Synthesis, spectral characterization and antimicrobial evaluation of Schiff base Cu (II), Ni (II) and Co (II) complexes

European Journal of Medicinal Chemistry 45 (2010) 3056e3062

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European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech

Original article

Synthesis, spectral characterization and antimicrobial evaluation of Schiff base Cu (II), Ni (II) and Co (II) complexes Gajendra Kumar a, Dharmendra Kumar b, Shoma Devi c, Rajeev Johari a, C.P. Singh b, * a

Department of Chemistry, Vardhaman College, Bijnor 246701, Uttar Pradesh, India Department of Chemistry, Sahu Jain College, Najibabad 246763,Uttar Pradesh, India c Department of Zoology, Vardhaman College, Bijnor 246701, Uttar Pradesh, India b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 11 November 2009 Received in revised form 17 February 2010 Accepted 24 March 2010 Available online 29 March 2010

M(II) complexes of the type [HLCu2Cl3], [HLCu2(O(CO)CH3)3], [HLM2Cl4(H2O)3] and [HLM2(OC(O) CH3)4(H2O)3], where M ¼ Ni(II), Co(II) have been synthesized by condensation of 3-acyl-2-one indol and hydrazinecarbothioamide (2:1) in the presence of divalent metal salt in methanolic medium. The complexes have been characterized with the help of elemental analysis, conductance measurements, magnetic measurements and their structural configuration have been determined by various spectroscopic (electronic, IR, 1H NMR, 13C NMR, GCMS) techniques. Electronic and magnetic moments of the complexes indicate that the geometries of the metal centers are either distorted octahedral, or square planer. These metal complexes were also tested for their antibacterial and antifungal activities to assess their inhibiting potential. Crown Copyright Ó 2010 Published by Elsevier Masson SAS. All rights reserved.

Keywords: Schiff basde Metal complexes Antimicrobial activity Spectroscopic study

1. Introduction Schiff bases have often been used as chelating ligands in coordination chemistry [1,2]. Schiff base with donors (N, O, S, etc) have structure similarities with neutral biological systems and due to presence of imine group are utilized in elucidating the mechanism of transformation of rasemination reaction in biological system [3e5]. Thiosemicarbazide and its derivatives as ligands with potential sulphur and nitrogen bands are interesting and have gained special attention not only the structural chemistry of their multifunctional coordination modes but also of their importance in medicinal and pharmaceutical field. They show biological activities including antibacterial antifungal [6e18], antidiabetic [19], antitumor [20e23], antiproliferative [24,25], anticancer [26,27], herbicidal [28], anticorrosion and anti-inflammatory activities [8e10]. Schiff bases represent an important class of compounds because they are utilized as starting materials in the synthesis of industrial products [29]. Moreover, Schiff bases are regarded as privileged ligands [30]. Due to their capability to form complexes with different transition metals can act as catalysts for many different reactions [31e40]. The structure of the thiosemicarbazide moiety confers a good chelating capacity and this property can be increased in thiosemicarbazone by inserting suitable aldehyde or ketone possessing

* Corresponding author. Fax: þ91 1342260020. E-mail address: [email protected] (C.P. Singh).

a further donor atom to render the ligand polydentate [41]. On the other hand, schiff bases derived from coumarin and its metal complexes have been found to exhibit biological activities and plant regulating activities [29,42]. The verity of possible Schiff bases metal complexes with wide choice of ligands and coordination environments has prompted us to undertake research in this area [43]. In the present article, we report the synthesis and characterization of Schiff base derived from 3-acetyl-2-one indol and hydrazinecarbothioamide, and its metal complexes to gain more information about related structural and spectral properties as well as their antimicrobial activities. 2. Chemistry 2.1. Reagents The entire chemicals used were of the analytical reagent grade, 3-acetyl-2-one indol and hydrazinecarbothioamide procured from Acros and s.d.-fine, respectively. Metal salts were purchased from Merck. 2.2. Synthesis of the ligand The ligand was prepared by the condensation of 3-acetyl-2-one indol with hydrazinecarbothioamide (2:1). A mixture of ethanol/1, 2-dichloroethane (1:3) was used as a solvent in the presence of

0223-5234/$ e see front matter Crown Copyright Ó 2010 Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2010.03.036

G. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 3056e3062

3. Pharmacology

S

CH3

C

O

3.1. Antifungal activity

NH2

N

H 2N

+

2

O

MgSo4

S

CH3

N N

The free ligand, its metal complexes, fungicide Micronazole and the control DMSO (dimethylsulfoxide) were screened for their antifungal activity against various fungi viz. Rizoctonia sp., Aspergillus sp., and penicillium sp. These species were isolated for the infected organs of the host plants on potato dextrose agar (potato 250 g þ dextrose 20 g þ agar 20 g) medium. The culture of the fungi was purified by single spore isolation technique. The solution of different concentrations 1, 1.5 and 2 mg/ml of each compound (free ligand, its metal complexes and fungicides Miconazole) in DMSO were prepared for testing against spore germination. A drop of the solution of each concentration was kept separately on glass slides. The conidia, fungal reproducing spores (approx. 200) lifted with the help of an inoculating needle, which was mixed in every drop of each compound separately. Each treatment was replicated thrice and a parallel DMSO solvent control set was also run concurrently on separate glass slide. All the slides were incubated in humid chambers at 25  C for 24 h. Each slide was observed under the microscope for spore germination and percent germination was finally calculated. The results were compared with a standard fungicide Micronazole at the same concentrations.

H

O

C2H5OH/C2H4Cl2 Reflux

N

C

CH3

H

O

N

N

N

3057

Ligand Scheme 1. Formation of Schiff base ligand.

anhydrous magnesium sulphate as a dehydrating agent [44] (Scheme 1). 2.3. Synthesis of the metal complexes

3.2. Antibacterial activity The metal complexes of the ligand HL (1) were prepared by mixing a hot methanolic solution of the metal salts with required amount of a hot ethanolic solution of the ligand to form metal/ ligand complexes (Scheme 2).

Antibacterial activities were investigated using agar well diffusion method [45]. The activity of the free ligand, its metal complexes and standard drug lmipenem were studied against the

N N

O

S

CH3

C

N

N CH3

H

O lt Sa I( I)

l I) Sa

t

Cu

N

N N

O

Cu

S

CH3

Cu

C

N

X2

H

O

M (I

Y1 N

N CH3

X1

Complex (1): HLCu2Cl3, X1=X2=Y1=Cl Complex (2): HLCu2(OC(O)CH3)3, X1=X2=Y1=OC(O)CH3 S

CH3 N X1 N

O

Y1

Y3

M X2

C X4

N H

X3

Y2 O

M

N

N CH3

Complex (3): HLM2Cl4(H2O)3, M=Ni, X1=X2=Y1=Y2=Cl, X3=X4=Y3=H2O Complex (4): HLM2(OC(O)CH3)4(H2O)3, M=Ni, X1=X2=Y1=Y2=OC(O)CH3, X3=X4=Y3=H2O Complex (5): HLM2Cl4(H2O)3, M=Co, X1=X2=Y1=Y2=Cl, X3=X4=Y3=H2O Complex (6): HLM2(OC(O)CH3)4(H2O)3, M=Co, X1=X2=Y1=Y2=OC(O)CH3, X3=X4=Y3=H2O Scheme 2. Formation of Schiff base metal complex.

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due to molecular ion (Mþ). The proposed molecular formula of these complexes was confirmed by comparing their molecular formula weight with m/e values. The molecular ion (Mþ) peaks obtained from various complexes are as follows: (1) m/e ¼ 401.45 (Ligand), (2) m/e ¼ 724.39 (complex 1), (3) m/e ¼ 818.54 (complex 2), (4) m/e ¼ 714.69 (complex 3), (5) m/e ¼ 809.05 (complex 4), (6) m/e ¼ 715.17 (complex 5), (7) m/e ¼ 809.53 (complex 6). This data is in good agreement with the proposed molecular formula for these complexes. In addition to the peaks due to the molecular ion, the spectra exhibit peaks assignable to various fragments arising from the thermal cleavage of the complexes. The peal intensity gives an idea of the stability of the fragments. The pathway fragmentation pattern of the mass spectrum of the ligand is described in Scheme 3.

Staphylococcus aureus and Bacillus subtilis (as gram positive bacteria) and Pseudomonas aeruginoca, Escherichia coli and Salmonella typhi (as gram negative bacteria). Strain were obtained from Microbial Type Collection and Gene Bank, Institute of Microbial Technology (IMTECH) Chandigarh, India The solution of 2 mg/ml of each compound (free ligand, its metal complexes and standard drug lmipenem) in DMSO was prepared for testing against bacteria. Centrifuged pelletes of bacteria from a 24 h old culture containing approximately 104e106 CFU (colony forming unit) per ml were spread on the surface of Muller Hinton Agar plates. Wells were created in medium with the help of a sterile metallic bores and nutrients agar media (agar 20 g þ beef extract 3 g þ peptones 5 g) in 1000 ml of distilled water (PH 7.0), autoclaved and cooled down to 45  C. Then it was seeded with 10 ml of prepared inocula to have 106 CFU/ml. Petri plates were prepared by pouring 75 ml of seeded nutrient agar. The activity was determined by measuring the diameter of the inhibition zone (in mm). The growth inhibition was calculated according to reference [45].

4.2. IR spectra The IR spectra of all complexes showed that the ligand HL (1) behaves as a neutral pentadentate of the type ONSNO with two coordinating sites (ON and SNO). This behaviour was proved by: (i) the shift of n(C]O), n(C]S), n(C]N) signals to lower frequencies (4e18, 2e17, and 12e39 cm1, respectively) together with their weak appearance; (ii) the occurrence of the n(NeN) band at higher wave numbers; (iii) the simultaneous appearance of new bands in the 340e390, 422e467, and 487e530 cm1 regions due to the n(MeS), n

4. Results and discussion 4.1. Mass spectra The FAB mass spectra of Cu (II), Ni (II) and Co (II) Schiff base complexes have been recorded. All the spectra exhibit parent peaks

S

N N

C

N

O N N H

O

CS m/e = 44 NH

N

O N m/e = 172

O

S

N

O

C

.

N N

N

HN

m/e = 186

m/e = 229

CH3CN O

.N

.

N

N2

m/e = 171 O

N m/e = 130

N

O N N

O

.

. m/e = 158

m/e = 156

N

O

. m/e = 130 Scheme 3. The pathway fragmentation pattern of the mass spectrum of ligand.

G. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 3056e3062

(MeN) and n(MeO) vibrations, respectively [46] and (iv) the presence of the NH group indicating the neutrality of the ligand. The appearance of two characteristic bands in the ranges 1561e1559 cm1 and 1370e1367 cm1 in the case of complexes was attributed to nasym(COO) and nsym(COO), respectively, indicating the participation of the carboxylate oxygen in the complexes formation. The mode of coordination of carboxylate group has often been deduced from the magnitude of the observed separation between the nasym(COO) and nsym(COO). The separation value, Dn (COO), between nasym(COO) and nsym(COO), in these complexes were more than 190 cm1 (191e193 cm1) suggesting the coordination of carboxylate group in a monodentate fashion [47]. 4.3.

1

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Table 1 Fungicidal screening data of the ligand and their corresponding metal complexes. Compounds

% Inhibition of spore germination Aspergillus sp. (mg/ml)

Ligand HLCu2Cl4(H2O)3 HLCu2(OAc)4(H2O)3 HLNi2Cl4(H2O)3 HLNi2(OAc)4(H2O)3 HLCo2Cl4(H2O)3 HLCo2(OAc)4(H2O)3 Miconazole (standard)

Penicillium sp. (mg/ml)

Rizoctonia sp. (mg/ml)

1.0

1.5

2.0

1.0

1.5

2.0

1.0

1.5

2.0

62 85 90 91 94 89 88 55

69 90 92 97 96 92 93 62

75 94 99 99 100 95 99 92

42 77 75 79 81 75 76 62

49 80 79 82 85 76 80 75

55 86 85 92 94 89 87 88

64 69 66 65 75 71 68 71

66 75 62 70 78 74 72 80

69 80 78 78 86 83 82 90

H NMR

A survey of literature reveals that the NMR spectroscopy has been proved useful in establishing the structure and nature of many Schiff base ligand and their complexes. The 1H NMR spectra of Schiff base ligand (HL) was recorded in d6-dimethylsulfoxide (DMFO-d6) solution using Me4Si (TMS) as internal standard. The 1H NMR spectra of the ligand shows broad signal at 9.4e12.1 ppm due to the eNH [48]. The multiplets in the region 7.54e8.76 ppm may be assigned to aromatic proton [49, 50] 13 C NMR of the Schiff base ligand, the signal appeared in the region 113e158 are assigned to aromatic carbon. The signal at 198.3e185.6, 182.8e171.2, 165.4e150.7 and 148.1e15.8 ppm are due to C]S, C]N, C]O and CH3 respectively. 4.4. Magnetic, electronic and electron spin resonance spectral studies The electronic spectrum of the copper complexes 1 and 2 shows single broad ded band centered at 500 nm, as expected for square planar geometry as encountered for related copper(II) complexes [51]. The ESR spectrum of this complex is of axial shape with gjj > gt characteristic of complexes with 2 B1ðdx2 y2 Þ ground state. The average g values were calculated according to the equation gav ¼ 1/3[gjj þ 2gt]. Complex (1 and 2) exhibits gjj < 2.3, suggesting covalent characters of the coppereligand bonding in this complex. The parameter G ¼ gjj  2.0023/gt  2.0023 shows the possibility of exchange interaction in the Cu(II) complex. The G values for the complex (G > 4) indicate that there is no direct copperecopper interaction in the solid state [52]. The gjj/Ajj is taken as an indication for the stereochemistry of the copper(II) complexes. Addison [53] has suggested that this ratio may be an empirical indication of the tetrahedral distortion of the square planar geometry. The values lower than 135 cm are observed for square planar structures and those higher than 150 cm for tetrahedrally distorted complexes. The value of gjj/Ajj quotient for the complex under investigation lies below 135 cm, indicating square planar geometry around copper in this complex. The magnetic moment value for this complex was found to be 1.76 B.M. per Cu ion [52] which was in the usual range for square planar copper complexes and indicating no direct interaction between the two copper centers in the solid state at room temperature [52]. The absorption spectral bands of nickel(II) complexes 3, 4 showed three spin allowed transitions: 3A2g(F) / 3T2g(F), 3A2g(F) / 3T1g(F), 3 A2g(F) / 3T1g(P) appearing in the ranges 1145e1054, 706e695 and 461e443 nm, respectively consistent with a typical Ni(II) in an octahedral environment [54]. The magnetic moment values for these complexes were found in the range 3.10e3.14 B.M. [54] expected for octahedral nickel complexes. The electronic spectra of the cobalt (II) complexes (5) and (6) gave three bands at 1200e1051, 700e622 and 489e433 nm, which could be assigned to the transitions 4T1g (F) / 4T2g (F) (n1) 4T1g

(F) / 4A2g (F) (n2) and 4T1g(F) / 4T2g (P) (n3), respectively, suggesting an octahedral geometry around Co(II) ion [17]. The complexes 5 and 6 show magnetic moment values in the range 3.2e3.5 B.M., which is smaller than the calculated value for two Co (II) ions in octahedral geometries and this may be due to antiferromagnetism between the two ion-centers. 4.5. Antifungal activity For the experimental data Table 1, it has been observed that the ligand as well as its complexes shows a significant degree of antifungal activity against Aspergillus sp., Rizoctonia sp. and Penicillium sp. at 1, 1.5 and 2 mg/ml concentration. The effect is susceptible to the concentration of the compound used for inhibition. The activity is greatly enhanced at the higher concentration. DMSO control has showed a negligible activity as compare to the metal complexes and ligand. However, the metal complexes are show better activity than the ligand [55,56]. The complexes are highly effective against Aspergillus sp. and show 94e100% activity at 2 mg/ml concentration. C29H33N5Ni2O13S is the only complex to show 100% activity against Aspergillus sp. the antifungal activity of the complexes varies in the following order of fungal species: Aspergillus sp. > Penicillium sp. > Rizoctonia sp. The antifungal experimental results of the compounds were compared with the standard antifungal drugs Miconazole at the same concentration. All the metal complexes exhibited greater antifungal activity against Aspergillus sp. as compare to the standard drug Miconazole. However, they show slightly lesser activity against Rizoctonia sp. than standard drug Miconazole. The Co (II) and Ni (II) complexes are more effective against Penicillium sp. than the standard drug. From the data it has been also observed that the activity depends upon the type of metal ion and varies in the following order of the metal ion: Ni > Co > Cu. 4.6. Minimum inhibitory concentration (MIC) The antibacterial screening concentrations of the compounds to be used were estimated from the minimum inhibitory concentration (MIC) value. The MIC values for ligand against B. subtilis, S. aureus, E. coli, S. typhi and P. aeruginosa were 126, 126, 65, 65 and 65 mg/ml for ligand 62, 62, 40, 40 and 40 mg/ml for the HLCu2Cl4(H2O)3, 50, 50, 30, 30 and 30 mg/ml for HLCu2(OAc)4 (H2O)3, 15, 15, 20, 20 and 15 mg/ml for HLNi2Cl4(H2O)3, 10, 10, 12, 12 and 10 mg/ml for HLNi2(OAc)4(H2O)3, 30, 40, 25, 25 and 25 mg/ml for HLCo2Cl4(H2O)3, 20 ,30, 20, 25 and 25 mg/ml HLCo2(OAc)4(H2O)3, 8, 8, 6, 6 and 6 mg/ml for standard drug Imipenem represented in Table 2. The values of MIC showed that the Ni complexes were found more potent as compared to the other studied complexes.

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Table 2 Minimum Inhibition Concentration (MIC) values for the ligand, their corresponding metal complexes and standard drug. Microorganism

Gram-positive Staphylococcus aureus Bacillus subtilis

Ligand

Complexes

Imipenem

1

2

3

4

5

6

126 126

62 62

50 50

15 15

10 10

30 40

20 30

8 8

65 65 65

40 40 40

30 30 30

20 20 15

12 12 10

25 25 25

20 25 25

6 6 6

Gram-negative Escherichia coli Salmonella typhi Pseudomonas aeruginoca

Complex 1 ¼ HLCu2Cl4(H2O)3, 2 ¼ HLCu2(OAc)4(H2O)3, 3 ¼ HLNi2Cl4(H2O)3, 4 ¼ HLNi2(OAc)4(H2O)3, 5 ¼ HLCo2Cl4(H2O)3, 6 ¼ HLCo2(OAc)4(H2O)3, Imipenem ¼ Standard drug.

4.7. Antibacterial activity The ligand, its metal complexes and standard drug Imipenem (C12H17N3O4S) were screened separately for their antibacterial activity against the bacteria Staphylococcus aureus and Bacillus subtilis (as gram positive bacteria) and Pseudomonas aeruginoca, Escherichia coli and Salmonella typhi (as gram negative bacteria). The diffusion agar technique was used to evaluate the antibacterial activity of the synthesized metal complexes [57]. The results of the bactericidal study of the synthesized compounds are displayed in Table 3. From the bactericidal activity, it is apparent that the complexes were more toxic towards gram positive strains than gram negative strains. The reason is the difference in the structure of the cell walls. The walls of gram negative cells are more complex than those of gram positive cells. The zones of inhibition (ZOI) values obtained indicate that the ligand has moderate activity against S. typhi and E. coli but no activity against P. aeruginosa. Ligand also showed a significant activity towards B. subtilis and S. aureus. Cu (II) complex 1 showed significant activity against B. subtilis, moderate activity against S. aureus, E . coli, S.typhi and P. aeruginoca. Complex 2 showed significant activity against all the gram positive and gram negative bacteria. Ni (II) complex 3 exhibited good activity against S. aureus, B. subtilis and S. typhi, significant activity against P. aeruginoca but moderate activity against E. coli. Complex 4 exhibited excellent activity against S. aureus and B. subtilis but good activity against E. coli, S. typhi and P. aeruginoca. Co (II) complex 5 showed significant activity against all the gram positive and gram negative bacteria. Complex 6 showed good activity against S. aureus, B. subtilis, S. typhi and P. aeruginoca but exhibited significant activity against E. coli. Further to it, the ligand showed moderate, and the complexes moderate to high activities as compared to standard drug towards the entire organism. Table 3 Bactericidal screening data of the ligand and their corresponding metal complexes (inhibition zone in mm). Microorganism

Ligand Complexes 1

Gram-positive Staphylococcus aureus Bacillus subtilis

þþ þþ

Gram-negative Escherichia coli þ Salmonella typhi þ Pseudomonas aeruginoca na

2

3

Imipenem 4

5

6

þ þþ þþþ þþþþ þþ þþþ þþþþ þþ þþ þþþ þþþþ þþ þþþ þþþþ þ þ þ

þþ þ þþþ þþ þþþ þþþ þþ þþ þþþ

þþ þþ þþþþ þþ þþþ þþþþ þþ þþþ þþþþ

þþþþ ¼ Excellent activity (100% inhibition), þþþ ¼ Good activity (60e70% inhibition), þþ ¼ Significant activity (30e50% inhibition), þ ¼ negligible activity (10e20% inhibition), na ¼ no activity, Size of well: 6 mm (diameter), Complex 1 ¼ HLCu2Cl4(H2O)3, 2 ¼ HLCu2(OAc)4(H2O)3, 3 ¼ HLNi2Cl4(H2O)3, 4 ¼ HLNi2(OAc)4(H2O)3, 5 ¼ HLCo2Cl4(H2O)3, 6 ¼ HLCo2(OAc)4(H2O)3, Imipenem ¼ Standard drug.

The variation in the antimicrobial activity of different metal complexes against different microorganisms depends on their impermeability of the cell or the differences in ribosomes in microbial cell [58]. The lipid membrane surrounding the cell favors the passage of any lipid soluble materials and it is known that liposolubility is an important factor controlling antimicrobial activity [59]. In the present study low activity of the some metal complexes is may be due to their low lipophilicity, because of which penetration of the complex through the lipid membrane was decreased and hence, they could neither block nor inhibit the growth of the microorganism. 5. Conclusion The straightforward condensation of 3-acetyl-2-one indol and hydrazinecarbothioamide to yield the novel Schiff base ligand has been reported. Its flexible back bone, together with the presence of N, S and O donor atoms, renders this compound interesting for studying its coordination behaviour with transition metals ion. In this work some complexes with copper, nickel and cobalt have been characterized and all the data collected in agreement with the proposed structures. The spectral data indicate that ligand behaves as a neutral pentadentate ligand, with two different coordinating sites, one provided by a nitrogen and an oxygen donor atoms and one by the C]N, C]O and C]S groups, each one accommodating a metal ion. Antimicrobial study reveals that, metal complexes have more biological activity than free ligand. Complex (4) HLNi2(OAc)4(H2O)3 shows best antimicrobial activity against all microorganism. 6. Experimental protocols The microanalysis of C, H and N were estimated by elemental analyzer (Perkin Elmer 2400 and the metal contents of Cu (II), Ni (II) and Co (II) were determined by atomic absorption spectrophotometer (Perkin Elmer 5000). IR spectra were recorded on a FT-IR spectrophotometer (Perkin Elmer) in the range 4000e200 cm1 using Nujol Mull. 1H NMR and 13C NMR spectra (at room temperature) (in DMSO-d6) were recorded on a Bruker AVANCE II 300 DRX or average 400 DRX spectrometer with reference to Me4Si (0.0 ppm). The FAB mass spectra (at room temperature) were recorded on JEUL JMS-AX-500 mass spectrometer, GC-MS analysis was performed on a Shimadzu GCMS- QP5050A instrument, Indian Institute of Petroleum Dehradun, India. Magnetic susceptibility measurements were carried out at SAIF, IIT Roorkee, on vibrating sample magnetometer (Model PAR 155). Electronic spectra in DMSO were recorded on a Hitachi 330 spectrophotometer (1300e200 nm) at room temperature. The conductivity was measured on digital conductivity meter (HPG system, G-3001). 6.1. Synthesis of the Schiff base ligand HL Hydrazinecarbothioamide (218.0 mg, 2.4 mmol) in ethanol (10 ml) was added to a hot solution (75  C) of 3-acetyl-2-one indol (0.900 g, 4.8 mmol) in ethanol (25 mL), the solid hydrazinecarbothioamide was dissolved gradually to yield a clear solution. The solution was stirred at 75  C for 2 h. After it then anhydrous magnesium sulphate (250.0 mg, 2.5 mmol) was added to the mixture. The reaction mixture was refluxed for 80 h, 1,2- dichloroethane (40 mL) was added and the solution was filtered and dried, recrystallized from ethanol and dried under vacuum in a desiccator over anhydrous CaCl2 (0.7145 g, 58% yield). 1H NMR (300 MHz, DMSO): d ¼ 10.43 (bs, 1H, NH), 8.65 (s, 1H, H(40 )), 8.46 (s, 1H, H(4)), 7.95 (d, J ¼ 7.7 Hz, 1H, H(60 )), 7.77 (d, J ¼ 7.7 Hz, 1H, H(6)) overlapping with 7.75 (pst, 1H, H(80 ), 7.65 (t, J ¼ 7.7 Hz, 1H, H(8)),

G. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 3056e3062

3061

7.48/7.37 (m, 4H, H(7), H(70 ), H(9) and H(90 )), 2.60 (s, 3H, CH3(120 )), 2.26 (s, 3H, CH3(12)). 13 C NMR (300 MHz, DMSO, 300 K): 196.0 (C]S), 180.1 (C]N), 160.0 (C]O), 155.5 (C]O), 154.2 (C]N), 147.9, 146.8, 142.8, 135.3, 133.2, 131.6, 130.0, 126.7, 125.8, 125.6, 125.3, 119.8, 119.0, 117.0, 116.8, 30.9, (CH3), 16.5 (CH3). One quaternary carbon was not detected. UV/vis (Nujol mul (nm)): l ¼ 280, 330, 340. UV/vis (1 104 mol, DMSO): l ¼ 270, 290, 345. IR (KBr): n(N2H) 3245 m, n(C]O), 1719 s, n(C]S) 861 s, n(C]N) 1678 s, n(NeN) 1115 s cm1. Elemental analysis for C21H15N5O2S (401.45): calcd. C 62.82, H 3.76, N 17.44; found C 62.95, H 4.12, N 17.83.

ethanol (23 mL), and the reaction mixture was refluxed for 4 h. The precipitate was filtered off, washed with methanol and dried under vacuum over anhydrous CaCl2 (0.484 g, 78% yield). Conductance Lm: 8 U1 cm2 mol1. UV/vis (Nujol mul (nm)): l ¼ 255, 270, 340, 461, 676 and 1135. IR (KBr): n(H2O) 3340 (br), n(N2H) 3260 (br), n(C]O) 1706 (s), n(C]S) 859 (w), n(C]N) 1657 (s), n(NeN) 1123 cm1 (m), nsym(OC (O)CH3) 1559 (m), nasym(OC(O)CH3) 1368 cm1 (m), (Dn ¼ 191 cm1). Elemental analysis for C29H33N5Ni2O13S (809.05): calcd. C 43.05, H 4.11, N 8.65, Ni 14.50; found C 42.92, H 4.08, N 8.54, Ni 14.32.

6.2. Synthesis of the metal complex (1)

Synthesis of HLCo2Cl4(H2O)3 complex (5). A solution of CoCl2$6H2O (0.390 g, 1.653 mmol) in methanol (15 mL) was added to a hot solution (75  C) of HL (1) (0.340 g, 8.46  101 mmol) in ethanol (32 mL), the reaction mixture was refluxed for 6 h. The precipitate was filtered off, washed with methanol and dried under vacuum over anhydrous CaCl2 (0.547 g, 75% yield). Conductance Lm: 19 U1 cm2 mol1. UV/vis (Nujol mul (nm)): l ¼ 260, 279, 320, 417, 652 and 1061. IR (KBr): n(H2O) 3344 (br), n(N2H) 3268 (br), n(C] O) 1714 (s), n(C]S) 840 (m), n(C]N) 1632 (s), n(NeN) 1145 cm1 (s). Elemental analysis for C21H21Cl4N5Co2O5S (715.17): calcd. C 35.26, H 2.95, N 9.79, Co 16.48; found C 35.14, H 2.92, N 9.51, Ni 16.25.

Synthesis of HLCu2Cl3 complex (1). A solution of CuCl2$2H2O (0.292 g, 1.716 mmol) in methanol (8 mL) was added to a hot solution (75  C) of HL (1) (0.35 g, 8.71 101 mmol) in ethanol (25 mL), and the reaction mixture was refluxed for 2 h. The brown solution was concentrated under vacuum. The precipitate was filtered off, washed with methanol and dried under vacuum over anhydrous CaCl2 (0.419 g, 68% yield). Conductance Lm: 79 U1 cm2 mol1. UV/vis (Nujol mul (nm)): l ¼ 260, 280, 300, 500, 715 and 1155. IR (KBr): n(H2O) 3411 (br), n(N2H) 3277 (br), n(C]O) 1714 (w), n(C]S) 847 (m), n(C]N) 1644 (m), n(NeN) 1122 cm1 (w). Elemental analysis for C21H15Cl3Cu2N5O2S (634.87): calcd. C 39.72, H 2.38, N 11.03, Cu 20.01; found C 39.42, H 2.36, N 11.15, Cu 20.08. 6.3. Synthesis of the metal complex (2) Synthesis of HLCu2(OC(O)CH3)3 complex (2). A solution of Cu (OAc)2$2H2O (0.366 g, 1.681 mmol) in methanol (6 mL) was added to a hot solution (75  C) of HL (1) (0.38 g, 9.46  101 mmol) in ethanol (28 mL), and the reaction mixture was refluxed for 2 h. The brown solution was concentrated under vacuum. The precipitate was filtered off, washed with methanol and dried under vacuum over anhydrous CaCl2 (0.462 g, 61% yield). Conductance Lm: 76 U1 cm2 mol1. UV/vis (Nujol mul (nm)): l ¼ 255, 271, 320, 515, 724 and 1145. IR (KBr): n(H2O) 3410 (br), n(N2H) 3272 (br), n(C]O) 1707 (s), n(C]S) 861 (m), n(C]N) 1651 (m), n(NeN) 1146 cm1 (w). nsym(OC(O)CH3) 1558 (m), nasym(OC(O)CH3) 1369 cm1 (m), (Dn] 190 cm1). Elemental analysis for C27H24Cu2N5O8S (705.67): calcd. C 45.95, H 3.42, N 9.92, Cu 18.00; found C 45.56, H 3.51, N 9.94, Cu 17.92. 6.4. Synthesis of the metal complex (3) Synthesis of HLNi2Cl4(H2O)3 complex (3). A solution of NiCl2$6H2O (0.341 g, 1.437 mmol) in methanol (15 mL) was added to a hot solution (75  C) of HL (1) (0.288 g, 7.18  101 mmol) in ethanol (16 mL), the reaction mixture was refluxed for 4 h. The precipitate was filtered off, washed with methanol and dried under vacuum over anhydrous CaCl2 (0.433 g, 81% yield). Conductance Lm: 11 U1 cm2 mol1. UV/vis (Nujol mul (nm)): l ¼ 260, 279, 320, 445, 706, 1145. IR (KBr): n(H2O) 3440 (br), n(N2H) 3265 (br), n(C] O) 1715 (s), n(C]S) 845 (m), n(C]N) 1650 (s), n(NeN) 1146 cm1 (s). Elemental analysis for C21H21Cl4N5Ni2O5S (714.69): calcd. C 35.29, H 2.96, N 9.79, Ni 16.42; found C 35.09, H 2.89, N 9.78, Ni 16.35. 6.5. Synthesis of the metal complex (4) Synthesis of HLNi2(OC(O)CH3)4(H2O)3 complex (4). A solution of Ni(OAc)2$4H2O (0.415 g,1.669 mmol) in methanol (10 mL) was added to a hot solution (75  C) of HL (1) (0.360 g, 8.96  101 mmol) in

6.6. Synthesis of the metal complex (5)

6.7. Synthesis of the metal complex (6) Synthesis of HLCo2(OC(O)CH3)4(H2O)3 complex (6). A solution of Co(OAc)2$4H2O (0.450 g, 1.808 mmol) in methanol (12 mL) was added to a hot solution (75  C) of HL (1) (0.390 mg, 9.71 101 mmol) in ethanol (26 mL), the reaction mixture was refluxed for 6 h. The precipitate was filtered off, washed with methanol and dried under vacuum over anhydrous CaCl2 (0.478 g, 71% yield). Conductance Lm: 17 U1 cm2 mol1. UV/vis (Nujol mul (nm)): l ¼ 255, 270, 340, 433, 622, 1051. IR (KBr): n(H2O) 3344 (br), n(N2H) 3263 (br), n(C]O) 1705 (s), n(C]S) 854 (w), n(C]N) 1639 (s), n(NeN) 1122 (w), nsym(OC(O) CH3) 1560 (m), nasym(OC(O)CH3) 1367 cm1 (m) (Dn ¼ 193 cm1). Elemental analysis for C29H33Co2N5O13S (809.53): calcd. C 43.02, H 4.10, N 8.65, Co 14.55; found C 42.86, H 4.05, N 8.45, Co 14.34. Acknowledgement We wish to express our cordial thanks to prof. A.K. Singh, Deptt. of applied chemistry Division, IIT Roorkee for fruitful discussion and suggestion for performing this research work. References [1] Y. Shibuya, K. Nabari, M. Kondo, S. Yasue, K. Maedo, F. Uchida, H. Kawaguchi, Chem. Lett. 37 (2008) 78. [2] A. Roth, J. Becher, C. Herrmann, H. Gorls, G. Vaughn, M. Reiher, D. Klemm, W. Plass, Inorg. Chem. 45 (2006) 10066. [3] E. Keskioglu, A.B. Gunduzalp, S. Cete, F. Hamurcu, B. Erk, Spectrochim. Acta A 70 (2008) 634. [4] J.Z. Wu, L. Yuan, J. Inorg. Biochem. 98 (2004) 41. [5] K.P. Balasubramanian, K. Parameswari, V. Chinnusamy, R. Prabhakaran, K. Natarajan, Spectrochim. Acta A 65 (2006) 678. [6] P.G. More, R.B. Bhalvankar, S.C. Pattar, J. Indian Chem. Soc. 78 (2001) 474. [7] A.H. El-Masry, H.H. Fahmy, S.H.A. Abdelwahed, Molecules 5 (2000) 1429. [8] M.A. Baseer, V.D. Jadhav, R.M. Phule, Y.V. Archana, Y.B. Vibhute, Orient. J. Chem. 16 (2000) 553. [9] S.N. Pandeya, D. Sriram, G. Nath, E.D. Clercq, Il Farmaco 54 (1999) 624. [10] W.M. Singh, B.C. Dash, Pesticides 22 (1988) 33. [11] D.P. Singh, K. Kumar, C. Sharma, Eur. J. Med. Chem. 44 (2009) 3299. [12] D.P. Singh, R. Kumar, J. Singh, Eur. J. Med. Chem. 44 (2009) 1731. [13] R.S. Kumar, S. Arunachalam, Eur. J. Med. Chem. 44 (2009) 1878. [14] A. Kulkarni, S.A. Patil, P.S. Badami, Eur. J. Med. Chem. 44 (2009) 2904. [15] G.B. Bagihalli, P.G. Avaji, S.A. Patil, P.S. Badami, Eur. J. Med. Chem. 43 (2008) 2639. [16] K. Singh, M.S. Bharwa, P. Tyagi, Eur. J. Med. Chem. 42 (2007) 394. [17] K. Singh, M.S. Bharwa, P. Tyagi, Eur. J. Med. Chem. 41 (2006) 147. [18] R. Ramesh, S. Maheswaran, J. Inorg. Biochem. 96 (2003) 457.

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