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Jain S. Mixed Ligand Complexes of Calcium (II) and Magnese (II) With Pyrazinecarboxamide and Isonicotinic Acid Hydrazide. Biosci Biotechnol Res Asia 2009;6(1)
Manuscript received on : December 06, 2008
Manuscript accepted on : January 07, 2009
Published online on:  28-06-2009
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Mixed Ligand Complexes of Calcium (II) and Magnese (II) With Pyrazinecarboxamide and Isonicotinic Acid Hydrazide

Sangeeta Jain

Department of Biochemistry, People’s Dental Academy, Bhopal (India).

ABSTRACT: Mixed Ligand Metal Complexes of Pyrazinecarboxamide and Isonicotinic Acid Hydrazide prepared by using salts of Ca(II), Mg (II). Stoichiometry of Mixed Ligand Metal Complexes was determined by conductometric titration, which was found in 1:1:1 ratio. These complexes were characterized on the basis of I.R., NMR, Spectroscopy and screened for biological activities.

KEYWORDS: Infrared spectroscopy; nuclear magnetic resonance spectroscopy

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Jain S. Mixed Ligand Complexes of Calcium (II) and Magnese (II) With Pyrazinecarboxamide and Isonicotinic Acid Hydrazide. Biosci Biotechnol Res Asia 2009;6(1)

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Jain S. Mixed Ligand Complexes of Calcium (II) and Magnese (II) With Pyrazinecarboxamide and Isonicotinic Acid Hydrazide. Biosci Biotechnol Res Asia 2009;6(1). Available from: https://www.biotech-asia.org/?p=8490

Introduction

Coordination chemistry of Magnese and Calcium has received consideration interest in recent years, mainly due to the realization of the involvement of these elements in many biological process. (1,2)

Coordination of organic molecule to metal ions significantly alters the effectiveness of biomolecule. The use of PZA as antitubercular drug was suggested by Kushner & Coworker (3), which is important antitubercular drug effective against slow multiplying bacilli formed in macrophages. The drug shows antitubercular activity in “vitro” at an acidic pH. INH is another antitubercular drug effective as bacteriocidal agent against replicating bacilli and also as bacteriostatic agent against non replicating bacilli, both the drug have tremendous tendency of chelation and due to suitable geometrical arrangement they have property to form protonated species.

With reference to multidrug chemotherapy in 1984 MDR TB (Multidrug resistant) tuberculosis concept was proposed.

Experimental

Synthesis of Mixed Ligand Complexes

The Mixed Ligand Metal Complexes were prepared by mixing aqueous solution of metal salt, pyrazinamide and Isoniazid in 1:1:1 molar ratio and keeping the reaction mixture in hot water bath for about 6 hours. The complexes were filtered, washed with distilled water, dried in vacuum and stored in air tight bottles. All the complexes are soluble in water, ethyl alcohol and acetone but insoluble in Benzene and Carbon Tetrachloride. Analytical data of the complexes are given in Table No. 1.

Table 1: Analytical Data of Mixed – Ligand complexes.

Complexes C H N Metal O
PZA 49.48 3.86 34.00 15.03
INH 51.55 5.10 34.14 11.67
Mixed Ligand complexes of  Ca 41.52 4.52 34.10 12.25 9.98
Mixed Ligand complexes of  Mn 34.29 4.30 33.89 16.58 11.19

The stoichiometry of the complex in solution was ascertained by conductometric titration using 20 ml of each ligand (PZA/INH) solution (0.01m) with 0.1 m metal solution. Metal – Ligand – Ligand   (M + L + L’) constants of various species have been evaluated potentiometrically at 300C and 0.1 m ionic concentration by adopting the pH titration technique of Calvin – Bjerrum Titration Method modified by Irrving – Rossoti Method.(4,5)

Metal–Ligand–Ligand (M + L + L’) stability constants were calculated with Job’s method by spectro-photometrically, which is quite adequate with the value obtained by Irriving Rossoti Method.

Metal Ligand stability constant was determined by formation curves by plotting ň & pL – ion by using various computational method presented in Table No. 2.

Table 2: Proton- Ligand stability constant of PZA & INH.

Temp. 300C

m = 0.1 M

Method PZA INH
  Log K,H Log K2H Log pH Log K, H
Half ň A method point wise calculation Linear plot method 7.70

7.65

7.7

(7.68)

6.7

6.6

6.7

(6.6)

14.37

14.35

14.37

(14.33)

6.40

6.84

6.67

(6.63)

Stability constants of metal complexes of PZA – INH

Temp. 300C

m = 0.1(KNO3)

Metals Log K DG kcal / mole
Ca complex 7.35 – 5.1
Mn complex 7.70 – 5.3

Log K & thermodynamic parameter values reveals that the divalent transitional metals in which filling of 3d orbital takes places and the order of stability in the order Mn2+ = 7.70, Ca2+ = 7.35 as predicted by Irving

Rossoti  method.

The IR data of  the isolated mixed ligand complexes are given in Table No.3,shows  -NH primary stretching frequency of MLC of Ca $ Mn in the region 3400 cm ,while PZA $ INH shows these frequency at 3413cm-1,3161 cm-1,3300 cm-1,3100cm-1 respectively.

Similarly MLC of Ca $ Mn shows primary bending –NH frequency in the region 1660 cm while secondary bending – NH frequency at 1540 cm-1, PZA and INH shows these frequencies at 1610 cm-1 and 1650 cm-1 respectively and secondary bending  – NH frequency at 1578 cm-1 and 1575 cm-1. The C = 0 stretching frequency was appeared at 1660 cm-1 and 1715 cm-1, 1650 cm-1 in PZA and INH.

These observation clearly indicated the complexation of metal take place through the carbonyl group and nitrogen – NH2 moiety of hydrazine group.             Most of the bands of the PZA and INH remain unchanged on chelation, while it shows change in the n – NH stretching frequency of PZA and INH. Tertiary Nitrogen aromatic frequency in PZA occurs at 1377 cm-1 and in INH this frequency occurs at 1375 cm-1 but in MLC of Ca & Mn, this frequency lowers at 1310 cm-1 and 1380 cm-1 respectively because of electrons from nitrogen atom to the metal which is on turn weakens the – NH bonds.(6)

The presence of coordinated water finds absorption band at 869 cm-1 in PZA and INH at 875 cm-1 but in MLC of Ca and Mn this frequency lowers about 860 cm-1 and 852 cm-1 respectively.

Chemical shift data of PZA(pure) in the solvent DMSO-D6 shows two different kinds of protons (Aromatic) signal at 7.85 d , 8.22 d , 8.62d , 8.77 d , 9.11 d  chemical shift data of PZA in the solvent D20 + DCl shows proton signal at 8.55 d , 8.62 d , 8.77 d . These signals are also present in the complex shows no exchange of proton from aromatic nucleus. In complex formation deprotonation takes place from – CoNH2 moiety.

Table 4: Proton Nucler, Magnetic Resonance Spectroscopy

COMPLEXES SOLVENT CHEMICAL SHIFT
PZA (Pure) DMSO-D6 7.85d

8.22d

8.72d

8.77d

9.11d

PZA (Pure) D20-DCI 8.44d

8.62d

8.77d

PZA-INH+ Ca2+ DMSO-D6 7.85 d

8.22d

8.70d

8.88d

9.14d

PZA-INH+Ca2+ D20+DCI 8.48d

8.62d

8.81d

PZA-INH-Mn2+ DMSO-D6 7.81d

8.82d

8.66d

9.18d

PZA-INH+Mn2+ D20-DCI 8.48d

8.85d

Result and Discussion

I.R. data reveals that the bonding between pyrazinamide and metal ions involves tertiary nitrogen and – NH2 group to form five membered chelate ring. In case of isoniazid bonding involves –CO and –NH2 group forming the five membered ring.

NMR spectra data also supports that the deprotonation takes places from –CONH2 moiety.

The antitubercular study revealed an effective increase in potency of isoniazid and pyrazinamide when chelated with Mn2+,Ca2+. In these cases pronounced decrease in the number of colonies as compared to pure isoniazid and pyrazinamide. The values of log K is also supported for these activity. This is due to low dissociation constant (High stability constant) and shows a strong metal-ligand-ligand bond.

Effect of Mixed –Ligand Complex of PZA-INH on  Mycobacterium Tuberculosis

Temp.370C                           Concentration-0.01mg

Time-21 days                       MIC of  PZA-0.10mg

MIC of INH-0.10 mg

S.No. Compound CFU Obtained
1. Pure pyrazinamide (PZA) Control 30 colonies
2. Pure Isoniazide (INH) Control 40 colonies
3. INH – PZA – Ca2+ 06 colonies
4. INH – PZA – Mn2+ 04 colonies

IR spectra of the isolated complexes were recorded on Perkin-Elmer FR spectrophotometer model 337 by the KBR disc techniques. NMR spectra were recorded at Lupin Laboratory,Bhopal.

References

  1. Koch, R., Berlin, Klin, Wochschr 19(1982) 221.
  2. Rich, A.R., and Follis, R.H., Jr. Bull. John Hopkins Hosp. 62, (1938) 77-81.
  3. Kushner, S., Dalalian. H., Sanjurio, J.L. J. Am.Chem. Soc., 74 (1952) 3617 – 3621.
  4. Bjerrum. J, “Metal amine formation in aqueous solution, “P. Hasse and Sons., Copenhagen (1957)
  5. Irving, H., & Rossotti, H.S., J. Chem. Soc, (1954) 2904, (1953) 3397, (1955), 176.
  6. Nakamoto, K., “Infraredspectra of inorganic and Coordination compound. “John Wiley and sons N.Y. (1963).
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