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Synthesis, Characterization and Antimicrobial Activities of Transition Metal Complexes of methyl 2-{[(E)-(2-hydroxyphenyl)methylidene]amino}benzoate.

Byline: Muhammad Ikram and Sadia Rehman

Abstract: New metal complexes with Schiff base ligand methyl 2-{[(E)-(2- hydroxyphenyl)methylidene]amino}benzoate, were synthesized and characterized. Elemental analyses, EI-MS, 1H and 13C{1H}-NMR were used for ligand characterization whereas elemental analyses, EI-MS, IR and UV-Visible spectroscopic techniques were used for the transition metal compounds. All these analyses reveal the bis arrangement of the ligand around the metal centres. The compounds were studied for their antimicrobial activities against different pathogenic microbial species. It was found that the Schiff base ligand was completely inactive in comparison to the transition metal compounds. It was also observed that nickel based metal complex shown good results against Candida albican (25 mm) and zinc based metal complex against Agrobacterium tumefaciens (16 mm).

Key words: Schiff base, Transition metal complexes, Spectroscopic studies, Antibacterial, Antifungal studies.

Introduction

Imine or Schiff base compounds are becoming one of the emerging fields in both organic and inorganic chemistry. Different heteroatoms like Oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), Polonium (Po), arsenic (As) etc can be substituted to produce variety of Schiff base compounds [1,2]. Many enzyme inhibitors [3], catalysts [4], medicines [5,6], reagents etc bear Schiff base linkage as active moiety. These properties are dominated by the steric factors, electronic arrangements and orientation of groups in space [3]. Many Schiff bases are known to be medicinally important and used to design compounds which may pave its way as antimicrobial, antibacterial, antifungal, antiviral, anti-leishmanial, antimalarial, anticancer agent etc [5,6]. Schiff bases either belong to natural derivatives or they may be synthetic analogs [5-7].

Variety of transition metals may react with Schiff base ligands to yield the coordination compounds [8, 9]. The metals mostly used for such purpose belong to first row essential metals e.g; V, Fe, Co, Cu, Zn, etc. Complexation process effect the lipolicity, reorientation of the active sites, metabolism, redox chemistry, metal mediated virus killing, enhanced antibiotic properties of many active drugs like tetracycline, enhanced DNA interaction etc [8-11]. Therefore, we aimed to synthesize the Schiff base derivative and complex it with metal ions like Co (II), Ni (II), Cu (II), and Zn (II) to produce the coordination compounds. The antimicrobial activities of all the compounds were also tested using different plant and animal pathogenic bacteria and fungi.

Experimental

Materials and methods

Analytical grade chemicals, buffers and solvents were used during the entire experimental manipulations. Solvents were purified and distilled at least twice before use. Chemicals like metal (II) acetates (where metal (II) = Co, Ni, Cu and Zn) were obtained from Riedel-de-Haen. These metal salts were partially dehydrated by keeping in a vacuum oven for several hours set at 80 - 100o C. Methyl anthranilate was obtained from Sigma Aldrich and salicylaldehyde was obtained from Acros Organics.

Instrumentation

Elemental analyses were carried out using Varian Elementar II CHNS analyser. Atomic absorption spectrophotometer (Vario 6, Analytic Jena) operated on single beam mode was used for metal ion content in all samples. The concentration of each metal was determined against standard calibration curve with regression value (R2) of 0.9997 obtained with commercial standards (CPA Chem. Ltd Bulgaria). Melting points were recorded on a Gallenkamp apparatus.

IR spectra were recorded using Shimadzu FTIR Spectrophotometer Prestige-21.1H-NMR were measured with Bruker DPX 400MHz (400.23 MHz) whereas, 13C{1H}NMR were recorded on Bruker AV 400MHz (150.9 MHz) spectrometers in deuterated solvents at room temperature. Chemical shifts are reported in ppm and standardized by observing signals for residual protons. UV-Visible spectra were recorded on a BMS UV-1602. Molar conductance of the solutions of the metal complexes was determined with a conductivity meter type HI-8333. All measurements were carried out at room temperature with freshly prepared solutions. Magnetic susceptibilities were measured on a Sherwood Gouy Balance at room temperature calibrated with Hg[Co(SCN)4]. Mass spectra were recorded on a LCT Orthogonal Acceleration TOF Electrospray mass spectrometer.

Antimicrobial Activity

About 2.8 g/L nutrient agar and nutrient broth were prepared in deionized water and kept in autoclave set at 1.5 Pounds pressure for about 15 min. Under inert atmosphere the nutrient agar media were poured aseptically into sterilized petri dishes in laminar flow. The petri dishes were kept for about 24 hr at 37 C in inverted position. Bacterial cultures were adjusted to 0.5 McFarland turbidity standards and Candida albican was adjusted to 108 cfu/ml. Sterile filter paper of diameter 6 mm was used for bacterial strains whereas its thickness ranged upto 13 mm for fungal strain. These filter papers were in the form of discs and were seeded with 0.5 McFarland and 106 cfu/ml cultures of bacteria and fungi respectively. Solutions (0.5 mM) of the synthesized compounds were applied to the prepared discs and incubated for 18 hr at 37 C. Subsequent measurements of the zone of activity were carried out [11].

Synthesis of methyl 2-{[(E)-(2-hydroxyphenyl)methylidene]amino}benzoate (H-HAB)

10 mmol of the methyl anthranilate was added to 10 cm3 distilled methanol and stirred for 10 min. 12 mmol salicylaldehyde was added to the methylanthranilate solution and the resulting mixtur stirred for 2 hrs at 40 C. On concentrating the solution orange product was isolated which was washed with 5% copious n-hexane and methanol solution (scheme 1).

(Equation)

Scheme-1: Synthesis of methyl 2-{[(E)-(2-hydroxyphenyl)methylidene]amino}benzo ate(H-HAB) Schiff base ligand.

(Equation)

Scheme-2: Atoms numbering for NMR peak assignment.

Yield: 88%, D. pt: 256 C, IR: 3043(m), 1791(w), 1683(w), 1618(s), 1570(s), 1485(s), 1446(s), 1386(s), 1317(s), 1269(s), 1197(s), 1147(s), 1105(s), 1031(s), 983(s), 943(m), 893(s), 852(m), 783(s), 746(s), 727(s), 682(s), 610(m) cm-1, 1H-NMR (400.23 MHz, CDCl3, 303k): d = 11.0 (s, 1H, Ar- OH), 10.2 (s, 1H, HC=N), 8.02 (d, 3JHH= 8.35Hz, 1H, H12), 7.95 (d, 3JHH= 7.8Hz, 1H, H15), 7.4 (d, 3JHH= 7.35Hz, 1H, H6), 7.2 (d, 3JHH= 8.21Hz, 1H, H13), 7.11 (d, 3JHH= 8.13Hz, 1H, H5), 7.0 (d, 3JHH= 7.83Hz, 1H, H13), 6.5 (d, 3JHH= 7.1Hz, 1H, H4), 4.2 (s, 3H, H18), 13C{1H}-NMR (150.9 MHz, CDCl3, 303k): d = 178 (C=O, C, C10), 158(CH=N, CH, C8), 156 (aromatic C-OH, C1), 150 (C, C10), 143 (C, C11), 142.7 (CH, C6), 141 (CH, C12), 139 (CH, C15), 137 (CH, C3), 133 (CH, C13), 126 (CH, C5), 123 (CH, C4), 120 (CH, C14), 76 (CH3, C18), Elemental Analysis (C15H13NO3), Calc. C: 70.58%, H: 5.13%, N: 5.49%, Exp. C: 70.11%, H: 4.78%, N: 5.38%, EI- MS: m/z (%)255.0889 (100%) [C15H13NO3+], m = 54.3 u S

Synthesis of [M(HAB)2] where M= Ni, Co, Cu and Zn (II)

All the coordination complexes were synthesized by following the same method. 10 mmol solution of H-HAB prepared in 15 cm3 distilled methanol was reacted with 10 mmol solution of metal acetate salt in 10 cm3 methanol. An abrupt color change was observed. The mixture was stirred for some time. The precipitates were filtered, washed with methanol and then with n-haxane (scheme 3).

(Equation)

Scheme-3: Metal complexes of the Schiff base H-HAB.

Bis(methyl 2-{[(E)-(2-hydroxyphenyl) methylidene] amino} benzoate)nickel(II) (1) Yield: 34%, D. pt: 202 C, IR: 3437(s), 3294(m), 3078(w), 1614(s), 1581(s), 1529(s), 1469(s), 1446(m), 1417(m), 1361(m), 1321(s), 1298(w), 1267(s), 1192(s), 1147(s), 1099, (s) 1022, 952(s), 896(s), 860(w), 802(s), 752(s), 704(s), 671(s), 640(s), 602(m) cm, lmax= 520, 590, 700 nm [a = 220.6, 134, 13.7 M cm A2g (F) - T1g (P), A2g (F) -3T1g (F), 3A2g (F) -3T2g (F)], u eff = 2.30 B.M.

Elemental Analysis (C30H24N2NiO6), Calc. C: 63.52%, H: 4.26%, N: 4.94%, Ni: 10.35%, Exp. C: 63.22%, H:4.89%, N: 4.90%, Ni: 10.30%, EI-MS: m/z (%) 566.0982 (100%) [C30H24N2NiO6+], m = 0.31 u S

Bis(methyl 2-{[(E)-(2-hydroxyphenyl) methylidene] amino}benzoate)cobalt(II) (2)

Yield: 64%, D. pt: 228 C, IR. 3280(s), 3138(w), 1620(s), 1591(s), 1544(s), 1446(s), 1420(s), 1300(s), 1199(s), 1103(s), 1031(s), 956(s), 889(s), 804(s), 740(s), 644(s), 560(s) cm-1, lmax = 430, 680 nm (a = 331.8, 13.4 M-1cm-1, 4T1g (F) -4A2g, 4T1g (F)-4T1g (P), 4T1g (F) -4T2g, u eff = 3.92 B.M. Elemental Analysis (C30H24CoN2O6), Calc. C: 63.50%, H: 4.26%, Co: 10.39%, N: 4.94%, Exp. C: 63.40 %, H: 4.96%, Co:10.41%, N: 4.60%, EI-MS: m/z (%) 567.0960 (100%) [C30H24CoN2O +], = 0.11 u S.

Bis(methyl 2-{[(E)-(2-hydroxyphenyl)methylidene] amino}benzoate)copper(II) (3)

Yield: 55%, D. pt: 254 C, IR: 1651(s), 1589(s), 1556(s), 1492(s), 1456(s), 1408(s), 1348(s), 1303(s), 1267(s), 1199(m), 1138(s), 1076(m), 1020(w), 935(m), 898(w), 854(s), 817(s), 767(s), 748(s), 729(s), 694(s), 632(s) cm-1, lmax = 780 nm (a = 12.7 M-1cm-1,T2g-eg), ueff = 2.02 B.M. Elemental Analysis (C30H24CuN2O6), Calc. C: 62.99%, H: 4.23%, Cu: 11.11%, N: 4.90%, Exp. C: 62.77%, H: 4.21%, Cu: 11.87%, N: 4.30%, EI-MS: m/z (%) 562.0934 (100%) [C30H24CoN2O6+Na] +, m = 0.01 u S

Bis(methyl 2-{[(E)-(2-hydroxyphenyl) methylidene] amino}benzoate)zinc(II) (4)

Yield: 44%, D. pt: 190 C, IR: 3437(s), 3307(w), 1614(s), 1587(s), 1537(s), 1469(s), 1446(m), 1361(m), 1311(s), 1269(s), 1193(s), 1147(s), 1089(s), 1033(m), 974(s), 935(w), 908(s), 860(s), 796(s), 754(s), 705(s), 667(s), 610(s) cm-1, 1H-NMR (400.23 MHz, CD3OD, 303k): d = 14.1 (s, 1H, HC=N), 8.02 (d, 3JHH= 8.35Hz, 1H, H12), 7.95 (d, 3JHH= 7.8Hz, 1H, H15), 7.4 (d, 3JHH= 7.35Hz, 1H, H6), 7.2 (d, 3JHH= 8.21Hz, 1H, H13), 7.11 (d, 3JHH= 8.13Hz, 1H, H5), 7.0 (d, 3JHH= 7.83Hz, 1H, H13), 6.5 (d, 3JHH= 7.1Hz, 1H, H4), 4.2 (s, 3H, H18), Elemental Analysis (C30H24N2O6Zn), Calc. C: 62.78%, H:4.21%, N:4.88%, Zn:11.40%, Exp. C: 62.18%, H:4.73%, N:4.67%, Zn:11.32%, EI-MS: m/z (%) 540.1028 (100%) [C30H24N2O6Zn+], m = 0.11 u S

Results and Discussions

Analytical and Spectroscopic Characterization

The Schiff base ligand H-HAB was fully characterized using the spectroscopic techniques which include the 1H and 13C{1H}-NMR. The 1H- NMR was assigned on the basis of the expected analytical techniques including the elemental analysis and EI-MS. 1H-NMR of the ligand shown (scheme 2) an up field peak at 11 ppm which was assigned to hydroxyl proton. The Schiff base proton appeared at 10.2 ppm. The methyl group of the ester appeared at 4.3 ppm. Rest of the 1H-NMR was in good agreement with the aromatic protons and their corresponding coupling constants.

The C{ H}-NMR was also studied for the H-HAB ligand. The ester carbonyl appeared at 178 ppm, the Schiff base carbon appeared at 158 ppm whereas the phenolic carbon appeared at 156 ppm. Rest of the spectrum was assigned to the aromatic carbon atoms. The methyl group of the ester appeared at 76 ppm. The 1H and 13C{1H}-NMR spectra support the formation of the Schiff base ligand derived from methyl anthranilate and salicylaldehyde. The EI(+) MS was also recorded for the ligand which gave the respective peak for the ligand. The mass spectral data was also supported by the elemental analyses, confirming the composition considered for the condensation reaction between the methyl anthranilate and salicylaldehyde. The characterization was further supported by the IR analysis. The IR spectrum was recorded in the range 500-4000 cm-1.

The hydroxyl peak was not observed because of the probable involvement of the group in the formation of hydrogen bonding with the nitrogen of CH=N, thus producing the zwitterionic Schiff base ligand. The ester carbonyl was observed to be vibrating at 1791 cm-1, whereas the Schiff base vibration was observed at 1618 cm-1 as strong stretching band. In metal complexes the IR bands of the hydroxyl groups was either observed as strong band or not observed at all. The esteric carbonyl frequency diminished and was not observed in either of the complex. Similarly the C=N vibrating frequency was observed to be shifting by = 15-40 cm-1. Hence it can be suggested that the ligand H- HAB is acting as tridentate monoanionic ligand which is attacking the metal center through hydroxyl group, carbonyl group and the Schiff base nitrogen group. Thus the ligand can be classified as one of the representative in the category of N, O, and O1- group of ligands.

All the metal complexes were found to be paramagnetic in nature except zinc therefore the NMR recorded for it gave broad peaks which were found to be non-interpretable. The zinc complex shown the broadening of the HC=N proton frequency whereas the hydroxyl group diminished as a result of loss of the proton. Therefore zinc was also assigned the same geometry based on the NMR, mass and elemental studies.

The UV-Visible spectra for all the compounds were recorded in the 200-800 nm range. Compound 1 exhibit two clear bands, one is observed around at 520 nm and the other at 590 nm. Whereas the third broader ones is weakly observed at about 700 nm. The peak at 520 nm can be assigned to the 3A2g (F) -3T1g (P) and the peak at 590 nm can be assigned to the 3A2g (F) -3T1g (F). The broad peak is of 3A2g (F) -3T2g (F) transition. The spin only value is 2.30 B.M. which is also in close agreement with the octahedral geometry around nickel center. Similarly, compound 2 show two asymmetric bands i.e. at 430nm and 680nm. The peak at 430 nm may be due to the two spin allowed transitions such as 4T1g (F) -4A2g and the 4T1g (F) -4T1g (P). Whereas the peak at 680nm corresponds to the 4T1g (F) -4T2g. The spin only value for this complex is 3.92 B.M. which corresponds to the three unpaired electrons in the t2g/e.g. level of the orbitals.

Copper based metal complex of H-HAB show one broad peak around 780 nm which is considered to be carrying many overlapping peaks [12, 13]. This transition was assigned to the T2g-eg. The magnetic susceptibility for the complex is 2.02 B.M., which shows the only unpaired electron. The complexes were also found to be non-electrolyte because the molar conductance values are very lower than 50 u S [13]. Therefore the presence of free ions from the ligand or that from the complexes is completely ruled out.

Antimicrobial Activities

Different pathogenic microbes bear resistance to the antibiotic drugs. Therefore effective drugs must be developed which can kill the bacterial or fungal strain and become candid drug for the disease being treated. It is actually medical obligation to develop a drug of novel and more efficient mechanistic approach. Schiff bases have been pointed as promising antibacterial agents. For example, N- (salicylidene)-2-hydroxyaniline is effective against Mycobacterium tuberculosis H37Rv, exhibiting an MIC value of 8l g/mL [14]. There is an increasing interest in the synthesis, characterization and biological studies of the Schiff base chemistry in medicinal applications. Variety of Schiff bases have been reported from time to time which were derived from aldehyde and various amines [15].

The Schiff base ligand and its divalent metal complexes were exposed for their antibacterial and antifungal activities against different pathogenic microbes including Gram positive bacteria Bacillus atrophaeus, Bacillus subtilis, Staphylococcus aureus, Gram negative bacteria Klebsiella pneumoniae, Salmonella typhus, Pseudomonas aeruginosa, Escherichia coli, Agrobacterium tumefaciens, Erwinia carotovora, fungal Strain Candida albican. Table 1 enlists the activities, which reveal that neither the ligand nor its divalent metal ion complexes are active against any of the bacterial or fungal strain tested. Compound 1 show very weak activities but high activity may be observed for 1 against Candida albican even better than the standard drug. Similarly compound 4 show better activity against Agrobacterium tumefaciens as compared to the standard drug.

Therefore it can be stated that H-HAB is not effecting so much the steric of the metal complexes that it can enhance the activities without few exceptions. The activities of all the compounds may be assigned to the presence of transition metal ions which impart geometric restrains and electronic effects. The new geometry may also enhance the lipophilicity of the compounds in cell matrix [13]. The neat ligand is found to be very less lipophilic which ultimately cause reduction in its activity. It was observed that the presence of metal ion enhances the antimicrobial activities because of the possible catalytic interaction of metal center with DNA of microbes. Results may be seen in Table-1.

Table-1: In Vitro antimicrobial activities of H-HAB and its metal complexes against different animal and plant pathogens.

Compounds###Bacilus atropheus (mm)###Bacilus subtilis (mm)###Klebsiella pneumoniae###Salmonella typhus (mm) Pseudomonas aeruginosa###Escherichia coli (mm)###Staphylococc us aureus###Candida albican (mm)###Agrobacterium###Erwinia carotovora (mm)

###(mm)###(mm)###(mm)###tumefaciens (mm)

H-HAB###-###-###-###-###-###-###13###-###-###12

###1###16###21###16###15###10###19###10###21###14###-

###2###12###-###-###-###8###-###11###8###-###-

###3###-###-###-###-###-###-###11###15###13###12

###4###-###-###-###-###9###11###16###7###20###-

Standard###25###26###29###42###36###38###34###16###15###26

Conclusions

New Schiff ligand H-HAB was synthesized by reacting methyl anthranilate with salicylaldehyde and was characterized by spectroscopic and analytical methods. The ligand was complexed with Co(II), Ni(II), Cu(II) and Zn(II) metal ions to yield M(HAB)2 metal complexes in which the ligand is acting as anionic tridentate O,O,N type of chelating agent. All the compounds were tested for the antimicrobial activities using different pathogenic microbes including Gram positive, Gram negative and a fungal strains. It was found that the Schiff base ligand was inactive against these microbes whereas the metal complexes were found to be weakly active except nickel based complex 1 which show 21 mm zone of inhibition against Candida albican as compared to the standard drug showing 16 mm zone of inhibition. The active compounds also include zinc based compound 4, showing 20 mm zone of inhibition against Agrobacterium tumefaciens as compared to the standard drug (15 mm zone of inhibition).

Conflict of interest

The author declares no conflict of interest.

Acknowledgment

The authors are gratefully acknowledged to the Higher Education Commission (HEC) Pakistan for providing financial assistance.

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Author:Ikram, Muhammad; Rehman, Sadia
Publication:Journal of the Chemical Society of Pakistan
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Date:Feb 29, 2016
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