Among all complexes pyridine ring containing complexes i.e. complexes 3 and 5 are potent.

3.6.4

3.6.4 Cleavage of pUC19 DNA by Pd(II) complexes

The DNA cleavage reaction of Pd(II) complexes was monitored by agarose gel electrophoresis. When circular plasmid DNA is subject to electrophoresis, relatively fast migration will be observed for the intact supercoiled form (Form I). The slower-moving migration is the open circular form (Form II) which was generated from the supercoil when scission occurred on one of its strands, and a linear form (Form III) which was generated when both strands were cleaved and migrates between Form I and II (Seng et al., 2008). To investigate the mechanism of cleavage studies of Pd(II) complexes, DNA cleavage activity was observed in the presence and absence of H₂O₂ as an oxidant. The gel electrophoretic separation of pUC19 DNA after incubation with all Pd(II) complexes is depicted in Fig. 7a and b. From Fig. 7a, no DNA-cleavage was observed for the control in which the metal complex was absent (lane control). When the pUC19 DNA was treated with the complexes (lane 1–5), no bands were observed in the lane 1, 3 and 5 probably due to the complete degradation of DNA into small pieces. It is reasonably expected due to the hydrolytic cleavage (absence of any reducing or oxidising agents). In lanes 2 and 4 no difference was observed compared to the control band, which indicates the inactivity of complexes 2 and 4 respectively. In the presence of H₂O₂ (Fig. 7b) complex 4 showed complete DNA cleavage and complex 2 showed partial cleavage. In this case, oxidative DNA cleavage was observed, which may be due to the formation of hydroxyl radicals. Many literature reports revealed the mechanism of the DNA cleavage of the metal complexes in the presence of oxidant H₂O₂ (Arish and Sivasankaran Nair, 2011).

Gel electrophoresis graphs of Pd(II) complexes. (a) DNA cleavage studies in the absence of H2O2. Lane 1. DNA + Complex 1; Lane 2. DNA + Complex 2; Lane 3. DNA + Complex 3; Lane 4. DNA+Complex 4; Lane 5. DNA + Complex 5; Lane FeSO4. DNA + FeSO4; Lane control. DNA alone (without complexes). (b) DNA cleavage studies in the presence of H2O2. Lane 1. DNA + Complex 1 + H2O2; Lane 2. DNA + Complex 2 + H2O2; Lane 3. DNA + Complex 3 + H2O2; Lane 4. DNA + Complex 4 + H2O2; Lane 5. DNA + Complex 5 + H2O2; Lane control. DNA + H2O2.

4 Conclusions

A series of Pd(II) complexes with tridentate/bidentate Schiff base ligands derived from 3-formyl chromone and aromatic amines were synthesised. Complexes were characterised by physico analytical techniques. Electronic and magnetic data suggest the square-planar geometry for all Pd(II) complexes. Powder XRD data revealed the crystalline nature of the complexes. All complexes displayed solid state fluorescence at room temperature. Pd(II) complexes exhibit less to moderate antimicrobial activity. Complex 1 was considered as lead compounds worthy of further structural optimization and development as potential antioxidants. The successful DNA cleavage was observed for complexes 1, 3 and 5 without any additives. But in the case of complexes 2 and 4 effective DNA cleavage was observed in the presence of H₂O₂. The cytotoxicity results of the complexes are not satisfactory when compared to cisplatin (anticancer drug).

Acknowledgements

The authors wish to thank Dr. M.R.P. Reddy, CMET (Centre for the materials for electronic technologies), Hyderabad, for providing TG–DTA facility. The authors are thankful to the Department of Biochemistry, SV University, Tirupathi, for antioxidant activity study, Vimta Labs Ltd., Hyderabad for DNA cleavage studies and the PSG college of Pharmacy, Coimbatore, Tamilnadu for anticancer activity studies. One of the authors P. Kavitha thanks the Ministry of Human Resource Development for providing the fellowship.

References

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Martens S., Mithofer A., . Flavones and flavone synthases. Phytochemistry. 2005;66:2399-2407.
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Montana A.M., Batalla C., . The rational design of anticancer platinum complexes: the importance of the structure–activity relationship. Curr. Med. Chem.. 2009;16:2235-2260.
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Patel M.N., Dosi P.A., Bhatt B.S., . Interaction of palladium(II) coordination compounds with calf thymus DNA and their antibacterial activity. Inorg. Chem. Commun.. 2012;21:61-64.
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Introduction

Experimental

Reagents and equipments
Synthesis of ligands
Synthesis of Pd(II) complexes
Pharmacology studies

Results and discussion

Electronic spectra
IR spectra
Thermogravimetric analysis
Fluorescence
X-ray powder diffraction
Pharmacology

Conclusions

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[1] Abu-Surrah A.S., Kettunen M., . Platinum group antitumor chemistry: design and development of new anticancer drugs complementary to cisplatin. Curr. Med. Chem.. 2006;13:1337-1357.
[Google Scholar]

[2] Abu-Surrah A.S., Al-Sa’doni H.H., Abdalla M.Y., . Palladium-based chemotherapeutic agents: routes toward complexes with good antitumor activity. Cancer Ther.. 2008;6:1-10.
[Google Scholar]

[3] Al-Noaimi M., Abu-Surrah A.S., Tahtamouni L., . Palladium(II) complexes incorporating phenylazo arylmethine ancillary ligands: synthesis, spectral and antitumor activity. Arabian J. Chem 2012
[CrossRef] [Google Scholar]

[4] Anitha C., Sheela C.D., Tharmaraj P., Johnson Raj S., . Synthesis and characterization of VO(II), Co(II), Ni(II), Cu(II) and Zn(II) complexes of chromone based azo-linked Schiff base ligand. Spectrochim. Acta Part A Mol. Biomol. Spectrosc.. 2012;98:35-42.
[Google Scholar]

[5] Arish D., Sivasankaran Nair M., . Synthesis, spectroscopic, antimicrobial, DNA binding and cleavage studies of some metal complexes involving symmetrical bidentate N, N donor Schiff base ligand. Spectrochim. Acta Part A Mol. Biomol. Spectrosc.. 2011;82:191-199.
[Google Scholar]

[6] Bahaffi S.O., Abdel Aziz A.A., El-Naggar M.M., . Synthesis, spectral characterization, DNA binding ability and antibacterial screening of copper(II) complexes of symmetrical NOON tetradentate Schiff bases bearing different bridges. J. Mol. Struct.. 2012;1020:188-196.
[Google Scholar]

[7] Ceyhan G., Celik C., Urus S., Demirtas I., Elmastas M., Tumer M., . Antioxidant, electrochemical, thermal, antimicrobial and alkane oxidation properties of tridentate Schiff base ligands and their metal complexes. Spectrochim. Acta Part A Mol. Biomol. Spectrosc.. 2011;81:184-198.
[Google Scholar]

[8] Di Braccio M., Grossi G., Roma G., Marzano C., Baccichetti F., Simonato M., Bordin F., . Pyran derivatives: part XXI. Antiproliferative and cytotoxic properties of novel N-substituted 4-aminocoumarins, their benzo-fused derivatives, and some related 2-aminochromones. II Farmaco. 2003;58:1083-1097.
[Google Scholar]

[9] Eastman A., . Lippert B., ed. Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug. Weinheim, Germany: Wiley-VCH; 1999. p. :111-115.

[10] Gao E., Liu C., Zhu M., Lin H., Wu Q., Liu L., . Current development of Pd(II) complexes as potential antitumor agents. Anti-Cancer Agents Med. Chem.. 2009;9:356-368.
[Google Scholar]

[11] Garoufis A., Hadjikakou S.K., Hadjiliadis N., . Palladium coordination compounds as anti-viral, anti-fungal, anti-microbial and anti-tumor agents. Coord. Chem. Rev.. 2009;253:1384-1397.
[Google Scholar]

[12] Geary W.J., . The use of conductivity measurements in organic solvents for the characterisation of coordination compounds. Coord. Chem. Rev.. 1971;7:81-122.
[Google Scholar]

[13] Grazul M., Budzisz E., . Biological activity of metal ions complexes of chromones, coumarins and flavones. Coord. Chem. Rev.. 2009;253:2588-2598.
[Google Scholar]

[14] Grazul M., Kufelnicki A., Wozniczka M., Lorenz I.P., Mayer P., Jozwiak A., Czyz M., Budzisz E., . Synthesis, structure, electrochemical properties, cytotoxic effects and antioxidant activity of 5-amino-8-methyl-4H-benzopyran-4-one and its copper(II) complexes. Polyhedron. 2012;31:150-158.
[Google Scholar]

[15] Guney E., Yilmaz V.T., Buyukgungor O., . Neutral and cationic palladium(II) and platinum(II) complexes of 2,2′-dipyridylamine with saccharinate: syntheses, spectroscopic, structural, fluorescent and thermal studies. Inorg. Chim. Acta. 2010;363:2416-2424.
[Google Scholar]

[16] Guney E., Yilmaz V.T., Buyukgun O., . Palladium(II) and platinum(II) saccharinate complexes containing pyridine and 3-acetylpyridine: synthesis, crystal structures, fluorescence and thermal properties. Polyhedron. 2011;30:1968-1974.
[Google Scholar]

[17] Jin Q.H., Cui L.N., Li Z.F., Jiang Y.H., Wu M.H., Gao S., Zhang C.L., . Four mono-/bi-nuclear palladium(II) complexes of triphenylphosphine and heterocyclic-N/NS ligands: synthesis, structural characterization and luminescence properties. Polyhedron. 2012;31:472-477.
[Google Scholar]

[18] Jones C.J., Thornbak J.R., . Medicinal Applications of Coordination Chemistry. Cambridge: RSC Publishing; 2007.

[19] Kavitha P., Laxma Reddy K., . Synthesis, spectral characterisation, morphology, biological activity and DNA cleavage studies of metal complexes with chromone Schiff base. Arabian J. Chem.. 2016;9(4):596-605.
[Google Scholar]

[20] Kavitha P., Rama Chary M., Singavarapu B.V.V.A., Laxma Reddy K., . Synthesis, characterisation, biological activity and DNA cleavage studies of tri dentate Schiff bases and their Co(II) complexes. J. Saudi Chem. Soc 2013
[CrossRef] [Google Scholar]

[21] Kavitha P., Saritha M., Laxma Reddy K., . Synthesis, structural characterization, fluorescence, antimicrobial, antioxidant and DNA cleavage studies of Cu(II) complexes of formyl chromone Schiff bases. Spectrochim. Acta Part A Mol. Biomol. Spectrosc.. 2013;102:159-168.
[Google Scholar]

[22] Khan K.M., Ambreen N., Mughal U.R., Jalil S., Perveen S., Choudhary M.I., . 3-Formylchromones: potential antiinflammatory agents. Eur. J. Med. Chem.. 2010;45:4058-4064.
[Google Scholar]

[23] Kostyuk V.A., Potapovich A.I., Vladykovskaya E.N., Korkina L.G., Afanas’ev I.B., . Influence of metal ions on flavonoid protection against asbestos-induced cell injury. Arch. Biochem. Biophys.. 2001;385:129-137.
[Google Scholar]

[24] Łakomska I., . Molecular structure and antitumor activity of platinum(II) complexes containing purine analogs. Inorg. Chim. Acta. 2009;362:669-681.
[Google Scholar]

[25] Li Y., Yang Z., . DNA-binding properties and antioxidant activity of lanthanide complexes with the Schiff base derived from 3-carbaldehyde chromone and isonicotinyl hydrazine. J. Coord. Chem.. 2010;63:1960-1968.
[Google Scholar]

[26] Mahalakshmi N., Rajavel R., . Synthesis, spectroscopic, DNA cleavage and antibacterial activity of binuclear Schiff base complexes. Arabian J. Chem.. 2014;7(4):509-517.
[Google Scholar]

[27] Martens S., Mithofer A., . Flavones and flavone synthases. Phytochemistry. 2005;66:2399-2407.
[Google Scholar]

[28] Middleton E. Jr., Kandaswami C., Theoharides T.C., . The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease and cancer. Pharmacol. Rev.. 2000;52:673-751.
[Google Scholar]

[29] Mohamed G.G., Omar M.M., Hindy A.M., . Metal complexes of Schiff bases: preparation, characterization, and biological activity. Turk. J. Chem.. 2006;30:361-382.
[Google Scholar]

[30] Montana A.M., Batalla C., . The rational design of anticancer platinum complexes: the importance of the structure–activity relationship. Curr. Med. Chem.. 2009;16:2235-2260.
[Google Scholar]

[31] Nijhawan M., Kakkar L.R., . Use of 6-Chloro-3-hydroxy-7-methyl-2-(2′-thienyl)-4H-chromen-4-one in the trace determination of zirconium. Jpn. Soc. Anal. Chem.. 1998;14:625-628.
[Google Scholar]

[32] Olczak-Kobza M., Mrozek A., . Zinc(II) and cadmium(II) complexes with o-hydroxybenzoic acid or o-aminobenzoic acid and 2-methylimidazole. J. Therm. Anal. Calorim.. 2009;96:553-560.
[Google Scholar]

[33] Patel M.N., Dosi P.A., Bhatt B.S., . Interaction of palladium(II) coordination compounds with calf thymus DNA and their antibacterial activity. Inorg. Chem. Commun.. 2012;21:61-64.
[Google Scholar]

[34] Polyanskaya T.V., Kazhdan I., Michelle Motley D., Walmsley J.A., . Synthesis, characterization and cytotoxicity studies of palladium(II)–proflavine complexes. J. Inorg. Biochem.. 2010;104:1205-1213.
[Google Scholar]

[35] Ramachandran E., Senthil Raja D., Bhuvanesh N.S.P., Natarajan K., . Mixed ligand palladium(II) complexes of 6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 4N-substituted thiosemicarbazones with triphenylphosphine co-ligand: synthesis, crystal structure and biological properties. Dalton Trans.. 2012;41:13308-13323.
[Google Scholar]

[36] Sathiyaraj S., Butcher R.J., Jayabalakrishnan Ch., . Synthesis, characterization, DNA interaction and in vitro cytotoxicity activities of ruthenium(II) Schiff base complexes. J. Mol. Struct.. 2012;1030:95-103.
[Google Scholar]

[37] Seng H.L., Ong H.-K.A., Rahman R.N.Z.R.A., Yamin B.M., Tiekink E.R.T., Tan K.W., Maah M.J., Caracelli I., Ng C.H., . Factors affecting nucleolytic efficiency of some ternary metal complexes with DNA binding and recognition domains. Crystal and molecular structure of Zn(phen)(edda) J. Inorg. Biochem.. 2008;102:1997-2011.
[Google Scholar]

[38] Shankar K., Rohini R., Ravinder V., Reddy P., Ho Y.P., . Ru(II) complexes of N₄ and N₂O₂ macrocyclic Schiff base ligands: their antibacterial and antifungal studies. Spectrochim. Acta A. 2009;73:205-211.
[Google Scholar]

[39] Sigg I., Haas G., Winkler T., . The reaction of 3-formylchromone with ortho-substituted anilines. Preparation of a tetraaza [14]annulene. Helv. Chim. Acta. 1982;65:275-279.
[Google Scholar]

[40] Spera M.B.M., Quintao F.A., Ferraresi D.K.D., Lustri W.R., Magalhaes A., Formiga A.L.B., Corbi P.P., . Palladium(II) complex with S-allyl-l-cysteine: new solid-state NMR spectroscopic measurements, molecular modeling and antibacterial assays. Spectrochim. Acta Part A Mol. Biomol. Spectrosc.. 2011;78:313-318.
[Google Scholar]

[41] Štarha P., Trávníček Z., Popa I., . Synthesis, characterization and in vitro cytotoxicity of the first palladium(II) oxalato complexes involving adenine-based ligands. J. Inorg. Biochem.. 2009;103:978-988.
[Google Scholar]

[42] Stemper J.E., Matsen J.M., . Device for turbidity standardizing of cultures for antibiotic sensitivity testing. J. Appl. Microbiol.. 1970;19:1015-1016.
[Google Scholar]

[43] Todd R.C., Lippard S.J., . Inhibition of transcription by platinum antitumor compounds. Metallomics. 2009;1:280-291.
[Google Scholar]

[44] Vogel A.I., . A Text Book of Quantitative Analysis (third ed.). London, UK: Longman; 1961.

[45] Wang B.D., Yang Z.Y., Qin D.D., Chen Z.N., . Synthesis, characterization, cytotoxic activity and DNA-binding properties of the Ln(III) complexes with ethylenediiminobi(6-hydroxychromone-3-carbaldehyde) Schiff-base. J. Photochem. Photobiol., A. 2008;194:49-58.
[Google Scholar]

[46] Warren B.E., . X-ray Diffraction (second ed.). New York: Dover; 1990.

Pd(II) complexes bearing chromone based Schiff bases: Synthesis, characterisation and biological activity studies

Abstract

Keywords

Antioxidant

Cytotoxicity

DNA cleavage

Formyl chromone

Palladium(II)

1 Introduction

2 Experimental

2.1 Reagents and equipments

2.2 Synthesis of ligands

2.3 Synthesis of Pd(II) complexes

2.4 Pharmacology studies

2.4.1 Antimicrobial activity

2.4.2 Free radical scavenging activity

2.4.2.1 Quantitative analysis

2.4.3 Cytotoxicity

2.4.3.1 Solutions

2.4.3.2 Cell culture and drug treatment

2.4.4 DNA cleavage activity

3 Results and discussion

3.1 Electronic spectra

3.2 IR spectra

3.3 Thermogravimetric analysis

3.4 Fluorescence

3.5 X-ray powder diffraction

3.6 Pharmacology

3.6.1 Antimicrobial activity

3.6.2 Free radical scavenging activity

3.6.3 Cytotoxicity

3.6.4 Cleavage of pUC19 DNA by Pd(II) complexes

4 Conclusions

Acknowledgements

References

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