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

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


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][2][3].ey 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 [(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 re�ux [6][7][8][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.us, cytosine is selected as the secondary ligand for the formation of ternary complexes.Its chemical name is 4-amino-1Hpyrimidine-2 one [10].

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.

Preparation of the Complexes. e solid complexes were prepared by mixing the aqueous solution of metal salts [(NO
with ethanolic solution of lansoprazole and cytosine in molar ratio 1 : 1 : 1. e resulting mixtures were then re�uxed for 4-5 hours to give the precipitate.Aer cooling at room temperature the solid complexes were �ltered as �ne precipitates.ese precipitates were washed   [11] has been applied to determine the stability constants of 1 : 1 : 1 ternary complexes at 26 ±  ∘ C and 36 ±  ∘ C. e proton ligand stability constant of the drug lansoprazole and cytosine has been calculated at 26 ±  ∘ C and 36 ±  ∘ C and at 0.1 M (KNO 3 ) ionic concentration, utilizing the Irving Rossotti pH titration technique [12].
e reaction will go in the direction written, when ΔG is negative.ese 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 KNO 3 :  2, accompanying the formations of the ternary complexes, using the standard equations are as in [14].e negative values of ΔG show that the driving tendency of the complexation reaction is from le to right and the reaction tends to proceed spontaneously.

Analytical Data of Complexes
e reaction of the inner transition metal with lansoprazole and cytosine was afforded in good yield (85-90%) of stable solid compound.e compounds prepared were coloured, soluble in ethanol, 1, 4 dioxane, DMF, DMSO and insoluble in water.e characterization of their molecular structure was made by elemental analysers conductivity and spectroscopy studies.e 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.e analytical data including yield percentage of the complexes are recorded in Table 3.

Elemental Analysis
e result of elemental analysis is recorded in Table 4.
5.1.FT IR Spectra.e relevant vibration bands of the free ligand and the complexes are in the region 4000-400 cm −1 [15,16].e 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 .e 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].
In 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.e 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 shis to lower frequencies at ∼50/60 −1 cm due to coordination of the sulfonyl oxygen with metals in all the complexes.us, lansoprazole molecule chelates with metal ions using its (C=N) group and (S=O) group, acting as bidentate ligand.
e C=O bonding of cytosine at ∼1700 −1 cm shis 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.e 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.

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 Table 6.

1 H NMR Spectra.
To con�rm the coordination of the ligands to the metal ion the complexes, 1 H NMR spectra were recorded for the ligands and its inner transition metal complexes.e important chemical shis for the ligands and the complexes are given in the Table 7. e 1 H NMR spectra of the ligand have the expected characteristic signals.e CH 3 proton shows singlet at  21 and O-CH 3 proton at  3 ppm and the peak observed at  4.71 is attributed to CH 2 protons.In addition multiplet peak at  6.8-8.2 may be due to aromatic protons and peak at  13.2 is observed due to NH proton of benzimidazole ring.
In case of ternary complexes of lansoprazole-cytosine, the chemical shis occur at low �eld� 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 of  8.18-8 due to the azomethine proton have either remained unaffected or shied slightly to higher �eld with reference to those of the parent ligand, and the T 5: IR bands of mixed ligand complexes of M-Lanso-Cyto.Metal complex Structure Spectral mass

Stretching
F 1: Proposed Scheme and Structure of representative ternary complex (M-Lanso-cyto).position of signal due to NH proton remains unaffected in the complexes.Rest of the chemical shi is more or less the same in the ligands and their complexes.ese 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 Tables 8(a) and 8(b).e electronic spectra of the lansoprazole display absorption bands at 219, 301 which is assigned to n- * and - * transition, respectively.e electronic spectra of the complexes show a shi towards lower frequency.is shi was attributed to the effects of the crystal �eld upon the inter electronic repulsion between the 4f electrons.Some red shi or nephelauxetic effect is observed in the alcohol solutions of these complexes.is red shi 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.is red shi of the hypersensitive bands has been utilized to calculate the nephelauxetic effect () in these chelate complexes.From the  values the covalence factors ( 1/2 ), Sinha parameter () (metal-ligand covalency percent), and the covalency angular overlap parameter () have been calculated using the following expressions [20]: e positive values for (1 − ) and  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.e values of parameter of bonding ( 1/2 ) and angular overlap parameter () were found to be positive, indicating covalent bonding.e mechanism of the formation and structure of representative ternary complex can be given in Figure 1.

Antifungal Activity
e antifungal activity of the ligand, metal salts and the corresponding complexes was assayed simultaneously against Serial no.kind of proton Lanso  Aspergillus niger fungusby paper disk method [21] at room temperature.e pure metal salts, and lansoprazole drug showed activity in Aspergillus niger.e zones of inhibition against microorganism were measured (in cm) aer 48 hours of incubation as shown in Table 9. e mixed ligand complexes showed higher inhibition zone as compared to parent drug.

Conclusion
e 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.e 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.e 1 H NMR spectra of nonequivalent proton of lansoprazole in complex exhibit chemical shi towards lower �eld due to complexation with metals.e complexes may be formulated (L Lanso ⋅M⋅L cyto ⋅4H 2 0) X⋅nH 2 0 where X is SO 4 2− or NO 3 2− .e result of antifungal activity indicates that the complexes are more active than free ligand (lansoprazole drug).e possible general structure of these representative ternary complexes is shown in Figure 1.

T 6 :
Mass spectra of mixed ligand complexes of Lanso and Cyto.

T 7: 1 H
NMR signals of the ligands and mixed ligand complexes of M-Lanso-Cyto.

T 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.
T 3: Analytical data of synthesized mixed ligand complexes of M-Lanso-Cyto.
Sensitivity test of lansoprazole, cytosine and their complexes against Aspergillus niger culture.