Indi:m Jo urn al of Che mi stry
\ '01. 3<)1\ , Aug ust 2000, pp. 874 - 876
Synthesis, characteri zation and
antiinflammatory effects of Cr(III), Mn(II) ,
Fe( III ) and Zn (II) complexes with
diclofenac sodium
An uradh a Singh & Pramil a Sin gh *
Dcpartmelll of Chemi stry Dr. HS Gour Vi shwav id yalaya.
Sagar (M P) 470 003. India
Receil'ed 25 OClOO('l' I999. rel'ised 3 1 Jalluarr 2000
Complexes of diclofe nac sod ium . 12-[(2.6-di ch loro phenyl)amino 1 benzeneacetic acid monosodium salt}. an an tiinflammalOry drug. wi th Cr(l ll ). Mn (II ). Fe( Il l) and Zn(II ) have been prepared and characteri zed by elemelllal anal ys is. magnct ic susceptibil it y. molar conductance . electronic and infrared spectroscopy.
The drug fu nction s as bidentate anioni c li gand . Ailliinilammatory
effect s ha ve becn evaluated by carrageenan-induced rat paw
oedema tcs!. The complex{:s of Cr (Ill ) and Zn (Il) have been
fo un d to be mo re effective than the dru g itself.
It has bee n reported that compl exes of meta llic sa lts
are more potent and less tox ic in many cases as
compared to the parent drug l ., . Diclofa nac sodium is a
non-steroidal antiinfl ammatory drug (NSAlD), widely
used as antiinflammatory and analgesic agent-l.
Severa l complexes of thi s drug ha ve been fo und more
g
ac ti ves. (Structure J).
In view of the increasing importance of drug
cOI1lplexes, a deta iled stud y of the interaction of
Cr(III), Mn(JI ), Fe(III) and Zn(lI) with dicl ofenac
sodium was und ertaken. Antiinfl ammatory activity of
the complexes has been carri ed out to see the change
in acti vity due to complexation (Structure 1I,lJI).
Experimental
All the chemicals used were of AR grade. The
liga nd Diclofenac sodium was obtained from Ari sto
Pharmaceuti ca l, Mumbai and used as suc h.
Preparation of complex
The stoichi ometri c rati o of the complexes were
determined by spectrophotometri c/conductometri c
meth 0ds. Cr(I ll), Mn(II ), Fe( III) and Zn(IJ)
complexes were prepared by refl ux ing aqueous
soluti on of metal salt and the ligand in the molar rati o
1:2 for CrOll), Fe(lll ) and Zn (II) and I: 1 for Mn(H)
complexes-2 h on a water bath . The pH was
maintained - 5-8 by addin g dil NH 3/HCI. The
precipitated co mplexes we re was hed with water and
finall y with ether and dri ed under reduced press ure at
room temperature. The purity of the compounds was
monitored by TLC using silica gel.
Melti ng points were determin ed on a Tos ni wa l CL0301 apparatus. Molec ul ar weights of the complexes
we re determined by Ras t's camp hor method9 .
Elemental analys is were carri ed out on a Herae us
Carl o Erba 11 08 an alyser at RSIC, CDRI Lucknow.
Metal and chl oride contents were determined by
standard methods 10. The IR spectra were recorded on
Shimadzu 820 1 PC infrared spectrophotometer in
KBr between the range 400-4000 cm· l . Electroni c
spectra were recorded on Shimadzu 2 10 A UVIV IS
Spectrophotometer. Mol ar conductance (in 10.3 M
DMF) was determined using an Elico CM 82 T
instrument. Magnetic susceptibility was meas ured on
Gouy's balance at room temperature using CUS0 4'
x,
I
o l CL oF ENAC
(I)
iL
SODIUM
Whe re.
Cr ti l l) complex" R, " R2 ° H20
X," CI
Fe (11 1) complex" R, • OH. R2" H~
Z n (I I ) complex " R,-R 2 " H2 0
M" Cr (lll).Fe ( II1).Zn (lI )
(11 )
y
till )
875
INDIAN .J CHEM , SEC. A, AUGUST 2000
The lowering in the value of B from free ion value for
Fe(IlI) (1315 cm-') suggests covalent nature (43.5 %)
of bonding' 2. The Mn(II) complex exhibits three
bands at 16600, 26500 and 28800 cm-' respectivel y
corresponding to transition 6A 'g ~~, g (G) (v, ), 6A ' g
~ 4T2g (G) (V2) and 6A 'g ~ 4£g (G) (V3) respecti vely.
The V2 / v" 10 Dq, Band () values were found to be
1.6, 10500 cm-' , 700 cm-' and 0.5 1 respecti ve ly' 2.
These are in fair agreement with octahedral geometry
for the Mn(lI) complex . The lowering in the value of
B from free ion for Mn(ll) (960 cm-') suggests
covalent (30.23 %) nature of bonding.
In the IR spec tra of the Cr(IlI) and Mn(ll)
complexes, one double hump at 3200-3500 cm-' and
in the Fe(III) and Zn(lI) complexes broad bands
-3300 cm-' fo ll owed by sharp peaks at - 1600,
830 cm-' assignable to OH stretching, bending and
rocking vibrations respectively indicates the presence
13
of coordinated water molecules in the complexes .
The ligand bands at 3400 (N H) and 1575 cm-' (C =
0) shifted by ± 15-20 cm-' in the complexes,
indicating the coordination through these groups. In
the far IR region , the chelates show new medi um
intensity bands at 520-544 and 470-450 cm-'
comparable with vM-O and vM-N respectivel y'4. In
Mn(lI) complex, additional bands at 1548, 145 2, 1301
and 701 cm-' can be assigned to v asym (COO), Sym
(COO), 8 (CH3) and 8 (COO) respectively indicating
the presence of acetate ion in the coordination
sphere'4.
5H20 as calibrant. Diamagnetic corrections were
applied using Pascal's constant.
Results and discussion
The analytical and physical data are given in Table
I. All the complexes are soluble in DMF and DMSO.
The molar conductance in DMF of Cr(lII) is 92.88
ohm-'cm2 mort which indicates its 1: 1 electrolytic
nature. Mn (II), Fe(IIl) and Zn(ll) complexes are none lectrolytic in nature. The presence of chlorine ion in
Cr(IlI) complex has been confirmed by elemental
analysis.
As expected, the Zn(II) complex is diamagnetic
while other complexes are paramagnetic . The room
temperature magnetic moment value (3.87 B.M.) of
Cr(lll) complex is close to the spin only value for
octahedral complex . Those of the Mn(II) (5.86 B.M.)
and Fe(III) (5 .8 1B .M .) complexes are in the range
required for six - coordinated spin - free octahedral
complexes" .
In the electronic spectra, C r(III) complex exhibits
three bands at 13800, 18100 and 19200 cm-'
corresponding to the transitions 4A 2g (F)~ 4 T2g (F)
(v,), 4A2g (F) ~ 4T 'g (F) (V2) and 4A 21( (F) ~ 4T 'x(P)
(V3) in an octahedral geometry' 2. The V2 / v, ratio
( 1.31) also confirms the octahedral geometry for the
complex. The 10 Dq, Band () values were found to be
12228, 402 cm-' and 0.41 respectively. The lowering
in the value of B from free ion for Cr(Ill) (1030 cm-')
I2
suggests hi gh covalent nature (62 %) of bonding .
The Fe(III) complex exhibits three bands at 11700,
19300 and 27000 cm-' whic h may be attributed to the
transitions 6A ' 8 ~4T' II (G) (v,), 6A ' g ~ 4T2g (G) (V2)
and 6A 'g ~ 4£iG) (V3), respec tively for octahedral
complexes. The V2 / v" 10 Dq, Band () values were
found to the 1. 7, 11872cm-' , 742cm-' and 0.56
respectively. These are in fair agreement with the
octahedral geometry suggested for Fe(III) complex.
Antiinflammatory activity
Antiinflammatory activity of the complexes were
performed using a plethysmometer to measure
carrageenan induced rat paw volume followin g the
method of Winter et al'5 . Adult male wister albino
rats (90-125g) were fasted for 18h but with free
access to water. Each treatment i.e. plain drug and
complexes was admi ni stered at a dose of 100 mg/kg
Table I--Characterizati on data o r the compl exes
Comp./Colour. m.ptOC
Mo l.wt. found
(caled.)
Found (calcd.), %
~
efr.
-'\n
M
C
H
N
CI
(B M)
Q-I cm 2 mo!, 1
[Cr(CI4 Hl oNCI20 zh2 H20] CI
Light blue 125
7 11.57
(7 13. 70)
708
(7 .28)
47 .96
(47 . 12)
3.46
(3.38)
3.98
(3.92)
24.62
(24.84)
3.87
92 .88
[Mn(C 14H IONC1 20 2)
CH)COO.3H 20] Light brown 140
[Fe(C I4 H IONC120 2)2 OH . H2 O]
Dark brown 180
464.67
(463 . 14)
11 .49
( 11.86)
41.95
(41.51 )
4 .07
(4. 10)
3. 15
(3.03)
15.01
( 15 3 1)
5.86
7.00
680.20
(681.12 )
8.07
(8.20)
49.54
(49 .37)
3.45
(3 .40)
4.17
(4 . 11 )
20.64
(20.82)
58 1
8. 12
[Zn(C I4H IONC lzOzh 2H20) White
120
694.03
(691.67)
9.3 1
(9.45)
48 .86
(48 .63)
3.54
(3.49)
4 .00
(4 .04)
20.36
(20.50)
Di amagnetic
9.00
876
INDIAN J CHEM , SEC. A, AUGUST 2000
Table 2-Effect of various compounds on carrageenan paw oedema in rats
No. of animals
used
Dose (mg/kg)
body wI.
Initi al vo l*
--U:-Oh
Final vol*
after 3h
Vol. of
oedema*
/0
100
0.615
1.145
0.530
' B' Plain drug
/0
100
0.683
0.996
0.3 13
40 .84
'C' Cr-drug complex
/0
100
1.006
1.176
0.170
67 .92
Compo
' A' Control
Percent inhibition
' 0 ' Mn-drug complex
/0
100
0.830
1.140
0.3 /0
41 .50
' E' Fe-drug complex
10
100
0.8/0
1.164
0. 354
33.20
.F' Zn-drug complex
/0
100
0.729
0.909
0. 180
66.03
* Average of 5 readings
body weight orally in 0.5 % CMC suspension. Half an
hour following the treatment, 0.1 ml. of 1% solution
of a carrageenan was injected in the right hind paw
planter aponeurosis, the paw volume was measured
immediately before giving carrageenan and again 3h
later by means of plethysmo meter. Edema was
measured in a precalibrated plethysmometer as the
difference between the vo lume of the paw measured
before and 3h after g iving carrageenan. The percent
inhibition of infl ammation after 3h was calculated by
l6
the method of Newbould . The values reveal that at
equal doses, the Cr(lll) and Zn(ll) complexes are
more active than the drug itself. Cr(lll) and Zn(ll)
complex possibly depressed the synthesis of the
proinflammatory (vasodilator) prostaglandin, PGE2 in
l7
the carrageenan pouch model of inflammation . This
l8
is in consistent with the work of Lee and Lands , and
l9
recently confirmed by Moddox , who found a
depression in PGE2 synthes is and a concomitant
increase in the antiinflammatory (vasoconstrictor)
prostaglandin , PGF2a , following the addition of
copper sulphate or chloride to semin al vesicle
homogenates. These results suggest that the
mechanism action of Cr(lII) and Zn(II) complexes
may be, at least in part, at the level of the
prostag landin mediati on o f infl ammation. This is to
say, these complexes may playa role in decreasing
the synthes is of the proinflammatory PGE 2 and
concomi tantl y, increasi ng the synthesis of the
antiinflammatory PGF 2a. CTa ble '2).
Acknowledgement
Authors are thankful to the Head, Department of
C hemistry, Dr. Hari si ngh Gour Vishwavidyalaya,
Sagar for fac ilities and to CDRI, Lucknow, for
elemental analysis and spectroscopic studies. The
authors gratefully ackno wledge the help of Aristo
Pharmaceutical Pvt Ltd., Mumbai, for providing
diclofenac sodium as gift sample.
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