Synthetic, spectroscopic, magnetic and thermal aspects of drug based metal complexes derived from 1st row transition metal ions

2.1 Materials

The chemicals used for the synthesis purpose were all of analytical grade, such as 1H-indole, 8-hydroxyquinoline (purchased from local market), Luria broth and agar–agar (from SRL, India). Metal (II) salts (chloride/nitrate/sulfate) of Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) were used in their hydrated form. Silica gel F254 thin-layer chromatographic plates of size 20 × 20 cm were purchased from the E. Merck (India) Limited, Mumbai and used for purity evaluation. The organic solvents were purified by the recommended method (Vogel, 1989. Textbook of Practical Organic Chemistry, 5th ed. Longman, London).

2.2 Instruments

The contents of carbon, hydrogen and nitrogen were analyzed with a Perkin Elmer (USA) 2400-II CHN analyzer. The metal contents of the metal complexes were analyzed by EDTA titration (Vogel, 1978. Textbook of Quantitative Inorganic Analysis, 4th ed. ELBS and Longman, London) after decomposing the organic matter with a mixture of concentrated HClO₄, H₂SO₄ and HNO₃ (1:1.5:2.5). The melting points were checked using a standard open capillary method and are uncorrected. Infrared spectra (4000–400 cm⁻¹) were recorded on a Nicolet-400D spectrophotometer using KBr pellets. ¹H, ¹³C NMR and DEPT-135 spectra were recorded on a Bruker Avance 400 FT-NMR instrument using DMSO-d⁶ as a solvent. The FAB mass spectrum of the metal complexes was recorded at SAIF, CDRI, Lucknow with a Jeol SX-102/DA-6000 mass spectrometer. The magnetic moments were obtained by Gouy’s method using mercury tetrathiocyanato cobaltate (II) as a calibrate (g = 16.44 × 10⁻⁶ c.g.s. units at 20 °C). Diamagnetic corrections were made using Pascal’s constant. The reflectance spectra of the free ligand (L) and their metal complexes were recorded in the range 1700–350 nm (as MgO disks) on a Beckman DK-2A spectrophotometer. A simultaneous TG/DTG was obtained using a Model 5000/2960 SDT, TA Instruments, USA. The experiments were performed in a N₂ atmosphere at a heating rate of 10 °C min⁻¹ in the temperature range 50–800 °C, using an Al₂O₃ crucible.

2.3 Synthesis of ligand

The ligand was synthesized by the condensation of 1H-indole and 5-chloromethyl-8-hydroxyquinoline hydrochloride. CMQ was prepared and used as the starting material for the synthesis of novel ligand (L) by condensing it with 1H-indole as reported in the literature method (Peng et al., 2007).

2.4 Bio assay

3.1 IR spectra

The important infrared spectral bands and their tentative assignments for the synthesized metal complexes were recorded using KBr disks and are summarized in Table 2. In the 8-hydroxyquinoline metal complexes of divalent metals, the υ(C–O) appeared in the 1117 cm⁻¹ region and the position of the band slightly varied with the metal (Charles et al., 1956). The υ(C–O), observed in the free oxine molecule at 1092 cm⁻¹, shifted to higher frequencies in all the metal complexes, giving a strong absorption band at ∼1156 cm⁻¹. This clearly indicates the coordination of 8-hydroxyquinoline in these metal complexes. The broad band at 3401 cm⁻¹ observed in the case of ligand was shifted at ∼3326 cm⁻¹, which was attributed to υ(O–H) of coordinated water molecule. In the investigated metal complexes, the bands observed in the region 3318–3337, 1278–1295, 865–875 and 705–710 cm⁻¹ were attributed to –OH stretching, bending, rocking and wagging vibrations respectively, due to the presence of water molecules. The presence of a rocking band indicates the coordination nature of the water molecule (Pansuriya and Patel, 2007). In the far-IR region, two new bands at ∼502 and ∼536 cm⁻¹ in the metal complexes were assigned to υ(M–O) and υ(M–N), respectively. All of these data confirm the fact that the ligand (L) behaves as a bidentate ligand. The IR spectra of ligand and [Cu(L)₂(H₂O)₂] complex are shown in Figs. 5 and 6.

3.2 Diffuse electronic spectral and magnetic properties data

The diffuse electronic spectra of [Cu(L)₂(H₂O)₂] exhibited two bands at 26234 cm⁻¹ due to charge transfer and a broad band having maxima at 1500 cm⁻¹ due to the ${}^2{\text{E}}_{\text{g}}\to {}^2{\text{T}}_{2\text{g}}$ transition (Abuhijleh et al., 1991). The broadening of the signal might be due to the Jahn–Teller distortion. The absorption bands of the diffuse electronic spectra and value of their magnetic moment favor a tetragonally distorted octahedral geometry around Cu(II) ion (Cotton and Wilkinson, 1992. The Elements of first row transition series. In: Advanced inorganic chemistry, third ed., Wiley, New York; Dixit et al., 2010). The spectra of [Mn(L)₂(H₂O)₂] showed weak bands at 16776, 18421 and 23807 cm⁻¹ assigned to the ${}^6{\text{A}}_{1\text{g}}\to {}^4{\text{T}}_{1\text{g}}\text{,}{}^6{\text{A}}_{1\text{g}}\to {}^4{\text{T}}_{2\text{g}}\text{,}{}^6{\text{A}}_{1\text{g}}\to {}^4{\text{A}}_{1\text{g}}\text{,}{}^4{\text{E}}_{\text{g}}$ transitions and their magnetic moment values suggest an octahedral geometry for the Mn(II) ion. [Ni(L)₂(H₂O)₂] showed three weak absorption bands at 9974, 16013 and 24464 cm⁻¹ corresponding to the characteristic transitions ${}^3{\text{A}}_{2\text{g}}\to {}^3{\text{T}}_{2\text{g}}\text{,}{}^3{\text{A}}_{2\text{g}}\to {}^3{\text{T}}_{1\text{g}}(\text{F})\text{,}{}^3{\text{A}}_{2\text{g}}\to {}^3{\text{T}}_{1\text{g}}(\text{P})$ . [Co(L)₂(H₂O)₂] exhibited three absorption bands at 9828, 15481 and 22107 cm⁻¹, respectively, due to ${}^4{\text{T}}_{1\text{g}}(\text{F})\to {}^4{\text{T}}_{2\text{g}}(\text{F})\text{,}{}^4{\text{T}}_{1\text{g}}(\text{F})\to {}^4{\text{A}}_{2\text{g}}(\text{F})\text{and}{}^4{\text{T}}_{1\text{g}}(\text{F})\to {}^4{\text{T}}_{1\text{g}}(\text{P})$ transitions. The absorption bands of the diffuse electronic spectra and values of their magnetic moments show an octahedral geometry around Ni(II) and Co(II) ions (Agarwal et al., 2004). As the spectrum of [Zn(L)₂(H₂O)₂] was not well resolved, it was not well interpreted, but its magnetic moment value shows its diamagnetic nature as expected (Cotton and Wilkinson, 1988. In: Advanced Inorganic Chemistry, 5th edn., Wiley Interscience, New York). The results of the magnetic moment value (Table 1) were shown to have octahedral geometry for all the metal complexes. Hence, the observed values of magnetic moments and the electronic spectra of metal complexes supported octahedral geometry for all the structures (Patel et al., 2008). The probable structure of the metal complex is given in Fig. 1.

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Figure 1

The structure of ligand and proposed structure of metal complexes.

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Figure 5

The FT-IR spectrum of ligand.

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Figure 6

The FT-IR spectrum of [Cu(L)₂(H₂O)₂] complex.

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3.3 Thermogravimetric analysis

In first decomposition step, the weight loss during 50–210 °C corresponded to two coordinated water molecules. A loss in weight observed in the second step corresponded to some part of the ligand molecule (L) in the temperature range 185–455 °C. Finally, liberation of the remaining part of the ligand molecule (L) in the temperature range 455–800 °C was observed and the remaining weight was consistent with metal oxide (Sekerci and Yakupoglu, 2004). The thermodynamic activation parameters of the decomposition process of dehydrated metal complexes such as activation entropy (S^∗), pre-exponential factor (A), activation enthalpy (H^∗) and free energy of activation (G^∗) were calculated using reported equations (El-Zaria, 2008). According to the kinetic data obtained from DTG curves, all the metal complexes have a negative entropy and indicate more ordered systems for the studied metal complexes (Modi and Patel, 2008). The energy of activation (Ea) is helpful in assigning the strength of the bonding of ligand moieties with the metal ion. The relatively high Ea value (Table 4) indicates a strong bonding between the metal ion and the ligand (Jani et al., 2010; Parekh et al., 2005). Thermo analytical and thermodynamic data of metal complexes are reported in Tables 3 and 4, respectively. TG/DTG curves of the Cu (II) metal complexes are shown in Fig. 7.

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Figure 7

TG/DTG curves of the [Cu(L)₂(H₂O)₂] complex.

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3.4 FAB mass spectra

In the mass spectra of [Cu(L)₂(H₂O)₂], the peak at m/z = 609 stands for the molecular ion peak of complex (without water of crystallization). The proposed fragmentation pattern of [Cu(L)₂(H₂O)₂] is given in the Scheme 1. The measured molecular weights were consistent with expected values and the mass spectrum of [Cu(L)₂(H₂O)₂] complex is shown in Fig. 8.

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Figure 8

Mass spectrum of [Cu(L)₂(H₂O)₂] complex.

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3.5 Antimicrobial screening

The antibacterial activity of the standard drug (ciprofloxacin), ligand (L) and their metal complexes was screened against different bacterial strains as stated above. S. aureus is the preliminary screening test organism of choice for several reasons. Being a systemic pathogen with an ability to develop antibiotic resistance more readily than any other bacteria, the laboratory animals can be readily infected.

The inhibition of growth for these Gram-positive organisms produced by various concentrations of the test compounds was compared under identical conditions with the inhibition of growth for same organisms by ciprofloxacin (a standard antibiotic showing resistance to the growth of organism). Similarly, the inhibitions of the Gram-negative organism growth produced by the test compounds were compared with those for same concentrations of ciprofloxacin, which is a broad spectrum antibiotic. A standard volume (5 ml) of Luria broth medium (2%) to support the growth of the test organism was added to several labeled sterile stopper identical assay tubes. A solution of each test compound was prepared in DMSO and a series of dilutions was prepared. Concentrations tested were 0.25–20 ppm of the ligand and their metal complexes under investigation, a broad-spectrum antibiotic, the respective metal salt (20–800) ppm dissolved in DMSO and a blank (DMSO). A control tube containing no test compound was also included. A 0.1 ml aliquot of the test organism from the overnight grown test cultures was added. All these operations were carefully performed under aseptic conditions. Assay tubes were incubated at 30 °C for 24 h. The resultant turbidities were measured using a Systronics spectrophotometer model number 106. The minimum inhibitory concentration (MIC) of a test compound is the lowest concentration showing no visible turbidity. However, the final concentration of bacterial growth inhibition produced by a certain concentration of the test compound was calculated using the following relationship: $$\%\text{inhibition}=[\text{Tc}-\text{Tt}/\text{Tc}]\times 100$$ where Tc is the turbidity of the control and Tt is the turbidity of the specific treatment or the test compound. The metal complexes exhibited strong activities against two Gram-negative (E. coli, S. marcescens) and two Gram-positive (S. aureus, B. subtilis) microorganisms (Parekh et al., 2005). The minimum inhibitory concentration of antimicrobial activity data of the compounds is summarized in Table 5.A comparative analysis showed a higher antibacterial activity of the metal complexes than free ligands and metal salt. Some of the metal complexes exhibited moderate activities as compared with the standard drug ciprofloxacin. It was also observed that some of the metal complexes were more potent bactericides than the ligands. This enhancement in antibacterial activity is rationalized on the basis of Overtone’s concept, Tweedy’s chelation theory and the partial sharing of the positive charge of metal ions with donor groups (Talaviya and Chaudhari, 2013; Chohan et al., 2004). This may support the argument that some type of bimolecular binding to the metal ions or intercalation or electrostatic interaction causes the inhibition of biological synthesis and prevents the organisms from reproducing. The results of our studies (Table 5) indicate that metal complexes have a good activity against ligand and all bacterial strains. The strong antimicrobial activities of these compounds against tested organisms suggest further investigation on these compounds.