Transition Metal Complexes of Omeprazole An Anti-Ulcerative Drug

Omeprazole (OME) is a proton pump inhibitor (PPI). PPI’s have enabled to improve the treatment of various acidpeptic disorders. OME is a weak base and it can...


INTRODUCTION
A peptic ulcer, also known as PUD or peptic ulcer disease is an ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful .Ulcer results from a complex interplay of acid and chronic inflammation induced by H. Pylori infection [1][2] .Most of the times, ulcers are associated with Helicobacter pylori, a spiral-shaped bacterium that lives in the acidic environment of the stomach.Reflux of acid and stomach contents can cause irritation or damage the lining of lower esophagus.If this damage is continuous, it can cause gastro-esophageal disease (GERD) [3][4][5].Ulcers can also be caused or worsened by drugs such as aspirin and anti-inflammatory drugs.A class of drugs, called, proton pump inhibitors (PPIs) [6][7][8], blocks the production of acid by the stomach.PPIs are substituted benzimidazoles and are lipophilic weak bases that cross the parietal cell membrane and enter the acidic parietal cell canaliculus.In this acidic environment, the PPIs become protonated producing the activated sulphonamide from the drug that binds covalently with the H + , K + -ATPase enzyme that results Omeprazole (OME) is a proton pump inhibitor (PPI).PPI's have enabled to improve the treatment of various acidpeptic disorders.OME is a weak base and it can form several complexes with transition and non-transitions metal ions.In the present paper, we are describing series of trantion metal complexes of omeprazole i.e.,5-methoxy-2[(4methoxy-3,5dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole with Cu II , Mn II , Co II , Ni II , Fe II , Zn II and Hg II .These complexes were characterized by elemental analysis, molar conductance, IR, NMR, magnetic susceptibility, UV-visible spectral studies, ESR, SEM and X-ray diffraction.Based on the above studies, the ligand behaves as bidentate O, N donor and forms coordinate bonds through C=N and S=O groups .The complexes were found to non-electrolytic in nature on the basis of low values of molar conductance .Analytical data and stochiometry suggest ligand metal ratio of 2:1 for all the complexes.Electronic Spectra and Magnetic susceptibility measurements reveal octahedral geometry for Mn(II),Co(II), Ni(II),Fe(II) and Cu(II) complexes and tetrahedral for Hg(II) and Zn(II) complexes.Ligands and their metal complexes have been screened for their antibacterial and antifungal activities against bacteria Pseudomonas, Staphylococcus Aureus and fungi Aspergillus niger and A. flavous.

Synthesis of complexes
The complexes were synthesized by mixing the solutions (70% methanol) of metal salt with that of ligand in 1:2 molar ratios respectively.The thick precipitates of different colors for different metal salts were observed.By adjusting the pH with the addition of dilute NaOH solution and refluxing the mixtures for three and a half hours.Colored crystalline complexes were obtained.The complexes were filtered, washed with (70:30) mixture of methanol water and dried.Carbon, hydrogen, nitrogen, metal and water were estimated micro analytically at CDRI, Lucknow.

RESULTS AND DISCUSSION
The synthesized complexes are stable solids.They are soluble in DMF and DMSO and insoluble in all other organic solvents.Analytical data and conductometric studies suggest 2:1 [L: M] ratio.Measured conductance values of these complexes are too low to account for their electrolytic behavior.The magnetic studies indicate the Mn(II),Co(II),Ni(II),Fe(II) and Cu(II) complex to be paramagnetic while Zn(II) andHg(II) complexes to be diamagnetic.

I.R. Spectra:
The vibrational spectra [18][19][20][21] for the free ligand omeprazole when compared with those of its complexes provided meaningful information regarding the bonding sites of the ligand (Table -2).The IR spectra of the complexes indicate that the ligand behaves as bidentate and co-ordinate to the metal via C=N and sulphonic acid group.The shift of the ν C = N and ν S = O by 10-15cm -1 in the complexes indicates that these groups are involved in the complexation.In the IR spectra of omeprazole, strong band at 3456 cm -1 is assigned to secondary NH stretching vibrations.This band remains unaltered or shifted to the higher wave number in the complexes suggesting non-involvement of secondary NH group in coordination with metal ions.The medium to strong bands appearing at 1585cm -1 in the free ligand are assigned to C=N stretching vibration of the azomethine group based on the available reports.This band shifts to lower wave number in all the complexes by about 10-15cm -1 indicates involvement of the azomethine N in bonding.Theshifting of S=O stretching vibration to the lower wave number as compared to the free ligand is indicative of participation of sulphonic acid group in coordination.

Ligand -metal ratio
To confirm the ligand-metal ratio, conductometric titrations using mono-variation method were carried out at 21 0 C. 0.01M solution of omeprazole drug was prepared in 70:30 mixture of methanol and water.Similarly, 0.02M solutions of metal salts were prepared in the same solvent .The ligand was titrated against metal salt solutions using mono-variation method.Conductance was recorded after each addition.From the equivalence point in the graph , it has been concluded that the complex formation has taken place in the ratio of 2:1 (L:M) .Stability constants and free energy changes were also calculated by using Job's method [16]of continuous variation modified by Turner and Anderson [17].decomposition continuous up to 700 0 C and on further increasing the temperature no weight loss is observed which may be attributed to formation of stable metal oxide.

Antimicrobial activity
The antimicrobial activity of the ligand and the complexes was determined by the disc diffusion technique [29].The compounds were screened in vitro against Pseudomonas, Staphylococcus aureus and two strain of fungi, Aspergillus niger and A. flavous.A 1mg/ ml solution in DMF was used.The standard used was gentamycin sulphate 1mg/ml and solvent control was used to know the activity of the solvent.The bacterium was maintained on nutrient agar and the agar media were incubated for different microorganism culture tests.After 24h of incubation at 37 0 C for bacteria and 72h of incubation at 25 0 C for fungi, the diameter of zone of inhibition (mm) thus formed around each disc containing the test compound was measured accurately.All complexes show significant activity against bacteria Pseudomonas and Staphylococcus aureus as compared to ligand.The Co(II) complex is shown to be less active than the ligand in fungi Aspergillus niger and Mn(II) complex in fungi A.flavous .These preliminary results show that the activity of the ligand is enhanced when it is presented in the form of metal complex.Better activities of some metal complexes as compared to the ligand can be explained by chelation theory .The theory explains that decrease in polarizability of the metal could enhance the liphophilicity of the complexes which leads to the break-down of permeability of the cells resulting in interference with normal cell process.In view of the foregoing discussions, the high melting points and insolubility in common organic solvents, we have assigned following probable structure of the complexes of omeprazole.

X-RAY Diffraction
The crystallinity of the material was analyzed with XRD with K-alpha radiation The X-ray diffraction of Cu (II) complex of L 1 is studied as a representative system.The observed 2θ values with relative intensity more than 10% are indexed and have been used for evaluation.The X-ray diffraction pattern of the complex with respect to their prominent peaks has been indexed by using computer software [28].The above index method also yielded miller indices (h, k, l) values, unit cell parameters, volume of unit cell and space group.The observed values fit well with orthorhombic system to give a unit cell dimensions a= 6.3314 Å, b=8.5059Å and c =15.405Å.

Thermal analysis
The thermal decompositions of the Ni(II)complex was studied using the TG and DSC technique.The thermo gravimetric studies of the complex was carried out in the temperature range 30-700 0 C with a sample heating rate 10 0 C/min in air atmosphere.The weight-loss step between 175-200 0 C may correspond the elimination of coordinated water molecules.The weight-loss step between 250-450 0 C may be attributed to the loss of organic moiety of the complex molecule .The final

Table 2 :
Stability Constant, Free Energy Change, Molar Conductance and Magnetic-Moment Data of Complexes

Table 3 :
IR Absorption data of the complexes

Table 4 :
Antibacterial Activity -Zone of Inhibition {in mm}