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Iron(III) and copper(II) complexes bearing 8-quinolinol with amino-acids mixed ligands: Synthesis, characterization and antibacterial investigation
⁎Corresponding author at: Department of Chemistry, Graduate School of Science and Technology, Kumamoto University, 2-39-1 Kurokami, Kumamoto 860-8555, Japan. Tel.: +81 8039637659. amolegbesa@funaab.edu.ng (Saliu A. Amolegbe) amolegbesa@sci.kumamoto-u.ac.jp (Saliu A. Amolegbe)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
Four d-orbital metal complexes with mixed ligands derived from 8-hydroxyquinoline (HQ) and amino acids (AA): l-alanine and methionine have been synthesized through a mild reflux in alkaline solution and characterized by elemental analyses, infrared, electronic transition, and temperature dependant magnetic susceptibility. The IR spectroscopy revealed that iron and copper ions coordinated through carbonyl (C⚌O), hydroxyl group (O—H) of the amino acids, N-pyridine ring of hydroxyquinoline. The elemental analysis measurement with other obtained data suggested an octahedral geometry for the iron(III) complexes and tetrahedral geometry for the copper(II) complexes. From the molar magnetic susceptibility measurement, the iron(III) system (S = 5/2) d5 (non-degenerate 6A1) with χmT = 0.38 cm3 Kmol−1 showed an antiferromagnetic while Cu2+ ions system (S = ½) (2T2g) has χmT = 4.77 cm3 Kmol−1 described as paramagnetic behaviour. In vitro antimicrobial investigations of the metal complexes against standard bacteria species gave significant inhibition with, copper complex showing highest inhibitions against Pseudomonas aeruginosa (ATCC27853) of 43 mm at 10 μg/ml signalling its potential as pharmaceutical or chemotherapeutic agents.
Keywords
Metal complexes
Mixed ligands
Magnetic susceptibility
Antibacterial activity
1 Introduction
The coordination compounds of mixed ligands such as benzoheterocyclic rings and amino acids have been the focus of a considerable number of investigations for their good coordination ability with metal ions, (Kumar et al., 2013; Ndosiri et al., 2013; Solanki et al., 2009; Patil et al., 2012) and pharmacological values (Eddie et al., 2010; Khalil et al., 2010; Gaurav et al., 2011; Patel, 2011; Albert et al., 1953; Mashaly et al., 2004; Coyle et al., 2004). These properties could be attributed to the presence of nitrogen (N) atom and hydroxyl group in the ligand moieties (Moustafa, 2005) found to be of microbial inhibitory character similar to the benzimidazole (Khalafi-Neshad et al., 2005; Podunavac-Kuzmanovic and Cvetkovic, 2011) or phenanthroline class (Agwara et al., 2010). Since Barnett Rosenberg’s initial discovery of cisplatin (Roserberg, 1978), many more transition metal complexes and in particular those with N-and O – donor atoms have been known to have antimicrobial properties. (Prafulla et al., 2012; Mwadham and Eno, 2013; Albert, 1979). It is evident that formation of chelates metal ions increases the lipophilicity of the bioactive compounds through diverse array of biological oxidation–reduction mechanism for the effective permeability of the compounds into the site of action (Zarranz et al., 2003; Irbaraj et al., 2003).
Interestingly, metal complexes of 8-hydroxyquinoline as a primary ligand can exhibit biological activity (Noorulla and Sreenivasulu, 2011; Singh et al., 2010; Freeman, 1973; Che and Siu, 2010; Podunavac-Kuzmanovic and Cvetkovic, 2007) and an amino acid as a secondary ligand were significant as potential model for enzyme metal ions substrate complexes (Patel et al., 2012). Literature survey to the best of our knowledge showed that our newly synthesized compounds inhibit the standard test microorganisms favourably (Patel et al., 2012; Eddie et al., 2010; Khalil et al., 2010; Gaurav et al., 2011). We believe based on chelating concept that the release of electron(s) from the transition metals decreases the polarizability of the metal which has been proven to enhance the cytoxicity of the metal complex (Khalafi-Neshad et al., 2005). Bearing in mind the aforementioned and in continuation of our research on bioinorganic of bioactive compounds, we hereby report synthesis, characterization and antibacterial activities of synthesized iron(III) and copper(II) complexes of mixed ligands, 8-hydroxyquinoline and alanine or methionine amino acids: [M(HQ)(AA)⋅nH2O, n = 0–2; M = Fe(III) and Cu(II)].
2 Experimental
2.1 Materials and methods
All the reagents and solvents used for the syntheses were obtained commercially from Sigma–Aldrich Chemical Co. and were used without any further purification. The test microorganisms (Staphylococcus aureus – ATCC25923, Pseudomonas aeruginosa – ATCC27853, Escherichia coli – ATCC36218, Enterococcus faecalis – ATCC29212 were obtained from Nigerian Institute of Medical Research (NIMR), Lagos State, Nigeria.
2.2 Physical measurements
Elemental analyses of carbon, hydrogen and nitrogen were carried out at the Service Center of Elemental Analyses of Pharmacy campus Kumamoto University, Japan. Metal analyses were done on a Shimadzu AA-625-11 Atomic Absorption/Flame Emission Spectrometer. Infrared spectra were measured using KBr pellets with FTIR-8700 SHIMADZU Fourier Transform infrared spectrophotometer in the 4000–400 cm−1 region. The magnetic susceptibilities measurements χm (T) for the transition metal complexes between 5 and 400 K were measured with a superconducting quantum interference device (SQUID) magnetometer (Quantum Design MPMS-5S) in an external field of 1.0 T. Samples were carefully weighed into gelatin capsules, with empty gelatin capsules above and below to eliminate background contributions from the gelatin, which were loaded into plastic straws, and attached to the sample transport rod. Diamagnetic corrections were made using Pascal’s constants.
2.3 Synthesis of Fe(III) – mixed ligand complexes (4a–b)
The iron complexes (4a–b) were synthesized with slight modification to the previously reported method (Patil et al., 2012). To a mixed solution of 0.81 g FeCl3 (5 mmol) and (0.725 g, 5 mmol) 8-hydroxyquinoline in 20 mL methanol, the amino acid (0.445 g alannine (ALA) or 0.746 g methionine (MET) that is 5 mmol) was added with constant stirring at 60 °C mild reflux. Precipitates were formed at pH ca 8 of the reaction mixture with 4 mL of dilute 0.2 M sodium hydroxide solution which enhanced deprotonation of the oxine hydroxyl group for chelation. The reaction mixture was cooled, and the solid product was collected by filtration, washed with diethyl ether and dried in vacuo.
([Fe (HQ)(ALA)]Cl⋅2H2O) 4a: Yield. 770 mg, 42.8%, Anal. Calc. for C12H16ClFeN2O5, C, 40.08; H, 4.49; N, 7.79; Found: C, 40.10; H, 4.36; N, 7.81; IR (KBr, cm−1): 3741, 1600, 1465, UV (nm) 338, 382.
([Fe (HQ)(MET)]Cl⋅2H2O) 4b: Yield. 410 mg, 19.5%, Anal. Calc. for C14H20ClFeN2O5S, C, 40.07; H, 4.80; N, 6.67; Found: C, 40.10; H, 4.65; N, 6.68; IR (KBr, cm−1): 3741, 1610, 1500, UV (nm) 334, 378.
2.4 Synthesis of Cu(II) – mixed ligand complexes (4c–d)
The copper(II) complexes (4c–d) were prepared by the same method as described for iron complexes.
([Cu (HQ)(ALA)]) 4c Yield. 1250 mg, 84.5%, Anal. Calc. for C12H1lCuN2O3, C, 48.73; H, 4.09; N, 9.47; Found: C, 48.196; H, 4.10; N, 9.49; IR (KBr, cm−1): 3417, 3050, 1620, 1465, UV (nm); 340, 404.
([Cu (HQ)(MET)]) 4d Yield. 1320 mg, 74.2%, Anal. Calc. for C14H16CuN2O3S, C, 47.25; H, 4.53; N, 7.87; Found: C, 47.36; H, 4.55; N, 7.83; IR (KBr, cm−1): 3500, 2954, 1615, 1411, UV (nm) 338, 380 (see Scheme 1).
- Synthesis of the metal complexes (4a–d).
2.5 Antibacterial screening in vitro
The antibacterial activities of the metal complexes 4a–d were screened against some pathogens using the agar well diffusion method (Anacona and Rodriguez, 2004). The 3% acetic acid was prepared by measuring 3 mL acetic acid into 97% distiled water. Stock solutions of the complexes were prepared by dissolving 10 mg of the complex in 10 mL of 3% sterile acetic acid. Sterile nutrient agar inoculated with the test organisms (media) was poured into sterilized petri-dishes and allowed to stand for some minutes, then a cork-borer with a diameter of 12 mm was used to bore uniform holes on the surfaces of the dried agars and into each hole was added 0.1 mL, 0.2 mL and 0.4 mL diluted aliquots (equivalent of 10, 20 and 40 μg/mL) from the stock solution of 1000 μg/mL. The plates were covered and incubated for 24 h at 37 °C. The process was repeated with sterilized water as a control while all other reagents were also screened. The observed zones of inhibition were measured in mm and average zone inhibitions were determined. Triplicate data were taken for the calculation of mean inhibition.
3 Results and discussion
3.1 Analytical and spectroscopic studies
3.1.1 Molecular Structure Characterization of the compounds
All complexes are analytically pure. The iron(III) complexes 4a–b obtained are black while copper(II) 4c–d are greenish/grey colour powdery solids and air stable. The synthetic route yielded complexes of appreciable amount except complex 4b with 19.5% yield. The complexes are partly soluble in less polar solvents but soluble in DMSO. The molar conductance values of the complexes in methanol are higher than their mixed ligands indicating relative ionic character, for instance 4a is 15.3 μS cm−1 and 4b is 8.20 μS cm−1 while 4c and 4d are 4.2 μS cm−1, 3.2 μS cm−1 respectively. All the complexes did not melt but decompose at temperature greater than their ligands; 4a–d decompose from 164, 230, 220 and 199 °C respectively. Efforts to grow single crystals of complexes suitable for X-ray crystallography using variety of different techniques and solvent combinations have been unsuccessful. However, the elemental analysis results fit well with the proposed molecular formula; and on the basis of FT-IR and electronic transitions spectra we were able to predict the metal coordination upon the shift to lower energy level or disappearance in the vibrational frequencies of the donor atoms synonymous with previous reports (Labisbal et al., 2006; Anacona and Rodriguez, 2004). For iron complexes 4a–b, there is disappearance of hydroxyl (O—H) hydrogen bond attributed to coordination with the iron metal centre. The carbonyl group (C⚌O) vibrational frequency appeared red shifted with very weak intensity. The pyridine ring of the complexes showed strong absorption but with a bathochromic shift ca 25 cm−1 due to electron contribution to the coordination. No free O—H group was observed in the IR copper complexes 4c–d spectra but the hydroxyl (O—H) appeared at 3417 cm−1 broad vibrational frequency while carbonyl bond (C⚌O) appeared around 1615–1620 cm−1 sharp and strong vibrational frequency. These bathochromic effects (ca 20 cm−1) in the groups were attributed to coordination. See Fig. 1. The UV/visible spectra band assignment of the ligands and their complexes in dimethylsulphoxide gave electronic transitions in terms of bands due to their electron transfer within the ligands, charge transfer transition from ligand orbitals to the central atom or d–d electronic transition as case may be. No visible region was observed for iron complexes i.e. there is no d-d transition, non-degenerate 6A1 however, complex 4c contains a visible spectrum around 404 nm attributed to MLCT or d–d transition 2Eg → 2T2g.
IR spectra of the ligands and complexes (4a–d).
3.2 Magnetic properties
The magnetic behaviour for the complexes was followed by measurements of the molar magnetic susceptibility (χm) as a function of temperature (T). The temperature dependence of χmT for iron complexes is displayed in Fig. 2a. The χmT value for the complexes 4a–b equals 4.77 cm3 Kmol−1 1 at 400 K, which shows that Fe(III) site, is in the high spin (HS) state (S = 5/2), and χmT value steadily decrease until it reaches zero. This is antiferromagnetic behaviour, as no spin-cross over (SCO) phenomenon (LS–HS) was observed between the iron d-orbitals suspected to be due to ligand field effect. The iron complexes were cooled from 400 to 5 K (2-cycles) and then warmed from 5 to 400 K (1-cycle) at a rate of 2 K min−1. The temperature dependence of χmT for copper complexes is displayed in Fig. 2b. The magnetic behaviour of the copper complexes 4c–d was investigated between 100 and 5 K at a rate of 2 K min−1. The χmT value for the complexes is equal to 0.38 cm3 Kmol−1 1 at 22 K, corresponds to copper(II) oxidation state with spin state (S = 1/2), and only one unpaired electron (paramagnetic). The Cu2+ is not a spin crossover d-orbital and therefore exhibits no molecular bistability (HS–LS) spin transition. It is thought that the decrease of χmT value below 15 K is due to zero field splitting (Singh et al., 2010; Kahn, 1993) (see Figs. 3a and 3b).
χmT versus T plots for complex (4a–b).
χmT versus T plots for complex (4c–d).
Iron octahedral geometry complexes.
Copper tetrahedral geometry complexes.
3.3 Antibacterial activities
The antibacterial activities of all the compounds were screened against some standards bacterial agents (Table 1). Different concentrations for each compound were investigated against standard bacterial strains. The result showed that the metal complexes were found to be more active than the ligands and metal salts. At 10 ppm, Fe(III) – methionine-quinolinol mixed ligand complex 4b was found to exert greater inhibitory activity against all the organisms than the alanine-quinolinol chelates 4a. This may be due to the presence of sulphur in the methionne. The control (sterile water) did not show any inhibitory level as expected. Whereas, acetic acid showed the inhibitory level of 8 mm in P. aeruginosa but showed no inhibitory level in all other microbes. The metal salts showed only little or no inhibition. This further confirms that chelation tends to make the ligand to act as more powerful and potent bacterial agent (Crowder et al., 2006; Page and Badarau, 2008). The copper chelates system complex 4c was found to demonstrate higher inhibition (43 mm) at 10 ppm against P. aeruginosa compared with all other chelates, this may be attributed to the mobilized electron in the copper orbital as indicated by its magnetic property (Mwadham, 2013; Podunavac-Kuzmanovic, 2007; Patel et al., 2012). Presence of free electron in the Cu2+ empowers its strong oxidative molecular activity for inhibitory ability on microorganisms as this re-emphasize the copper(II) ions as a key cofactor in a diverse array of biological oxidation–reduction reactions (Mwadham, 2013; Podunavac-Kuzmanovic, 2007; Jezowska, 2001; Jezowska et al., 1998; Solomon et al., 1996).
Ligands
Microorganisms
S. aureus (μg/ml)
P. auruginosa (μg/ml)
E. coli (μg/ml)
E. feacalis (μg/ml)
Complexes
1
2
4
1
2
4
1
2
4
1
2
4
Oxine (1)
31 mm
30 mm
27 mm
25 mm
23 mm
29 mm
20 mm
24 mm
32 mm
30 mm
30 mm
38 mm
Alanine (2)
30 mm
29 mm
30 mm
31 mm
29 mm
31 mm
30 mm
26 mm
26 mm
28 mm
26 mm
27 mm
Methionine (3)
31 mm
28 mm
–
30 mm
29 mm
–
29 mm
27 mm
–
23 mm
21 mm
–
FeCl3
08 mm
10-
12-
30 mm
35 mm
36 mm
Nil
Nil
6 mm
Nil
Nil
Nil
Cu (ac)2⋅H2O
04 mm
08 mm
10 mm
29 mm
29 mm
30 mm
Nil
Nil
12 mm
Nil
Nil
06 mm
3% Acetic acid
0 mm
Nil
Nil
Nil
Nil
8 mm
Nil
Nil
Nil
Nil
Nil
Nil
Sterile water
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
4a
34 mm
32 mm
31 mm
30 mm
28 mm
29 mm
28 mm
33 mm
31 mm
21 mm
25 mm
25 mm
4b
34 mm
30 mm
35 mm
34 mm
30 mm
30 mm
32 mm
28 mm
31 mm
25 mm
24 mm
21 mm
4c
41 mm
25 mm
28 mm
43 mm
21 mm
25 mm
35 mm
24 mm
34 mm
39 mm
28 mm
30 mm
4d
24 mm
28 mm
25 mm
32 mm
30 mm
32 mm
24 mm
26 mm
26 mm
20 mm
18 mm
18 mm
4 Conclusions
Hydroxyquinoline (HQ) and amino acids (AA) mixed ligands with Fe(III) and Cu(II) ions producing four bioactive metal complexes have been synthesized. The results of spectroscopy, elemental analyses and molar magnetic susceptibility parameters indicate that geometry of the two iron complexes: [Fe(HQ)(AA)⋅2H2O]Cl (4a–b) are octahedral geometry while the two copper complexes: [Cu(HQ)(AA)] (4c–d) are tetrahedral geometry. The spin transition of χmT = 0.38 cm3 Kmol−1 characteristic of Fe(III) complexes showed antiferromagnetic while Cu(II) of χmT = 4.77 is a paramagnetic property. The synthesized metal complexes show excellent inhibition on the standard test microorganisms particularly the Cu2+ complex 4c than their parent ligands which was attributed to the enhanced kinetic lability of the alanine-amino acid ligand which, through Jahn–Teller distortion, may assist the ligand exchange and binding to the organisms. We would in nearest future based on our quest for metal based antiparasitic drugs research into construction of more highly active free electrons metal-chelates and/or with ferromagnetic property optimistic to be of interesting property for achieving robust antimicrobial therapy formulations.
Acknowledgements
The authors gratefully acknowledge Nigerian Institute of Medical Research (NIMR) for kind donation of the standard bacterial strains and Prof. Shinya Hayami of Kumamoto University, Japan for the use of magnetic measurements instrument. S.A.A (P13340) is thankful to Japan Society for the Promotion of Science (JSPS) for the postdoctoral fellowship.
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