Synthesis, Spectral and Biological Studies of some Transition Metal Complexes Derived from Schiff base of Xipamide Drug

306

Synthesis, Spectral and Biological Studies of some Transition Metal Complexes Derived from Schiff base of Xipamide Drug

Suparna Ghosh

Suman Malik

and Bharti Jain

1Department of Chemistry, Career College, Bhopal-462023 (India)

2Department of Chemistry, S.V. College, Bairagarh, Bhopal - 462030 (India)

3Department of Chemistry, Sarojini Naidu Govt. Girls P.G. (Auto) College, Shivaji Nagar, Bhopal (India).

* Corresponding author. E-mail: [email protected]. Tel: 9009797554.

Received 19 Jan 2015, Revised 20 Fev 2015, Accepted 05 Mars 2015.

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Abstract

Transition metal complexes of Mn(II), Fe(II), Ni(II), Co(II) have been synthesized from Schiff base of Xipamide drug, that is, 5-aminosulfonyl-4-chloro-N-2,6-dimethyl phenyl-2- hydroxybenzamide. Elemental analyses suggest ML₂ stoichiometry for all metals. All the complexes are non-electrolytic in nature as suggested by conductivity data. The ligand behaves as bidentate O, N donor and forms coordinate bonds through C=N and phenolic oxygen. Magnetic susceptibility, electronic, IR, ESR spectral studies suggest that the complexes possess octahedral geometry. The ligand and some of the synthesized complexes were screened for their antibacterial and diuretic activity also.

Keywords: Schiff base, xipamide, stoichiometry, non-electrolytic, antibacterial, diuretic activity.

1. Introduction

Schiff bases are generally bi- or tri-dentate ligands capable of forming very stable complexes with transition metals. The co-ordination chemistry of Schiff bases gained much importance because of their biological and industrial applications [1,2]. Schiff base derived from salicylaldehyde have found to be biologically active as well as excellent chelating agents [3, 4]. The study of transition metal complexes is of great interest due to their biological activities[5,6] . In view of the interest involved in these compounds on account of their biological uses, the present study deals with the preparation of Schiff base(xipamide- salicylaldimine) derived from 5-aminosulfonyl-4-chloro-N-2,6-dimethyl phenyl-2- hydroxybenzamide and salicylaldehyde and its chelates with Mn(II), Fe(II), Ni(II) and Co(II). The solid complexes have been synthesized and studied by elemental analyses, spectroscopic characterization, thermal and biological studies. The diuretic activity of ligand and some complexes have also been studied.

2. Materials and methods

All the chemicals used were of AR/GR grade and purchased from E-Merck (USA). Chemicals were used without any purification. Xipamide drug was provided by Dishman Pharmaceuticals which was used as such

307 for the synthesis of ligand.

Elemental analyses were carried out on model 240 Perkin elemental analyzer at CDRI, Lucknow. Metal contents were determined gravimetrically using standard methods [7].Conductivity measurements were made in anhydrous DMF on a Systronics model 305 (India) Conductivity Bridge. Magnetic susceptibility measurements of the complexes in the solid state were determined by vibrating sample magnetometer at Centre for Advance Technology, Indore at room temperature. The electronic spectra of the metal complexes in DMF were recorded on a Perkin-Elmer UV WinLab Spectrophotometer at School of Studies in Chemistry and Biochemistry, Vikram University, Ujjain. The infrared spectra of the ligand and complexes were recorded in KBr pellets using Perkin-Elmer FT- IR spectrophotometer in the range of 4000-400 cm^-1 at School of Studies in Chemistry and Biochemistry, Vikram University, Ujjain. Particle size analysis was carried out at SICART, Gujarat using laser diffraction particle size analyzer. The instrument used was CILAS 1064L/D model in the range of .04-500 μm. The melting points of the ligand and complexes were recorded in open capillaries on a capillary melting point apparatus.

The biological activities were tested in vitro and in vivo. In vitro tests were conducted for growth inhibitory against Escherichia coli and Bacillus subtilis using Streptomycin as standard by filter paper disc method [8].

The diuretic activity of the compounds (FeL2, NiL2 and CoL2) was tested in white albino mice at Jawaharlal Nehru Cancer Hospital and Research Centre, Bhopal. Mice were fed with standard rodent pallet diet and acidified double distilled water. All the selected test compounds, ligand and standard drug acetazolamide (AZM) at a dose of 0.24 mg suspended in 0.5% gum acacia were administrated to animals of respective group. One group of animal was taken as control. For the measurement of weight of urine Whatman no.1 filter paper was used.The urine weight was recorded after two hours.

2.1 Synthesis of the ligand (xipamide-salicylaldimine)

Equimolar (0.01M) solutions of pure drug (0.22 gm) and salicyladehyde (0.14ml) were separately dissolved in methanol-water mixture (1:1) and refluxed for four hours and kept for a day. Peach colour crystals of xipamide Schiff base were formed in the reaction mixture which were filtered and washed thoroughly with 50% methanol-water mixture, dried over vacuum and weighed. Melting point of Schiff base was recorded.

The structure of the synthesized ligand is shown in Fig.1

Fig. 1 Structure of ligand

2.2 Synthesis of complexes

For the synthesis of complexes, 0.006 M ligand solution was prepared in 50% acetone-water solvent and refluxed for four hours with 0.003 M solution of metal salts separately. The refluxed solutions were kept

308 for some days. Solid crystalline compounds appeared in the solution, which were filtered, washed with 50%

acetone-water mixture, dried and weighed. Melting points of the complexes were recorded.

3. Results and discussion

The analytical data of the complexes and their molar conductance values are given in Table 1.All these complexes are analyzed for 1:2 stoichiometry of the type ML2. On the basis of these characterizations it has been found that all the complexes are non-hygroscopic, stable at room temperature, insoluble in water but fairly soluble in DMSO. The molar conductance values of these complexes are too low to account for their electrolytic behavior [9,10].

Table 1: Analytical data and molar conductance values for ligand and metal complexes Sl.

no.

Ligand/

Complexes

Elemental analysis (%): Found (Calcd.)

C N S Cl M

M.pt.

(^oC)

Color Molar ConductanceΩ^-

1cm²mol^-1

1 L 56.87

(57.57)

5.84 (5.96)

6.91 (6.97)

7.50 (7.61)

---- 250 Peach ----

2 MnL2 52.26

(52.38)

5.58 (5.55)

6.27 (6.34)

7.12 (7.04)

5.33 (5.45)

208 Off- White

15.2

3 FeL₂ 51.36

(52.44)

5.68 (5.56)

6.02 (6.36)

7.18 (7.05)

5.28 (5.55)

360 Black 10.6

4 NiL₂ 52.01

(52.29)

5.34 (5.54)

6.39 (6.33)

7.05 (7.03)

5.75 (5.81)

230 Light green

14.6

5 CoL₂ 51.98

(52.29)

5.45 (5.54)

6.03 (6.33)

7.01 (7.03)

5.79 (5.83)

232 Bluish green

12.3

3.1 Spectral studies of ligand and its complexes 3.1.1. IR spectra

The characteristic vibrations and assignments of ligand and its complexes are described in Table 2. The IR spectra of the complexes indicate that the ligand behaves as bidentate and the metal coordinates via azomethine nitrogen and phenolic –OH groups[11]. The shift of vC=Nto lower wave number by 30-40 cm^-1 in the complexes indicates that these groups are involved in complexation[12].

Table 2: IR spectral data (cm^-1) of ligand and its complexes

Sl.no. Ligand/Complexes V_N-H v_C=N V_C-O v_C=O v_M-N v_M-O

1 C22H19N2O5ClS 3302 1639 1282 1671 ---- ---

2 C₄₄H₄₀N₄O₁₂Cl₂S₂Mn 3376 1611 1325 1665 521 582 3 C44H40N4O12Cl2S2Fe 3320 1615 1321 1720 505 570

309 4 C₄₄H₄₀N₄O₁₂Cl₂S₂Ni 3300 1616 1320 1720 507 578 5 C44H40N4O12Cl2S2Co 3380 1627 1327 1710 521 580 The ligand shows strong band at 3386 cm^-1 due to phenolic –OH group [13]. This band is absent in all the metal complexes indicating the involvement of this group in complex formation [14]. Moreover, the shift of thev_C-O phenolic bands from 1282 cm^-1 in ligand to 1282-1327 cm^-1 in the spectra of metal complexes supports the coordination of the phenolic oxygen atom to the metal ion [15]. The bands for vM-O modes appeared in the range of 570 cm^-1 - 582 cm^-1 in all the complexes [16] The presence of sharp band in the region 505-521 cm^-1 in the spectra of all the complexes assigned to vM-N mode [17] further support the involvement of nitrogen atom in coordination.

3.1.2. Electronic spectra

The electronic spectra of manganese(II) complex showed four weak bands 16000, 19780, 20680 and 26720 cm^-1 which have been assigned to ⁶A_1g→⁶T_1g, ⁶A_1g→⁴T_2g, ⁶A_1g→⁴E_g and⁶A_1g→⁴T_1g respectively[18].

Electronic spectra of iron(II) complex showed a weak intensity band at 11300 cm^-1 which is assigned to ⁵T2g

→ ⁵E_g transition and the second at 19700 cm^-1 which may be due to charge transfer transition [19]. The electronic spectra of cobalt(II) complex showed two bands at 18230 cm^-1 and 22510 cm^-1 assignable to

4T1g (F) →⁴A2g (F) and ⁴T1g(F) → ⁴T1g(P) transitions respectively[20].This suggest an octahedral geometry for cobalt(II) [21]. The nickel(II) complex exhibited three bands at 10242 cm^-1, 16925 cm^-1 and 23530 cm^-1 corresponding to spin allowed transitions ³A_2g(F) →⁴T_2g(F), ³A_2g(F) →⁴T_1g(F)and ³A_2g(F) → ⁴T_1g(P) indicating an octahedral geometry [22]around the metal ion.

3.1.3. Magnetic susceptibility

The manganese(II) complex exhibits magnetic moment value 5.50 B.M., which is close to spin only value of 5.90 B.M.for high spin octahedral, manganese(II) complexes[23]. The magnetic moment obtained for iron(II) complex is 5.18 B.M. which supports the expected octahedral configuration[24]. The cobalt(II) complex shows magnetic moment of 4.63 B.M. suggesting an octahedral environment around the metal ion [25].The nickel(II) complex exhibit magnetic moment value 2.94 B.M. suggesting that it may have octahedral geometry [26].

3.1.4. ESR Spectra

The ESR spectra of iron(II) complex were recorded in DMSO at LNT(Liquid nitrogen temperature) and RT (room temperature) consists of single broad peak of high intensity explaining its paramagnetic character and it is supported by the value of magnetic moment also. The values of g║ = g┴ and g_av less than two predicts the presence of vacant energy shells in Fe(II) ion to accept the electron pair from ligand[27].

3.1.5. Particle size analysis

Parent drug, ligand and synthesized complexes were evaluated for particle size distribution and average particle diameter using microscopic method [28] and recorded in Table 3.

Table 3: Particle size measurement of pure drug, ligand and its complexes

S.No. Sample Code Particle Size (μm)

310

1 XM 112

2 L 95.6

3 FeL₂ 61.5

4 CoL2 58.2

The bioavailability of low solubility drug is often intrinsically related to the drug particle size. Smaller particle size of the complexes is responsible for the enhanced solubility of the drug [29]. These results reveal that after complexation, the size of the ligand and complexes got reduced too much extent as compared to their parent drug xipamide (XM). Thus from the result it can be concluded that complexation enhanced the absorption and potency of the drug [30] .

3.2 Biological studies of ligand and its complexes 3.2.1. Antibacterial activity

Antibacterial activity of ligand and their metal complexes are given in Table 4. Antibacterial activity of the ligand and complexes reveal that the activity zone of inhibition for all the complexes against Escherichia coli are higher as compared to ligand. The standard drug Streptomycin showed 18 mm inhibition at the same concentration.

The antibacterial activity of all the complexes against Bacillus subtilis except Ni(II) complex with 6.39 mm inhibition, showed higher activity with 12-23 mm inhibition. Standard drug Streptomycin showed only 16.23 mm inhibition at the same concentration as of the test drug. On the basis of these observations it can be said that complexation or chelation increases the antibacterial activity [31](Fig.2).

Fig. 2 Antibacterial screening of Mn(II) complex of ligand

Table 4: Antibacterial screening data of the ligand L and its complexes

Sl.no. Ligand/complexes Dose Antibacterial activity zone of inhibition (in mm) Escherichia coli Bacillus subtilis

1 Xipamide 500 ppm 63 68

2 XM-SA (L) 500 ppm 68 71

311

3 [MnL2(H2O)2] 500 ppm 69 73

4 [FeL2(H2O)2] 500 ppm 71 77

5 [CoL₂(H₂O)₂] 500 ppm 61 68

6 [NiL2(H2O)2] 500 ppm 51 49

7 Streptomycin (Standard)

500 ppm 55 61

3.2.2. Diuretic activity

The diuretic activity of the compounds Mn(II) and Co(II) were tested in white albino mice and recorded in Table 5. All the selected test compounds, ligand and standard drug Xipamide (XM) at a dose of 0.24 mg suspended in 0.5% gum acacia administrated to animals of the respective group. The result revealed that metal complexes appear to have more diuretic activity as compared to the respective ligand and pure drug.

Out of the selected complexes [MnL2(H2O)2] and [CoL2(H2O)2] both have significant diuretic activity as compared to ligand and parent drug. Thus it is revealed that complexation can increase the diuretic activity of the parent drug [32](Fig.3).

Fig. 3 Diuretic screening (T.S kidney) of Co(II) complex of ligand

Table 5: Diuretic screening data of the pure drug, ligand and its complexes Group Ligand/

Complexes

Average vol. of urine (μl) Final average (μl)

1:00 pm 3:00 pm 5:00 pm

I Control 113.94 167.22 118.01 133.06±29.656

II XM 155.66 208.09 266.91 210.22±55.656

III L 175.75 235.48 289.10 233.44±56.702

IV [MnL2(H2O)2] 265.54 283.12 343.12 297.26±40.677

V [CoL2(H2O)2] 386.66 375.29 378.57 380.17±5.852

Statistical analyses were performed by using one way analysis of variance ANOVA followed by GraphPadInStat 3. Statistical significance was accepted at the 5% level (P< 0.05). The Co(II) complex is found to be more significant with P< 0.001 whereas Mn(II) complex is also found to be significant with P<

312 0.05.

4. Conclusion

Hence on the basis of elemental analysis, magnetic moment data, conductivity measurements and spectral studies we propose octahedral structure for all the complexes shown in Fig.4. The present work will be extended to the synthesis of other metal complexes and their biological activities.

(M=Mn^II, Fe^II, Co^II, Ni^II)

Fig.4 Proposed structure of metal complexes

Acknowledgements: The authors wish to thank Dishman Pharmaceuticals, Ahemdabad (India) for the gift sample of Xipamide, CDRI Lucknow, SICART Gujrat, IIT Chennai for and Vikram University Ujjain for carrying out spectral and particle size analysis. Authors are thankful to Jawaharlal Nehru Cancer Hospital and Research Centre and Blossom Research centre Bhopal for diuretic activity and biological studies.

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