ABSTRACT A series of mixed ligand copper(II) complexes, namely Cu(L)SO4.2H2O(1) and Cu(L-ONN-L1) where L2-Hydroxy-2-Methyl Propiophenone Picolylamine, L1 Bipyridine(bipy)(2), 1,10-phenanthroline(phen)(3) and 6-Methyl bipyridine (6-Me-bipy)(4) have been synthesis and characterized by various spectroscopic techniques like IR, EPR, electronic absorption, fluorescence spectroscopy and cyclic voltammetry. Aforesaid spectral data, it is evident that the heterocyclic bases like bipy, phen, 6-Me bipy acts as neutral bidentate ligand coordinating to the metal ion through two nitrogen donor atoms. Spectral data concluded that the complexes (1-4) have distorted trigonal bipyramidal structures, around Cu(II) centre with co-ordination of Cu(N2O3 ) and Cu(N4O2) respectively. But the complexes (1-4) have redox reaction CuII /CuI, which slightly improves its reversibility with considerable decrease in current intensity. The synthesized complexes were tested for antimicrobial and antioxidant activities. The results shown a significant growth inhibitory activity (antimicrobial antibacterial and antifungal) against bacterial strain streptococcus aureus(ATCC 25923), Bacillus subtilis ( ATCC 6633), Escherichia coli (ATCC 25922), Klebsiell pneumonia (ATCC 13882).The activity against streptococcus aureus is an interesting observation as the commercially available streptomycin is found to be an active against this bacterial strain, and the antioxidant activities also showed good results when compared to the standard Ascorbic acid. In particular, complex 3 formed by 1, 10-Phenanthroline has shown novel antimicrobial and antioxidant activities against various bacterias were investigated. Keywords Copper (II) complex, bipyridine, 1, 10-Phenanthroline, 6-Me bipyridine, IR, UV-Vis, EPR, CV and Biological activity (Antimicrobial and antioxidant activities). 1. INTRODUCTION Transition metal complexes have been studied extensively due to their potential applications in biological processes 1-3. Among transition metals, copper has its own distinctive identification due its coordinating ability with various ligands to form variety of geometrical structures such as square planar, square pyramidal, distorted square pyramidal, and octahedral. The copper complexes with N-donor ligands have proven to be active catalysts for the hydrolysis of phosphate ester and carbonyl compounds 4, synthesis of many complexes by using 1,10-phenanthroline and 2,2-bipyridine are attractive building blocks that are incorporated with various transition metals to form complexes. Both nitrogen atoms in each ligand are ideally placed for cooperative binding with many metal cations. In addition, metal complexes of the aforesaid ligands are frequently employed for catalytic reactions 5 6. Metal complexes have attracted considerable attention in modern medicine due to their antibacterial, antifungal and anti oxidant properties 78. The abusive use of antimicrobials has resulted in high levels of resistance which constitute a major problem coupled with the emergence of strains resistant to almost all drugs 9. The copper (II) complexes have been investigated against a variety of bacterial, fungal as well as antioxidant strains and showed profound activities against various diseases 1011. Literature survey reveals that synthesis of many complexes it is evident that ligands, co-ligands and counter ions, play a vital role in the coordination geometry of the Cu (II) complexes 12. Due to varied stereo and physiochemical properties, lot of work is being carried out on five coordinate Cu(II) complexes with N,N-chelating ligands and monodentate co-ligands13,14,15. As many investigations were performed and reported on a few mixed ligand complexes involving hetero cyclic bases such as phenanthroline and bypiridine1617. Based on their structural diversity and wide applications, the present study intends to investigate the coordination chemistry of transition metal using ligand. In the present work, 2-hydroxy-2-methyl propiophenone with picolylamine (Scheme 1) and heterocyclic bases like 1,10-phenanthroline (phen) 2,2 bipyridine and 6-Me-bipyridine (6-Me-bipy) have been used as co-ligands for the synthesis of copper(II) complexes. The main objective of the study is to investigation of synthesis copper (II) complexes, and characterized by IR spectra, EPR analysis, UV spectra, CV analysis and florescence spectroscopy. Furthermore the complexes (1-4) were initially screened for their anti-microbial activity and anti- oxidant activity. As it showed good cytotoxicity. EMBED ChemDraw.Document.6.0 Scheme 1 Chemical structure of Ligand 2. MATERIALS AND METHODS The reagents 2-Hydroxy-2-Methyl Propiophenone (Aldrich), 2-picolylamine (Aldrich), Cu(II) salts, 2,2- Bipyridine,6-Me bipyridine and 1,10-Phenanthroline(1,10-Phen) (Sigma) and Solvents like methanol, acetic acid and water were used in the synthesis and analysis in analytical grade without any further purification. 2.1 Physical Measurements Infrared spectra were recorded (FT IR) (KBR pellets) in the range 4000 400 cm-1 using KBr pellets. UV spectra were recorded on a cary 5000 version spectrophotometer in the range 200 800 nm using solutions in DMF (at room temperature). The electrochemical behavior of Cu (II) complexes was studied by using cyclic voltametric technique (CV)(CH-Instrument CH1610D). The EPR spectra of all the complexes were recorded in polycrystalline state at room temperature on X-band ESR spectrometer. Fluorescence spectra were measured on a Hitachi (U-3400) in the wavelength range 250-800 nm with a spectral resolution of 1 nm. 3. EXPERIMENTAL 3.1. Synthesis of Ligand Methanolic solution (10 ml) of 2-Picolylamine(0.01 mol) was slowly added to a solution of 2-hydroxy-2-methyl propiophenone (0.01 mol) in absolute methanol (10 ml) for the synthesis of (E)-2-methyl-1-phenyl-1-((pyridine-2-ylmethy)imino)propan-2-ol. Then the mixture was stirred at 50oC for 2 hours. The reaction mixture was allowed to stand for slow evaporation of the solvent till yellow oil was formed. After this, it was re-dissolved in a minimum amount of methanol. The purity of the compound was tested with the help of the TLC technique. The product was characterized by IR, IHNMR, 13CNMR and Mass spectroscopy. Cu(II)SO4.2H2O(I) A methanolic solution of CuSO4.2H2O (0.001 mol, 0.2496 g) was added to a solution of the ligand (L) (0.001 mol, 0.2543 g) in hot ethanol for 4 hrs at 700C with constant stirring and green colour was obtained. The formed complexes were filtered, washed with cold ethanol and ether, and then dried in vacuo over anhydrous CaCl2. Cu (L-ONN-L1) (L1-N, N-bipy(2), Phen(3) and 6-Me-bipy(4) The complexes 2, 3 and 4 were prepared by refluxing a methanolic solution of CuSO4.2H2O (0.5 mmol, 0.1248 g). This was added to a solution of the ligand (L) (0.5 mmol, 0.1271g) in hot ethanol for 30 minutes at 500C with constant stirring and green color was obtained. Then methanolic solution of the heterocyclic base (L1)(0.5mmol,0.0780g bipy)(2), (0.5mmol,0.0901g, Phen)(3), (0.5mmol, 0.0998g, 6-Me-bipy) (4) in 111 molar ratio was added to the above solid mixture and stirred continuously for about four hours. The green coloured compounds formed in the process was filtered, washed with cold methanol and ether, and then dried in vacuum over anhydrous CaCl2. EMBED ChemDraw.Document.6.0 EMBED ChemDraw.Document.6.0 (1) (2) (3) (4) Bipy Phen 6-Me-Bipy Scheme 3 Synthetic scheme of Cu (II) complexes (1-4) 3.3. Antibacterial Activity Preparation of the Media The weighed nutrient agar(Hi media) of 6.5gmwas dissolvedwithin the500mlofdistilled water. The medium was sterilizedunderneath15lbs pressure forquarter-hourinanautoclave. 30ml of this sterilized semi-solidnutrient agarmedium was poured in pre-sterilized 90mm glass Petri platesunderneathasepticconditions inlaminalair flow chamber. The plates were permittedto coolatroom temperaturefor solidification of the medium. 3.4. Anti Fungal Activity Preparation of the Media The weighed PotatodextroseAgar (Hi media) of 4.875gmwas dissolvedwithin the125mlofdistilled water. The medium was sterilizedunderneath15lbs pressure forquarter-hourinanautoclave. 30ml of this sterilized semi-solidnutrient agarmedium was poured in pre-sterilized 90mm glass Petri platesunderneathasepticconditions instratified air flow. The plates were then permittedto coolatroom temperaturefor solidification of the medium. Paper disc diffusion technique Paper disc diffusion technique was employedfor the determination oftheantimicrobialactivities (antibacterialandantifungalactivities). These assaysareadapted to establish a dose response curve for a given strain ofbacteriaagainst a giventestcompound.By utilizing the subsequentprotocol, 20mlof agar medium was poured in to the90mmglass Petri plate and seeded with thebacteria,within whichcase the inoculums densityought tobenotedas 100l. Theinoculantwasequallydistributed throughout the agar mediumusingpipettes or a sterile glass rod. Thentestdiscsareloaded witha fixedvolume of anotedconcentration of thetestcompound andarethen dried. The disksareplaced on the agar plateseveryplatehave to toincludea positivecontroladditionallyto thetestcompounds treated discs. Finally the petri plates were incubated at 37C inincubatorfor 24hoursand also thezone of inhibition was measured (Diameter in mm) tothe nearest0.1 mm,with avernier calipers.This couldbe performed across2perpendicular diametersfor everydisc. 3.5. Antioxidant Activity In-vitro analysis ofantioxidantandfree radicalscavenging activities of synthesis compounds were done by DPPHtechnique. The solvent extracts has shownthe highestantioxidantactivity by DPPH andmaximumincreasewithin theabsorbance of the reaction mixture indicatingenhancedreducing power by ferric-reducingantioxidant power (FRAP) assay followed by synthesis compounds as shown in Scheme 3. DPPH (2, 2-Diphenyl-1-picryl hydrazyl) activity A 0.1 M solution of DPPH was prepared in methanol and 500 L of this solution was added to 1 mL of the crude extract (dissolved in 10 DMSO) at different concentrations (20 – 100 g/mL). These solutions were mixed and incubated in the dark for about 30 min at room temperature. The absorbance was measured at 517 nm against a blank lacking scavenger. Vitamin C was used as a standard. The antioxidant or free radical inhibitory activity was calculated according to the following formula. inhibition ((Ac As) / Ac) x 100 Where, Ac Absorbance of control, As Absorbance of sample 4. RESULTS AND DISCUSSION The experimental procedures and characterization data are presented below 4.1. Infrared spectral studies Phen 4.2. Electronic spectral studies The energy level sequence will depend on the amount of distortion due to ligand field and John Teller effect 24. The absorption band shows lower energy in the complexes 3 and 4 at 595 and 594 nm, owing to the structural difference between the complexes in the presence of the aromatic ring of the ligand 27. 6-Me-Bipy complex permits low energy to copper (II) charge transfer (LMCT) band near 346 nm, the complexes 2 and 3 also display two such bands. The lower energy band can be attributed to nitrogen to copper (II) CT transition, while the other may involve heterocyclic base. EPR3 EPR 4 By using the g factors, the value of the geometric parameter (G), which is a measure of the exchange interaction between Cu (II) centers in polycrystalline compounds, can be estimated using the following formula. QUOTE for axial symmetry SVL1 Cu-Phen-Em 4.5. Electrochemical studies 4.6. Biological activity Antimicrobial activity Synthesized complexes (1-4) were evaluated in vitro for their antimicrobial activity against various pathogenic bacteria and fungal strains by paper disc method. The anti bacterial activities are carried out against two Gram- positive bacteria strains, Bacillus subtilis and Staphylococcus aureus and two Gram-negative bacteria strains, Escheriachia coli and Klebsiella pnuemoniae. Antifungal activity was carried out with three fungal strains, Aspergillus niger and Aspergillus flavus and Rhizopus. Streptomycin and Fluconazole were used as antibacterial and antifungal reference drugs respectively. Synthesized complexes were found to be moderately active and slightly active compared to the standard drugs (See Table 1). 4 (ZOIS.a 1.2 mm) 2(ZOIS.a 1.0 mm) 3(ZOIB.s 1.0 mm, 4(ZOIK.p 1.1 mm) 3 (ZOIE.c 1.0 mm) were showed moderate activity. But complex 1 showed low antibacterial activity. Based on the above bacterial activity results the following observations can be made due to presences of bipyridyl, 6-Me bipyridyl, 1, 10-phenonthroline co-ligands of copper (II) complexes low toxic, suitable for good bacterial activity. Table 1 Antimicrobial activity of compounds Zone of inhibition (Paper Disc Method) ComplexesZone of Inhibition (mm)BacteriaFungiGram- positiveGram-negativeB. sS. aE. ck.pA. nA. fR1.0.90.70.70.60.60.80.82.0.91.00.80.70.70.80.83.1.00.91.00.70.60.90.94.0.81.20.81.10.70.60.6Streptomycina1.72.83.52.30.7Fluconazolebf1f2f3 B.s Bacillus subtilis S. a Staphylococcus aureus E. c Escheriachia coli S Salmonella A. n Aspergillus niger A. f Aspergillus flavus R Rhizopus No Activity a Reference Drug( Antibacterial activity) b Reference Drug (Antifungal activity). f1, f2, Standard value 2.9 mm for compounds 4a-e 3.2 mm for 5a-e. f1 Standard value 0.7 mm for complexes (1-4) f2, f3 Standard value 2.1 mm for complexes (1-3), f2, f3 standard value 2.8 mm, 2.9 mm for complex 4 4.7. Antioxidant activity CONCLUSIONS REFERENCES Hazoor A Shad, KH Thebo, MA Malik, M Helliwell (2011) Synthesis, characterization and X-ray diffraction of Cu(malonate)(phen)2217H2O complex. J Mol Structure 1001(1-3) 12-15. 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Yg/JBT/BqQsR(0)-k k.7A.y3aKUGRxMDV(9nITTvyu/FJTRzqJo 0x 9 Node Shift Base Inc. Comment (ppm rel. to TMS) C 159.0 149.8 2-pyridine 8.8 1 -C 0.4 general corrections CH 148.6 149.8 2-pyridine -0.4 1 -C -0.8 general corrections C 140.1 128.5 1-benzene 8.8 1 -CN-C 2.8 general corrections CH 120.9 123.6 2-pyridine -3.0 1 -C 0.3 general corrections CH 128.2 128.5 1-benzene 0.5 1 -CN-C -0.8 general corrections CH 122.2 123.6 2-pyridine -0.6 1 -C -0.8 general corrections CH 128.2 128.5 1-benzene 0.5 1 -CN-C -0.8 general corrections CH 136.2 135.7 2-pyridine 0.2 1 -C 0.3 general corrections CH 128.8 128.5 1-benzene 0.1 1 -CN-C 0.2 general corrections CH 128.8 128.5 1-benzene 0.1 1 -CN-C 0.2 general corrections CH 131.0 128.5 1-benzene 2.3 1 -CN-C 0.2 general corrections C 74.4 -2.3 aliphatic 14.9 1 alpha -CN 18.2 2 alpha -C 49.0 1 alpha -O 9.3 1 beta -1CCCCCC1 -2.5 1 gamma -C 0.3 1 delta -1CRRRRR1 -12.5 general corrections C 164.6 162.8 1-imine 0.9 1 -CR 0.9 1 -C 0.0 1 -C from N-imine CH2 61.2 -2.3 aliphatic 24.3 1 alpha -1CRRRRR1 40.0 1 alpha -NC -2.6 1 gamma -1CCCCCC1 -2.5 1 gamma -C 0.6 2 delta -C 0.3 1 delta -O 3.4 general corrections CH3 24.9 -2.3 aliphatic 9.1 1 alpha -C 3.3 1 beta -CN 9.4 1 beta -C 10.1 1 beta -O -2.6 1 gamma -1CCCCCC1 0.3 1 delta -C -2.4 general corrections CH3 24.9 -2.3 aliphatic 9.1 1 alpha -C 3.3 1 beta -CN 9.4 1 beta -C 10.1 1 beta -O 0.3 1 delta -C 9 Node Shift Base Inc. Comment (ppm rel. to TMS) C 159.0 149.8 2-pyridine 8.8 1 -C 0.4 general corrections CH 148.6 149.8 2-pyridine -0.4 1 -C -0.8 general corrections C 140.1 128.5 1-benzene 8.8 1 -CN-C 2.8 general corrections CH 120.9 123.6 2-pyridine -3.0 1 -C 0.3 general corrections CH 128.2 128.5 1-benzene 0.5 1 -CN-C -0.8 general corrections CH 122.2 123.6 2-pyridine -0.6 1 -C -0.8 general corrections CH 128.2 128.5 1-benzene 0.5 1 -CN-C -0.8 general corrections CH 136.2 135.7 2-pyridine 0.2 1 -C 0.3 general corrections CH 128.8 128.5 1-benzene 0.1 1 -CN-C 0.2 general corrections CH 128.8 128.5 1-benzene 0.1 1 -CN-C 0.2 general corrections CH 131.0 128.5 1-benzene 2.3 1 -CN-C 0.2 general corrections C 74.4 -2.3 aliphatic 14.9 1 alpha -CN 18.2 2 alpha -C 49.0 1 alpha -O 9.3 1 beta -1CCCCCC1 -2.5 1 gamma -C 0.3 1 delta -1CRRRRR1 -12.5 general corrections C 164.6 162.8 1-imine 0.9 1 -CR 0.9 1 -C 0.0 1 -C from N-imine CH2 61.2 -2.3 aliphatic 24.3 1 alpha -1CRRRRR1 40.0 1 alpha -NC -2.6 1 gamma -1CCCCCC1 -2.5 1 gamma -C 0.6 2 delta -C 0.3 1 delta -O 3.4 general corrections CH3 24.9 -2.3 aliphatic 9.1 1 alpha -C 3.3 1 beta -CN 9.4 1 beta -C 10.1 1 beta -O -2.6 1 gamma -1CCCCCC1 0.3 1 delta -C -2.4 general corrections CH3 24.9 -2.3 aliphatic 9.1 1 alpha -C 3.3 1 beta -CN 9.4 1 beta -C 10.1 1 beta -O -2.6 1 gamma -1CCCCCC1 0.3 1 delta -C y8axnyCszy_/y
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