Cyclometalated rhodium(III) complexes bearing dithiocarbamate derivative: Synthesis, characterization, interaction with DNA and biological study

Accepted Manuscript Cyclometalated rhodium(III) complexes bearing dithiocarbamate derivative: synthesis, characterization, interaction with DNA and biological study Titas Mukherjee, Buddhadeb Sen, Animesh Patra, Snehasis Banerjee, Geeta Hundal, Pabitra Chattopadhyay PII: DOI: Reference:

S0277-5387(13)00787-0 http://dx.doi.org/10.1016/j.poly.2013.11.028 POLY 10441

To appear in:

Polyhedron

Received Date: Accepted Date:

31 August 2013 22 November 2013

Please cite this article as: T. Mukherjee, B. Sen, A. Patra, S. Banerjee, G. Hundal, P. Chattopadhyay, Cyclometalated rhodium(III) complexes bearing dithiocarbamate derivative: synthesis, characterization, interaction with DNA and biological study, Polyhedron (2013), doi: http://dx.doi.org/10.1016/j.poly.2013.11.028

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1

Cyclometalated rhodium(III) complexes bearing dithiocarbamate derivative: synthesis,

2

characterization, interaction with DNA and biological study

3 4

Titas Mukherjeea, Buddhadeb Sen,a Animesh Patra,a Snehasis Banerjeeb, Geeta Hundalc,

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Pabitra Chattopadhyaya* a

6 7 8

b

Department of Chemistry, Burdwan University, Golapbag, Burdwan-713104, India

Govt. College Of Engineering and Leather Technology, Salt Lake Sector-III, Kolkata 98 c

Department of Chemistry, Guru Nanak Dev University, Amritsar-143005, India

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Abstract

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Reaction of three different dithiocarbamates (4-MePipzcdtH, L1H; MorphcdtH, L2H and 4-

13

BzPipercdtH, L3H) with [Rh(2-C6H4py)2Cl]2.1/4CH2Cl2 afforded a class of rhodium(III)

14

complexes of the type [RhIII(2-C6H4py)2(L)]. The complexes were fully characterized by several

15

spectroscopic tools along with a detailed structural characterization of [Rh(2-C6H4py)2(L1)] (1)

16

by single crystal X-ray diffraction. Structural analysis of 1 showed a distorted octahedron in

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which both of the 2-phenylpyridyl nitrogens are in axial positions, trans to one another and the

18

sulfur atoms are opposite to the phenyl rings. Electrochemical analysis by cyclic voltammetry

19

reveals irreversible redox behavior of the rhodium centre in 1, 2 and 3. Their DNA binding

20

ability have been also evaluated from the absorption spectral study as well as fluorescence

21

quenching properties, suggesting the intercalative interaction of the complexes with CT-DNA

22

due to the stacking between the aromatic chromophore and the base pairs of DNA. Antibacterial

23

activity of complexes has also been studied by agar disc diffusion method against some species

1

24

of pathogenic bacteria (Escherichia coli, Vibrio cholerae, Streptococcus pneumonia and Bacillus

25

cereus).

26

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Keywords : Cyclometalated rhodium(III) complex; dithiocarbamates, crystal structure, DFT,

28

DNA binding, antimicrobial study

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*Corresponding author: E-mail: [email protected]

32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

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1. Introduction

48

Rhodium(III) complexes are the subject of current research activity in the interaction of

49

complexes with biomolecules as well as the rhodium catalyst is able to fulfill its role over the

50

other conventional catalysts due to the capability of the metal to change its coordination number

51

from six to four and also the oxidation state from Rh(III) to Rh(I). This change appears as a

52

chemically irreversible two-electron reduction involving ligand loss from octahedral Rh(III) to

53

form square planar Rh(I) complexes. Loss of the ligand depends on the nature of the ligands

54

present in mixed ligand systems which allow one to tune the electrochemical potential and affect

55

the reactivity of the rhodium metal center [1]. The discovery of the catalytic properties of

56

Wilkinson’s catalyst, viz. [RhCl(PPh3)3] naturally brought about a widespread search for other

57

rhodium phosphines with catalytic activity [2,3]. Further, octahedral diimine rhodium(III)

58

complexes are of interest as they have been used in the process of photochemical reduction of

59

H2O to H2 [4].

60

The dithiocarbamates (R2NCS2-) have been considered as versatile ligands for bonding to

61

transition as well as main group metal ions [5-17], and got an enormous attention because of their

62

importance in several fields such as the chemical industry, biology and biochemistry [18-21]. The

63

nature of the heterocycle attached to dithiocarbamate fragment appears crucial so as to vary the

64

electron properties of these ligands and thus to control the potential pharmacological attributes as

65

well as the catalytic efficiency of the metal complexes [22]. Coordination complexes of

66

platinoids with dithiocarbamato ligands are known in the literature [9-13] and also palladium(II)

67

and platinum(II) complexes of dithiocarbamato groups together with mono- or diamine ligands

68

[14-17]. But to the best of our knowledge so far, report of rhodium(III) cyclometalated

69

complexes bearing dithiocarbamate derivative is still unexplored.

3

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The binding interactions of these complexes with DNA have also been studied

71

systematically to explore the biological activity of the new complexes as we know the fact of the

72

activity of cisplatin by coordination to DNA [23,24]. And from thorough pharmacological

73

mechanistic studies it is also known that small molecules interact with DNA via electrostatic

74

forces, groove binding, or intercalation [25], and their effectiveness depends on the mode and

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affinity of the binding [26]. Intercalation is one of the most important among these interactions.

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Therefore, the search for drugs that show intercalative binding to DNA has been an active

77

research area for the past several decades [27]. Moreover, although rhodium metal is not bio-

78

essential element but its compounds have useful applications in the biological field [28-31] and

79

have significant pharmacological effects through the interaction with DNA [32].

80

Encouraged by the advantages of the facts stated above, we isolated a new series of

81

cyclometalated rhodium(III) complexes bearing dithiocarbamate derivatives by a high yield

82

synthetic pathway under mild reaction conditions. The present report deals with the chemistry of

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these [RhIII(2-C6H4py)2(SS)] complexes, where SS = 4-MePipzcdtH, MorphcdtH, 4-BzPipercdtH

84

with special reference to their formation, structural characterization and electrochemical

85

behavior. The binding interactions of these complexes with calf thymus-DNA (CT-DNA) have

86

also been studied systematically to explore the mode of biological activity as part of our

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continuing interest [12,33]. In addition, antibacterial activity of the complexes (1, 2 and 3)

88

against some pathogenic bacteria, namely Escherichia coli, Vibrio cholerae, Streptococcus

89

pneumonia and Bacillus cereus has also been studied by agar disc diffusion method.

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2. Experimental

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2.1. Materials and physical measurements

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Rhodium trichloride, 2-phenylpyridine (2-C6H4py), morpholine and 4-benzylpiperidine

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(Aldrich) were purchased and used without further purification. [Rh(2-C6H4py)2Cl]2.1/4CH2Cl2

98

was prepared following the reported procedure [34]. 4-Methylpiperazine (Aldrich) has been dried

99

by refluxing over NaOH beads, the colorless liquid obtained after distillation and stored over

100

NaOH beads. Solvents used for spectroscopic studies and for synthesis were purified and dried

101

by standard procedures before used. The organic moieties, 4-methylpiperazine-l-carbodithioic

102

acid (4-MePipzcdtH, L1H), morpholine-4-carbodithioic acid (MorphcdtH, L2H) and 4-benzyl-

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piperidine-l-carbodithioic acid (4-BzPipercdtH, L3H) were obtained as solid products following

104

the reported procedure [12].

105

The Fourier transform infrared spectra of the ligand and the complexes were recorded on a

106

Perkin-Elmer FTIR model RX1 spectrometer using KBr pellet in the range 4000 - 300 cm-1. The

107

solution phase electronic spectra were recorded on an JASCO UV–Vis/NIRspectrophotometer

108

model V-570 in the range 200-1100 nm. Elemental analyses were carried out on a Perkin-Elmer

109

2400 series-II CHNS Analyzer. The fluorescence spectra complex bound to DNA were obtained

110

at an excitation wavelength of 522 nm in the Fluorimeter (Hitachi-2000). Mass spectra of 1, 2

111

and 3 were recorded on Micromass Q-Tof microTM. NMR spectrum of the ligands and complexes

112

has been recorded on Bruker DPX-300. Solution conductivity and redox potentials were

113

measured using Systronics Conductivity Meter 304 model and CHI620D potentiometer in DMF

114

at complex concentration of ~10-3 mol L-1. Viscosity experiments were conducted on an

115

Ostwald’s viscometer, immersed in a thermostated water-bath maintained to 25oC.

116 117

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2.2. Syntheses of [Rh(2-C6H4py)2(L1)] (1) [Rh(2-C6H4py)2(L2)] (2) and [Rh(2-C6H4py)2(L3)] (3)

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The complexes have been synthesized following a common procedure stated as below. The

120

ligand, L1H (89.4 mg, 0.508mmol) for complex 1, L2H (83.8 mg, 0.508 mmol) for complex 2 or

121

L3H (127.0 mg, 0.508 mmol) for complex 3 was dissolved in DMSO-MeCN (v/v 1:1) solvent

122

mixture and to this ligand solution dropwise MeCN solution of [Rh(2-C6H4py)2Cl]2.1/4CH2Cl2

123

(468mg, 0.5mmol) was added. The mixture was then refluxed in nitrogen atmosphere for 12 h

124

and the color changed from faded yellow to orange. On slow evaporation of this solution orange

125

coloured microcrystalline solid appeared, which was purified by extracting the orange band in

126

column chromatography using MeCN as an eluant. Needle shaped crystals of [Rh(2-

127

C6H4py)2(L1)] suitable for X-ray diffraction study were grown from this solution on evaporation

128

at ambient temperature.

129

Rh(2-C6H4py)2(L1)] (1): [C28H27N4RhS2]; Yield: 85 %. Anal. Calc.: C, 57.33; H, 4.64; N,

130

9.55; Anal. Found: C, 57.21; H, 4.58; N, 9.32; IR (cm-1): νC=N, 1495; νa(SCS), 1005, 996; ESI-MS

131

(m/z): [M+Na+], 609.576(25% abundance); [M+H+] 587.588 (69 % abundance). Conductivity

132

(Λo, M-1 cm-1) in DMF: 130 ; 1H NMR (δ, ppm in dmso-d6): 4.36 (m, 3H of N-CH3); 3.82 (m, 4H

133

of S2C-N(CH2)2); 3.20 (m, 4H of -N(CH2)2); protons of 2-C6H4py: C1(8.84, d, 2H), C2(7.27, m,

134

2H), C3(8.01, d, 2H), C4(7.69, d, 2H), C5(7.43, m, 2H), C6(7.68, d, 2H).

135

[Rh(2-C6H4py)2(L2)] (2): C27H24N3ORhS2; Yield: 80 %. Anal. Calc.: C, 56.54; H, 4.22; N,

136

7.33. Anal. Found: C, 56.52; H, 4.06 N, 7.29; IR (cm-1): νC=N, 1485; νa(SCS), 1030, 1014; ESI-MS

137

(m/z): [M+Na+], 596.528 (20 % abundance); [M+H+], 574.538 (64 % abundance). Conductivity

138

(Λo, M-1 cm-1) in DMF: 127. 1H NMR (δ, ppm in dmso-d6): 3.86 (m, 4H of S2C-N(CH2)2); 3.66

139

(m, 4H of O(CH2)2); protons of 2-C6H4py: C1(8.84, d, 2H), C2(7.27, m, 2H), C3(8.01, d, 2H),

140

C4(7.69, d, 2H), C5(7.43, m, 2H), C6(7.68, d, 2H).

6

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[Rh(2-C6H4py)2(L3)] (3): C35H32N3RhS2; Yield: 73 %. Anal. Calc.: C, 63.53; H, 4.87; N,

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6.35. Anal. Found: C, 63.44; H, 4.79; N, 6.02; IR (cm-1): νC=N, 1505; νa(SCS),1035, 1020; ESI-MS

143

(m/z): [M+Na+], 684.682 (18 % abundance); [M+H+], 662.688 (42 % abundance). Conductivity

144

(Λo, M-1 cm-1) in DMF: 132. 1H NMR (δ, ppm in dmso-d6): 7.29-7.32 (m, 5H of C6H5); 3.94 (m,

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4H of S2C-N(CH2)2); 3.21 (t, 2H of CH2); 2.23 (m, 4H of CH2); protons of 2-C6H4py: C1(8.84, d,

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2H), C2(7.27, m, 2H), C3(8.01, d, 2H), C4(7.69, d, 2H), C5(7.43, m, 2H), C6(7.68, d, 2H).

147 148

2.3. X-Ray crystallography

149

X-ray data of the suitable crystal of complex 1 were collected on a Bruker’s Apex-II CCD

150

diffractometer using MoKα (λ = 0.71069). The data were corrected for Lorentz and polarization

151

effects and empirical absorption corrections were applied using SADABS from Bruker. A total of

152

13691 reflections were measured out of which 4012 were independent and 2299 were observed

153

[I > 2σ(I)] for theta (θ) 32°. The structure was solved by direct methods using SIR-92 and refined

154

by full-matrix least squares refinement methods based on F2, using SHELX-97 [35]. The two fold

155

axis passes through the metal ion, nitrogens of the piprazine ring and their substituent carbon

156

atoms. Therefore the asymmetric unit contains half the molecule. All non-hydrogen atoms were

157

refined anisotropically. The refinement showed rotational disorder in the piprazine ring which

158

could be resolved by splitting the two unique carbon atoms into two components and refining

159

their sof and thermal parameters as free variables with restraints over the bond distances. All

160

hydrogen atoms were fixed geometrically with their Uiso values 1.2 times of the phenylene and

161

methylene carbons and 1.5 times of the methyl carbons. All calculations were performed using

162

Wingx package [36, 37]. Important crystallographic parameters are given in Table 1.

163

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2.4. Theoretical calculation

165

To clarify the configurations and energy level of the complexes 1, 2 and 3, DFT calculations

166

were carried out in G09W program using B3LYP/6-31G(d) calculation and correlation function

167

as implemented in the Gaussian program package Gaussian 09. Thermal contribution to the

168

energetic properties was considered at 298.15 K and one atmosphere pressure.

169 170

2.5. DNA binding experiments

171

All the experiments involving CT-DNA were studied by spectroelectronic titration and

172

fluorescence quenching technique by using ethidium bromide (EB) as a DNA scavenger and

173

performed the experiment as our previously standardized method [38].

174

Tris–HCl buffer solution was used in all the experiments involving CT-DNA. This tris–HCl

175

buffer (pH 7.9) was prepared using deionized and sonicated HPLC grade water (Merck). The CT-

176

DNA used in the experiments was sufficiently free from protein as the ratio of UV absorbance of

177

the solutions of DNA in tris–HCl at 260 and 280 nm (A260/A280) was almost ~1.9. The

178

concentration of DNA was determined with the help of the extinction coefficient of DNA

179

solution at 260 nm (ε260 of 6600 L mol-1 cm-1) [38]. Stock solution of DNA was always stored at

180

4 oC and used within four days. Concentrated stock solution of the complex 1 was prepared by

181

dissolving the compound in DMSO and suitably diluted with tris–HCl buffer to the required

182

concentration for all the experiments. Absorption spectral titration experiment was performed by

183

keeping constant the concentration of the complex 1 and varying the CT-DNA concentration. To

184

eliminate the absorbance of DNA itself, equal solution of CT-DNA was added both to the

185

complex 1 solution and to the reference solution.

186

In the ethidium bromide (EB) fluorescence displacement experiment, 5 µL of the EB tris–

187

HCl solution (1.0 mmol.L-1) was added to 1.0 mL of DNA solution (at saturated binding levels), 8

188

stored in the dark for 2.0 h. Then the solution of the compound was titrated into the DNA/EB

189

mixture and diluted in tris–HCl buffer to 5.0 mL to get the solution with the appropriate complex

190

1/CT-DNA mole ratio. Before measurements, the mixture was shaken up and incubated at room

191

temperature for 30 min. The fluorescence spectra of EB bound to DNA were obtained at an

192

excited wavelength of 522 nm in the Fluorimeter (Hitachi-2000). The interaction of the complex

193

1 with calf thymus DNA (CT-DNA) has been investigated by using absorption and emission

194

spectra.

195 196

2.6. Antimicrobial screening

197

The biological activities of free dithiocarbamic acids and the rhodium(III) derivatives of

198

dithiocarbamates (1, 2 and 3) have been studied for their antibacterial activities by agar well

199

diffusion method [39-41]. The antibacterial activities were done at 100 µg/mL concentration of

200

different compounds in DMF solvent by using three pathogenic gram negative bacteria

201

(Escherichia coli, Vibrio cholerae, Streptococcus pneumoniae) and one gram positive pathogenic

202

bacteria (Bacillus cereus). DMF was used as a negative control. The Petri dishes were incubated

203

at 37 °C for 24 h. After incubation plates were observed for the growth of inhibition zones. The

204

diameter of the zone of inhibition was measured in mm.

205 206

3. Results and Discussion

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3.1. Synthesis and characterization of complexes

208

The bidentate sulphur ligands (L1H, L2H, and L3H) were synthesized by the reaction between

209

carbon disulfide with different amines in ethanol, and later characterized by FTIR and 1H NMR.

210

Treatment of these ligands with [Rh(2-C6H4py)2Cl]2.1/4CH2Cl2 at refluxing condition in DMSO-

211

MeCN (v/v 1:1) solvent mixture having nitrogen atmosphere resulted in cleavage of the chloro 9

212

bridge and led to formation of mononuclear rhodium(III) complexes of general formula of

213

[RhIII(2-C6H4py)2(L)] which were obtained from the column chromatography using acetonitrile

214

as orange colored microcrystalline solid on evaporation. Here, the dithiocarbamates behaves as

215

bidentate monobasic ligands (see Scheme 1). The complexes (1-3) are sparingly soluble in

216

common organic solvents except hexane but fairly soluble in DMF and DMSO, and are stable in

217

both the solid state and solution in air. The molar conductivity of freshly prepared solution (~1 x

218

10-3 M concentration) of 1 (ΛM = 130 M-1 cm-1), 2 (ΛM = 127 M-1 cm-1) and 3 (ΛM = 132 M-1

219

cm-1) in DMF are fairly consistent with a non-electrolyte, respectively. The complexes are

220

diamagnetic in nature. The formulations of the complexes have been confirmed by spectroscopic

221

methods and elemental analyses.

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3.2. Structural description of complex 1

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An ORTEP view of the complex [Rh(2-C6H4py)2(L1)] (1) with atom labeling scheme is

225

illustrated in Fig.1, and a selection of bond distances and angles is listed in Table 2. The

226

structural analysis evidenced that the complex resides on a C 2/c site in the monoclinic crystal

227

system. The crystal structure of 1 shows a distorted octahedron in which both of the 2-

228

phenylpyridyl nitrogens are in axial positions, trans to one another and the sulfur atoms are

229

opposite to the phenyl rings. As would be expected, both Rh-C σ-bonds are equal in length

230

(1.994(4) Å) and significantly shorter than the Rh-N dative bond lengths of 2.039(3) Å due to

231

the Rh-C σ-bonds increasing electron density on the metal center. The bond distance of Rh-C in 1

232

is comparable with the previously reported Rh-C bonds in cyclometalated complex (1.996(9) Å)

233

but the bond Rh-N is slightly longer than those (1.987(7) Å) [42], but both are comparable with

234

the reported values [43]. Both Rh–S distances are also equal in length (2.4854(11) Å), and these

10

235

are longer than those in [Rh(Et2NCS2)3] (2.364(3) Å) [44] due to trans influence of the strong σ-

236

donating carbon atoms of the phenyl groups and shorter than those in similar type complex

237

[{Rh(Bu2-C6H4py)2}2{S2P(OMe)2}] (2.548(2) Å) due to attachment of sulphur atoms to carbon

238

to of more electronegativity than phosphorous, for this reason, the S-Rh-S angle of 71.00(5)o is

239

smaller compared to the observed value of 79.40(1)o in the previous report [43].

240 241

3.3. IR Spectra

242

The IR spectrum of the ligands display an intense stretch at 2850 cm-1 and 1445-1430 cm-1

243

correspond to γC-H of N-Me and γC=N respectively. The γC-H of N-Me of L1H for 1 (2910cm-1) is blue

244

shifted than the γC-H

245

The band around 1590 cm-l indicates a double bond character of C-N bond in the ligand frame,

246

which is confirmed from the bond length of the X-ray structure. This fact could be attributed to

247

the electron releasing ability of the heterocyclic group towards the sulphur atoms, a feature that

248

induces an electron delocalization over the carbon-nitrogen bond and the CS2 fragment. This is

249

shown by the νC=N shift to higher energies (ca. 1510-1465 cm-l) with respect to the free acids (ca.

250

1445-1430 cm-1), and these bands lie in between the stretching frequencies expected for a double

251

C=N (1610-1690 cm-l) and single C-N bond (1250-1350 cm-1). The blue-shift of the C=N

252

stretching frequency on going from the free acids to their metal complexes gives support to the

253

typical bidentate character [45] of the carbodithioic acid ligands. Two bands in the region of

254

1040-965 cm-l (separated by less than 20 cm-l) assignable to the νa(SCS) and one band for the vs(SCS)

255

stretch in the region 705-675cm-l of the complexes suggest the unsymmetrical chelating bidentate

256

mode of coordination to rhodium(III) ion [46]. The stretchings due to νCOC (asym and sym), νN-Me

257

and νCCC (asym and sym) remain unchanged in the spectra of the complexes and in the free

of N-Me

of the free ligand (2850 cm-1) indicating metal ligand coordination.

11

258

ligands. This observation helps to exclude any coordination to the metals via nitrogen and oxygen

259

donors.

260 261

3.3 Electronic Spectra

262

The electronic spectra of 1, 2 and 3 in DMF were shown in Fig 2. The spectral data have

263

been tabulated in Table 3. Complexes 1, 2 and 3 display a lower energy band at 675nm, 672nm

264

and 675nm, respectively with low extinction coefficient values that correspond to the d–d

265

transition. The higher energy band at 360 nm for all three complexes with high extinction

266

coefficient values are due to the coordinated carbon atom from pipyridine moiety, C(σ)-Rh(III)

267

charge transfer (LMCT) transition. The other higher energy intense transitions at 374 nm and 360

268

nm are due to the n→π* and π→π* charge transfer transitions.

269 270

3.5. Redox studies

271

The cyclic voltammograms (CV) of the complexes 1, 2 and 3 were recorded in DMF solvent

272

at room temperature. Three electrode cell set up such as platinum, Ag/Ag+ (non-aquous) and a

273

platinum wire as a working, reference and auxiliary electrode respectively have been used for

274

measurements. The cyclic voltammograms of all the three complexes 1, 2 and 3 have been shown

275

in Fig. 3 and the electrochemical data have been tabulated in Table 4. The complexes exhibit an

276

irreversible reductive response at E1/2 value ≈ -0.697 V to -0.767 V versus Ag/Ag+ (non-aqueous)

277

corresponds to Rh3+/Rh+ couple. Small differences in the ∆Ep values 652 mV, 658mV, 654 mV

278

for 1, 2 and 3 respectively) have been observed that increases in the order 2> 3>1. This indicates

279

that the ease of reduction from Rh(III) to Rh(I) with respect to ligand electronic environment is

280

supposed to be much more in case of complex 1 and least in complex 2. The trend of reduction

12

281

potential values followed can be explained by the availability of the electrons on the donor atoms

282

of the dithiocarbamate ligands. The electron donating capacity through σ bond of the six

283

membered heterocyclic ring increases in the order 2< 3<1 owing to the presence of different

284

substituents at the heteroatom i.e. highly electronegative O atom (2), -R effect of benzylic group

285

(3), +I effect of Me group (1) and so the trend of reduction potential followed as such, which is

286

further supported by theoretical calculation obtained from DFT study (viz. supporting

287

information).

288 289

3.6. DNA binding study of [Rh(2-C6H4py)2(L1)]

290

Absorption spectral study: Electronic absorption spectroscopy is an effective method to

291

examine the binding modes of complex 1 with DNA. In general, binding of the compound to the

292

DNA helix is testified by an increase of the CT band complex 1 due to the involvement of strong

293

intercalative interactions between an aromatic chromophore of compound and the base pairs of

294

DNA [47-49]. The absorption spectra of complex 1 in the absence and presence of CT-DNA is

295

given in Fig. 4. The extent of the hyperchromism in the absorption band is generally consistent

296

with the strength of intercalative binding/interaction [50,51]. Fig. 5 indicates that the complex 1

297

interacts strongly with CT-DNA (Kb = 1.54 x105 M-1), and the observed spectral changes may be

298

rationalized in terms of intercalative binding [52]. In order to further illustrate the binding

299

strength of the complex 1 with CT-DNA, the intrinsic binding constant Kb was determined from

300

the spectral titration data using the following equation [53]:

301

[DNA]/(εa–εf) = [DNA]/(εb–εf) + 1/[Kb (εb–εf)]

(1)

302

where [DNA] is the concentration of DNA, εf, εa and εb correspond to the extinction coefficient,

303

respectively, for the free complex 1, for each addition of DNA to the complex 1 and for the

304

complex 1 in the fully bound form. A plot of [DNA]/(εa–εf) versus [DNA], gives Kb, the intrinsic 13

305

binding constant as the ratio of slope to the intercept. From the [DNA]/( εa–εf) versus [DNA] plot

306

(Fig. 5), the binding constant Kb for complex 1 was estimated to be 1.54 x 105 M-1 (R = 0.99746

307

for five points), indicating a strong binding of the complex 1 with CT-DNA.

308

Fluorescence quenching technique: Fluorescence intensity of EB bound to DNA at 612

309

nm shows a decreasing trend with the increasing concentration of the compound. The quenching

310

of EB bound to DNA by the compound is in agreement with the linear Stern–Volmer equation

311

[54]: I0/I = 1 + Ksv [Q]

312

(2)

313

where I0 and I represent the fluorescence intensities in the absence and presence of quencher,

314

respectively. Ksv is a linear Stern–Volmer quenching constant, Q is the concentration of

315

quencher. In the quenching plot in Fig. 7 of I0/I versus complex 1 Ksv value is given by the ratio

316

of the slope to intercept. The Ksv value for the complex 1 is 0.87 x 104 (R = 0.98873 for five

317

points), suggesting a strong affinity of 1 to CT-DNA.

318

Number of binding sites: Flurorescence quenching data were used to determine the binding

319

sites (n) for the compound 1 with CT-DNA. Fig. 6 shows the fluroscence spectra of EB-DNA in

320

the presence of different concentrations of compound 1. It can be seen that the fluroscence

321

intensity at 612 nm was used to estimate Ksv and n.

322

If it is assumed that there are similar and independent binding sites in EB-DNA, the

323

relationship between the fluroscence intensity and the quencher medium can be deduced from the

324

following Eq. (3):

325

nQ + B → Qn….B

(3)

326

where B is the flurophore, Q is the quencher, [nQ + B] is the postulated complex between the

327

flurophore and n molecules of the quencher [47]. The constant K is given by Eq. (4):

328

K = [Qn….B]/[Q]n.[B] 14

(4)

329

If the overall amount of biomolecules ( bound or unbound with the quencher) is Bo, then [Bo] =

330

[Qn…B]+ [B], where [B] is the concentration of unbound biomolecules, and the relationship

331

between the fluorescence intensity and the unbound biomolecule as [B]/[Bo] = I/Io , that is: log[(Io-I)/I] = logK + nlog[Q]

332

(5)

333

Where (n) is the number of binding site of compound complex 1 with CT-DNA, which can be

334

determined from the slope of log[(Io-I)/I] versus log[Q],as shown in the Fig. 8. The calculated

335

value of the number of binding sites (n) is 1.10 (R= 0.99869 for five points). The value of (n)

336

approximately equals 1, and thus indicates the existence of one binding site in DNA for

337

compound 1.

338

Viscosity Measurement: To further clarify the nature of interaction between complex 1 and

339

CT DNA, viscosity measurements were carried out. Upon binding, a DNA intercalator causes an

340

increase in the viscosity of the DNA double helix due to its insertion between the DNA base pairs

341

and consequently to the lengthening of the DNA double helix. In contrast, a partial and/or

342

nonclassical intercalation could bend (or kink) the DNA helix, reducing the effective length and

343

its viscosity [55]. The method is generally considered the least unambiguous to probe the mode

344

of binding of a compound to DNA. The effect of 1 on viscosity of CT DNA is shown in Fig. 9.

345

The viscosity of DNA increased dramatically upon addition of complex 1 and is nearly linear

346

(R2 = 0.99621 for nine points). These results strongly indicate that the complex 1 deeply into the

347

DNA base pairs in intercalative fashion.

348 349

3.7. Antibacterial activity

350

Antibacterial activity of the dithicarbamic acids (HL) and the corresponding complexes are

351

tabulated in Table 5. Comparisons of the biological activity of the dithicarbamates and their

352

rhodium(III)

derivatives with the standard 15

antibiotics,

chloramphenicol

at

different

353

concentrations have been carried out taking usual precautions. From this study, it is inferred that

354

all the rhodium(III) complexes have higher activity than the ligand only, but little less efficient

355

than the antibiotics. The increased activity may be due to the increase of the delocalization of π-

356

electrons over the whole chelate ring imparts the increased lipophilic character to the metal

357

complexes. This higher lipophilicity of the complexes facilitates the penetration ability with a

358

greater extent into the bacterial cell membranes, and as result it perturbs the respiration process of

359

the bacteria and diminish the further growth of the microorganisms.

360 361

4. Conclusion

362

Three

complexes

of

diimine

dithiocarbamate

mixed

ligand

framework

Rh(2-

363

C6H4py)2(L1)](1), Rh(2-C6H4py)2(L2)](2), Rh(2-C6H4py)2(L3)] (3) have been synthesized and

364

characterized by means of solid and solution phase spectroscopic studies including the X-ray

365

structure of 1. With the knowledge gained from the present study, attempts are now underway to

366

bind these ligands in the C,N,S-coordination fashion to iridium and other metal ions having

367

octahedral geometry. The present study of interaction with CT-DNA shows that these

368

cyclometalated rhodium(III) complexes having dithiocarbamate moieties are good intercalative

369

binding to with CT-DNA with an adequate number of coordination sites and this strongly binding

370

ability of the complexes as intercalator encourage to develop these materials as good anticancer

371

candidates. From the antibacterial studies it is found that all the metal complexes have higher

372

activities than the free dithiocarbamic acids (LH) against four pathogenic bacteria (Escherichia

373

coli, Vibrio cholerae, Streptococcus pneumonia and Bacillus cereus, among these three complex

374

2 has more antibacterial effect.

375 376

16

377

Supporting material

378

Crystallographic data for complex 1 have been deposited with the Cambridge Crystallographic

379

Data Centre, CCDC No. 932588. Copies of this information are available on request at free of

380

charge from CCDC, 12 Union Road, Cambridge, CB21EZ, UK (fax: +44-1223-336-033; e-mail:

381

[email protected] or http://www.ccdc.cam.ac.uk).

382 383

Acknowledgements

384

Financial support from the Council of Scientific and Industrial Research (CSIR), New Delhi,

385

India is gratefully acknowledged.

386 387 388 389 390

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391

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392

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393

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394

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395

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396

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398

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399

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400

Leung, J. Organomet. Chem. 689 (2004) 2401. 17

401

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R. Graziani, J. Inorg. Biochem. 83 (2001) 31. [21] L. Giovagnini, L. Ronconi, D. Aldinucci, D. Lorenzon, S. Sitran, D. Fregona, J. Med. Chem. 48 (2005) 1588.

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[25] J.G.M. Segura, M. J. Prieto, M.F. Bardia, X. Solans, V. Moreno, Inorg. Chem., 45 (2006)

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438

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439

[35] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, J. Appl. Crystallogr. 26 (1993)

440

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441

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444

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445

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446

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447 448

(2004) 710. [41] S. Shivhare, D. G. Mangla, J. Curr. Pharm. Res. 6 (2011) 16. 19

449 450 451 452

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453

[44] C.L. Raston, A.H. White, J. Chem. Soc., Dalton Trans. (1975) 2422.

454

[45] D. Coucouvanis, S. J. Lippard, Interscience Publications: New York 11 (1970) 233.

455

[46] P. Bonati, R. Ugo, J. Organomet. Chem. 10 (1967) 257.

456

[47] J.K. Barton, J.M. Goldberg, C.V. Kumar, N.J. Turro, J. Am. Chem. Soc. 108 (1986) 2081.

457

[48] K. Dhara, J. Ratha, M. Manassero, X.Y. Wang, S. Gao, P. Banerjee, J. Inorg. Biochem. 101

458

(2007) 95.

459

[49] K. Dhara, P. Roy, J. Ratha, M. Manassero, P. Banerjee, Polyhedron 26 (2007) 4509.

460

[50] V.A. Bloomfield, D.M. Crothers, I. Tinoco, Physical Chemistry of Nucleic Acids, Harper

461

and Row, New York, 1974, p. 432.

462

[51] A. Ambroise, B.G. Maiya, Inorg. Chem. 39 (2000) 4264.

463

[52] S.A. Tysoe, R.J. Morgan, A.D. Baker, T.C. Strekas, J. Phys. Chem. 97 (1993) 1707.

464

[53] A.M. Pyle, J.P. Rehmann, R. Meshoyrer, C.V. Kumar, N.J. Turro, J.K. Barton, J. Am.

465

Chem. Soc. 111 (1989) 3051.

466

[54] O. Stern, M. Volmer, Z. Phys. 20 (1919) 183.

467

[55] S. Satyanarayana, J.C. Dabrowiak, J.B. Chaires, Biochemistry 31 (1992) 9319.

468 469 470 471

20

472

Figures’ Legend

473

Fig. 1. ORTEP view of the complex [Rh(2-C6H4py)2(L1)] (1) with atom labeling scheme

474

(excluded H for clarity). (Symmetry codes: (i) -x,y,z; (ii) x,-y,-z; (iii) -x,-y,-z).

475 476 477

Fig. 2. Electronic absorption spectra of 1, 2 and 3 in DMF Fig. 3. Cyclic voltammograms (scan rate 50 mV/s) of 1, 2 and 3 in DMF solution of 0.1 M TBAP, using platinum working electrode.

478

Fig. 4. Electronic spectral titration of complex 1 with CT-DNA at 267nm in tris-HCl buffer;

479

[Compound] = 1.09 x 10-4 ; [DNA]: (a) 0.0, (b) 1.25 x 10-6 , (c) 2.50 x 10-6 , (d) 3.75 x 10-6,

480

(e) 5.00 x 10-6 , (f) 6.25 x 10-6 mol.L-1. Arrow indicates the increase of DNA concentration.

481 482

Fig. 5. Plot of [DNA]/(εa–εf) versus [DNA] for the absorption of CT-DNA with the complex 1 in tris-HCl buffer

483

Fig. 6. Emission spectra of the CT-DNA-EB system in tris–HCl buffer upon the titration of the

484

compound complex 1. Kex = 522 nm; [EB] =0.96 x 10-4 molL-1 ; [DNA] = 9.9 x 10-6 molL-1 ;

485

[Compound]: (a) 0.0, (b) 1.36 x 10-5 , (c) 2.72 x 10-5 , (d) 4.08 x 10-5 , (e) 5.44 x 10-5

486

(f) 6.80 x 10-5 molL-1 . Arrow indicates the increase of compound concentration.

,

487

Fig. 7. Emission spectra of the CT-DNA-EB system in Tris-HCl buffer upon titration with

488

complex 1c. λex = 522 nm; [EB] = 9.6×10-5 mol L-1, [DNA] = 1.25×10-5 ; [Complex]: (a) 0.0,

489

(b) 1.25×10-5, (c) 2.5×10-5 ,(d) 3.75×10-5, (e) 5.00×10-5, mol L-1. The arrow denotes the

490

gradual increase of complex concentration. Inset: plot of I0/I vs. [complex] of 1c; Ksv = 0.82 ×

491

104 (R = 0.99965, n = 5 points).

492

Fig. 7. Plot of I0/I versus complex 1 for the titration of CT-DNA–EB system with complex 1

493

using spectrofluorimeter; linear Stern–Volmer quenching constant (Ksv) for complex 1 =0.87

494

x 104 ; (R = 0.98873 for five points).

21

495

Fig. 8. The linear plot shows log[(Io-I)/I] versus log[Q], where R = 0.99869 for five points

496

Fig. 9. Effect of increase of amount of 1 on the relative viscosity of CT DNA in tris-HCl having

497 498

50 mM NaCl buffer. Scheme 1. Synthetic method of rhodium(III) complexes

22

499

Table 1. Crystallographic data for complex 1

500

Empirical Formula

C28 H27 N4 Rh S2

501

Identification code

shelxl

Fw

586.59

Crystal system

Monoclinic

503

Space group

C 2/c

504

a, Å

16.683(5)

b, Å

17.840(4)

c, Å

10.251(5)

506

β, deg

126.223(5)

507

V, Å3

2461.3(15)

508

Z

502

505

4 –3

Dcalcd. (g cm )

1.583

µ (MoKα), mm–1

0.889

510

F(000)

1200

511

θ range, deg

1.90 -31.84

No. of reflns collcd

13691

No. of independent reflns

4012

513

Rint

0.0544

514

No. of reflns (I > 2σ(I))

2299

515

No. of refined paramaters

357

509

512

Goodness-of-fit (F2)

1.034

516

R1, wR2 (I >2σ(I)) [a]

0.0473, 0.1041

517

R indices (all data)

R1 = 0.1053, .1342

518 519 520 521 522

23

523

Table 2. Coordination Bond lengths [Å] and angles [°] for complex 1 524

Bond length (Å) 525

Rh(1) - C(11)

1.994(4)

Rh(1) - C(11)#1

1.994(4)

Rh(1) - N(1)

2.039(3)

Rh(1) - N(1)#1

2.039(3)

Rh(1) - S(1)

2.4854(11) Rh(1) - S(1)#1

Bond angle (o)

534

C(11)-Rh(1)-N(1)

80.30(13)

C(11)#1-Rh(1)-N(1)#1

80.29(13)

C(11)-Rh(1)-N(1)#1

93.30(13)

C(11)#1-Rh(1)-N(1)

93.30(13)

N(1)-Rh(1)-S(1)

170.86(11) N(1)-Rh(1)-N(1)#1

530 171.09(17)

C(11)-Rh(1)-S(1)

100.14(11) C(11)#1-Rh(1)-S(1)#1

100.15(11) 531

C (11)#1-Rh(1)-S(1)

90.15(9)

N(1)#1-Rh(1)-S(1)#1

90.15(9)

N(1)#1-Rh(1)-S(1)

97.12(9)

N(1)-Rh(1)-S(1)#1

97.11(9)

S(1)-Rh(1)-S(1)#1

71.00(5)

C(11)-Rh(1)-C(11)#1

88.8(2) 533

529

532

Symmetry transformations used to generate equivalent atoms: #1 -x+1, y, -z+3/2

536

Table 3. Electronic absorption spectral data Compound 1

λmax(nm) (10-5, ε/dm3 mol-1cm-1)a 360(7845),

374sh(6780),

385(6840),

375sh(6680),

390(6700),

382sh(6600),

390(6640),

675(160) 2

360(7900), 672(210)

3

360(7800), 675(200)

538

527 2.4855(11) 528

535

537

526

a

in DMF solvent

24

539

Table 4. Electrochemical dataa for the complexes 1, 2 and 3. Complex

Epc(V)

Epa(V)

∆Ep(mV)

E1/2(V)

1

-1.023

-0.371

652

-0.697

2

-1.096

-0.438

658

-0.767

3

-1.077

-0.413

654

-0.744

540

a

541

electrolyte: tetra-N-butylammonium perchlorate (0.1 M).

Potentials versus non-aqueous Ag/Ag+ reference electrode, scan rate 50 mV/s, supporting

542 543 544 545

Table 5. Antibacterial data of free dithiocarbamic acids (LH) and rhodium(III) complexes (1, 2 and 3) (100 µg/ ml) Compound for Treatment

Inhibition zone in mm E. coli

V.cholerae

S.pneumoniae

B. cereus

L1H

05

05

04

03

L2H

05

04

08

04

L3

04

07

06

03

1

11

14

17

06

2

16

17

20

08

3

12

14

18

07

Chloramphenicol

22

29

24

09

DMF

0

0

0

0

546 547 548

25

550 552 554 556 558 560 562 564 565

Fig. 1. ORTEP view of the complex [Rh(2-C6H4py)2(L1)] (1) with atom labeling scheme

566

(excluded H for clarity). (Symmetry codes: (i) -x,y,z; (ii) x,-y,-z; (iii) -x,-y,-z).

567 569 4

571 573

-----(1) -----(2) -----(3)

575 577 579

Absorbance

3

2

1

581 583

0 350

400

450

500

Wavelength(nm)

585 586

Fig. 2. Electronic absorption spectra of 1, 2 and 3 in DMF

587 588

26

590

10

31 2

592

8 594

6 598

I (µA)

596

4 2

600

0 602

-2 604

-1.5

-1.2

606 607 608

-0.9 -0.6 E (V)

-0.3

0.0

Fig. 3. Cyclic voltammograms (scan rate 50 mV/s) of 1, 2 and 3 in DMF solution with 0.1 M TBAP, using platinum working electrode.

609 611 0.4

613 615

f

0.3

617

Abs.

a 0.2

619 621 623

0.1

0.0 300

625

400

500 λ(nm)

600

700

626

Fig. 4. Electronic spectral titration of complex 1 with CT-DNA at 267nm in tris-HCl buffer;

627

[Compound] = 1.09 x 10-4 ; [DNA]: (a) 0.0, (b) 1.25 x 10-6 , (c) 2.50 x 10-6 , (d) 3.75 x 10-6,

628

(e) 5.00 x 10-6 , (f) 6.25 x 10-6 mol.L-1. Arrow indicates the increase of DNA concentration.

27

630 9.0

634 636 638 640

[DNA]/(ε a-εf) x 1010

632

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0

642

1

2

3

4

5

644 645 646

6

7

6

Fig. 5. Plot of [DNA]/(εa–εf) versus [DNA] for the absorption of CT-DNA with the complex 1 in tris-HCl buffer

649 651 653 655 657 659 661 663

Flurescence intensity (a.u.)

647

1200

a

1000 f

800 600 400 200 560

600

640

680

720

760

λ (nm)

664

Fig. 6. Emission spectra of the CT-DNA-EB system in tris–HCl buffer upon the titration of the

665

compound complex 1. Kex = 522 nm; [EB] =0.96 x 10-4 molL-1 ; [DNA] = 9.9 x 10-6 molL-1 ;

666

[Compound]: (a) 0.0, (b) 1.36 x 10-5 , (c) 2.72 x 10-5 , (d) 4.08 x 10-5 , (e) 5.44 x 10-5 , (f)

667

6.80 x 10-5 molL-1. Arrow indicates the increase of compound concentration.

668

28

669 671

1.7

673

1.6 1.5

677

I / Io

675

1.4 1.3

679

1.2

681

1.1 1.0

683

1

2

3

4

5

6

7

8

9

[Complex 1] x 105

685 686

Fig. 7. Plot of I0/I versus complex 1 for the titration of CT-DNA–EB system with complex 1

687

using spectrofluorimeter; linear Stern–Volmer quenching constant (Ksv) for complex 1 =

688

0.87 x 104 ; (R = 0.98873 for five points).

689 -0.2

693

-0.4

695

-0.6

697 699 701 703

log[(Io-I)/I]

691

-0.8 -1.0 -1.2 -4.0

-4.2

-4.4

-4.6

-4.8

log[Complex 1] 705 706

Fig. 8. The linear plot shows log[(Io-I)/I] versus log[Q],where R = 0.99869 for five points

707 708

29

710 712

1.16 1.12

(n/no)

716

1/3

714

1.08

718

1.04

720

1.00

722

0

724

2

4

6

8

10

[Complex 1]/[DNA] 726 727 728

Fig. 9. Effect of increasing amount of 1 on the relative viscosity of CT DNA in tris-HCl, 50 mM NaCl buffer (R2 = 0.99621 for nine points).

729 731

LnH + [Rh(2-C6H4py)2Cl2]2

733

DMSO-MeCN

Reflux,12 h

S

735 N

737

[Rh(2-C6H4py)2(Ln)] n = 1, Complex 1 n = 2, Complex 2 n = 3, Complex 3

SH

X

739 741

X= -N-CH3 , 4-MePipzcdtH (L1H) X= -O, MorphcdtH (L2H) X= -CH-CH2Ph , 4-BzPipercdtH(L3H)

N

2-C6H4py

ppy

742 743 744

Scheme 1. Synthetic method of rhodium(III) complexes

745 746 747

30

748 749 750

Graphical Abstract (Pictogram)

752

S

+ [Rh(2-C 6H 4 py)2Cl2 ]2

N

SH

X

762

Rh(2-C6H4py)2(L1)] (1) 764 766 768 770 772 774 3

[Rh(2-C6H4py)2(L )] (3)

[Rh(2-C6H4py)2(L2)] 776 (2) 778

779 780 781 782 783 784 785

31

786 787 788 789 790 791 792 793 794

Graphical Abstract (Synopsis)

795

Three new cyclometalated rhodium(III) complexes containing dithiocarbamate derivatives

796

(1, 2 and 3) have been synthesized and structurally characterized. Irreversible redox behavior of

797

the rhodium(III) centre in the complexes have been observed in the cyclic voltammetric

798

experiments. Study of interaction with DNA showed the strong intercalative binding nature of the

799

complexes with CT-DNA, and antibacterial study exhibited the complexes have higher activities

800

than the free dithiocarbamic acids (LH) against four pathogenic bacteria.

801

802 803

32