Current Trends in Medicinal Chemistry

Volume 2016; Issue 01
11 May 2017

Substituted O-Vanillin Schiff Base Derived Organotin(IV) Complexes: Synthesis, Characterization, Antimicrobial Evaluation and QSAR Studies

Review Article

Rajesh Malhotra*, Ankit Ravesh, Vikramjeet Singh

Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar-125001, Haryana, India

*Corresponding author: Rajesh Malhotra, University of Science and Technology, Haryana, India, Tel: +91 1662276240, E-mail: malhotra_ksrk@yahoo.co.in

Received Date: 15 November, 2016; Accepted Date:1 December, 2016; Published Date:7 December, 2016

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Abstract

Introduction

References

Figures

Tables

Suggested Citation

Abstract

 

The synthesis and in vitro antimicrobial activity of new Schiff bases and their organotin(IV) complexes has been tested against pathogenic Gram positive bacteria (viz. Klebsiella pneumoniae, Staphylococcus aureus) Gram negative bacteria (viz. Escherichia coli, Enterobacter aerogenes) and fungi (viz. Aspergillus niger and Candida albicans). The QSAR studies of these synthesized compounds has been carried out which indicate that antimicrobial activity of target compounds is governed by topological descriptors and electronic energy of molecule.

 

Keywords:  Schiff bases; Organotin (IV) complexes; Antimicrobial activity; QSAR

Introduction

 

Schiff base molecules obtained by the condensation of amine with an aldehyde or ketone have been studied widely due to their structural resemblance with natural biological substances and the presence of azomethine group (-N=CH-) which is responsible for the wide range of biological activities including anti-malarial, anti-bacterial, anti-fungal, anti-viral [1-6].Anti tubercular and anti HIV activity. The Schiff bases are the versatile ligands, when combined with organometallic tin form compounds of high stability with varied stereochemistry [7] .And having variety of biological applications [8-10].

Quantitative Structure Activity Relationship (QSAR) is one of the most important areas in computational chemistry which can extensively be used as valuable tool in drug design and medicinal chemistry. The statistically valid QSAR model is to predict the activities of the molecules and to identify the structural feature that play an important role in biological processes [11]. QSAR approach is based on the assumption that the behavior of a compound expressed by any measured activities is correlated with the molecular features of the compound [12]. In the present study we have synthesized some new biologically active Schiff bases and studied their ligational behaviour towards dichloro diorganotin(IV) along with their antimicrobial evaluation and QSAR analysis.

Results and Discussion

Chemistry

 

The reaction of substituted o-vanillin with p-toluic hydrazide or benzhydrazide in equimolar molar ratio afforded four air and moisture stable Schiff base ligands HLI–HL4. These ligands were soluble in dimethyl sulfoxide and dimethyl formamide at room temperature and soluble in methanol and ethanol on heating. These bidentate ligands reacted with R2SnCl2 (where R = Me, Et, Bu or Ph) in methanol under dry nitrogen atmosphere to form their Sn (IV) complexes (Scheme 1). All the synthesized metal complexes were coloured and insoluble in organic solvents except DMSO. The spectral data and elemental analysis of the synthesized ligands and their metal complexes were well in agreement with their proposed structure (Table 1).

 

Electronic Spectra

 

The electronic spectral data of the ligands and their tin complexes were recorded by dissolving these compounds in dry DMSO. The absorption spectra of HLI-HL4 were characterized by observing absorption bands at 387-393 nm which is attributed to transition between n-π* localized on the central azomethine bond. The polarization within the >C=N__ group resulting in metal-ligand interaction was shown by the blue shift in the complexes, revealed the involvement of azomethine nitrogen. The π- π* transition of benzene ring of Schiff base ligands was attributed to bands of medium intensity at 243 nm, 246 nm and 262 nm, which remain unchanged in the complexes.

 

IR Spectra

 

The IR spectra of ligands and their complexes were recorded using KBr pellets in the range of 400-4000 cm-1 and is given in experimental part. These ligands can coordinate through the nitrogen of azomethine and oxygen atom after the deprotonation. The ligands HLI–HL4 displayed band at 1615-1695 cm-1 [13] and 3412–3373 cm-1 due to v (C=O) and v (N-H) vibrations, respectively indicating their ketonic nature in the solid state. These bands disappeared in the complexes suggesting enolization of the ligand after deprotonation on coordination. The azomethine v (C=N) group of Schiff base ligands exhibited a sharp band around 1546-1557cm-1 which shifted to lower frequency in the complexes, thereby suggesting the involvement of nitrogen of this group in coordination with metal. Further confirmation of the complexes was supported by appearance of some new bands in the range 447-497 cm-1 [14] and 555-567 cm-1 [15] which were assigned to ν(Sn-N) and ν(Sn-O) modes respectively.

 

1H NMR

 

1H NMR spectra of the Schiff bases ligand and their complexes were recorded in DMSO-d6 and their chemical shifts (δ) are given the experimental part. The 1H NMR spectra of the Schiff base ligands HLI–HL4 showed a characteristic NH proton at δ 8.70-8.74 ppm [15]. Which disappeared in the spectra of the complexes after deprotonation of NH (via enolization). The azomethine proton of these ligands appeared as a sharp singlet around δ 11.78-11.87 ppm [16]. The downfield shifting of this azomethine proton signal in the complexes was observed as a consequence of coordination through nitrogen of this group. The aromatic and aliphatic protons of ligands exhibited signals in the range δ 7.12-7.92 ppm and δ 2.30-5.16 ppm respectively which remain unaltered in the spectra of the complexes indicated non participation of the atoms in bonding to which these protons are attached. The signals present at δ 1.19-1.26 ppm, δ 1.21-3.11 ppm, δ 1.00-3.11 ppm and δ 6.66-7.50 ppm were related to the methyl, ethyl, butyl and phenyl protons directly attached to tin atom. Integrated proton ratios confirmed the formation of complexes of type R2Sn(L)Cl.

 

13C NMR

 

13C NMR spectra of the Schiff bases ligand and their complexes were recorded in DMSO-d6 and are given in the experimental part. The ligands HLI–HL4 displayed characteristic signal of carbon of carbonyl and azomethine (CH=N) groups at δ 163.2– 163.3 ppm and δ 152.3– 152.6 ppm respectively [17].Which shifted towards lower values in the complexes, revealed the participation of carbonyl and azomethine carbon in coordination. The signals at δ 113.5-147 ppm and δ 20.8-74.7 ppm were assigned to carbons of aromatic and aliphatic regions of ligands, respectively. The signals at δ 8.5-8.6 ppm, δ 8.5-13.2 ppm and δ 8.2-28.4 ppm revealed the attachment of methyl, ethyl and n-butyl groups with the central metal atom. Similarly the signal at δ 128.1-129.2 ppm were assigned to the phenyl group attached to the tin.

 

119Sn NMR

 

119Sn NMR is a influential technique to find the coordination number of the central tin atom. The characteristic resonance peaks in the 119Sn NMR spectra of all of the complexes were recorded in CDCl3 and DMSO-d6. The 119Sn chemical shifts of organotin(IV) derivatives were in the range of -138.5 to -147.6 ppm [18] indicating penta-coordinated environment around tin atom.

 

Antimicrobial activity

 

The Schiff base ligands and their organotin(IV) complexes were screened for their in vitro antimicrobial activities along with conventional bactericide norfloxacin and fungicide fluconazole for comparing the activity of the compounds. The microorganisms used in the present study include S. aureus, K. pneumonia, E. coli and E. aerogenes and fungi C. albicans and A. niger.

The antimicrobial activity test results of all the tested compounds revealed their ability to act against bacterial and fungal strains appreciably and some of the compounds exhibited better activity than the standard drugs used in the assay. In the entire series, the pMIC of the compounds ranged between 0.874–2.066 μmol/mL and 0.890–2.066 μmol/mL against Gram-positive and Gram-negative bacteria, respectively. Compounds 12, 16 and 20 showed highest antibacterial activity followed by compounds 7, 8, 11, and 19 in the entire series. Similarly, antifungal data suggested that almost same results were obtained as in the antibacterial assay and compounds 11, 12, 15, 16, 19 and 20 displayed better activities than other compounds of the series and pMIC for antifungal activity of the entire series ranged from 0.890–2.066 μmol/mL.

The antimicrobial data reveals that the organotin (IV) complexes were found to be better antimicrobial agent as compared to their respective free ligands. The enhancement in the antimicrobial activity of complexes may be due to the delocalization of electron over the whole chelate ring, thereby increasing the lipophilicity of the target compound. This increased lipophilicity of the drug molecule favours its permeation through the cell membrane of microorganism [19]. The other factors which may affect the bioactivity of metal complexes include the number and the nature of the organic groups/halogen atoms directly bound to tin atom. The mode of action of metal complexes may be linked with the formation of hydrogen bond with the active centers of the cell constituents by interfering with normal cell processes.

 

QSAR analysis

 

Quantitative structure activity relationship (QSAR) studies between the in vitro antimicrobial activity and descriptors coding for lipophilic, electronic, steric and topological properties of four substituted o-vanillin Schiff bases and their sixteen organotin(IV) complexes were performed to find out the relationship between structural variants and antimicrobial activity using the Linear Free Energy Relationship model (LFER) described by Hansch and Fujita [20]. The dependent variable pMIC (i.e. –log MIC) used as in QSAR study was obtained by taking negative logarithm of observed antimicrobial activities (Table 2).

 

The different independent variables (molecular descriptors) like log of octanol–water partition coefficient (log P), Molar Refractivity (MR), Kier’s molecular connectivity (0c, 0cv, 1c, 1cv, 2c, 2cv) and shape (k1, k2, k3, ka1, ka2, ka3) topological indices, Randic topological index (R), Balaban topological index (J), Wiener topological index (W), Total energy (Te), energies of Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO), dipole moment (m), Nuclear repulsion Energy (Nu.E) and Electronic Energy (Ele.E), calculated for ligands and their organotin (IV) complexes are presented in (Table 3) [21-26]

 

High collinearity (r > 0.8) was observed between different parameters i.e. molecular descriptors. The high interrelationship was observed between k1 and Ele.E (r = 0.996), W and 1χ (r = 0.995), 0χ and Ele.E (r = 0.995) and low interrelationship was observed between HOMO and W (r = 0.022) and HOMO and 1χ (r = 0.028). The correlation matrix indicated that the antimicrobial activity of synthesized ligands and their organotin (IV) complexes are governed by topological parameters like molecular connectivity, shape indices and electronic energy.

The antifungal activity of synthesized derivatives against A. niger is governed by the second order shape attribute (Kappa shape indices), κ2 (Eq. 1).

 

QSAR model for antifungal activity against A. niger

pMICan = 0.134 κ2 – 0.358 Eq. 1

n = 20                     r = 0.958                r2 = 0.918               q2 = 0.898              s = 0.095                F = 201.482

Here and thereafter, n – number of data points, r – correlation coefficient, r2 -squared correlation coefficient, q2 – cross validated r2 obtained by leave one out method, s – standard error of the estimate and F – Fischer statistics.

 

The QSAR model represented by Eq. 1 for antifungal activity against A. niger demonstrated the importance of second order Kappa shape indices (κ2). According to Kier, the shape of a molecule may be partitioned into attributes, each describable by the count of bonds of various path lengths [27]. The basis for devising a relative index of shape is given by the relationship of the number of path of length l in the molecule i, lPi, to some reference values based on molecules with a given number of atoms, n, in which the values of lP are maximum and minimum, lPmax and lPmin [28]. The second order shape attribute, κ2, is given by the following expression:

 

κ2 = (n-1)(n-2)2/(2Pi)2

 

The equation 1 highlighted the positive correlation between second order Kappa shape indices (κ2) for the synthesized compounds and antifungal activity against A. niger which depicts that compounds having high κ2 values (Table 3) will have high antifungal potential and the results presented in the Table 6 are in concordance with the model expressed by Eq. 1.

 

The linear regression model expressed by Eq. 1 was cross validated by its high q2 values (q2 = 0.898) obtained with Leave One Out (LOO) method. The basic requirement for becoming a QSAR model to be valid one is that it must possess q2 value higher than 0.5 thus supporting the fact that model expressed by Eq. 1 is valid one [29]. The comparison of observed and predicted antifungal activities is presented in (Table 6).

 

The results of observed and predicted antifungal activities lie close to each other as evidenced by their low residual values (Table 6) which again supported the validity of model expressed by Eq. 1. The statistical validity of QSAR model was also cross checked by plotting the graphs of observed, predicted and residual pMIC activity values. The plot of predicted pMICan against observed pMICan (Figure 1)

 

QSAR models 2 – 8 were obtained by linear regression of the antibacterial and antifungal activity of synthesized derivatives against S. aureus, C. albicans, K. pneumoniae, E. coli, and E. aerogenes with molecular descriptors.

 

QSAR model for antibacterial activity against S. aureus

pMICsa = – 0.000025 Ele.E + 0.083                                                                      Eq. 2

n = 20                     r = 0.941                r2 = 0.886               q2 = 0.855              s = 0.109                F = 140.08

QSAR model for antifungal activity against C. albicans

pMICca = 0.119 1χ – 0.565                                                                                                     Eq. 3

n = 20                     r = 0.936                r2 = 0.877               q2 = 0.830              s = 0.115                F = 127.974

QSAR model for antifungal activity against C. albicans

pMICca = 0.119 R – 0.565                                                                                                     Eq. 4

n = 20                     r = 0.936                r2 = 0.877               q2 = 0.830              s = 0.115                F = 127.974

QSAR model for antibacterial activity against K. pneumoniae

pMICkp = 0.112 1χ – 0.327                                                                                     Eq. 5

n = 20                     r = 0.924                r2 = 0.853               q2 = 0.825              s = 0.120                F = 104.331

 

QSAR model for antibacterial activity against K. pneumoniae

pMICkp = 0.112 R – 0.327                                                                                     Eq. 6

n = 20                     r = 0.924                r2 = 0.853               q2 = 0.825              s = 0.120                F = 104.331

QSAR model for antibacterial activity against E. coli

pMICec = 0.123 κ2 – 0.239                                                                                    Eq. 7

n = 20                     r = 0.915                r2 = 0.837               q2 = 0.804              s = 0.128                F = 92.54

QSAR model for antibacterial activity against E. aerogenes

pMICea = 0.056 κ1 – 0.175                                                                                    Eq. 8

n = 20                     r = 0.900                r2 = 0.811               q2 = 0.764              s = 0.115                F = 77.022

 

The linear regression model represented by Eq. 2 revealed that the antibacterial activity against S. aureus is governed by the Electronic Energy of the molecule (Ele.E). As the coefficient of electronic energy is negative, therefore the antibacterial activity against S. aureus will increase with decrease in Ele.E values, that can be checked from the results presented in Table 3 and 6.

 

Eq. 3 and 4 were obtained for the regression model describing the antifungal activity of the synthesized derivatives against C. albicans both of which indicated that first order molecular connectivity index (1χ) and Randic (R) topological parameter were equally affecting the antifungal activity against C. albicans as all the statistical parameters for both these equations were same. The positive coefficient of first order molecular connectivity index (1χ) and Randic (R) parameter in Eq. 3 and 4 demonstrated that the antifungal of the synthesized derivatives will increase with increase in value of first order molecular connectivity index (1χ) and Randic (R) parameter.

 

Similarly the regression analysis for antibacterial activity of synthesized derivatives against K. pneumoniae came out with two models represented by Eq. 5 and 6 thus indicating the fact that antibacterial activity against K. pneumoniae is governed by two parameters viz. first order molecular connectivity index (1χ) and Randic (R) parameter to an equal extent. Both of these models have same statistical parameters and thus indicated that the predicted antibacterial activity against K. pneumoniae will be same whatever the parameter we use for prediction of activity out of these two molecular descriptors. The outcome of QSAR models represented by Eq. 3 to 6 revealed the fact that K. pneumoniae and C. albicans may have similar type of binding site in their target receptor to which these molecules are binding.

 

QSAR model represented by Eq. 7 indicated the importance of second order Kappa shape indices (κ2) in describing the antibacterial activity against E. coli. The positive correlation of the molecular descriptor second order Kappa shape indices (κ2) with antibacterial activity revealed that increase in the value of κ2 will lead to an increase in antibacterial activity against E. coli.

 

The antibacterial activity of synthesized derivatives against E. aerogenes was governed by first order Kappa shape indices (κ1) as demonstrated by Eq. 8. The QSAR models represented by Eq. 2-8 have got high r, r2, q2 and F values and low s values which indicated that that the models are valid one. The low residual values obtained after prediction of activity using these models (Table 6) confirmed the fact that models expressed by Eq. 2 – Eq. 8 were also valid ones.

 

Materials and methods

 

The chemicals used were of analytical grade (Aldrich) and solvents were purified according to standard procedures. The complexes were synthesized under anhydrous condition in inert atmosphere. The molar conductance was measured in dry DMSO using Systronics conductivity bridge model-306. The IR spectra were recorded using a Spectrum BX Series FT-IR spectrophotometer in the range 400-4000 cm-1, using KBr pellets. Multinuclear magnetic resonance spectra (1H, 13C, 119Sn) were recorded on a Bruker Avance II 400 MHz NMR Spectrometer and all chemical shifts δ were reported in ppm relative to Tetra Methyl Silane (TMS) as an internal standard in CDCl3 and DMSO-d6. Elemental analyses were carried out on a Perkin Elmer 2400 analyzer. Tin/chlorine was estimated gravimetrically. Bacterial and fungal strain was procured from Microbial Type Culture Collection (MTCC), IMTECH, Chandigarh.

 

Synthesis of Schiff base Ligands

 

Synthesis of ligands (HL1-HL4) were carried out in the following two steps:-

  • Synthesis of 2-(4-methyl/nitro-benzyloxy)-3-methoxy-benzaldehyde (I).

The solution of o-vanillin (10 mmol) and K2CO3 (20 mmol) in 26 ml of DMF was stirred and p-methyl benzyl bromide (10 mmol) was added slowly. The mixture was allowed to stir overnight. Benzylation of o-vanillin with p-methyl benzyl bromide took place through Williamson ether formation resulted in the formation of 2-(4-methyl-benzyloxy)-3-methoxy-benzaldehyde. The reaction mixture was then quenched with ice followed by the addition of 50 ml of water. The solid product obtained was filtered over the vaccum pump and dried. The same procedure was adopted for the synthesis of 2-(4-nitro-benzyloxy)-3-methoxy-benzaldehyde.

  • Synthesis of Schiff base ligands (HL1-HL4)

Ligands HL1-4 were synthesized by reacting substituted o-vanillin (I) with p-toluic Hydrazide or benzhydrazide (II) in equimolar ratio in dry methanol. The solid product obtained after refluxing the reaction mixture for about 3-4 hrs was filtered and recrystallized in methanol. The same procedure was adopted for the synthesis of other Schiff base ligands.

 

Benzoic acid [3-methoxy-2-(4-methyl-benzyloxy)-benzyledene]-hydrazide [(HL1, C23H22N2O3), (1)]

Yield: 82 %; m.p.: 170-171 °C; IR (KBr): ν = 3385 (NH), ν = 1689 (C=O), ν = 1550 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.87 (s, 1H, -CH=N), 8.71 (s, 1H, -NH ), 7.90-7.92 (d, 2H, C2’-H & , C6’-H), 7.49-7.58 (m, 4H, C3’-H, C4’-H , C5’-H & C2-H), 7.35-7.37 (d, 2H, Cb-H & Cf-H), 7.16-7.18 (d, 2H, Cc-H & Ce-H), 7.10-7.12 (m, 2H, C3-H & C4-H), 4.97 (s, 2H, -OCH2), 3.88 ( s, 3H, -OCH3), 2.30 ( s, 3H, -CH3) ppm; 13C NMR: δ = 163.3 (C=O), 152.6 (C=N), 146.4 (C-6), 143.5 (C-5), 137.2 (C-a), 133.8 (C-d), 133.4 (C-1’), 131.4 (C-4’), 128.6 (C-c & C-e), 128.4 (C-3’ & C-5’), 128.2 (C-2 ’& C-6’), 128.1 (C-b & C-f), 127.6 (C-2), 124 (C-3), 117.2 (C-1), 113.7 (C-4), 74.7 (OCH2), 55.3 (OCH3), 20.8 (CH3 at Ph ring) ppm.

4-Nitro-Benzoic acid [3-methoxy-2-(4-methyl-benzyloxy)-benzyledene]-hydrazide [(HL2, C22H19N3O5), (2)]

Yield: 86 %; m.p.: 174-175 °C; IR (KBr): ν = 3412 (NH), ν = 1695 (C=O), ν = 1557 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.86 (s, 1H, -CH=N), 8.73 (s, 1H, -NH ), 8.25-8.27 (d, 2H, Cc-H & Ce-H), 7.89-7.91 (d, 2H, C2’-H & , C6’-H), 7.77-7.79 (d, 2H, Cb-H & Cf-H), 7.49-7.58 (m, 4H, C2-H, C3’-H, C4’-H & C5’-H), 7.14-7.17 (m, 2H, C3-H & C4-H), 5.16 (s, 2H, -CH2), 3.87 ( s, 3H, -OCH3) ppm; 13C NMR: δ = 163.3 (C=O), 152.4 (C=N), 147 (C-6), 146.1 (C-5), 144.7 (C-d), 143.2 (C-a), 133.4 (C-1’), 131.5 (C-4’), 128.6 (C-3’ & C-5’), 128.2 (C-b & C-f), 128.1 (C-2 ’& C-6’), 127.6 (C-c & C-e), 124.5 (C-2), 123.2 (C-3), 117.3 (C-1), 113.8 (C-4), 73.5 (OCH2), 55.7 (OCH3) ppm.

4-Methyl-Benzoic acid [3-methoxy-2-(4-methyl-benzyloxy)-benzyledene]-hydrazide [(HL3, C24H24N2O3), (3)]

Yield: 83 %; m.p.: 164-165 °C; IR (KBr): ν = 3373 (NH), ν = 1687 (C=O), ν = 1546 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.79 (s, 1H, -CH=N), 8.70 (s, 1H, -NH ), 7.82-7.84 (d, 2H, C2-H & C6’-H), 7.48-7.50 (d, 1H, C2-H), 7.35-7.37 (d, 2H, C3’-H & C5’-H), 7.30-7.32 (d, 2H, Cb-H & Cf-H), 7.16-7.18 (d, 2H, Cc-H & Ce-H), 7.10-7.11 (m, 2H, C3-H & C4-H), 4.97 (s, 2H, -OCH2), 3.88 ( s, 3H, -OCH3), 2.39 ( s, 3H, -CH3 at Hydrazide ring), 2.30 ( s, 3H, -CH3 at Ph ring) ppm; 13C NMR: δ = 163.2 (C=O), 152.5 (C=N), 146.4 (C-6), 143.3 (C-5), 141.5 (C-4’), 137.2 (C-a), 133.8 (C-d), 130.5 (C-1’), 128.7 (C-c & C-e), 128.6 (C-3’ & C-5’), 128.4 (C-2 ’& C-6’), 128.3 (C-b & C-f), 127.6 (C-2), 124 (C-3), 117.3 (C-1), 113.5 (C-4), 74.7 (OCH2), 55.5 (OCH3), 21.1 (CH3 at Hydrazide ring), 20.8 (CH3 at Ph ring) ppm.

4-Methyl-Benzoic acid [3-methoxy-2-(4-nitro-benzyloxy)-benzyledene]-hydrazide [(HL4, C23H21N3O5), (4)]

Yield: 79 %; m.p.: 169-170 °C; IR (KBr): ν = 3394 (NH), ν = 1692 (C=O), ν = 1553 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.78 (s, 1H, -CH=N), 8.74 (s, 1H, -NH ), 8.24-8.27 (d, 2H, Cc-H & Ce-H), 7.77-7.80 (d, 4H, C2’-H, C6’-H, Cb-H & Cf-H), 7.54-7.55 (d, 1H, C2-H), 7.28-7.30 (d, 2H, C3-H & C5’-H), 7.10-7.17 (m, 2H, C3-H & C4-H), 5.16 (s, 2H, -OCH2), 3.87 ( s, 3H, -OCH3), 2.39 ( s, 3H, -CH3 at Hydrazide ring) ppm; 13C NMR: δ = 163.3 (C=O), 152.4 (C=N), 146.8 (C-6), 145.2 (C-5), 144.6 (C-d), 142 (C-a), 140.3 (C-4’), 135.2 (C-1’), 129.4 (C-3’ & C-5’), 128.4 (C-b & C-f), 128.1 (C-2 ’& C-6’), 127.6 (C-c & C-e), 122.4 (C-2), 123.2 (C-3), 117.4 (C-1), 113.6 (C-4), 73.5 (OCH2), 55.6 (OCH3), 21 (CH3 at Hydrazide ring) ppm.

 

General procedure for the synthesis of organotin complexes (5-20)

 

The sodium salt of Schiff base ligand was prepared by reacting ligand HL1 (4.56 g, 10 mmol) and sodium metal (0.225 g, 10 mmol) in 30 mL dry methanol followed by the slow addition of Me2SnCl2 (2.19 g, 10 mmol) and then the reaction mixture was refluxed for 4h. The precipitated NaCl was filtered and solvent was evaporated on rotary evaporator under reduced pressure. The final product obtained was recrystallized from dry methanol and hexane and finally dried under reduced pressure. The other tin complexes were synthesized by reacting the ligands, HL2/HL3/HL4 with R2SnCl2 in 1:1 molar ratio by the same procedure.

 

[(Me2Sn(L1)Cl, C25H27ClN2O3Sn), (5)]

Yield: 74 %; m.p.: 126-127 °C; IR (KBr): ν = 1548 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.98 (s, 1H, -CH=N), 7.94-7.96 (d, 2H, C2’-H & , C6’-H), 7.48-7.56 (m, 4H, C3’-H, C4’-H , C5’-H & C2-H), 7.36-7.38 (d, 2H, Cb-H & Cf-H), 7.14-7.16 (d, 2H, Cc-H & Ce-H), 7.07-7.10 (m, 2H, C3-H & C4-H), 4.96 (s, 2H, -OCH2), 3.86 ( s, 3H, -OCH3), 2.28 ( s, 3H, -CH3), 1.19(s, 6H, -CH3) ppm; 13C NMR: δ = 155.6 (C=O), 151.4 (C=N), 146.4 (C-6), 143.6 (C-5), 137.2 (C-a), 133.9 (C-d), 133.4 (C-1’), 131.6 (C-4’), 128.7 (C-c & C-e), 128.5 (C-3’ & C-5’), 128.3 (C-2 ’& C-6’), 128.4 (C-b & C-f), 127.6 (C-2), 124.2 (C-3), 117.2 (C-1), 113.9 (C-4), 74.7 (OCH2), 55.7 (OCH3), 20.8 (CH3 at Ph ring), 8.5 (Me) ppm.

[(Et2Sn(L1)Cl, C27H31ClN2O3Sn), (6)]

Yield: 72 %; m.p.: 124-125 °C; IR (KBr): ν = 1545 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.84 (s, 1H, -CH=N), 7.89-7.91 (d, 2H, C2’-H & , C6’-H), 7.50-7.56 (m, 4H, C3-H, C4-H, C5’-H & C2-H), 7.33-7.35 (d, 2H, Cb-H & Cf-H), 7.15-7.17 (d, 2H, Cc-H & Ce-H), 7.08-7.11 (m, 2H, C3-H & C4-H), 5.01 (s, 2H, -OCH2), 3.87 ( s, 3H, -OCH3), 2.28 ( s, 3H, -CH3), 3.06-3.11 (m, 4H,-CH2), 1.23-1.26 (t, 6H,-CH3) ppm; 13C NMR: δ = 155.6 (C=O), 151.6 (C=N), 147.3 (C-6), 144.3 (C-5), 141.7 (C-a), 138.2 (C-d), 134.9 (C-1’), 130.6 (C-4’), 129.9 (C-c & C-e), 129.1 (C-3’ & C-5’), 128.6 (C-2 ’& C-6’), 128.1 (C-b & C-f), 127.6 (C-2), 123 (C-3), 117.3 (C-1), 113.3 (C-4), 74.9 (OCH2), 55.4 (OCH3), 21 (CH3 at Ph ring), 12.6 (Et), 8.6 (Et) ppm.

[(Bu2Sn(L1)Cl, C31H39ClN2O3Sn), (7)]

Yield: 66 %; m.p.: 121-122 °C; IR (KBr): ν = 1549 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.99 (s, 1H, -CH=N), 7.94-7.96 (d, 2H, C2’-H & , C6’-H), 7.49-7.58 (m, 4H, C3’-H, C4’-H, C5’-H & C2-H), 7.37-7.39 (d, 2H, Cb-H & Cf-H), 7.16-7.18 (d, 2H, Cc-H & Ce-H), 7.09-7.12 (m, 2H, C3-H & C4-H), 4.97 (s, 2H, -OCH2), 3.88 ( s, 3H, -OCH3), 2.29 ( s, 3H, -CH3), 3.07-3.11 (m, 4H,-CH2), 1.20-1.24 (m, 8H,-CH2), 1.00-1.10 (t, 6H,-CH3) ppm; 13C NMR: δ = 155.6 (C=O), 151.6 (C=N), 146.4 (C-6), 143.3 (C-5), 141.6 (C-a), 137.2 (C-d), 133.9 (C-1’), 130.5 (C-4’), 128.8 (C-c & C-e), 128.7 (C-3’ & C-5’), 128.5 (C-2 ’& C-6’), 128.4 (C-b & C-f), 127.7 (C-2), 124.1 (C-3), 117.2 (C-1), 113.7 (C-4), 74.7 (OCH2), 55.7 (OCH3), 26.4 (Bu), 24.5 (Bu), 20.8 (CH3 at Ph ring), 12 (Bu), 8.6 (Bu) ppm.

[(Ph2Sn(L1)Cl, C35H31ClN2O3Sn), (8)]

Yield: 73 %; m.p.: 139-140 °C; IR (KBr): ν = 1548 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.87(s, 1H, -CH=N), 8.76-8.90 (d, 2H, C2’-H & , C6’-H), 8.11-8.51 (m, 4H, C3’-H, C4’-H, C5’-H & C2-H ), 7.85-7.95 (d, 4H, Cb-H, Cf-H, Cc-H & Ce-H), 6.66-7.50 (m, 10H Ph and 2H, C3-H & C4-H), 4.97 (s, 2H, -OCH2), 3.87 (s, 3H, -OCH3), 2.38 (s, 3H, -CH3) ppm; 13C NMR: δ = 155.7 (C=O), 151.5 (C=N), 146.4 (C-6), 143.3 (C-5), 140.4 (C-a), 134.7 (C-d), 133.9 (C-1’), 131.1 (C-4’), 128.8 (Ph), 128.7 (Ph), 128.6 (Ph), 128.5 (Ph), 128.4 (C-c & C-e), 128.2 (C-3’ & C-5’), 127.7 (C-2 ’& C-6’), 127.6 (C-b & C-f), 127.2 (C-2), 124.1 (C-3), 117.1 (C-1), 113.8 (C-4), 74.7 (OCH2), 55.7 (OCH3), 21.1 (CH3 at Ph ring) ppm.

[(Me2Sn(L2)Cl, C24H24ClN3O5Sn), (9)]

Yield: 77 %; m.p.: 128-129 °C; IR (KBr): ν = 1553 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.85 (s, 1H, -CH=N), 8.24-8.27 (d, 2H, Cc-H & Ce-H), 7.86-7.88 (d, 2H, C2’-H & , C6’-H), 7.72-7.74 (d, 2H, Cb-H & Cf-H), 7.52-7.57 (m, 4H,C2-H, C3’-H, C4’-H & C5’-H), 7.13-7.17 (m, 2H, C3-H & C4-H), 5.01 (s, 2H, -OCH2), 3.87 ( s, 3H, -OCH3), 1.23 (s, 6H, -CH3) ppm; 13C NMR: δ = 155.4 (C=O), 151.4 (C=N), 146.9 (C-6), 145.9 (C-5), 144.9 (C-d), 142.9 (C-a), 133.4 (C-1’), 131.6 (C-4’), 128.8, (C-3’ & C-5’), 128.1 (C-b & C-f), 127.9 (C-2 ’& C-6’), 127.7 (C-c & C-e), 124.5 (C-2), 123.3 (C-3), 117.5 (C-1), 113.8 (C-4), 73.6 (OCH2), 55.7 (OCH3), 8.6 (Me) ppm.

[(Et2Sn(L2)Cl, C26H28ClN3O5Sn), (10)]

Yield: 81 %; m.p.: 126-127 °C; IR (KBr): ν = 1555 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.86 (s, 1H, -CH=N), 8.25-8.28 (d, 2H, Cc-H & Ce-H), 7.85-7.87 (d, 2H, C2’-H & , C6’-H), 7.73-7.75 (d, 2H, Cb-H & Cf-H), 7.51-7.56 (m, 4H,C2-H, C3’-H, C4’-H & C5’-H), 7.12-7.15 (m, 2H, C3-H & C4-H), 4.98 (s, 2H, -OCH2), 3.85 ( s, 3H, -OCH3), 3.08-3.11 (m, 4H,-CH2), 1.22-1.26 (t, 6H,-CH3) ppm; 13C NMR: δ = 155.3 (C=O), 151.5 (C=N), 145.3 (C-6), 142.3 (C-5), 135.9 (C-d), 132.9 (C-a), 132.2 (C-1’), 131.3 (C-4’), 129.7, (C-3’ & C-5’), 128.7 (C-b & C-f), 128.2 (C-2 ’& C-6’), 128 (C-c & C-e), 127.5 (C-2), 125 (C-3), 117.1 (C-1), 113.5 (C-4), 74.7 (OCH2), 55.5 (OCH3), 13.2 (Et), 8.8 (Et) ppm.

[(Bu2Sn(L2)Cl, C30H36ClN3O5Sn), (11)]

Yield: 75 %; m.p.: 123-124 °C; IR (KBr): ν = 1554 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.84 (s, 1H, -CH=N), 8.23-8.26 (d, 2H, Cc-H & Ce-H), 7.84-7.86 (d, 2H, C2’-H & , C6’-H), 7.72-7.74 (d, 2H, Cb-H & Cf-H), 7.54-7.57 (m, 4H,C2-H, C3’-H, C4’-H & C5’-H), 7.11-7.16 (m, 2H, C3-H & C4-H), 4.99 (s, 2H, -OCH2), 3.88 ( s, 3H, -OCH3), 3.08-3.11 (t, 4H,-CH2), 1.62-1.66 (m, 8H,-CH2), 1.21-1.24 (t, 6H, -CH3) ppm; 13C NMR: δ = 155.4 (C=O), 151.5 (C=N), 146.8 (C-6), 145.7 (C-5), 144.7 (C-d), 142.8 (C-a), 133.5 (C-1’), 131.5 (C-4’), 128.7, (C-3’ & C-5’), 127.9 (C-b & C-f), 127.3 (C-2 ’& C-6’), 127.2 (C-c & C-e), 124.5 (C-2), 123.3 (C-3), 117.4 (C-1), 113.6 (C-4), 73.6 (OCH2), 55.8 (OCH3), 28.4 (Bu), 26.4 (Bu), 13.2 (Bu), 7.9 (Bu) ppm.

[(Ph2Sn(L2)Cl, C34H28ClN3O5Sn), (12)]

Yield: 68 %; m.p.: 144-145 °C; IR (KBr): ν = 1555 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.86 (s, 1H, -CH=N), 8.26-8.29 (d, 2H, Cc-H & Ce-H), 7.82-7.91 (d, 4H, C2’-H , C6’-H, Cb-H & Cf-H), 7.53-7.56 (m, 4H,C2-H, C3’-H, C4’-H & C5’-H), 7.03-7.21 (m, 10H Ph and 2H, C3-H & C4-H), 4.97 (s, 2H, -OCH2), 3.86 (s, 3H, -OCH3) ppm; 13C NMR: δ = 155.4 (C=O), 151.5 (C=N), 146.8 (C-6), 145.6 (C-5), 144.8 (C-d), 142.8 (C-a), 133.5 (C-1’), 131.5 (C-4’), 129.2 (Ph), 128.8 (Ph), 128.4 (Ph), 128.1 (Ph), 128.6, (C-3’ & C-5’), 128 (C-b & C-f), 127.3 (C-2 ’& C-6’), 126.9 (C-c & C-e), 124.5 (C-2), 123.3 (C-3), 117.2 (C-1), 113.8 (C-4), 73.5 (OCH2), 55.9 (OCH3) ppm.

[(Me2Sn(L3)Cl, C26H29ClN2O3Sn), (13)]

Yield: 74 %; m.p.: 127-128 °C; IR (KBr): ν = 1545 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.78 (s, 1H, -CH=N), 7.83-7.85 (d, 2H, C2’-H & , C6’-H), 7.47-7.49 (d, 1H,C2-H), 7.34-7.36 (d, 2H, C3’-H & C5’-H), 7.28-7.30 (d, 2H, Cb-H & Cf-H), 7.18-7.20 (d, 2H, Cc-H & Ce-H), 7.08-7.11 (m, 2H, C3-H & C4-H), 5.01 (s, 2H, -OCH2), 3.87 (s, 3H, -OCH3), 2.37 (s, 3H, -CH3 at Hydrazide ring), 2.30 (s, 3H, -CH3 at Ph ring), 1.23 (s, 6H, -CH3) ppm; 13C NMR: δ = 155.4 (C=O), 151.6 (C=N), 146.4 (C-6), 143.3 (C-5), 141.5 (C-4’), 137.3 (C-a), 133.8 (C-d), 129.9 (C-1’), 128.5 (C-c & C-e), 128.4 (C-3’ & C-5’), 128.2 (C-2 ’& C-6’), 128.2 (C-b & C-f), 127.6 (C-2), 123.9 (C-3), 117.3 (C-1), 113.4 (C-4), 73.6 (OCH2), 55.4 (OCH3), 21.2 (CH3 at Hydrazide ring), 20.8 (CH3 at Ph ring), 8.6 (Me) ppm.

[(Et2Sn(L3)Cl, C28H33ClN2O3Sn), (14)]

Yield: 69 %; m.p.: 124-125 °C; IR (KBr): ν = 1542 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.91 (s, 1H, -CH=N), 7.86-7.88 (d, 2H, C2’-H & , C6’-H), 7.51-7.53 (d, 1H,C2-H), 7.37-7.38 (d, 2H, C3’-H & C5’-H), 7.28-7.30 (d, 2H, Cb-H & Cf-H), 7.15-7.17 (d, 2H, Cc-H & Ce-H), 7.06-7.09 (m, 2H, C3-H & C4-H), 4.9 (s, 2H, -OCH2), 3.87 (s, 3H, -OCH3), 2.37 (s, 3H, -CH3 at Hydrazide ring), 2.29 (s, 3H, -CH3 at Ph ring), 3.01-3.07 (m, 4H,-CH2), 1.22-1.28 (t, 6H,-CH3) ppm; 13C NMR: δ = 155.3 (C=O), 151.7 (C=N), 145.4 (C-6), 143.4 (C-5), 141.6 (C-4’), 137.3 (C-a), 133.6 (C-d), 130.1 (C-1’), 128.8 (C-c & C-e), 128.4 (C-3’ & C-5’), 128.3 (C-2 ’& C-6’), 128.2 (C-b & C-f), 127.8 (C-2), 123.7 (C-3), 117.2 (C-1), 113.4 (C-4), 74.6 (OCH2), 55.4 (OCH3), 21.1 (CH3 at Hydrazide ring), 20.6 (CH3 at Ph ring), 12.8 (Et), 7.6 (Et) ppm.

[(Bu2Sn(L3)Cl, C32H41ClN2O3Sn), (15)]

Yield: 73 %; m.p.: 120-121 °C; IR (KBr): ν = 1545 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.87 (s, 1H, -CH=N), 7.88-7.90 (d, 2H, C2’-H & , C6’-H), 7.53-7.55 (d, 1H,C2-H), 7.35-7.37 (d, 2H, C3’-H & C5’-H), 7.25-7.27 (d, 2H, Cb-H & Cf-H), 7.16-7.18 (d, 2H, Cc-H & Ce-H), 7.08-7.11 (m, 2H, C3-H & C4-H), 5.00 (s, 2H, -OCH2), 3.88 (s, 3H, -OCH3), 2.38 (s, 3H, -CH3 at Hydrazide ring), 2.29 (s, 3H, -CH3 at Ph ring), 3.01-3.07 (m, 4H,-CH2), 1.61-1.66 (m, 8H, -CH2),1.21-1.26 (t, 6H, -CH3) ppm; 13C NMR: δ = 155.2 (C=O), 151.6 (C=N), 145.4 (C-6), 142.2 (C-5), 135.8 (C-4’), 132.8 (C-a), 132.6 (C-d), 130.9 (C-1’), 129.8 (C-c & C-e), 128.5 (C-3’ & C-5’), 128.2 (C-2 ’& C-6’), 127.6 (C-b & C-f), 127.3 (C-2), 124.2 (C-3), 117.2 (C-1), 113.3 (C-4), 74.6 (OCH2), 55.4 (OCH3), 28.4 (Bu), 24.4 (Bu), 21.1 (CH3 at Hydrazide ring), 20.3 (CH3 at Ph ring), 13.1 (Bu), 8.2 (Bu) ppm.

[(Ph2Sn(L3)Cl, C36H33ClN2O3Sn), (16)]

Yield: 79 %; m.p.: 139-140 °C; IR (KBr): ν = 1543 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.78 (s, 1H, -CH=N), 7.86-7.88 (d, 2H, C2’-H & C6’-H), 7.50-7.51 (d, 1H, C2-H), 7.37-7.46 (d, 4H, C3’-H, C5’-H, Cb-H & Cf-H), 7.33-7.35 (d, 2H, Cc-H & Ce-H), 7.01-7.23 (m, 10H, Ph & m,2H, C3-H & C4-H), 4.97 (s, 2H, -OCH2), 3.84 (s, 3H, -OCH3), 2.38 (s, 3H, -CH3 at Hydrazide ring), 2.30 (s, 3H, -CH3 at Ph ring) ppm; 13C NMR: δ = 155.3 (C=O), 151.7 (C=N), 145.2 (C-6), 143.5 (C-5), 141.5 (C-4’), 137.3 (C-a), 133.7 (C-d), 129.9 (C-1’), 128.8 (Ph), 128.7 (C-c & C-e), 128.6 (Ph), 128.5 (C-3’ & C-5’), 128.4 (Ph), 128.3 (C-2 ’& C-6’), 128.2 (C-b & C-f), 128.2 (Ph), 127.7 (C-2), 123.9 (C-3), 117.3 (C-1), 113.4 (C-4), 74.6 (OCH2), 55.3 (OCH3), 21.2 (CH3 at Hydrazide ring), 20.7 (CH3 at Ph ring) ppm.

[(Me2Sn(L4)Cl, C25H26ClN3O5Sn), (17)]

Yield: 67 %; m.p.: 129-130 °C; IR (KBr): ν = 1550 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.76 (s, 1H, -CH=N), 8.22-8.26 (d, 2H, Cc-H & Ce-H), 7.78-7.81 (d, 4H, C2’-H, C6-H, Cb-H & Cf-H), 7.53-7.56 (d, 1H, C2-H), 7.24-7.26 (d, 2H,C3-H & C5’-H), 7.12-7.18 (m, 2H, C3-H & C4-H), 5.16 (s, 2H, -OCH2), 3.87 (s, 3H, -OCH3), 2.37 (s, 3H, -CH3 at Hydrazide ring), 1.26 (s, 6H, -CH3) ppm; 13C NMR: δ = 155.3 (C=O), 151.7 (C=N), 146.8 (C-6), 145.9 (C-5), 144.6 (C-d), 143 (C-a), 141.5 (C-4’), 130.5 (C-1’), 128.7 (C-3’ & C-5’), 128.5 (C-b & C-f), 128 (C-2’ & C-6’), 127.6 (C-c & C-e), 124.5 (C-2), 123.0 (C-3), 117.3 (C-1), 113.8 (C-4), 73.3 (OCH2), 55.7 (OCH3), 22.9 (CH3 at Hydrazide ring) ppm.

[(Et2Sn(L4)Cl, C27H30ClN3O5Sn), (18)]

Yield: 71 %; m.p.: 127-128 °C; IR (KBr): ν = 1552 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.75 (s, 1H, -CH=N), 8.24-8.27 (d, 2H, Cc-H & Ce-H), 7.77-7.80 (d, 4H, C2’-H, C6-H, Cb-H & Cf-H), 7.52-7.55 (m, 1H, C2-H), 7.23-7.25 (d, 2H,C3’-H & C5’-H), 7.13-7.16 (m, 2H, C3-H & C4-H), 5.0 (s, 2H, -OCH2), 3.85 (s, 3H, -OCH3), 2.38 (s, 3H, -CH3 at Hydrazide ring), 3.06-3.10 (m, 4H,-CH2), 1.21-1.25 (t, 6H,-CH3) ppm; 13C NMR: δ = 155.3 (C=O), 151.8 (C=N), 146.3 (C-6), 145.9 (C-5), 144.6 (C-d), 143 (C-a), 141.6 (C-4’), 130.5 (C-1’), 128.7 (C-3’ & C-5’), 128.5 (C-b & C-f), 128 (C-2’ & C-6’), 127.7 (C-c & C-e), 124.3 (C-2), 123.1 (C-3), 117.3 (C-1), 113.8 (C-4), 73.4 (OCH2), 55.6 (OCH3), 23 (CH3 at Hydrazide ring), 12.9 (Et), 8.7 (Et) ppm.

[(Bu2Sn(L4)Cl, C31H38ClN3O5Sn), (19)]

Yield: 68 %; m.p.: 124-125 °C; IR (KBr): ν = 1551 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.74 (s, 1H, -CH=N), 8.21-8.25 (d, 2H, Cc-H & Ce-H), 7.76-7.80 (d, 4H, C2-H, C6-H, Cb-H & Cf-H), 7.51-7.55 (m, 1H, C2-H), 7.24-7.26 (d, 2H,C3’-H & C5’-H), 7.12-7.15 (m, 2H, C3-H & C4-H), 4.98 (s, 2H, -OCH2), 3.89 (s, 3H, -OCH3), 2.37 (s, 3H, -CH3 at Hydrazide ring), 3.07-3.11 (t, 4H,-CH2), 1.61-1.65 (m, 8H,-CH2), 1.23-1.26(t,6H,-CH3) ppm; 13C NMR: δ = 155.3 (C=O), 152 (C=N), 146.2 (C-6), 145.9 (C-5), 144.6 (C-d), 143.1 (C-a), 141.4 (C-4’), 130.5 (C-1’), 128.7 (C-3’ & C-5’), 128.5 (C-b & C-f), 127.9 (C-2’ & C-6’), 127.6 (C-c & C-e), 124.4 (C-2), 123 (C-3), 117.3 (C-1), 113.8 (C-4), 73.5 (OCH2), 55.5 (OCH3), 27.4 (Bu), 25.4 (Bu), 23.2 (CH3 at Hydrazide ring), 12.2 (Bu), 8.2 (Bu) ppm.

[(Ph2Sn(L4)Cl, C35H30ClN3O5Sn), (20)]

Yield: 75 %; m.p.: 141-142 °C; IR (KBr): ν = 1554 (C=N) cm-1; 1H NMR (DMSO-d6 and CDCl3): δ = 11.75 (s, 1H, -CH=N), 8.22-8.24 (d, 2H, Cc-H & Ce-H), 7.73-7.81 (d, 4H, C2’-H, C6’-H, Cb-H & Cf-H), 7.48-7.50 (d, 1H, C2-H), 7.27-7.29 (d, 2H,C3-H & C5’-H), 7.12-7.24 (m, 10H, Ph & m,2H, C3-H & C4-H), 5.00 (s, 2H, -OCH2), 3.88 (s, 3H, -OCH3) , 2.38 (s, 3H, -CH3 at Hydrazide ring) ppm; 13C NMR: δ = 155.3 (C=O), 151.5 (C=N), 145.4 (C-6), 142.4 (C-5), 136.2 (C-d), 132.4 (C-a), 132.3 (C-4’), 131.2 (C-1’), 129.8 (C-3’ & C-5’), 129 (Ph), 128.7 (Ph), 128.7 (C-b & C-f), 128.4 (Ph), 128.1 (Ph), 127.9 (C-2’ & C-6’), 127.6 (C-c & C-e), 127.4 (C-2), 123.9 (C-3), 117.4 (C-1), 113.3 (C-4), 74.4 (OCH2), 55.4 (OCH3), 20.4 (CH3 at Hydrazide ring) ppm.

 

Antimicrobial activity

 

Test Microorganisms

 

Gram positive bacteria (viz. Klebsiella pneumoniae [NCDC No. 138], Staphylococcus aureus [MTCC No. 3160] Gram-negative bacteria (viz. Escherichia coli [MTCC No. 443], Enterobacter aerogenes [NCDC No. 106) and fungus (Aspergillus niger [MTCC No. 282] and Candida albicans [MTCC No. 227] were used for antimicrobial assay. All the microbial strains were procured from Microbial Type Culture Collection (MTCC), Institute of Microbial Technology (IMTECH), Chandigarh.

Ligands and their tin complexes were screened for in-vitro antimicrobial activity using serial dilution technique to find out their Minimum Inhibitory Concentration (MIC) value. The medium was prepared by dissolving weighed amount of nutrient broth/ sabouraud dextrose broth in 1L of distilled water and 1 ml of nutrient medium was transferred to each test tube. The test tubes having nutrient medium were autoclaved for 30 minutes at 120 °C. The solution of test compounds was prepared by dissolving 1.0 mg of synthesized compounds in dry DMSO which was further diluted to give a stock solution of 100 µg/ml. The solution of test compounds was transferred to test tubes having sterilized nutrient medium to get a set of five dilutions of test compounds having concentrations 50, 25, 12.5, 6.25 and 3.125 µg/ml. The inoculation of test strains was done with the help of micropipette with sterilized tips as 100 µL of freshly cultured strain was transferred in to test tubes and incubated at 37 °C for 24 hours for bacterial strains, 48 hours for C. albicans and 7 days at 25 °C for A. niger. The DMSO was taken as negative control whereas norfloxacin and fluconazole were taken as positive control for antibacterial and antifungal activity, respectively. The experiments were performed in triplicates and the mean values were observed.

 

QSAR studies

 

The structures of 1–20 were first pre-optimized with the Molecular Mechanics Force Field (MM) procedure included in Hyperchem 6.03 [31] And the resulting geometries were further developed by means of the semiempirical method PM3 (Parametric Method-3). A gradient norm limit of 0.01 kcal/A° ´was taken into consideration for the geometry optimization. The lowest energy structure was used for each individual molecule to calculate physicochemical properties using TSAR 3.3 software for Windows [32]. Further, the regression analysis was performed using the SPSS software package [33].

 

Conclusion

 

A series of novel compounds was synthesized and characterized using elemental analyses, various spectroscopic techniques like UV, IR and (1H, 13C and 119Sn) NMR. The substituted o-vanillin Schiff bases and their organotin(IV) complexes were screened for antimicrobial activity against representative microorganisms and the compounds evaluated had inhibited the growth of all the tested bacterial and fungal strains. The complexes were found to be more active antimicrobial agent in comparison to the Schiff bases. The QSAR studies were carried out to find out the relationship between structural features and antimicrobial activity of synthesized derivatives which revealed the fact that antimicrobial activity of these derivatives is governed by topological descriptors and electronic energy of the molecules.

 

Acknowledgements

 

Ankit Ravesh is grateful to the Council of Scientific and Industrial Research (CSIR) New Delhi, for financial support.

 

Conflict of interest

 

The authors declare that they have no conflict of interest.

References

 

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Figures

 

Figure 1: Plot of observed pMICan against the predicted pMICan for the linear regression model developed by Eq. 1 also supported the validity of model expressed by Eq. 1. The propagation of error was observed on both sides of zero while plotting the observed pMICan Vs residual pMICan (Figureure 2)

 

 

Figure 2: Plot of residual pMICan against the observed pMICan for the linear regression model developed by Eq.which depicted that there was no systemic error in model development [30].

 

 

Scheme 1. Synthetic route for HL1-4 and their tin complexes

Benzoic acid [3-methoxy-2-(4-methyl-benzyloxy)-benzyledene]-hydrazide [(HL1, C23H22N2O3), (1)]

 

IR FOR HL2

 

IR FOR Et2SnL2

 

1H-NMR FOR HL1

 

1H-NMR FOR Me2SnL1

1H NMR FOR HL3

 

1H NMR FOR Et2SnL3

 

13C-NMR FOR HL1

 

13C-NMR FOR Me2SnL1

 

13C NMR FOR Bu2SnL1

 

13C NMR FOR HL2

13C NMR FOR HL3

 

 

119Sn-NMR FOR Me2SnL1

 

119Sn NMR FOR Ph2SnL3

Tables

 

Sr. No. Compounds Molecular

formula

Molecular mass Yield (%)   Analysis (%)

Found(Calc.)

          C

 

H

 

N

 

Cl Sn

 

1 HL1 C23H22N2O3 374.16 82 73.78(73.84) 5.92(6.14) 7.48(7.27)
2 HL2 C22H19N3O5 405.13 86 65.18(65.43) 4.72(4.21) 10.37(9.92)
3 HL3 C24H24N2O3 388.18 83 74.21(74.47) 6.23(6.36) 7.21(9.95)
4 HL4 C23H21N3O5 419.15 79 65.86(66.11) 5.05(5.33) 10.02(10.31)
5 Me2Sn(L1)Cl C25H27ClN2O3Sn 558.07 74 53.84(54.13) 4.88(5.13) 5.02(5.23) 6.36(6.41) 21.29(20.75)
6 Et2Sn(L1)Cl C27H31ClN2O3Sn 586.10 72 55.37(55.62) 5.33(5.77) 4.78(5.16) 6.05(5.81) 20.27(20.42)
7 Bu2Sn(L1)Cl C31H39ClN2O3Sn 642.17 66 58.01(57.86) 6.12(6.34) 4.36(4.63) 5.52(5.88) 18.50(18.11)
8 Ph2Sn(L1)Cl C35H31ClN2O3Sn 682.10 73 61.66(61.42) 4.58(4.16) 4.11(5.94) 5.20(5.41) 17.41(17.22)
9 Me2Sn(L2)Cl C24H24ClN3O5Sn 589.04 77 48.97(49.12) 4.11(4.22) 7.14(6.87) 6.02(6.31) 20.17(19.87)
10 Et2Sn(L2)Cl C26H28ClN3O5Sn 617.07 81 50.64(50.83) 4.58(4.97) 6.81(6.45) 5.75(5.86) 19.25(19.41)
11 Bu2Sn(L2)Cl C30H36ClN3O5Sn 673.14 75 53.56(53.27) 5.39(5.58) 6.25(6.11) 5.27(5.15) 17.64(17.29)
12 Ph2Sn(L2)Cl C34H28ClN3O5Sn 713.07 68 57.29(56.96) 3.96(3.59) 5.90(5.51) 4.97(5.03) 16.65(16.26)
13 Me2Sn(L3)Cl C26H29ClN2O3Sn 572.09 74 54.62(54.24) 5.11(4.78) 4.90(4.85) 6.20(6.08) 20.77(20.86)
14 Et2Sn(L3)Cl C28H33ClN2O3Sn 600.12 69 56.07(56.34) 5.55(5.99) 4.67(4.73) 5.91(6.11) 19.79(19.63)
15 Bu2Sn(L3)Cl C32H41ClN2O3Sn 656.18 73 58.60(58.89) 6.30(6.11) 4.27(4.55) 5.41(5.45) 18.10(18.27)
16 Ph2Sn(L3)Cl C36H33ClN2O3Sn 696.12 79 62.14(62.55) 4.78(5.12) 4.03(4.34) 5.10(5.23) 17.06(17.35)
17 Me2Sn(L4)Cl C25H26ClN3O5Sn 603.06 67 49.82(49.38) 4.35(4.88) 6.97(7.25) 5.88(5.63) 19.70(19.93)
18 Et2Sn(L4)Cl C27H30ClN3O5Sn 631.09 71 51.42(51.84) 4.79(4.44) 6.66(6.24) 5.62(5.84) 18.82(19.19)
19 Bu2Sn(L4)Cl C31H38ClN3O5Sn 687.15 68 54.21(54.13) 5.58(5.76) 6.12(6.59) 5.16(5.34) 17.28(17.55)
20 Ph2Sn(L4)Cl C35H30ClN3O5Sn 727.09 75 57.84(57.51) 4.16(4.31) 5.78(5.65) 4.88(4.93) 16.33(16.42)

 

Table 1: Physicochemical characterization and elemental analysis of synthesized compounds.

 

Comp. pMICsa pMICkp pMICec pMICea pMICca pMICan
1 0.874 1.175 1.175 1.175 1.175 1.175
2 1.210 1.511 1.511 1.210 1.210 1.511
3 0.890 1.191 1.191 0.890 0.890 1.191
4 1.224 1.224 1.224 1.224 1.224 1.224
5 1.349 1.349 1.349 1.349 1.349 1.349
6 1.370 1.671 1.671 1.370 1.370 1.671
7 1.711 1.711 2.012 1.711 1.711 2.012
8 1.737 2.038 2.038 1.737 2.038 2.038
9 1.372 1.673 1.673 1.673 1.372 1.673
10 1.392 1.693 1.693 1.693 1.392 1.693
11 1.731 2.032 2.032 1.731 1.731 2.032
12 2.057 2.057 2.057 1.756 2.057 2.057
13 1.058 1.360 1.360 1.360 1.360 1.360
14 1.380 1.380 1.380 1.380 1.380 1.681
15 1.720 1.720 1.720 1.720 1.720 2.021
16 1.746 2.047 1.746 1.746 2.047 2.047
17 1.382 1.382 1.683 1.382 1.382 1.683
18 1.402 1.703 1.703 1.402 1.402 1.703
19 1.740 1.740 2.041 1.740 1.740 2.041
20 1.765 2.066 2.066 1.765 1.765 2.066
Std. 2.61# 2.61# 2.61# 2.61# 2.64$ 2.64$

 

Norfloxacin#, Fluconazole$

Table 2 : Antimicrobial activity of synthesized derivatives (µM/ml).

 

Comp. 0χ 0χv 1χ 1χv 2χ 2χv k1 k2 R J W Te Ele.E LUMO HOMO
1 19.769 15.885 13.669 8.909 11.533 6.218 22.680 12.000 13.669 1.340 2340.000 -4619.890 -34474.400 -0.373 -8.813
2 21.347 16.148 14.580 8.998 12.432 6.156 24.639 12.889 14.580 1.343 2874.000 -5294.900 -38715.000 -1.129 -9.014
3 20.640 16.807 14.063 9.320 12.155 6.718 23.659 12.143 14.063 1.338 2602.000 -4775.780 -36833.800 -0.346 -8.722
4 22.217 17.071 14.974 9.409 13.054 6.656 25.620 13.032 14.974 1.342 3172.000 -5450.770 -41019.800 -1.099 -8.997
5 22.977 22.418 15.354 21.079 14.080 22.782 26.602 13.185 15.354 1.427 3257.000 -5403.110 -44837.300 -1.198 -8.664
6 24.391 23.832 16.475 20.507 14.037 22.697 28.569 14.667 16.475 1.463 3803.000 -5714.770 -50240.500 -1.151 -8.682
7 27.219 26.661 18.475 22.507 15.537 22.999 32.514 17.734 18.475 1.511 5137.000 -6338.010 -60132.100 -1.289 -8.724
8 29.202 27.192 20.564 21.510 17.695 20.872 33.366 17.066 20.564 1.154 6399.000 -6736.740 -64539.200 -1.613 -8.737
9 24.554 22.682 16.264 21.168 14.979 22.720 28.569 14.074 16.264 1.425 3917.000 -6078.150 -48713.100 -1.314 -8.980
10 25.968 24.096 17.386 20.596 14.936 22.635 30.540 15.556 17.386 1.459 4531.000 -6389.760 -54736.100 -1.473 -8.856
11 28.797 26.925 19.386 22.596 16.436 22.937 34.490 18.617 19.386 1.506 6013.000 -7013.010 -65764.100 -1.437 -8.846
12 30.780 27.455 21.475 21.598 18.594 20.810 35.311 17.953 21.475 1.143 7415.000 -7411.790 -70322.400 -1.713 -8.888
13 23.847 23.341 15.747 21.490 14.702 23.282 27.585 13.347 15.747 1.436 3550.000 -5558.990 -46990.900 -1.177 -8.607
14 25.261 24.755 16.869 20.918 14.659 23.197 29.554 14.810 16.869 1.476 4114.000 -5870.110 -52360.700 -1.653 -8.711
15 28.089 27.584 18.869 22.918 16.159 23.499 33.502 17.840 18.869 1.529 5490.000 -6493.950 -63949.400 -1.140 -8.621
16 30.073 28.114 20.958 21.920 18.317 21.372 34.338 17.237 20.958 1.166 6790.000 -6892.650 -68649.100 -1.670 -8.747
17 25.424 23.605 16.658 21.579 15.601 23.220 29.554 14.235 16.658 1.433 4246.000 -6233.990 -51156.700 -1.388 -8.853
18 26.838 25.019 17.779 21.007 15.558 23.135 31.527 15.700 17.779 1.471 4878.000 -6545.590 -56548.600 -1.531 -8.844
19 29.667 27.847 19.779 23.007 17.058 23.437 35.479 18.726 19.779 1.523 6402.000 -7168.880 -68278.600 -1.420 -8.779
20 31.650 28.378 21.868 22.009 19.216 21.310 36.285 18.123 21.868 1.155 7842.000 -7567.630 -71255.100 -1.810 -8.914

 

Table 3 P: Value of selected descriptors used in the regression analysis.

The correlations of different structural parameters with antimicrobial activities are presented in (Table 5).

Mol. Descriptor pMICsa pMICkp pMICec pMICea pMICca pMICan
0χ 0.934 0.903 0.896 0.889 0.911 0.943
0χv 0.870 0.811 0.829 0.876 0.852 0.906
1χ 0.933 0.924 0.887 0.872 0.936 0.933
1χv 0.712 0.638 0.696 0.790 0.677 0.750
2χ 0.900 0.880 0.848 0.859 0.910 0.889
2χv 0.605 0.532 0.599 0.705 0.557 0.651
3χ 0.363 0.274 0.354 0.469 0.321 0.367
3χv 0.253 0.167 0.262 0.407 0.228 0.266
k1 0.935 0.887 0.908 0.900 0.890 0.955
k2 0.929 0.870 0.915 0.887 0.872 0.958
k3 0.772 0.635 0.786 0.809 0.669 0.820
R 0.933 0.924 0.887 0.872 0.936 0.933
B -0.235 -0.372 -0.157 -0.113 -0.396 -0.142
W 0.923 0.911 0.883 0.856 0.916 0.917
Te -0.923 -0.895 -0.912 -0.887 -0.859 -0.922
Ele.E -0.941 -0.901 -0.896 -0.897 -0.917 -0.954
Nu.E 0.940 0.899 0.893 0.896 0.919 0.954
LUMO -0.784 -0.739 -0.706 -0.758 -0.730 -0.754
HOMO -0.023 -0.094 -0.096 -0.012 0.099 0.039
Μ 0.226 0.204 0.319 0.304 0.004 0.272

 

Table 5 : Correlation of molecular descriptors with antimicrobial activity of synthesized derivatives.

 

Comp. pMICan pMICsa pMICca pMICkp pMICec pMICea
Obs Pre Res Obs Pre Res Obs Pre Res Obs Pre Res Obs Pre Res Obs Pre Res
1 1.175 1.250 -0.075 0.874 0.952 -0.078 1.175 1.055 0.120 1.175 1.201 -0.026 1.175 1.241 -0.066 1.175 1.083 0.092
2 1.511 1.369 0.142 1.210 1.059 0.151 1.210 1.163 0.047 1.511 1.303 0.208 1.511 1.351 0.160 1.210 1.191 0.019
3 1.191 1.269 -0.078 0.890 1.011 -0.121 0.890 1.101 -0.211 1.191 1.245 -0.054 1.191 1.259 -0.068 0.890 1.137 -0.247
4 1.224 1.388 -0.164 1.224 1.117 0.107 1.224 1.209 0.015 1.224 1.347 -0.123 1.224 1.369 -0.144 1.224 1.246 -0.022
5 1.349 1.408 -0.059 1.349 1.213 0.136 1.349 1.254 0.095 1.349 1.389 -0.040 1.349 1.387 -0.038 1.349 1.300 0.049
6 1.671 1.607 0.064 1.370 1.349 0.021 1.370 1.387 -0.017 1.671 1.515 0.156 1.671 1.570 0.101 1.370 1.409 -0.039
7 2.012 2.018 -0.006 1.711 1.598 0.113 1.711 1.624 0.087 1.711 1.739 -0.028 2.012 1.948 0.064 1.711 1.628 0.083
8 2.038 1.928 0.110 1.737 1.709 0.028 2.038 1.872 0.166 2.038 1.972 0.066 2.038 1.866 0.172 1.737 1.675 0.062
9 1.673 1.528 0.145 1.372 1.310 0.062 1.372 1.362 0.010 1.673 1.491 0.182 1.673 1.497 0.176 1.673 1.409 0.264
10 1.693 1.726 -0.033 1.392 1.462 -0.070 1.392 1.495 -0.103 1.693 1.617 0.076 1.693 1.680 0.013 1.693 1.519 0.174
11 2.032 2.136 -0.104 1.731 1.740 -0.009 1.731 1.732 -0.001 2.032 1.840 0.192 2.032 2.057 -0.025 1.731 1.738 -0.007
12 2.057 2.047 0.010 2.057 1.855 0.202 2.057 1.980 0.077 2.057 2.074 -0.017 2.057 1.975 0.082 1.756 1.783 -0.027
13 1.360 1.430 -0.070 1.058 1.267 -0.209 1.360 1.301 0.059 1.360 1.434 -0.074 1.360 1.407 -0.047 1.360 1.355 0.005
14 1.681 1.626 0.055 1.380 1.402 -0.022 1.380 1.434 -0.054 1.380 1.559 -0.179 1.380 1.588 -0.208 1.380 1.464 -0.084
15 2.021 2.032 -0.011 1.720 1.694 0.026 1.720 1.671 0.049 1.720 1.783 -0.063 1.720 1.961 -0.241 1.720 1.683 0.037
16 2.047 1.951 0.096 1.746 1.813 -0.066 2.047 1.918 0.129 2.047 2.016 0.031 1.746 1.887 -0.141 1.746 1.729 0.017
17 1.683 1.549 0.134 1.382 1.372 0.010 1.382 1.409 -0.027 1.382 1.535 -0.153 1.683 1.517 0.166 1.382 1.464 -0.082
18 1.703 1.745 -0.042 1.402 1.508 -0.106 1.402 1.542 -0.140 1.703 1.661 0.042 1.703 1.697 0.006 1.402 1.573 -0.171
19 2.041 2.151 -0.110 1.740 1.803 -0.063 1.740 1.779 -0.039 1.740 1.884 -0.144 2.041 2.071 -0.030 1.740 1.792 -0.052
20 2.066 2.070 -0.004 1.765 1.878 -0.113 1.765 2.026 -0.261 2.066 2.118 -0.052 2.066 1.996 0.070 1.765 1.837 -0.072

 

Table 6: Comparison of observed and predicted antibacterial and antifungal activity obtained by QSAR model.

 

0χ 0χv 1χ 1χv 2χ 2χv k1 k2 R B W Te Ele.E HOMO pMICan
0χ 1.000
0χv 0.939 1.000
1χ 0.990 0.905 1.000
1χv 0.774 0.929 0.707 1.000
2χ 0.979 0.913 0.976 0.766 1.000
2χv 0.671 0.864 0.592 0.985 0.662 1.000
k1 0.992 0.951 0.971 0.799 0.951 0.703 1.000
k2 0.947 0.903 0.932 0.725 0.871 0.620 0.972 1.000
R 0.990 0.905 1.000 0.707 0.976 0.592 0.971 0.932 1.000
J -0.270 -0.043 -0.381 0.172 -0.389 0.276 -0.155 -0.071 -0.381 1.000
W 0.986 0.881 0.995 0.676 0.975 0.556 0.966 0.926 0.995 -0.395 1.000
Te -0.980 -0.894 -0.959 -0.746 -0.956 -0.651 -0.978 -0.928 -0.959 0.230 -0.966 1.000
Ele.E -0.995 -0.948 -0.984 -0.781 -0.960 -0.679 -0.996 -0.969 -0.984 0.215 -0.977 0.969 1.000
HOMO 0.043 0.302 0.028 0.374 0.031 0.399 0.067 0.083 0.028 0.279 -0.022 0.115 -0.094 1.000
pMICan 0.943 0.906 0.933 0.750 0.889 0.651 0.955 0.958 0.933 -0.142 0.917 -0.922 -0.954 0.039 1.000

 

Table 4 :Correlation matrix for antibacterial activity of synthesized derivatives against K. pneumoniae

Suggested Citation

 

Citation: Ankit Ravesh, Vikramjeet Singh, Rajesh Malhotra (2016) Substituted o-vanillin Schiff base derived organotin(IV) complexes: Synthesis, characterization, antimicrobial evaluation and QSAR studies. Curr Trends Med Chem 2016: G101.

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