# Synthesis, Characterization, and Physicochemical Studies of Mixed Ligand Complexes of Inner Transition Metals with Lansoprazole and Cytosine

Authors: Sarika Verma; Sarita Shrivastva; Rashmi Shrivastva
Journal: Journal of Chemistry
 (2013)

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## Abstract

Few complexes of inner transition metals [Th(IV), Ce(IV), Nd(III), Gd(III)] have been synthesized by reacting their metal salts with lansoprazole, 2-([3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl)-1H-benzoimidazole	and  cytosine. All the complexes were synthesized in ethanolic medium. The yield percentage rangs from 80 to 90%. The complexes are coloured solids. The complexes were characterized through elemental analyses, conductance measurements, and spectroscopic methods (FT IR, FAB Mass, 1H NMR and UV). An IR spectrum indicates that the ligand behaves as bidentate ligands. The metal complexes have been screened for their antifungal activity towards Aspergillus niger fungi. The interaction of inner transition metals with lansoprazole, in presence of cytosine, has also been investigated potentiometrically at two different temperatures 26±1°C and 36±1°C and at 0.1 M (KNO3) ionic strength. The stability constants of ternary complexes indicate the stability	order as Th(IV) < Ce(IV) < Gd(III) < Nd(III). logK values obtained are positive and suggest greater stabilization of ternary complexes. The values of thermodynamic parameters (free energy (ΔG), enthalpy (ΔH), and entropy (ΔS) are also calculated.


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## Body

## 1. Introduction

Inner transition metal complexes are of continuing interest mainly due to their structural and catalytical properties and their application in diagnostic pharmaceutical and laser technology [1–3]. They have been found to exhibit anticancer and fungicidal properties also [4].Investigations are going on the formation of metal complexes with benzimidazole ring containing ligands because benzimidazole and its derivatives play an important role in analysis and in several biological reactions [5]. Considering the importance of drugs and their complexes it has been desired to synthesize and characterize some ternary complexes of inner transition metal [Th(IV), Ce(IV), Gd(III), Nd(III)] with a Benzimidazole derivative, lansoprazole, and cytosine. Lansoprazole being an antiulcer drug reduces gastric acid secretion and has successfully been used to heal and relieve symptoms of gastric or duodenal ulcers and gastroesophageal reflux [6–9].As the interaction of metal ions with nucleobases is of great interest because of their relevance to the essential, medical or toxic bioactivity of metal, where nucleobase molecule can coordinate as exogenous ligands in metalloproteins, function as cofactors in the enzymatic systems. Thus, cytosine is selected as the secondary ligand for the formation of ternary complexes. Its chemical name is 4-amino-1H-pyrimidine-2 one [10].


## 2. Experimental

All the chemicals used throughout the course of experiments were either of BDH or E merck quality. Spectroscopic grade solvents were employed for recording the spectra.


### 2.1. Preparation of the Complexes

The solid complexes were prepared by mixing the aqueous solution of metal salts [Th(NO3)4·4H2O, Ce(SO4)2·xH2O, Nd(NO3)3·6H2O, Gd(NO3)3·6H2O] with ethanolic solution of lansoprazole and cytosine in molar ratio 1 : 1 : 1. The resulting mixtures were then refluxed for 4-5 hours to give the precipitate. After cooling at room temperature the solid complexes were filtered as fine precipitates. These precipitates were washed twice with water. Then they were dried and stored in a desiccators containing dry calcium chloride. The compounds obtained were stable coloured solids.


### 2.2. Physical Measurement

The melting point was recorded on Labotech instrument. Elemental analysis was performed on a Carlo Erba mod 1108 elemental analyzer. The Mass spectra was done on a Jeol SX-102 spectrometer using argon as the FAB gas Elico and SL191 double beam uv-vis spectrophotometer is used for recording uv-vis spectra. The1H NMR spectra were recorded on Bruker DRX-300. The FT IR spectrum was recorded on Varian 1000 FTIR using KBR Pallets. The antifungal activity is studied by paper disk method and data was recorded after 48 hours of incubation.


#### 2.2.1. Ligand-Metal Ratio

The metal-ligand-ligand ratio was confirmed by conductometric titration method.


#### 2.2.2. Stability of Complexes

Stepwise and overall proton ligand stability constants were computed by Bjerrum clavin pH titration technique as adapted by Irving and Rossotti. The extension of this titration technique to ternary system, as suggested by Chidambaram and Bhattacharya [11] has been applied to determine the stability constants of 1 : 1 : 1 ternary complexes at 26±1°C and 36±1°C.The proton ligand stability constant of the drug lansoprazole and cytosine has been calculated at26±1°C and 36±1°C and at 0.1 M (KNO3) ionic concentration, utilizing the Irving Rossotti pH titration technique [12].


### 2.3. Thermodynamic Parameters

Thermodynamic parameters computed for the complexation reactions studied in this investigation are free energy (ΔG),  enthalpy (ΔH),        and          entropy  (ΔS)   changes  [13].The reaction will go in the direction written, whenΔG is negative.  These have been calculated  using the Vant Hoff isotherm, Vant Hoff equation, and the Gibbs-Helmholtz equations, respectively, at 26°C and 36°C and at ionic strength of 0.1 M with KNO3:
(1)ΔG=-2.303RTlog10K,ΔH=4.576T1×T2T2-T1log10K,ΔS=ΔH-ΔGΔT.


## 2.1. Preparation of the Complexes

The solid complexes were prepared by mixing the aqueous solution of metal salts [Th(NO3)4·4H2O, Ce(SO4)2·xH2O, Nd(NO3)3·6H2O, Gd(NO3)3·6H2O] with ethanolic solution of lansoprazole and cytosine in molar ratio 1 : 1 : 1. The resulting mixtures were then refluxed for 4-5 hours to give the precipitate. After cooling at room temperature the solid complexes were filtered as fine precipitates. These precipitates were washed twice with water. Then they were dried and stored in a desiccators containing dry calcium chloride. The compounds obtained were stable coloured solids.


## 2.2. Physical Measurement

The melting point was recorded on Labotech instrument. Elemental analysis was performed on a Carlo Erba mod 1108 elemental analyzer. The Mass spectra was done on a Jeol SX-102 spectrometer using argon as the FAB gas Elico and SL191 double beam uv-vis spectrophotometer is used for recording uv-vis spectra. The1H NMR spectra were recorded on Bruker DRX-300. The FT IR spectrum was recorded on Varian 1000 FTIR using KBR Pallets. The antifungal activity is studied by paper disk method and data was recorded after 48 hours of incubation.


### 2.2.1. Ligand-Metal Ratio

The metal-ligand-ligand ratio was confirmed by conductometric titration method.


### 2.2.2. Stability of Complexes

Stepwise and overall proton ligand stability constants were computed by Bjerrum clavin pH titration technique as adapted by Irving and Rossotti. The extension of this titration technique to ternary system, as suggested by Chidambaram and Bhattacharya [11] has been applied to determine the stability constants of 1 : 1 : 1 ternary complexes at 26±1°C and 36±1°C.The proton ligand stability constant of the drug lansoprazole and cytosine has been calculated at26±1°C and 36±1°C and at 0.1 M (KNO3) ionic concentration, utilizing the Irving Rossotti pH titration technique [12].


## 2.2.1. Ligand-Metal Ratio

The metal-ligand-ligand ratio was confirmed by conductometric titration method.


## 2.2.2. Stability of Complexes

Stepwise and overall proton ligand stability constants were computed by Bjerrum clavin pH titration technique as adapted by Irving and Rossotti. The extension of this titration technique to ternary system, as suggested by Chidambaram and Bhattacharya [11] has been applied to determine the stability constants of 1 : 1 : 1 ternary complexes at 26±1°C and 36±1°C.The proton ligand stability constant of the drug lansoprazole and cytosine has been calculated at26±1°C and 36±1°C and at 0.1 M (KNO3) ionic concentration, utilizing the Irving Rossotti pH titration technique [12].


## 2.3. Thermodynamic Parameters

Thermodynamic parameters computed for the complexation reactions studied in this investigation are free energy (ΔG),  enthalpy (ΔH),        and          entropy  (ΔS)   changes  [13].The reaction will go in the direction written, whenΔG is negative.  These have been calculated  using the Vant Hoff isotherm, Vant Hoff equation, and the Gibbs-Helmholtz equations, respectively, at 26°C and 36°C and at ionic strength of 0.1 M with KNO3:
(1)ΔG=-2.303RTlog10K,ΔH=4.576T1×T2T2-T1log10K,ΔS=ΔH-ΔGΔT.


## 3. Result and Discussion

### 3.1. Stability of Complexes

TheΔlogK values obtained in the present study (recorded in Table 1) are positive indicating greater stabilization (greater degree of chelation) of ternary complexes.Table 1
Stability constants of ternary complexes of  Lanso (L) and Cyto (C) at26±1°C and 36±1°C.
Metal complexes
log
K
MLC
M
At  temp.  26 ± 1°C
36 ± 1°C
Th
5.50
5.35
Ce
6.5
6.4
Gd
7.5
7.1
Nd
8.3
8.1The stability order obtained in the present investigation is shown below:(2)(M-LANSO-CYTO)Th<Ce<Gd<Ndat26±1C°,Th<Ce<Gd<Ndat36±1C°.


### 3.2. Thermodynamic Parameters

The values of changes in free energy (ΔG), enthalpy (ΔH), and entropy (ΔS) recorded in Table 2, accompanying the formations of the ternary complexes, using the standard equations are as in [14]. The negative values of ΔG show that the driving tendency of the complexation reaction is from left to right and the reaction tends to proceed spontaneously.Table 2
Ligation free energy, enthalpy, and entropy change of mixed ligand complexes of  M-Lanso-Cyto at26±1°C and 36±1°C  and at  μ=0.1 m (KNO3).
Metal complexes
−ΔG (K·cal./mole)
−ΔH (K·cal./mole)
−ΔS (K·cal./mole)
26 ± 1°C
36 ± 1°C
26 ± 1°C
36 ± 1°C
26 ± 1°C
36 ± 1°C
[Th·Lanso·Cyto·4H2O]NO3·xH2O
1.012
1.029
313.01
307.93
31.19
30.69
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
1.112
1.139
343.68
340.83
34.25
33.96
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
1.197
1.203
369.95
359.89
36.87
35.86
[Nd·Lanso·Cyto·4H2O]NO3·xH2O
1.257
1.284
388.568
384.090
38.73
38.28


## 3.1. Stability of Complexes

TheΔlogK values obtained in the present study (recorded in Table 1) are positive indicating greater stabilization (greater degree of chelation) of ternary complexes.Table 1
Stability constants of ternary complexes of  Lanso (L) and Cyto (C) at26±1°C and 36±1°C.
Metal complexes
log
K
MLC
M
At  temp.  26 ± 1°C
36 ± 1°C
Th
5.50
5.35
Ce
6.5
6.4
Gd
7.5
7.1
Nd
8.3
8.1The stability order obtained in the present investigation is shown below:(2)(M-LANSO-CYTO)Th<Ce<Gd<Ndat26±1C°,Th<Ce<Gd<Ndat36±1C°.


## 3.2. Thermodynamic Parameters

The values of changes in free energy (ΔG), enthalpy (ΔH), and entropy (ΔS) recorded in Table 2, accompanying the formations of the ternary complexes, using the standard equations are as in [14]. The negative values of ΔG show that the driving tendency of the complexation reaction is from left to right and the reaction tends to proceed spontaneously.Table 2
Ligation free energy, enthalpy, and entropy change of mixed ligand complexes of  M-Lanso-Cyto at26±1°C and 36±1°C  and at  μ=0.1 m (KNO3).
Metal complexes
−ΔG (K·cal./mole)
−ΔH (K·cal./mole)
−ΔS (K·cal./mole)
26 ± 1°C
36 ± 1°C
26 ± 1°C
36 ± 1°C
26 ± 1°C
36 ± 1°C
[Th·Lanso·Cyto·4H2O]NO3·xH2O
1.012
1.029
313.01
307.93
31.19
30.69
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
1.112
1.139
343.68
340.83
34.25
33.96
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
1.197
1.203
369.95
359.89
36.87
35.86
[Nd·Lanso·Cyto·4H2O]NO3·xH2O
1.257
1.284
388.568
384.090
38.73
38.28


## 4. Analytical Data of Complexes

The reaction of the inner transition metal with lansoprazole and cytosine was afforded in good yield (85–90%) of stable solid compound. The compounds prepared were coloured, soluble in ethanol, 1, 4 dioxane, DMF, DMSO and insoluble in water. The  characterization of their molecular structure was made by elemental analysers conductivity and spectroscopy studies. The studied complexes of inner transition metal showed 1 : 1 : 1 (M : LANSO : CYTO) composition as indicated from elemental analyser  and exhibited corresponding conductivities suggesting 1 : 1 : 1 electrolytic behaviour. The analytical data including yield percentage of the complexes are recorded in Table3.Table 3
Analytical data of synthesized mixed ligand complexes of M-Lanso-Cyto.
Serial  no.
Complex
Color
Melting point
Molar conductance (/∧Scm2mol-1)
1
[Th·Lanso·Cyto·4H2O]NO3·xH2O
Lightbrown
322°C
96.1
2
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
Lightbrown
319°C
89.6
3
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
Orange
300°C
94.2
4
[Nd·Lanso·Cyto·4H2O]NO3·xH2O
Black
320°C
80.2
5
[Sm·Lanso·Cyto·4H2O]NO3·xH2O
Black
319°C
79.2
6
[Ytt·Lanso·Cyto·4H2O]NO3·xH2O
Black
315°C
83.2


## 5. Elemental Analysis

The result of elemental analysis is recorded in Table4.Table 4
Elemental  analysis of mixed ligand complexes of Lanso and Cyto.
Metalcomplex
Found mass   (calculated mass %)
C
H
N
O
F
S
Metal
[Th·Lanso·Cy to·4H2O]NO3·xH2O
30.26    (30.6)
3.4 (3.4)
10.59   (10.71)
12.1 (12.24)
7.18 (7.27)
4.03 (4.08)
32.44 (31.65)
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
33.99   (34.6)
3.82   (3.9)
11.89   (12.13)
13.59   (13.5)
8.07   (8.23)
4.53   (4.64)
24.11   (22.55)
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
34.13 (33.8)
3.84  (3.8)
11.94   (11.8)
13.65 (3.54)
8.1   (8.0)
4.55  (4.51)
23.79   (24.4)
[Nd·Lanso·Cyto·4H2O]NO3·xH2O
34.23   (34.4)
3.85   (3.87)
11.98   (12.06)
13.69   (13.7)
8.13   (8.1)
4.56   (4.5)
23.56   (23.03)


### 5.1. FT IR Spectra

The relevant vibration bands of the free ligand and the complexes are in the region 4000–400 cm−1   [15, 16]. The characteristic frequencies of the ligands and metal complexes are given in Table 5. In case of Lanso molecule the N–H (aromatic sec. amine) stretching occurs at 3050 cm−1, whereas sulfoxide (S=O) stretching occurs at 1090 cm−1. The band of  C=N occurs at 1590 cm−1 [17]. In free cytosine molecule, the C–N ring band is shown in 1276 cm−1  and C=O is at 1700 cm−1 [18].Table 5
IR bands of mixed ligand complexes of M-Lanso-Cyto.
Metal complexes
ν (S=O) cm−1
ν (C=N) cm−1
ν (C=O) cm−1
ν  (C–N) RING cm−1
ν  (M–O)
ν  (coordinated H2O) cm−1
Stretching
Bending
Lanso
1090
1590
547
—
—
—
—
—
Cyto
—
—
—
1700
1276
—
—
—
[Th·Lanso·Cyto·4H2O]NO3·xH2O
10771035   (s)
1578  (s)
529
1636
1240  (m)
759
3428
824
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
1079
1550  (w)
525
1637
1232  (s)
745
3450
821
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
1038   (s)
1573  (s)
520
1637  (s)
1255  (s)
764
3490
821
[Nd·Lanso·Cyto·4H2O]NO3·xH2O
1052 (w)
1554  (s)
520/576
1633  (s)
1242  (m)
740
3450
859
[Sm·Lanso·Cyto·4H2O]NO3·xH2O
1080
1560  (s)
520
1632  (s)
1250
740
3471
859In case of ternary  complexes  of M-lansoprazole-cytosine, all the complexes  showed frequency of (N–H) at ~3050 cm−1 showing that there is no involvement (N–H) group in complex formation. The frequency of (C=N) bands appears at different region in complexes, that is, lowered by ~40 cm−1 indicating the coordination of nitrogen atom of (C=N) with metal, whereas sulfoxide stretching shifts to lower frequencies at ~50/60−1 cm due to coordination of the sulfonyl oxygen with metals in all the complexes. Thus, lansoprazole molecule chelates with metal ions using its (C=N) group and (S=O) group, acting as bidentate ligand.The C=O bonding of cytosine at ~1700−1 cm shifts to lower frequency on coordination and change in C–N ring is also reported. Hence in these complexes cytosine also acts as bidentate ligand coordinating through the nitrogen at N(3) and the oxygen of C=O. Additional bands in the complex in the region 740–765 cm−1 compared with IR spectra of free ligand have tentatively been assigned to M–O frequency and new band appearing at 1380–1390 cm−1  in the complexes might be due to chelate ring formation in the complexes. The appearance of strong band at ~820 cm−1 and ~3380 cm−1 in the spectra of all the ternary complexes indicates the presence of coordinated water.


### 5.2. Mass Spectra

In the present investigations, the mass spectrum of the lansoprazole shows the formation of molecular ion peak at M/Z 344 corresponding to the total molecular weight of the ligand. Data on the molecular weight of complexes are present in table along with the values calculated on the basis of established molecular formulae of the complexes as shown in Table6.Table 6
Mass spectra of mixed ligand complexes of Lanso and Cyto.
Metal complex
Structure
Spectral mass
[Th·Lanso·Cyto·4H2O]NO3·xH2O
1 : 1 : 1 : 4H2O
793
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
1 : 1 :1 : 4H2O
706
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
1 : 1 : 1 : 4H2O
703
[Nd·Lanso·Cyto·4H2O]NO3·xH2O
1 : 1 : 1 : 4H2O
701


### 5.3.1H NMR Spectra

To confirm the coordination of the ligands to the metal ion the complexes,1H NMR spectra were recorded for the ligands and its inner transition metal complexes. The important chemical shifts for the ligands and the complexes are given in the Table 7. The 1H NMR spectra of the ligand have the expected characteristic signals. The CH3 proton shows singlet at δ2.16 and O–CH3 proton at δ3.69 ppm and the peak observed at δ 4.71 is attributed to CH2 protons. In addition multiplet peak at δ 6.8–8.2 may be due to aromatic protons and peak at δ13.2 is observed due to NH proton of benzimidazole ring.Table 7
1H NMR signals of the ligands and mixed ligand complexes of M-Lanso-Cyto.
Serial no.
kind of proton Lanso
[Th·Lanso·Cyto·4H2O]NO3·xH2O
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
[Nd·Lanso·Cyto·4H2O]NO3·xH2O
1
Aromaticbenzimidazole
7.35–7.63
7.33–7.69
7.25–7.70
7.38–7.64
7.1
2(a)
Aromaticpyridine
8.18
8.20
8.30
8.2
8.2
(b)
Aromaticpyridine
6.98
6.90
6.94
6.5
3(a)
Methylene-CH2-
4.81
4.7 (sharp)
4.7 (sharp)
4.7  (sharp)
4·6 (sharp)
4
Methyl-CH3
2.20
2.26
2.24
2.3
2.39
Cyto
6
N(1) –H
10.7
10.52
—
—
—In case of ternary complexes of lansoprazole-cytosine, the chemical shifts occur at low field; that is, deshielding of proton occurs in methylene group proving the involvement of electron of S=O in bonding. Signals observed in the complexes at region ofδ 8.18–8 due to the azomethine proton have either remained unaffected or shifted slightly to higher field with reference to those of the parent ligand, and the position of signal due to NH proton remains unaffected in the complexes. Rest of the chemical shift is more or less the same in the ligands and their complexes. These observations support the assigned structure to the complex.


### 5.4. Electronic Spectra

Typical spectral data of the metal salts, ligand and ternary complexes of inner transition metal complexes  have been investigated in ethyl alcohol and are shown in Tables8(a) and 8(b). The electronic spectra of the lansoprazole display absorption bands at 219, 301 which is assigned to n-π* and π-π* transition, respectively. The electronic spectra of the  complexes show a shift towards lower frequency. This shift was attributed to the effects of the crystal field upon the inter electronic repulsion between the 4f electrons.Table 8
(a) Electronic spectral data of mixed ligand complexes of Lanso-Cyto. (b) Electronic spectral data  and related bonding parameter of   ternary complexes of Lanso-Cyto.
(a)
Serial no.
Metals complexes
λ max (nm)
ABS
ε max (Lmol−1cm−1)
Assignment
1
[Th·Lanso·Cyto·4H2O]NO3·xH2O
221
0.2057
2057
n-π*
293
0.0913
913
π-π*
2
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
218
0.4268
4268
n-π*
298
0.3822
3822
π-π*
3
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
225
0.7008
7008
n-π*
295
0.5243
5243
π-π*
(b)
Serial no.
Complex
Lanthanide salts (cm−1)
Complex band (cm−1)
β
1−β
b
1
/
2
δ%
η
1
[Th·Lanso·Cyto·4H2O]NO3·xH2O
47619
44248
0.9292
0.0708
0.13304
7.61945
0.03475
43290
35461
0.81914
0.18086
0.21263
22.0792
0.08592
2
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
47169
45455
0.96366
0.03634
0.09531
3.77103
0.01800
43859
35461
0.80852
0.19147
0.21878
23.6824
0.09065
3
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
47846
45248
0.94570
0.0543
0.11651
5.7417
0.05430
39525
34965
0.88462
0.11538
0.16983
13.0428
0.11538
4
[Nd·Lanso·Cyto·4H2O]NO3·xH2O
47169
45454
0.96364
0.03636
0.09534
3.7737
0.01801
42553
38610
0.90733
0.09267
0.15220
10.2134
0.04521Some red shift or nephelauxetic effect is observed in the alcohol solutions of these complexes. This red shift is usually accepted as evidence of a higher degree of covalency than the presence of aqua compounds [13, 19]. In all the complexes, marked enhancement in the intensity of the bond has been observed. This red shift of the hypersensitive bands has been utilized to calculate the nephelauxetic effect (β) in these chelate complexes. From the β values the covalence factors (b1/2), Sinha parameter (δ%) (metal-ligand covalency percent), and the covalency angular overlap parameter (η) have been calculated using the following expressions [20]:
(3)b1/2=12[(1-β)1/2],δ(%)=[(1-β)β]×100,η=[(1-β)1/2β1/2].The positive values for (1-β) and δ% in these coordination compounds suggest that the bonding between metal and ligand is covalent compared with the bonding between the metal and an aqua ion. The values of parameter of bonding (b1/2) and angular overlap parameter (η) were found to be positive, indicating covalent bonding. The mechanism of the formation and structure of representative  ternary complex can be given in Figure 1.Figure 1
Proposed Scheme and Structure of representative ternary complex (M-Lanso-cyto).


## 5.1. FT IR Spectra

The relevant vibration bands of the free ligand and the complexes are in the region 4000–400 cm−1   [15, 16]. The characteristic frequencies of the ligands and metal complexes are given in Table 5. In case of Lanso molecule the N–H (aromatic sec. amine) stretching occurs at 3050 cm−1, whereas sulfoxide (S=O) stretching occurs at 1090 cm−1. The band of  C=N occurs at 1590 cm−1 [17]. In free cytosine molecule, the C–N ring band is shown in 1276 cm−1  and C=O is at 1700 cm−1 [18].Table 5
IR bands of mixed ligand complexes of M-Lanso-Cyto.
Metal complexes
ν (S=O) cm−1
ν (C=N) cm−1
ν (C=O) cm−1
ν  (C–N) RING cm−1
ν  (M–O)
ν  (coordinated H2O) cm−1
Stretching
Bending
Lanso
1090
1590
547
—
—
—
—
—
Cyto
—
—
—
1700
1276
—
—
—
[Th·Lanso·Cyto·4H2O]NO3·xH2O
10771035   (s)
1578  (s)
529
1636
1240  (m)
759
3428
824
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
1079
1550  (w)
525
1637
1232  (s)
745
3450
821
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
1038   (s)
1573  (s)
520
1637  (s)
1255  (s)
764
3490
821
[Nd·Lanso·Cyto·4H2O]NO3·xH2O
1052 (w)
1554  (s)
520/576
1633  (s)
1242  (m)
740
3450
859
[Sm·Lanso·Cyto·4H2O]NO3·xH2O
1080
1560  (s)
520
1632  (s)
1250
740
3471
859In case of ternary  complexes  of M-lansoprazole-cytosine, all the complexes  showed frequency of (N–H) at ~3050 cm−1 showing that there is no involvement (N–H) group in complex formation. The frequency of (C=N) bands appears at different region in complexes, that is, lowered by ~40 cm−1 indicating the coordination of nitrogen atom of (C=N) with metal, whereas sulfoxide stretching shifts to lower frequencies at ~50/60−1 cm due to coordination of the sulfonyl oxygen with metals in all the complexes. Thus, lansoprazole molecule chelates with metal ions using its (C=N) group and (S=O) group, acting as bidentate ligand.The C=O bonding of cytosine at ~1700−1 cm shifts to lower frequency on coordination and change in C–N ring is also reported. Hence in these complexes cytosine also acts as bidentate ligand coordinating through the nitrogen at N(3) and the oxygen of C=O. Additional bands in the complex in the region 740–765 cm−1 compared with IR spectra of free ligand have tentatively been assigned to M–O frequency and new band appearing at 1380–1390 cm−1  in the complexes might be due to chelate ring formation in the complexes. The appearance of strong band at ~820 cm−1 and ~3380 cm−1 in the spectra of all the ternary complexes indicates the presence of coordinated water.


## 5.2. Mass Spectra

In the present investigations, the mass spectrum of the lansoprazole shows the formation of molecular ion peak at M/Z 344 corresponding to the total molecular weight of the ligand. Data on the molecular weight of complexes are present in table along with the values calculated on the basis of established molecular formulae of the complexes as shown in Table6.Table 6
Mass spectra of mixed ligand complexes of Lanso and Cyto.
Metal complex
Structure
Spectral mass
[Th·Lanso·Cyto·4H2O]NO3·xH2O
1 : 1 : 1 : 4H2O
793
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
1 : 1 :1 : 4H2O
706
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
1 : 1 : 1 : 4H2O
703
[Nd·Lanso·Cyto·4H2O]NO3·xH2O
1 : 1 : 1 : 4H2O
701


## 5.3.1H NMR Spectra

To confirm the coordination of the ligands to the metal ion the complexes,1H NMR spectra were recorded for the ligands and its inner transition metal complexes. The important chemical shifts for the ligands and the complexes are given in the Table 7. The 1H NMR spectra of the ligand have the expected characteristic signals. The CH3 proton shows singlet at δ2.16 and O–CH3 proton at δ3.69 ppm and the peak observed at δ 4.71 is attributed to CH2 protons. In addition multiplet peak at δ 6.8–8.2 may be due to aromatic protons and peak at δ13.2 is observed due to NH proton of benzimidazole ring.Table 7
1H NMR signals of the ligands and mixed ligand complexes of M-Lanso-Cyto.
Serial no.
kind of proton Lanso
[Th·Lanso·Cyto·4H2O]NO3·xH2O
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
[Nd·Lanso·Cyto·4H2O]NO3·xH2O
1
Aromaticbenzimidazole
7.35–7.63
7.33–7.69
7.25–7.70
7.38–7.64
7.1
2(a)
Aromaticpyridine
8.18
8.20
8.30
8.2
8.2
(b)
Aromaticpyridine
6.98
6.90
6.94
6.5
3(a)
Methylene-CH2-
4.81
4.7 (sharp)
4.7 (sharp)
4.7  (sharp)
4·6 (sharp)
4
Methyl-CH3
2.20
2.26
2.24
2.3
2.39
Cyto
6
N(1) –H
10.7
10.52
—
—
—In case of ternary complexes of lansoprazole-cytosine, the chemical shifts occur at low field; that is, deshielding of proton occurs in methylene group proving the involvement of electron of S=O in bonding. Signals observed in the complexes at region ofδ 8.18–8 due to the azomethine proton have either remained unaffected or shifted slightly to higher field with reference to those of the parent ligand, and the position of signal due to NH proton remains unaffected in the complexes. Rest of the chemical shift is more or less the same in the ligands and their complexes. These observations support the assigned structure to the complex.


## 5.4. Electronic Spectra

Typical spectral data of the metal salts, ligand and ternary complexes of inner transition metal complexes  have been investigated in ethyl alcohol and are shown in Tables8(a) and 8(b). The electronic spectra of the lansoprazole display absorption bands at 219, 301 which is assigned to n-π* and π-π* transition, respectively. The electronic spectra of the  complexes show a shift towards lower frequency. This shift was attributed to the effects of the crystal field upon the inter electronic repulsion between the 4f electrons.Table 8
(a) Electronic spectral data of mixed ligand complexes of Lanso-Cyto. (b) Electronic spectral data  and related bonding parameter of   ternary complexes of Lanso-Cyto.
(a)
Serial no.
Metals complexes
λ max (nm)
ABS
ε max (Lmol−1cm−1)
Assignment
1
[Th·Lanso·Cyto·4H2O]NO3·xH2O
221
0.2057
2057
n-π*
293
0.0913
913
π-π*
2
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
218
0.4268
4268
n-π*
298
0.3822
3822
π-π*
3
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
225
0.7008
7008
n-π*
295
0.5243
5243
π-π*
(b)
Serial no.
Complex
Lanthanide salts (cm−1)
Complex band (cm−1)
β
1−β
b
1
/
2
δ%
η
1
[Th·Lanso·Cyto·4H2O]NO3·xH2O
47619
44248
0.9292
0.0708
0.13304
7.61945
0.03475
43290
35461
0.81914
0.18086
0.21263
22.0792
0.08592
2
[Ce·Lanso·Cyto·4H2O]SO4·xH2O
47169
45455
0.96366
0.03634
0.09531
3.77103
0.01800
43859
35461
0.80852
0.19147
0.21878
23.6824
0.09065
3
[Gd·Lanso·Cyto·4H2O]NO3·xH2O
47846
45248
0.94570
0.0543
0.11651
5.7417
0.05430
39525
34965
0.88462
0.11538
0.16983
13.0428
0.11538
4
[Nd·Lanso·Cyto·4H2O]NO3·xH2O
47169
45454
0.96364
0.03636
0.09534
3.7737
0.01801
42553
38610
0.90733
0.09267
0.15220
10.2134
0.04521Some red shift or nephelauxetic effect is observed in the alcohol solutions of these complexes. This red shift is usually accepted as evidence of a higher degree of covalency than the presence of aqua compounds [13, 19]. In all the complexes, marked enhancement in the intensity of the bond has been observed. This red shift of the hypersensitive bands has been utilized to calculate the nephelauxetic effect (β) in these chelate complexes. From the β values the covalence factors (b1/2), Sinha parameter (δ%) (metal-ligand covalency percent), and the covalency angular overlap parameter (η) have been calculated using the following expressions [20]:
(3)b1/2=12[(1-β)1/2],δ(%)=[(1-β)β]×100,η=[(1-β)1/2β1/2].The positive values for (1-β) and δ% in these coordination compounds suggest that the bonding between metal and ligand is covalent compared with the bonding between the metal and an aqua ion. The values of parameter of bonding (b1/2) and angular overlap parameter (η) were found to be positive, indicating covalent bonding. The mechanism of the formation and structure of representative  ternary complex can be given in Figure 1.Figure 1
Proposed Scheme and Structure of representative ternary complex (M-Lanso-cyto).


## 6. Antifungal Activity

The antifungal activity of the ligand, metal salts and the corresponding complexes was assayed simultaneously againstAspergillus nigerfungusby paper disk method [21] at room temperature. The pure metal salts, and lansoprazole drug showed activity in Aspergillus niger. The zones of inhibition against microorganism were measured (in cm) after 48 hours of incubation as shown in Table 9. The mixed ligand complexes showed higher inhibition zone as compared to parent drug.Table 9
Sensitivity test of lansoprazole, cytosine and their complexes againstAspergillus niger culture.
Serial no.
Inhibition Diameter (cm)
Metal ion
Lanso
Cyto
M-Lanso-Cyto
1
Th
1.1
0.6
0.5
1.1
2
Ce
0.7
0.6
0.5
1.3
3
Gd
0.8
0.6
0.5
1.6


## 7. Conclusion

The studied ternary complexes of inner transition metals showed 1 : 1 : 1 (M : LANSO : CYTO) composition as indicated from elemental analyser and exhibited corresponding conductivities suggesting 1 : 1 : 1 electrolytic behaviour. The IR data reveals that all the ligands function as bidentate ligands. Lansoprazole molecules chelate with the metal ions using their C=N group and S=O group and the cytosine acts as a chelating ligand binding through its N(3) and the oxygen of C=O. The1H NMR spectra of nonequivalent proton of lansoprazole in complex exhibit chemical shift towards lower field due to complexation with metals.The complexes may be formulated (LLanso·M·Lcyto ·4H20) X·nH20 where X is SO42- or NO32-. The result of antifungal activity indicates that the complexes are more active than free ligand (lansoprazole drug). The possible general structure of these representative ternary complexes is shown in Figure 1.



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*Source: 309179-2012-11-18.xml*