Synthesis, antimicrobial, antioxidant and molecular docking studies of thiophene based macrocyclic Schiff base complexes

Journal of Molecular Structure 1100 (2015) 208e214

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Synthesis, antimicrobial, antioxidant and molecular docking studies of thiophene based macrocyclic Schiff base complexes Parveen Rathi*, D.P. Singh Chemistry Department, National Institute of Technology, Kurukshetra 136 119, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 5 January 2015 Received in revised form 14 July 2015 Accepted 14 July 2015 Available online 17 July 2015

The macrocyclic complexes of pharmaceutical importance with trivalent transition metals have been synthesized by [1 þ 1] condensation of succinyldihydrazide and thiophenedicarboxaldehyde, via template method, resulting in the formation of the complex [MLX] X2; where L is (C10H10N4O2S), a macrocyclic ligand, M ¼ Cr (III) and Fe (III) and X ¼ Cl, CH3COO or NO3 . These complexes have been characterized with the help of elemental analyses, molar conductance measurements, magnetic susceptibility measurements, ultraviolet, infrared, far infrared, electron spin resonance, mass spectral studies and powder x-ray diffraction analysis. On the basis of all these studies, mononuclear complexes having 1:2 electrolytic nature with a five coordinated square pyramidal geometry have been proposed. Powder diffraction XRD indicates the presence of triclinic crystal system with p bravais lattice for the representative complex. All the metal complexes have also been explored for their in vitro antimicrobial and antioxidant activities. © 2015 Elsevier B.V. All rights reserved.

Keywords: Powder XRD Template Thiophenedicarboxaldehyde TGA Antimicrobial Antioxidant Docking

1. Introduction Hydrazones are organic compounds characterized by the presence of eNHeN]CHe group in their molecule having an additional eC]O donor which determines the flexibility and versatility of the complexes. This type of ligand also have theoretical importance because they are capable of furnishing an environment with controlled geometry and ligand field strength [1,2]. Various hydrazones possess strong fungicidal, insecticidal, herbicidal and antibacterial properties [3,4]. The marcocyclic transition metal complexes containing heterocyclic rings in their frame have received great interest due to their co-ordination chemistry and the beneficial pharmacological properties [5]. Nitrogen and sulphur atoms play a important role in the coordination of metal complexes at the active sites of metalloenzymes [6]. Furthermore It seems reasonable to bear in mind the biological activity of the related compounds which contain heterocyclic rings instead of carbocycles. Thiophene derivatives were known to possess antibacterial and antitumour properties [7]. Singh et al. [8] had reported the synthesis and characterization of iron(III) and chromium(III) complexes derived from succinyldihydrazide and gloxal having

* Corresponding author. E-mail address: [email protected] (P. Rathi). http://dx.doi.org/10.1016/j.molstruc.2015.07.025 0022-2860/© 2015 Elsevier B.V. All rights reserved.

significant antimicrobial properties. Hence, keeping in view the above utilities of hydrazone and heterocyclic moiety, the attempts have been made to club the hydrazone and heterocyclic moiety (thiophene) in the form of macrocycles containing Cr(III) and Fe(III) by template condensation reaction of succinyldihydrzide and thiophenedicarboxaldehyde. Computational studies for the optimization of complexes have been done. A structure activity relation studies of literature of COX-2 inhibitor shows that the development of COX-2 inhibitors depends on the presence of sulphur containing heterocycle ring (DuP-697, main building block used for the synthesis of COX-2 inhibitors). It is only due to the presence of this moiety in our complexes that we tried for molecular docking against COX-2. In silico studies for the representative complex has also been carried out as COX-2 inhibitor. Amongst of all the tested complexes for in vitro antimicrobial activity and antioxidant activity few of them show very good biological activities.

2. Experimental section 2.1. Materials All the chemicals and solvents used were of AnalaR grade. Thiophenedicarboxaldehyde and DPPH were procured from sigmaaldrich. The metal salts were purchased from S.D.-fine, Mumbai,

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India, E-Merck, Ranbaxy, India and were used as received. 2.2. Analytical and physical measurements The microanalysis for C, H, N and S were carried out on EuroEA CHNS elemental analyzer. The metal contents in the complexes were determined by the reported literature methods [9]. The magnetic susceptibility measurements were made at SAIF, IIT Roorkee, on a vibrating sample magnetometer (Model PAR 155). The IR spectra were recorded on FTIR spectrophotometer (Agilent Technologies) in the range 4000e400 cm1. TGA was recorded on a Hitachi TG/DTA 7200. The electronic spectra (in DMSO) were recorded at room temperature on a Hitachi 330 spectrophotometer in the range 200e1100 nm. The powder X-ray diffraction (PXRD) analysis was carried out on Bruker D8 X-ray diffractometer at Central University Hyderabad. The molar conductance was measured on a digital conductivity meter (HPG system, G-3001) in DMSO. The melting points were determined in capillaries using electric melting point apparatus. ESR was obtained on a varian ESR spectrophotometer, at IIT Bombay, Mumbai using the DMSO solvent. TOF ESI Mass spectra were recorded at SAIF, PU, Chandigarh. 2.3. Biological assay 2.3.1. Test microorganisms Keeping in view the growing resistance of microbial strains and their clinical importance in causing diseases in human total five microbial strains were selected. Two yeast, (Candida albicans MTCC 3017 and Saccharomyces cerevisiae MTCC 170); one Gram-positive bacterium (Bacillus subtilis MTCC 96); two Gram-negative bacteria (Escherichia coli MTCC 1652 and Pseudomonas aeruginosa MTCC 741) and were screened for antifungal and antibacterial activity of the complexes. All the microbial cultures were procured from Microbial Type Culture Collection (MTCC), IMTECH, Chandigarh. The bacteria were subcultured on Nutrient agar whereas yeast on Malt yeast agar. The antimicrobial activities and minimum inhibitory concentration (MIC) were determined as per literature method [10]. 2.3.2. Antioxidant activity DPPH (2, 2-diphenyl-1-picrylhydrazyl) method was used to test the free radical scavenging activity of the samples [11]. Stock solution of 1 mM DPPH was prepared in methanol and the solutions of ascorbic acid and different concentrations of test compounds (0e500 mg/ml) were prepared using DMSO. To the 1.0 ml of sample solution of different concentration 3.0 ml of methanolic solution of DPPH (0.1 mM) was added. The samples were incubated for 30 min at room temperature. The control experiment was carried out as above without the test samples. The absorbance of test solutions was measured at 517 nm. Ascorbic acid was used as standard whereas DPPH was used as positive control and DMSO was used as negative control. The reduction of DPPH was calculated relative to the measured absorbance of control. %Inhibition or % Radical Scavenging activity was calculated using the following formula:

%Radical scavenging Activity ¼ ½ðAo  Ac Þ=Ao   100 where Ao is the absorbance of the control and Ac is the absorbance of the sample at concentration c. 2.3.3. Molecular docking studies The docking studies were carried out for the representative complex using Glide, Maestro 10.0(Glide version 65013, Schrodinger, LLC, New York, NY, 2014) The complex structure was drawn with the help of ACD12 chem sketch. These molecules were further

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processed using quantum mechanical optimization using Jaguar (Jaguar, Schrodinger, LLC, New York, NY, 2014). The optimized complex was used for docking purpose with X-ray crystal structure of COX-2 (PDB ID:5COX) [12]. 2.4. Synthesis of complexes The complexes were synthesized by template approach by dissolving trivalent chromium or iron salt (10 mmol) in the minimum quantity of methanol (~20.0 cm3) stirred with a methanolic solution of succinyldihydrazide (1.46 g, 10 mmol). The resulting solution was refluxed for 0.5 h, subsequently, methanolic solution of thiophenedicarboxaldehyde (1.40 g, 10 mmol) was added to the refluxing mixture and refluxing was continued for 10e12 h. The mixture was cooled to room temperature and filtered, washed with methanol, acetone and diethyl ether and dried in vacuo. The completion of reaction was checked by TLC and the yields were ~50e59%. 2.5. Analysis of metal content In all cases, the organic part of the complexes was completely decomposed before the estimation of metal ions from the complexes. The following general procedure was adopted for this purpose for all the metal complexes. A known amount (~0.1 g) of the metal complexes was decomposed with concentrated nitric acid at high temperature, the excess acid being expelled by evaporation with concentrated hydrochloric acid. This process was repeated till the organic part of the complex was completely removed. The residue was cooled and this residue was dissolved in distilled water in both the cases. 2.5.1. Fe(III) determination To the above obtained solution standard EDTA was added and then add hexamine to adjust the pH to 5e6. Now xylenol orange indicator was added into it. Titrated excess of EDTA with standard lead nitrate till end point reaches i.e., redeviolet colour appears. 2.5.2. Cr(III) determination To the solution obtained after decomposition of organic part added NaOH for neutralization until precipitates begin to form. Now acetate buffer (6M CH3COOH þ 0.6M CH3COONa) was added into it. Heat the contents, after addition of mixture of lead nitrate and potassium bromate into it, upto 90e95  C till precipitation completes. Cooled, filtered on sintered glass crucible and weighed as lead chromate. 2.6. Analytical data Complex 1: [Cr(C10H10N4O2S)Cl]Cl2: Yield-55%, Brown, Anal Cal. For: Cr, 12.72%; C, 29.39%; H, 2.47%; N, 13.71%; S, 7.85%; M. Wt., 408.63; Found: Cr, 12.60%; C, 28.99%; H, 2.40%; N, 13.54%; S, 7.81, m/ z [M]þ, 406.9; ^M, 141; meff, 4.30 B M. Complex 2: [Cr(C10H10N4O2S) NO3] (NO3)2: Yield-52%, Dark brown, Anal Cal. For: Cr, 10.65%; C, 24.60%; H, 2.06%; N, 20.08%; S, 6.57%; M. Wt., 488.29; Found: Cr, 10.59%; C, 24.67%; H, 2.02; N, 20.00%; S, 6.14%; m/z [M]þ, 487.1; ^M, 155; meff ¼ 4.51 B.M. Complex 3: [Cr(C10H10N4O2S) OAc] (OAc)2: Yield-49%, Brick red, Anal Cal. For: Cr, 10.85%; C, 40.09%; H, 3.99%; N, 11.69%; S, 6.69%; M.Wt., 479.4; Found: Cr, 10.68%; C, 40.03%; H, 3.65%; N, 11.52%; S, 6.56; m/z [M]þ, 478.2; ^M, 160; meff, 4.56 B.M. Complex 4: [Fe (C10H10N4O2S) Cl] Cl2: Yield-47%,Orange, Anal Cal. For: Fe, 13.54%; C, 29.12%; H, 2.44%; N, 13.58%; S, 7.77%; M.Wt., 412.48; Found: Fe, 13.38%; C, 29.01%; H, 2.37%; N, 13.49%; S, 7.75%; m/z [M]þ, 410.8; ^M, 175; meff, 5.76 B.M.

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Complex 5: [Fe (C10H10N4O2S) NO3] (NO3)2: Yield-50%, Brown, Anal Cal. For: Fe, 11.35%; C, 24.41%; H, 2.05%; N, 19.92%; S, 6.52%; M.Wt., 492.14; Found: Fe, 11.10%; C, 24.42%; H, 2.03%; N, 19.79%; S, 6.47%; m/z [M]þ, 490.8; ^M, 160; meff, 5.55 B.M. Complex 6: [Fe (C10H10N4O2S) OAc] (OAc)2: Yield-59%, Reddish brown, Anal Cal. For: Fe, 11.56%; C, 39.77%; H, 3.96%; N, 11.59%; S, 6.64%; M.Wt., 483.25; Found: Fe, 11.50; C, 39.80%; H, 3.39%; N, 11.44%; S, 6.56%; m/z [M]þ, 485.2; ^M, 153; meff, 5.95 B.M. 3. Results and discussion 3.1. Chemistry The analytical data of the metal complexes corresponds to the formula that may be represented as: [M(C10H10N4O2S)X]X2; where M ¼ Cr (III), and Fe (III) and X ¼ Cl1, NO3 1 and CH3COO1. The complexes were soluble in DMSO & DMF. They were thermally stable even at higher temperature and decomposed completely above 800  C. Higher value (150e180 U1 cm2 mol1) of molar Conductivity (measured in DMSO) indicated them to be 1:2 electrolytes [13]. As crystal developement for X-ray crystallography was not successful so powder X-ray diffraction has been carried out which indicates that the system belongs to triclinic crystal system. The analytical, spectroscopic and magnetic data enables us to predict the probable structure of the complexes (Scheme 1). 3.2. Infra-red spectra A pair of bands present in the spectrum of succinyldihydrazide at ~3287 and ~3198 cm1 corresponding to v(NH2), were absent in the infrared spectra of all the complexes. The disappearance of these bands and appearance of a new strong band near 1600e1630 cm1 points towards the formation of macrocyclic Schiff's base [14], as these bands may be assigned to v(C]N) stretching vibrations [15,16] (Fig. S1, Supplementary material). The bands due to >C]O group of the eCONH moiety in the spectrum of succinyldihydrazide were shifted to a lower frequency (~1659 & 1599 cm1) in the spectra of all complexes [17]. The lower value of v(C]O) of succinyldihdrazide and v(C]N) in the complexes may be explained on the basis of drift of the lone pair electron density from the heteroatoms (nitrogen & oxygen) towards the central metal atom [17] indicating that coordination occurred through oxygen of C]O of succinyldihydrazide and the nitrogen of the C]N group. The CeS band 805e815 cm1 remain unaltered in the spectra of complexes [18] pointing towards the nonparticipation of S in the coordination. The presence of a single medium band present in the range 3206e3342 cm1 may be assigned to (NeH) stretch [19] of succinyldihydrazide. The CeN stretch occurs in the range 1000e1300 cm1. The presence of the absorption bands at 1415e1440, 1280e1310 and 1090e1100 cm1 in the IR spectra of all the nitrato complexes suggest that both nitrate groups are coordinated to the central metal ion in an unidentate fashion [14]. The

IR spectra of all the acetate complexes show an absorption band in the region 1660e1670 cm1 i.e. assigned to the v(COO1) as asymmetric stretching vibrations of the acetate ion and another in the region 1235e1260 cm1 that can be assigned to the v(COO1) symmetric stretching vibrations of the acetate ion. The difference between vas and vs, which was around 390e370 cm1 i.e. greater than 144 cm1, indicates the unidentate coordination of the acetate group with the central metal ion. The far infrared spectra show bands in the region 430e475 cm1 and 220e250 cm1 corresponding to v(MN) & v(MO) stretching vibrations [20]. The presence of these bands in all complexes identifies coordination of the azomethine nitrogen and carbonyl oxygen of amide group. The bands present in the range 320e350 cm1 may be assigned to v(MCl) vibrations. 3.3. Magnetic measurements and electronic spectra 3.3.1. Chromium complexes The chromium(III) complexes have effective magnetic moments (meff) in the range 4.30e4.56 B. M. at room temperature, which indicates the presence of three unpaired electrons in the metal ion [21,22]. The electronic spectra of the chromium complexes show bands at 1080e1070, 738e720, 550e510, 341e327 and 246 nm. These spectral bands are consistent with that of a five coordinated square pyramidal geometry of chromium complexes, the structure of which were confirmed with the help of X-ray measurements [23]. 3.3.2. Iron complexes The effective magnetic moments (meff) of iron complexes varies in the range 4.99e5.05 B. M., corresponding to five unpaired electrons, which is close to the predicted high spin values for these metal ions [21,22]. The electronic spectra of the iron complexes show bands at 1045e1010, 670e655 and 378e370 nm, (Fig. 1) which are consistent with the reported square pyramidal geometry for iron(III) complexes [24,25]. Assuming C4v symmetry for these complexes, the various bands can be assigned as: dxy / dxz, dyz and dxy / d2z. 3.4. ESI mass spectra The electronic impact mass spectrum of all the complexes show [M]þ in addition to the other peaks due to fragmentation pattern. The molecular ion peak for various complexes were as follows: at m/z 406.9 [calcd M.Wt. ¼ 408.6]for [Cr(C10H10N4O2S) Cl] Cl2]þ; at m/z 487.1 [calcd M.Wt. ¼ 488.3]for [Cr(C10H10N4O2S) (NO3)](NO3)2]þ; at m/z 478.2 [calcd M.Wt. ¼ 479.4]for [Cr(C10H10N4O2S)OAc](OAc)2]þ; at m/z 410.8 [calcd M.Wt. ¼ 412.5] for [Fe(C10H10N4O2S) Cl] Cl2]þ; at m/z 490.8 [calcd M.Wt. ¼ 492.1] for [Fe(C10H10N4O2S) (NO3)](NO3)2]þ; at m/z 485.2 [calcd M.Wt. ¼ 483.3]for [Fe(C10H10N4O2S)OAc](OAc)2]þ. The observed data were in good agreement with the proposed molecular formula

Scheme 1. Scheme for synthesis of complexes derived from succinyldihydrazide and thiophene-2,5-dicarboxaldehyde in the presence of trivalent chromium and iron metal salts.

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Table 1 Selected bond lengths & bond angles of [Cr (C10H10N4O2S) Cl]þ2 complex. Parameters

Bond length(Å)

Parameters

Bond angles (degree)

28Cre10N 9Ne28Cr 28Cre5O 6Oe28Cr 29Cle28Cr 8Ne10N 11Ce9N 7Ne9N 10Ne18C

2.42 2.05 1.09 1.14 2.12 1.41 1.31 1.41 1.31

29Cle28Cre10N 9Ne28Cre29Cl 6Oe28Cre29Cl 29Cle28Cre5O 5Oe28Cre10N 9Ne28Cre10N 5Oe28Cre9N 6Oe28Cre5O 10Ne28Cre6O

95.52 85.30 118.97 60.94 116.35 171.08 71.79 86.94 52.11

3.7. Molecular modelling

Fig. 1. Electronic spectrum of [Fe(C10H10N4O2S) (OAc)] (OAc)2 complex.

that is [M(C10H10N4O2S)X]X2 and suggest the monomeric nature of the complexes. In addition to the molecular ion peaks, the spectra exhibit other peaks assignable to various fragments arising from the thermal cleavage of the complexes as illustrated by Fig. S2(A) and (B), Supplementary material. 3.5. Electron spin resonance spectra (ESR) The ESR spectrum of chromium(III) complexes were obtained at room temperature in the solid state on X-band at frequency of 9.1 GHz under the magnetic field strength of 3,000G. The spectra show a broad isotropic signal from which only giso parameters (from a & b values as shown in ESR, Fig. S3, Supplementary material) have been calculated. The observed data (giso ¼ 1.98 < 2.0023) indicates that the unpaired electron resides in dxy orbital with square-pyramidal geometry around the Cr (III) complexes [26].

g ¼ hv=bH where g ¼ Gyromagnetic ratio h ¼ Planck's constant; 6.62  1027 erg s v ¼ 9.11  109 cycles/sec. b ¼ 0.92731  1020 erg/gauss H ¼ aþb/2 where a ¼ 3110, b ¼ 3450; H ¼ 3280

The optimization of ligand-M(III) complexes was done to calculate the minimized energy geometry for the complexes with the aid of structure optimization and normal coordinate force field calculations based on density functional theory (DFT) B3LYP/631G(d,p) method using Gaussian 09W [28]. The selected bond angles and bond lengths for the representative complex [Cr(C10H10N4O2S)Cl]þ2 are shown in Table 1. The calculated energy for [Cr(C10H10N4O2S)Cl]2þ complex (Fig. 2) was 7.28  104 ev whereas the calculated energy of [Fe(C10H10N4O2S)Cl]2þ was 7.83  104 ev. The energy of HOMO and LUMO is 3.20 ev and 1.45 ev for [Cr(C10H10N4O2S)Cl]2þ complex and 13.00 ev (HOMO), 10.13 ev (LUMO) for [Fe(C10H10N4O2S)Cl]2þ complex respectively, as shown in Fig. S5, Supplementary material. The smaller the ELUMO smaller is the resistance to accept electrons or vice-versa. Thus, comparing both the complexes chromium complex has lower ability to donate but higher ability for the accepting the electrons [29]. 3.8. Powder X-ray diffraction The powder XRD graph of the [Fe(C10H10N4O2S) (NO3)] (NO3)2 is given in Fig. 3. The presence of sharp peaks in powder X-ray diffractograph pattern points towards the slightly crystalline nature of the complex. The lattice parameters were calculated using computer program Fullprof suite via dicvol04 [30]. The indexing was confirmed by comparing the observed and calculated 2q values. Fe(III) complex show triclinic crystal system. The calculated

    giso ¼ 6:62  1027  9:11  109 ÷ 0:92731  1020  3280 giso ¼ 1.98 3.6. Thermogravimetric analysis (TGA) The thermogram for the complex [Cr(C10H10N4O2S)OAc](OAc)2 was recorded from ambient to 800  C at a heating rate of 10  C/min in a nitrogen atmosphere. The complex decomposed completely above 800  C as shown in Fig. S4, Supplementary material. The absence of any decomposition step from 100 to 250  C indicates the absence of lattice water inside as well as outside the coordination sphere [27]. The decomposition step in the temperature range 280e520  C may corresponds to the slow decomposition of the complete organic part of the complex (C10H10N4O2S)O (Obs. ¼ 56.33%, calc. ¼ 55.58%).

Fig. 2. Geometry optimized structure of [Cr(C10H10N4O2S)Cl]þ2 & [Fe(C10H10N4O2S) Cl]þ2 complexes.

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Fig. 3. Powder XRD graph of [Fe(C10H10N4O2S) NO3] (NO3)2 complex.

interplanar-spacing (d values) and miller indices (h, k, l) have been reported in Table 2. The unit cell parameters are as follows a ¼ 4.9127, b ¼ 11.2517, c ¼ 12.1687 a ¼ 110.584 b ¼ 95.158, g ¼ 96.342 and volume ¼ 619.82. The condition asbsc and asgsb for Fe (III) complex satisfy triclinic crystal system. The system belongs to p Braivis lattice. 3.9. Biological results and discussion 3.9.1. Molecular docking The in silico molecular docking studies of the complex, [Fe(C10H10N4O2S) (Cl)]þ2, in the active site of COX-2 (PDB code: 5COX) were performed, in order to get insight into the nature of interaction between complex and active site of COX-2, using Glide in Maestro 10.0 release 2014-4. The docking studies show that the complex 4 bound at the binding pocket of the COX-2. The thiophene moiety of the macrocyclic complex is placed close to the side chain HIE 214 of protein resulting into piepi stacking interaction with the imidazole ring of histidine moiety whereas the eCH2 and eNH group of succinyldihydrazide involved in the hydrogen bonding (2.54 Å) and vanderwaal's interaction (2.05 Å, 2.02 Å) with the HIS 207 and HIS 386 moiety of COX-2 respectively, as shown in Fig. 4, thus affecting the activity of COX-2 in one or another way. The docking score for the screened complex was 2.14 and the docking energy is 34.75 kcal/mol.

Table 2 X-ray diffraction data of the [Fe(C10H10N4O2S) (NO3)] (NO3)2 complex. 2TH. obs

2TH. cal

d-spacing

h

K

l

Diff. 2TH.

8.416 9.140 14.787 18.262 18.842 20.290 21.158 24.633 26.371 27.385 28.398

8.413 9.137 14.795 18.259 18.851 20.287 21.159 24.636 26.373 27.377 28.398

10.49722 9.66734 5.98586 4.85392 4.70600 4.37331 4.19567 3.61108 3.37697 3.25424 3.14035

1 0 1 1 0 1 3 1 1 1 1

0 1 2 1 0 2 1 2 1 2 2

0 0 0 1 1 1 0 0 1 1 1

0.003 0.004 0.007 0.004 0.009 0.003 0.001 0.003 0.002 0.007 0.000

3.9.2. Antioxidant activity The newly synthesized macrocyclic complexes were evaluated for their antioxidant activity using DPPH. Antioxidant activity varies directly with the concentration of the complexes as shown in Table 3. All the complexes show moderate to significant activity. The quenching of DPPH radical can result from the paramagnetic property of the metal ion involved. The complex 2 and 5 are the best antioxidant agents showing the IC50 less than 50 mg/ml. The tested complexes contain the azomethine hydrogen which is acidic in nature and can be donated to the DPPH free radical thus converting it to stable free radical [31]. The chromium complexes possess higher antioxidative activity as compared to iron complexes, as they have lower IC50 values. This is directly related to electron affinity of the metal ion involved, higher the electron affinity higher will be the efficiency to release acidic hydrogen radical. Thus, chromium(III) having d3 configuration have higher electron affinity to complete its half-filled configuration as compared to iron which already have half-filled configuration (d5) due to which possess lower electron affinity. The electronegativity of counter ions further affects this strength to release hydrogen radical. Thus, the antioxidant activity of nitrate complexes was found to be higher than the other due to the higher electron withdrawing effect of nitrate ligand that makes the azomethine hydrogen more acidic and facilitate easy release of hydrogen. (Fig. 5, Table 3). 3.9.3. Antimicrobial activity All the synthesized macrocyclic complexes were also screened for their antibacterial and antifungal activity. All the complexes (1, 2, 3, 4, 5 and 6) possessed variable antimicrobial activity against all the tested microorganisms except gram negative bacteria (i.e. P. aeruginosa). The complexes show MIC in the range 8e128 mg/ml. However, the complex 5 was found to be best antipathogenic agent with an MIC value of 8 mg/ml. This may be due to the presence of iron which is involved in a number of biological phenomenons. Chelation of iron decreases its concentration in the nearby region of activity area of microorganisms. Enhanced activity of nitrate complex of iron may be explained on the basis of presence of extra nitrogen (in the form of nitrate ligands) which is involved in number of bacterial activities (for e.g., Nitrifying bacteria totally

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Fig. 4. Molecular docking of [Fe(C10H10N4O2S) Cl]2þ. a) complex showing interaction with COX-2, b) Iron complex in the active site.

Table 3 Absorbance of complexes at different concentration at 517 nm. Compound

Ascorbic acid 1 2 3 4 5 6

Table 4 Minimum inhibitory concentration (MIC) of compounds (in mg/ml) by using modified agar well diffusion method.

Concentration (mg/ml) 0

50

100

250

500

1.323 1.323 1.323 1.323 1.323 1.323 1.323

0.732 0.918 0.413 0.692 0.869 0.502 0.805

0.568 0.790 0.352 0.543 0.615 0.430 0.731

0.301 0.386 0.208 0.451 0.595 0.365 0.642

0.132 0.121 0.111 0.264 0.390 0.106 0.331

depend on nitrogen concentration) and the chelation increases (greater the number of heteroatoms greater is the possibility of chelation). Thus the polarity of complex is decreased to a larger extent or lipophilicity is enhanced, thereby increasing its possibility of cell permeation and inhibition of microorganisms. (Table 4, Fig. 6) The complexes were found to be more active against gram positive bacteria as compared to gram negative E.coli. According to Overtone's cell permeation and Tweedle's chelation theory chelation reduces the polarity of metal ion to a considerable extent due to partial sharing of positive charge with the donor group and possible p-electron delocalization over the whole chelate ring. Reduction in polarity in turn increases the lipophilicity of the complex and the interaction between metal ion and lipid bio layer

Fig. 5. Graphical representation of % antioxidant activity (% inhibition) of the complexes.

Compound no.

Bacillus subtilis

Escherichia coli

Saccharomyces cerevisiae

Candida albicans

1 2 3 4 5 6 Ciprofloxacin Amphotericin-B

32 8 16 32 8 32 6.25 Nt

16 32 8 128 8 8 6.25 Nt

32 8 16 8 16 128 Nt 12.5

8 32 8 16 8 32 Nt 12.5

Nt ¼ not tested. The bold number represents the complexes showing best activity or minimum MIC values i.e. best antimicrobial agent.

is enhanced, thus facilitating the diffusion of metal complex through the cell wall and resulting in the interference with the normal cell processes.

4. Conclusions In summary, a series of trivalent transition metal macrocyclic complexes containing heterocyclic ring have been synthesized and characterized with the aid of various physical and spectroscopic techniques. The results revealed a five coordinated square

Fig. 6. Bar graph representation of minimum inhibitory concentration (MIC) of complexes.

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pyramidal geometry for all of these complexes. The complex 5 i.e., [Fe (C10H10N4O2S) NO3] (NO3)2 was found to have best antipathogenic activity and complex (2)-[Cr(C10H10N4O2S) NO3] (NO3)2 and (5)-[Fe (C10H10N4O2S) NO3] (NO3)2 have the best antioxidant activity. The molecular docking studies shows that the screened complex may effectively inhibit COX-2 with Glide score 2.14. Many factors such as presence of heteroatoms, electronegativity, solubility, dipole moment, electronic factor, conductivity influenced by metal ion may be possible reasons for remarkable antimicrobial and antioxidant activities of these complexes [32]. Powder X-ray diffraction suggests the triclinic crystal system for the studied framework [33]. Acknowledgement Ms. Parveen thanks CSIR, New Delhi for financial support in the form of Senior Research Fellowship (File No. 09/1050 (0001)/2011EMR-1). Thanks are also due to NIT, Kurukshetra for providing necessary resarch facilities and Microbiology Department, Kurukshetra University, Kurukshetra for carrying out antimicrobial activity. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.molstruc.2015.07.025. References [1] a) L.F. Lindoy, The Chemistry of Macrocyclic Ligand Complexes, Cambridge University Press, New York, 1989; b) S. Chandra, L.K. Gupta, D. Jain, Spectrochim. Acta A 60 (2004) 2411e2417. [2] M.A. Malik, S.A. Al-Thabaiti, M.A. Malik, Int. J. Mol. Sci. 13 (2012) 10880e10898. [3] D.P. Singh, M. Kamboj, K. Jain, Int. J. Chem. Tech. Res. 3 (2012) 21e24. [4] S. Bondock, W. Fadaly, M.A. Metwally, Eur. J. Med. Chem. 45 (2010) 3692e3701. [5] S.M. Jadhav, V.A. Shelke, S.G. Shankarwar, A.S. Munde, T.K. Chondhekar, J. Saudi Chem. Soc. 18 (2014) 27e34. [6] K. Jamuna, B. Ramesh Naik, B. Sreenu, K. Seshaiah, J. Chem. Pharma. Res. 4 (2012) 4275e4282. [7] B. Bahramian, V. Mirkhani, M. Moghadan, S. Tangestaninejad, Appl. Catal. A 301 (2006) 169. J. Wen, J. Zhao, X. Wang, J. Dong, T. You, J. Mol. Catal. (A) 245(2006) 242e247. [8] D.P. Singh, V. Malik, R. Kumar, Res. Lett. Inorg. Chem. (2009). Article ID:

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