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Synthesis, characterization and antibacterial activity of aspirin and paracetamol-
metal complexes
Amudat LAWAL and Joshua A. OBALEYE*
Department of Chemistry, Faculty of Science, University of Ilorin, Ilorin, Nigeria
Received 27 December 2006
MS/No BKM/2006/040, © 2007 Nigerian Society for Experimental Biology. All rights reserved.
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Abstract
Novel complexes of Co (11), Ni (11) and Fe (111) with aspirin and paracetamol have
synthesized and characterized using infrared, electronic and Hnmr spectral, melting point and
conductivity measurements. The two ligands have been found to act as bidentate chelating
agents. Aspirin complexes coordinate through the carbonyl oxygen of the carboxyl and the ester
groups, while paracetamol complexes coordinate through the oxygen of the hydroxyl and the
amide groups. Antibacterial screening of the complexes against Bacillus substilis, Serratia
species and Escherichia coli, was also investigated. The metal complexes were found to have
varied degree of inhibitory effect against the bacteria.
.Keywords: Aspirin, Paracetamol, Metal Complexes, Antibacterial Activity
*To whom correspondence may be addressed, E-mail: jobaleye@yahoo.com, amudatlawal@yahoo.com Tel: +234-8033582048
BIOKEMISTRI
19(1):9-15 (June 2007)
This article is downloadable online in PDF
format at http://www.bioline.org.br/bk
10
INTRODUCTION
Aspirin is a derivative of salicylic acid. It has
analgesic, anti-inflammatory and antipyretic
actions and inhibits prostaglandrin synthetase1
while paracetamol is a derivative of 4-
aminophenol which also has analgesic and
antipyretic action2. Paracetamol is useful in the
treatment of pain such as headache, toothache,
rheumatism and neuralgia2.
However, it is known that some drugs act via
chelation or by inhibiting metalloenzymes but
for most of the drugs that act as potential
ligands, a lot of studies are being carried out to
ascertain how metal binding influences the
activities of the drugs3. Although, in 1987, Abu-
El-Wafa et al4 reported the synthesis of Co(ii),
Ni(ii) and Fe(ii) complexes of metformin(L),
also an analgesic, on the basis of analytical data
obtained, the prepared complexes were
formulated as ML2.
Metal complexes are gaining increasing
importance in the design of drugs on
coordination with a metal. This has led to lots of
study on metal drug complexes.
Therefore, it was considered necessary to have
some other analgesic drug-metal complexes, due
to their chemotherapeutic properties. We hereby
report the synthesis, characterization and
antibacterial activity studies of novel transition
metal complexes of aspirin and paracetamol.
MATERIALS AND METHODS
All the chemicals were reagent grade and used
as commercially obtained (Aldrich, BDH)
without further purification.
Aspirin and paracetamol were obtained from
Rajrab Pharmaceutical company Ltd., Ilorin,
Kwara State. Nigeria.
The melting points of the ligands and the
complexes were carried out using Gallenkemp
melting apparatus.
The thin layer chromatography of the complexes
was run using solvent mixture of ethanol,
acetone and petroleum ether in the 7:2:1 mole
ratio.
The molar conductively of the ligands and
the complexes in methanol at room
temperature (25 ± 0.10C) were made on
WTW Conductometer Bridge with a cell
constant of 0.82cm-1. The IR spectral were
recorded in solid state as KBr pellets using
Buck-Scientific M 500 model infrared
spectrophotometer form 4000cm-1 to 600cm- 1
The uv/visible spectra were made on Sp8 –400
uv/visible spectrophotometer using methanol as
solvents. The metal content of the complexes
were determined by using an SP9, atomic
absorption spectrophotometer with PM 8251
simple-pen recorder.
The proton nmr spectra of the ligands and the
complexes were obtained on Bruker AC 200/300
spectrometer using deuterated chloroform as
solvents.
Evaluation of antibacterial activity
The antibacterial activity of the test compounds
was assayed against three bacteria: Bacillus
Subtilis, Serratia Species and Escherichia coli.
The antibacterial activity of the compounds was
determined as reported by Abd E1-Wahab and
E1-sarrag5.
The antibacterial activity was determined on the
seeded nutrient agar on which 0.9cm diameter
wells punched. Different concentrations (0.1%
and 1.0%w/v) of sterile filtered solutions of the
ligands and the complexes were made using
methanol as solvents, 0.1 m1 of each
concentration was applied into the wells and
incubated at 370 C for one to three days.
The antibacterial activity was estimated on the
basis of the size of inhibition zone formed
around the well of the seeded agar plates and the
inhibition growth in percentage was determined
on the basis of the average diameter of bacterial
colony on the growth medium to their respective
controls as in the equation
% Inhibition = A – B x 100
A
11
Where A= Average diameter of bacterial growth
on the control and B= Average diameter of
bacterial growth on the test plate
Synthesis of Aspirin-metal complexes
The complexes were prepared by adding on
aqueous solution of the hydrated metal chloride
(0.01mol) to an ethanolic solution of the ligand,
Aspirin (3.604g, 0.02mol). The solution was
refluxed with constant stirring for 3 hours. The
complexes were recovered from their solutions
and followed by washing with ethanol and dried
in a desiccator.
Synthesis of Paracetamol- metal complexes
The preparation was similar to that of Aspirin
metal complexes. An aqueous solution of
hydrated metal chloride (0.01mol) in ethanol
(10ml) was added to an ethanolic solution of the
ligand, paracetamol 3.032g, 0.02mol) the
mixture was refluxed for 3 hours and left for
about three weeks before complexation. The
precipitated complex was removed by filtration
and washed with ethanol and dried in a
dessicator.
RESULTS AND DISCUSSION
The results of the analytical data, spectroscopic
and antibacterial studies are presented in Tables
1-5.
All the complexes were found to be stable. They
are non-hygroscopic solids with low melting
points. The molar conductance data for the metal
complexes in methanol show non-electrolytic
behavior in this solvent.
All the complexes synthesized were coloured.
The coloured complexes obtained for iron (III)
complexes (d5) were likely due to charge
transfer from ligand to metal and vice versa.
Table 1: Analytical data and some physical properties of the complexes
Compound Colour M.P (0C) Yield
% M
% Molar Conductance
-1g/dm3 Electronic Transition
(nm)
Aspirin(asp)
Co(Asp)2Cl2
Ni(Asp)2Cl2
Fe(Asp)2Cl3
Paracetamol
Co(Par)2C12
Ni(Par)2C12
Fe(Par)2C13
Whitish
Brown
White
Black
Whitish
Cream
Light Pint
Black
138-140
122-124
118-120
123-126
168-170
136-138
144-146
128-130
-
60.4
52.3
51.2
-
73.9
64.7.
54.3
-
12.10
(12.02)
10.98
(10.27)
9.30
(9.76)
-
12.14
(11.76)
13.59
(13.75
10.29
(10.24)
5.20x107
6.12x10-5
4.20x10-5
1.52x10-5
4.25x10-7
2.43x10-6
1.94x10-6
1.65x10-6
275,243
302,262,233
296,257,241
297,265,235
243
245,220212
248,218,210
238
Table 2: Selected IR spectral assignment of aspirin (asp) and its metal complexes
Aspirin (cm-1) Co(Asp)2C12 (cm-1) Ni (Asp)2C12 (cm-1) Fe(Asp)2C13 (cm-1) Tentative Assignment
3776.3m,b 3235.3w
3101.5w 3235.3 s,b
3101.5m 3764.2 s
3235w,b O-H str
1757.8 s
1675.6 v,s 1745.7m, b
1666.6 s,b
1745.7 m,b
1666.6 v,s
1754.7m
1666.6 s
C =O of ester
C =O of
Carboxylic acid
1374. 7 s
1308.0v .s 1301. 8 v.s
1247.2s 1247.2 v.s 1393 s,b
1295.9 v, s
C-O str of
Carboxylic acid
1095.2, b
1016.1 m, b 1156.0 v, s
1028.2 m 1156.Os 1156.0 s C-O str of ester
-
669.6 s 663.3 s, b 663.4 4s M-OH &
M-O =C
12
Table 3: Selected IR spectal assignment of pr/aracetamol (par) and its metal compexes
Paracetamol (Par) Co(Par)2C12 Ni(Par)2C12 Fe(Par)2C12 Tentaive Assignment
3785.2m,b
3694.9 w
3794.6w, b
3320.3 s
3162.3 w,b
3707.5 w,b
3758.2 b
3429.8 w,b
3320.3 m
3162.3 w
3782.4 m,b
3691.2 w,b
3630.4 w,b
O-H &
N-H str
1625 s, b 1612.0 s 1612.0 s 1617.9 m,b C=O str
- 693.8 s 681. 7 s,b - [M-OH] and
[M-O=C]
The selective infrared spectra assignment off
free Aspirin and its complexes are given in
Table 2. The assignments have been carried out
based on comparison of the spectra data with of
similar compounds6.
The absorption band at 3776.3cm-1 in the
spectrum of free Aspirin has been attributed to
O-H group. These bands undergo hypsochromic
shift to 3235.3cm-1 and 3101.5cm-1 in the metal
complexes. The shifting of these (O-H)
stretching vibrational band provide evidence that
this group is one of the coordination sites of
Aspirin. This is also supported by broad bands at
294.9cm 1, 852cm-1 and 803.3cm-1 attributed to
O-H bending6. The bands at 1460cm-1 and
1417.5cm-1 has been assigned to C=O of ester
and carboxylic acid respectively, these bands
13
also undergo hypsochromic shift in the spectra
of the complexes. The shifting of these (C=O)
stretching bands provides evidence that this
group is also one of the coordination sites of
Aspirin.
The strong absorption bands at 1374.7cm-1 and
1308cm-1 have been attributed to C-O stretching
vibration of the carboxylic acid while the
medium bands at 1095.2cm1- and 1016.1cm-1
and 1016.1cm-1 have been attributed to C-O
stretching vibration of the ester6.
The strong absorption bands between the ranges
of 651.3cm-1 on the spectra of the metal
complexes which could not be traced to free
Aspirin have been tentatively assigned to [M-
OH] and [M-O=C] stretch bands of the metal
complexes7.
The IR spectra assignment of Paracetamol (Par)
and its metal complexes are presented in Table
3.
The spectrum of free paracetamol was compared
with the spectral of its metal complexes. The
absorption bands at 3785.2cm-1 and 3694.9cm-1
of the free paracetamol have been assigned to O-
H and N-H stretching vibrations. These bands
have been shifted in the spectra of the metal
complexes due to coordination.
The strong absorption bands at 1625.0cm-1 in
the spectrum of free paracetamol has been
assigned to C=O stretching. These bands have
been shifted in the spectra of the metal that this
complexes. The shifting of C=O group provide
evidence of coordination through this group7.
The strong absorption bands at 693.8cm-1 and
681.7cm-1 in the spectra of the Co(Par)2C12 and
Ni (Par )2 C12 complexes which could not be
traced to free paracetamol have been tentatively
assigned to [M-O=C] and [M-OH] stretch bands
of the metal complexes7.
The H NMR signals of aspirin and it metal
complexes are presented in Table 4. The
multiplicity and integral values of the proton
signals support the structure of the ligand. The
assignment of the protons is supported by highly
reduced intensity of the proton signals after
deuterium exchange.
The Fe(Asp)2C13 complex was insoluble in
CDC13, therefore the signals obtained were
mainly the solvent peaks8.
By considering all the above analytical and
spectroscopic data and in the absence of X-ray
crystallographic data. The structures tentatively
proposed for the complexes are show in Figures
I and II.
OC
CH3
C
O
O
OH
C
O
OCO
CH3
OH
M
HN
HO
CH3
CH3
OH
HN
C
O
CO
M
Xn
Xn
Fig II: Proposed structure for M(Par)2Xn
M = CO(II), Ni(II), n = 2
M = Fe(III), n = 3
Fig I: Proposed structure for M(Asp)2Xn
The aspirin complexes, M(Asp)2Xn have
insignificant effect on serratia and E. coli
species at both concentrations (Table 5).
Co(Asp)2Cl2 have the greatest inhibitory effect
against Bacillus subtilis while Ni(Asp)2Cl2 have
the lowest inhibitory effect. At 1.0%
concentration, Aspirin metal complexes show
higher activity than the original aspirin.
The paracetamol complexes, M(Par)2Xn have
insignificant effect on serratia and Bacillus
subtilis species at both concentration.
Fe(Par)2Cl3 have the greatest inhibitory effect
against E. coli while Ni(Par)2Cl2 have the lowest
inhibitory effects at both concentration. The
14
Table 5: Result of antibacterial test
Compound Concentration Serratia
SP
Bacillus
SP
Escherichia
Coli
Asp
Co(Asp)2c12
Ni (Asp)2C12
Fe (Asp)2C13
0.1% - - -
- - -
- - -
- - -
0 0 0
50 51 50
32 32 34
45 47 48
- - -
- -
- -
- - -
Asp
Co(Asp)2C12
Ni(Asp)2C12
Fe(Asp)2C13
1.0% - - -
- - -
- - -
- - -
28 28 30
90 94 96
52 55 57
85 82 80
- -
- - -
- - -
- - -
Par
Co(Par)2C12
Ni(Par)2C12
Fe(Par)2C13
0.1% - - -
- - -
- - -
- - -
- - -
- - -
- - -
- - -
0 0 0
25 27 27
22 22 24
30 31 30
Par
Co(Par)2C12
Ni(Par)2C12
Fe(Par)2C13
1.0% - - -
- - -
- - -
- - -
- - -
- - -
- - -
- - -
18 20 18
55 58 60
50 52 55
60 62 64
paracetamol complexes also show higher
activity than the ligand9.
Acknowledgement
The authors are grateful to Rajrab
Pharmaceutical Company limited, Ilorin, Kwara
State, Nigeria for the supply of the ligands.
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