Synthesis, Characterization and Spectral Studies of Gold Complex With Gliclazide, an Oral Antidiabetic Allopathic Drug

Introduction

Metal ion are required for many critical function in humans .Scarcity  of some metal ions can leads to disease¹. Well – known  example  can  leads  to  pernicious anemia   resulting from  iron  deficiency;  growth  retardation  arising from  insufficient  dietary  zinc, and  heart  disease in  infants  owing  to   copper  deficiency. The ability to  recognize, to understand  at the  molecular  level, and to the diseases  caused  by  inadequate  metal- ion function  constitutes  an important  aspect  of  medicinal  bioinorganic chemistry.  Understanding   the  biochemistry  and  molecular biology of  natural  detoxification  mechanisms  and  designing  and  applying  ion –specific  chelating agents  to  treat  metal  over  -loads  are  the  two  components  of   a  second  major  aspect  of  the  new  science  that  is  evolving  at  the  interface  of   bioinorganic  chemistry  and  medicine.

Diabetes   is  a  deceptive  disease  and  if  not  detected  in  early  stage  may  cause  even  death.  It  is  considered  hereditary  but  actual  genetic  disorder  is  still  a  mystery.  Several  million  people  are  suffering from  this disease all over  the  world [Sadilot  and Phatak,²; Bloomgarden³, ; Sanger  and  Thompson,⁴ ]. Zinc- insulin was  discovered as early as in 1921 and later it proved to be a very  efficacious  medicine in the treatment  of  diabetes mellitus. To  avoid  the daily pricks  of hypodermic syringe, oral hypoglycemic agents were discovered which has revolutionized the treatment of  diabetes .It is worthwhile to mention here that the majority of the essential metallic elements   of biological importance  are transition metals ,whose ability to form coordination complexes and chelates is the characteristic aspects of their chemistry.

In  recent  years  much  attention is given to the use of  sulphonylureas  because of their high complexing  nature with essential  metals .Sulphonylureas  are effective  for non- insulin dependent  diabetes mellitus, [Sadilot and Phatak²,  Bioomgarden,³  Sanger and Thompson,⁴]. These compounds are completely absorbed  on oral  administration. They are metabolized by liver and are excreted  predominantly through urine.

Complexation  of sulphonylureas with lighter transition metals has been  studied in detail  by  Yoshinaga and Yamamotto^5-6, [ ,Iqbal.at.el. )^7,10-11,26 and other author synthesis the complexs of various metals with compound^30-37 . A perusal of available literature shows that systematic study of complexation of vanadium with Gliclazide is relatively scanty. It is interesting to have an insite in to the synthesis of vanadium complex with Gliclazide and to diagnose various structural aspects of the isolated complex.

Here the synthesis and characterization of gold with Gliclazide have been described

Structure of Gliclazide

Experiment

Ligand-Metal Ratio

a) Pure Gliclazide m.p. 180°C (Lit. 179.5-180.5), 0.005 M, were diluted to 100 ml as required  and titrated conductometrically against gold chloride at 30±1°C. Results were plotted in the form of a graph which indicate ligand metal ratio as 2:1 (L₂M).

b) Formation of 2:1 (L₂M) ratio was further confirmed by Job’s method⁸ of continuous variation as modified by Turner and Anderson⁹(Table-1) spectrophotometric studies were conducted using absorbance as index property, from these values the stability constant (log k) and free energy change    (-DF), were also calculated (Irving and Rossotti ^38-39 ) Tables 1, and fig. 1 given for Gliclazide -Gold complex.

Table 1: Click here to View table

Synthesis of Complexes

The chemicals used in this synthesis were all of analar grade Hi-media. A weighed quantity of Gliclazide(2 mol) (supplied by Zim lab.Nagpur) was dissolved separately in minimum quantity of 90% ethanol. The gold chloride solution was prepared by dissolving          (1 mol) separately in the same solvent. Ligand solution was added slowly with stirring into  the metallic salt solution at room temperature, maintain the pH between 6.0 to 6.5 by adding dilute NaOH solution. On refluxing the mixture for 3 hours and on cooling the complexes separated out. Which were filtered off, washed well with ethanol and finally dried in vacuum and weighed.

The elemental analyses of the isolated complexes were carried out using coleman analyzer at the departmental micro analytical laboratory CDRI Lucknow..

The IR spectrum of the ligand as well as of the complex was recorded on Perkin Elemer Spectrometer(I.I.T BOMBAY) and ¹H-NMR spectra of the ligand and isolated complex  was  recorded on a Bruker DRX-300 Spectrometer and d₆-DMSO was used as a solvent. IR and ¹H-NMR spectrums recorded in CDRI, Lucknow and IIT BOMBAY. India and X-Ray diffractrogram from Punjab University ,Chandigarh.

From stoichoimetry and analytical data, the composition of the complex comes out to be (C₁₅H₂₀N₃O₃S)₂·Au, which favours 2:1 (L₂M) ratio. The tentative structure( I) assigned to complex on the basis of analytical data and IR, NMR, Mass and X-ray.

Table 1: Gliclazide With Gold(Iii)Chloride (Modified Jobs Method⁸  ).

S. No.	Mole Metal:Ligand	Absorbance		Corrected Abs.	Corrected Abs.
		0.002M	0.005M	0.002M	0.005M
1	0:12	0.01	0.015	0.00	0.00
2	1:11	0.119	0.253	0.109	0.233
3	2:10	0.283	0.423	0.261	0.402
4	3:9	0.464	0.611	0.449	0.586
5	4:8	0.725	0.925	0.710	0.895
6	5:7	0.701	0.849	0.682	0.712
7	6:6	0.593	0.693	0.478	0.633
8	7:5	0.474	0.613	0.459	0.504
9	8:4	0.422	0.563	0.405	0.503
10	9:3	0.332	0.442	0.312	0.362
11	10:2	0.098	0.397	0.078	0.322
12	11:1	0.053	0.243	0.032	0.163
13	12:0	0.023	0.085	0.00	0.00

JOBS METHOD BY SPECTROPHOTOMETRICALLY   Gliclazide-0.002M,0.005M  Gold(III) chloride-0.002M.0.005M  Solvent: 90% Ethyl alcohol  Temperature: 30±1⁰C  Wavelength: 660 nm pH: 5.9

 

Figure 1: Gliclazide With Gold Chloride. Click here to View figure

Result and Discussion

Table 2: Pysico-chemical Characterstics of Gliclazide complex with Gold

Sl. No.	Complexes	Colour	Yield (%)	m.p.°C	–ΔF	Log K	Molar conductance W-1cm-1mole-1
1.	(C15H20N3O3S)2Au	Brown	36	183	16.66	11.97	33.6

Table 3: Elemental analysis of Gliclazide-Gold  complex.

Sl.No.	Formula of complexes	Molecular weight (g/mole)
			C	H	N	S	Metal(%)
1.	(C15H20N3O3S)2Au	842.45	42.76(43.82)	4.75(5.64)	9.57(9.85)	7.60(703)	23.4824.96

Infra-red Spectra Studies

The IR spectra of ligand and isolated complex was scanned within the range 4000-400 cm^-1. Assignments of the infrared spectral bands are based on literature (Table-3) IR spectrum shows important bands due to n(M-O) 400-600 cm^-1, n(Ar-S) 700-800 cm^-1, n(-S-N) 1085±20 cm^-1, n(SO₂-N) 1120±20 cm^-1, n(C-N) 1210±20 cm^-1, n(S=O) 1340±20 cm^-1, n(C=O) 1710 cm^-1( present only in pure drug and absent in complex),1600±20 cm-¹vs(coordinate H₂O molecule present only complex), n(NH-stretch) 3274±20 cm^-1.

The proposed structure for the isolated complex is also supported by IR absorption , C.N.Rao¹². , Bellamy ¹³, Weissberger¹⁴ .

Table 4: Specific IR assignment of Gliclazide,and Gliclazide complexes with Au.

Pure drug(Gliclazide)	Gliclazide-Au complex
632cm-1s,668cm-1 vs,1087cm-1vs1240cm-1vs,1348cm-1vs,1710cm-1vs,2867cm-1,2950cm-1vs,3274cm–1vsVs=very strong,s=strong,m=mediumW=weak	618cm-1 s ,672vs,1108cm-1s,1187cm-1s ,1620vs1340cm-1 s,1520cm-1s 2857cm-1 2924cm-13021cm-1s,3670cm-1mVs=very strong,s=strong,m=medium W=weak

 

Figure 2: IR Spectra of Gliclazide. Click here to View figure

 

 

Figure 3: IR Spectra of Gliclazide-Gold complex. Click here to View figure

¹H-NMR Studies

¹H-NMR spectral data are given in (Table-4). It was observed that the singlet due to the imide (NH) proton around (d8.033) in the spectrum of the ligand disappeared in the spectra of (NH) group in the complex molecule due to formation of M-O band. This also confirms the deprotonation of aimide NH group through enolization (the appearance of >C=N stretching band observed in IR spectra)

Other features of NMR spectrum were the aromatic presence of unresolved multiplet suggestive protons. Slichter¹⁵ , Akit¹⁶ , Siewers ¹⁷, Jacob and Iqbal ¹⁸ Afridi¹⁹,

Table 5:  NMR-Assignments of Gliclazide-Gold complex.

(C15H21N3O3S)2 pure drug Gliclazide	(C15H21N3O3S)2Au
δ8.041 (s,1H,NHCo, J=0.334Hz), δ7.817 (d,benzene J=1Hz), δ7.395(d,benzene, J=1Hz), δ6.28 (s,SO2NH), δ3.320 (NH-CO, J=0.929Hz), δ2.901(s,CH3 group attached to benzene, J=2.160 Hz), δ1.388 (s,CH3 group, J=2.955Hz	δ8.033 (d,1H,NH-CO, J=1.441Hz), δ7.806 (d,benzene, J=4.987Hz), δ7.395 (s,SO2-NH, J=1Hz), δ3.504 (s,NH-CO-Au, J=0.83Hz), δ2.618 (s,CH3-group attached to benzene, J=13.395Hz), δ1.571 (q,CH3 group, J=5.50Hz), δ1.224 (CH3 group,J=1.165Hz

s=singlet, d=doublet, t=triplet, q=quartrate, m=multiplet

X-Ray Diffraction Studies

X-ray diffraction studies also confirm the complex and formation due to new bonds^20-25,27-28. The number of peaks in gliclazide are 22 while  (GLZ)₂Au are 12 (Fig-6) . Thus indicating that complex  formed is a well kit one. All the reflections present are new ones and the patterns are fairly strong. On comparing the pattern obtained with available literature. It is evident that its pattern is not in good agreement with available information and thus confirms the formation of totally new complex. The X-ray pattern have been indexed by using computer software(FPSUIT 2.0V) and applying interactive trial and error method keeping in mind the characteristics of the various symmetry system, till a good fit was obtained between the observed and the calculated Sin²θ value. The unit cell parameters were calculated from the indexed data, from cell data and crystal lattice parameters of (GLZ)₂Au, indicates complexes attributed to Monoclinic crystal system Table given below

Figure 4: X-ray difractogram of Gliclazide-Gold complex. Click here to View figure

Cell data and crystal parameter of GLZ-Au Complex given in below Table -6

a(Å) = 21.762  Volume (abcsin b)Å= 14065.307

b(Å) = 23.4271    c(Å) = 27.274   Dobs =3.36041 g/cm³ Dcal = 3.35724 g/cm³  Standard deviation = 0.0026%Crystal system  =  orthorombic

α=90°, β=89.2, γ =90° Porosity(%)           =    2.361

Density =0.059845 g/cm³  Particle size  =    10.91microns

Space group = Pm

2θ	I/I0	D(Obs)	D(Cal)	h	k	l
26.5255	100	3.36041	3.35724	1	6	4
30.3724	40.21	2.94300	2.93864	-1	2	9
34.9471	63.10	2.56752	2.56734	-3	1	10
43.9242	31.47	2.06137	2.06019	8	3	8
51.9526	29.96	1.75867	1.35806	-8	11	8

 Mass spectral studies of gliclazide-gold complex

Mass spectrophotometric studies gave useful information regarding the accurate determination of molecular weight and which provided information about the structure of compounds by examination of the fragmentation pattern^40-41. Now a days, chemist have enthusiastically embarrassed mass spectroscopy to identify and characterize molecule           Mass spectrum of the compound is a plot which represents the intensities of the signals at various m/z value^42-43. It is highly characteristic of the compound ,no two compounds can have similar mass spectra. It provides information regarding the molecular structure of organic and inorganic compounds. We have studed gold complex of gliclazide and assignment is given table-7

Mass Spectrum of GLZ-Au Complex

Table-7   Mass Spectrum assignment  of GLZ-Au Complex

Structure(I)

Discussion

For supporting the proposed structure of gold-gliclazide complex, initially Jobs method of continuous variation as modified by Turner and Anderson was conducted which indicate 2:1 ligand:metal ratio of the complex , moreover  stability constant and free energy change was also calculated .Analytical data agrees to the molecular formula (C₁₅H₂₀N₃O₃S)₂Au    (L₂M) .

For determining the proposed structure on the basis of stoichiometry and analysis of the complex. Advance spectroscopic methods like IR , H¹-NMR , Mass were conducted which suggest the coordination of metal atom with enolic oxygen of the carbonyl group on one side and oxygen of the sulphonyl group from the other side .These observation were further supporting from the IR and NMR values of metal-oxygen and disappearance of M-H linkages in NMR. A detailed study of X-Ray also supports the complex formation and the various values like particle size , porosity , volume of unit cell , density as well as crystal system was evaluated  and discussed .Moreover looking to the higher electronegativity  of oxygen as compared to N²  and to enolization  is strongly supported.

Acknowledgement

The author is thankful to the principal of Gyan Ganga Institute of Technology &Management , Bhopal and Principal of Cresent College of Technology, Bhopal for providing all necessary facilities and IIT, BOMBAY ,PU CHANDIGARH for providing IR spectra  and x-Ray data.

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