Rev. Med. Chir. Soc. Med. Nat., Iaşi – 2015 – vol. 119, no.

PHARMACY ORIGINAL PAPERS

ANTIINFLAMMATORY ACTIVITY OF AN N, N’-

DISALICYLIDENEMETHYLENDIAMINE-DERIVED SCHIFF BIS BASE
AND ITS COPPER(II) COMPLEX

Gladiola Ţântaru1, M. Nechifor 2, M. Apostu1*, Mădălina Vieriu 1, Alina Diana Panainte 1,

Nela Bibire 1
University of Medicine and Pharmacy “Grigore T. Popa” - Iași
Faculty of Pharmacy
1. Department of Analytical Chemistry
Faculty of Medicine
2. Department of Pharmacology
* Corresponding author. E-mail: mihai_apostu@yahoo.com

ANTIINFLAMMATORY ACTIVITY OF AN N, N’-DISALICYLIDENEMETHYLEN-

DIAMINE-DERIVED SCHIFF BIS BASE AND ITS COPPER(II) COMPLEX. (Abstract)
Aim: The cooper(II) complex combination of N, N’-disalicylidenemethylenediamine and the
Schiff bis base were investigated for anti-inflammatory activity. Material and methods: In
vivo, the anti-inflammatory activity of the metallic complex in comparison with the activity
of the Schiff bis base was tested by the method of Winter and co-workers using the Levy
technique. Results and discussions: Our study on the anti-inflammatory activity of a new
Schiff bis base and its complex cooper(II) combination showed that the Schiff bis bases e x-
hibited significant anti-inflammatory action in acute experimental inflammation when com-
pared to the control group. The copper cation from the complex combination enhanced the
anti-inflammatory effect of the Schiff bis base, the effect being stronger at doses of 10
mg/kg cooper(II) complex. Conclusions: The Schiff bis base and its cooper(II) complex had
an anti-inflammatory effect comparable to that of indomethacin. Keywords: COPPER,
SCHIFF BIS BASE, COMPLEX, ANTI-INFLAMMATORY ACTIVITY.

The Schiff bis base compounds repre-
sent an important class of ligands that have
been extensively studied in coordination
chemistry, mainly due to their simple syn-
thesis and easy tunable steric, electronic
and catalytic properties (1-6). The complex
combinations of Schiff bis bases with vari-
ous cations represent a class of compounds
with very important properties from a
chemical and biological point of view (7).
There have already been reported many
complex combinations of Schiff bis bases
with different cations that showed antimi-
crobial, anti-inflammatory and antioxidant
effect (8-11).
This paper describes the evaluation of
the anti-inflammatory action of a new
Schiff bis base derived from N,N’-
disalicylidenemethylendiamine and its
copper (II) complex that was previously
synthesized and characterized (10-11).
MATERIAL AND METHODS
For the study of the anti-inflammatory
activity of the Schiff bis base and its
cooper(II) complex (fig. 1) the following

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 Gladiola Ţântaru et al.
reagents were used: carrageenan kalium
salt, indomethacin and carboxymethyl cel-
lulose purchased from Merk - Germany.
The method used to test the inflammation
was edema experimentally induced through
carrageenan in rats (adult Wistar rats, male
of 180-200 g purchased from Cantacuzino
Institute - Bucharest).
CH2
HC N N CH
Cu
O O
Fig. 1. Structure of cooper(II) complex
combination
The evaluation of the anti-
inflammatory effect was performed using
the carrageenan-induced rat paw edema
assay (14, 15). For each substance we
used six groups of adult male Wistar rats,
180-200 g, bred in laboratory condition
and identically fed. Acute inflammatory
paw edema was induced by injecting 0.2
mL carrageenan 2% solution in the left
posterior paw of the rat. Paw volume was
determined before and after the test sub-
stance was administered and also after 1h,
2h, 4h, 6h, 8h or 24h. A control group of
six Wistar received an identical carragee-
nan injection in order to achieve acute
inflammatory paw edema, but no any oth-
er substance. Paw volume of the control
group was determined at the same inter-
vals as the test groups.
We used the following groups of rats:
Group I was the control group, group II
received indomethacin sodium salts 10
mg/kg i.p., group III received 10 mg/Kg of
Schiff bis base, group IV received 10mg/kg
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cooper(II) complex and group V received 5
mg/Kg cooper(II) complex. The anti-
inflammatory activity was evaluated as the
variation of inflammation volume (tenths
of mL). The average sum and standard
deviation of that parameter were calculated
for every group of rats and then they were
compared to those of the control group.
The obtained data were statistically ana-
lyzed using ANOVA one way test.
In vivo, the anti-inflammatory activity
of the cooper(II) complex in comparison
with that of the Schiff bis base was tested
using 2% (w/v) carrageenan potassium salt
solutions and 2% (w/v) indomethacin in
0.1% sodium carboxymethyl cellulose solu-
tion. The stock solutions of the complex
and ligand were prepared in concentrations
of 0.1% (w/v) in methanol.
RESULTS AND DISCUSSION
Several studies proved that Schiff bis
bases and their complexes with various
cations (Cu(II), Mg(II), Ni(II), Co(II) etc.)
reduce the synthesis of some chemical
mediators of acute inflammation such as
leukotrienes which are involved in the
formation of free radicals (9, 12, 13).
The data showed that the anti-
inflammatory effect of the Schiff bis base
(10 mg/kg) was statistically significant
compared to the control group, after 4h
(P<0.05). The effect increases at 6h and 8h,
respectively (P<0.001) (tab. I).
The cooper(II) complex presented anti-
inflammatory activity compared with con-
trol group, the effect being significantly
stronger at a dose of 10 mg/kg, beginning
with 4h (P<0.001). The cooper(II) complex
at a dose of 5 mg/kg also presented strong
anti-inflammatory effect at 4h, 6h and 8h
(P<0.001), compared with the Schiff bis
base (10 mg/kg).
 Antiinflammatory activity of an N, N’-disalicylidenemethylendiamine-derived Schiff bis base
and its copper(ii) complex

TABLE I
Influence of the Schiff bis base (10mg/kg) and cooper(II) complex (10mg/kg and
5mg/kg) on carrageenan-induced inflammatory edema in rats (mean edema volume
variation (tenths of mL) ± SD)
3 0 1h 2h 4h 6h 8h 24h

Control 18.17± 1.02 27.83± 0.62 30.17± 0.32 35.17± 1.06 38.83± 2.36 38.5± 1.80 23.67± 1.18
Indome-
thacin 22.3±4.05 25.3±2.71 26.9±2.04 25.02±3.21 24.8±2.25 25.32±3.61 24.55±2.77
10mg/kg
Schiff bis
30.83 ± 0.63 31.00 ± 3.20 29.83 ± 3.62 20.83 ± 0.86
base 18.50 ± 0.62 26.33 ± 1.42 28.33 ± 0.80
* P<0.05 * P<0.001 * P<0.001 * P<0.01
10mg/Kg
cooper(II) 27.17 ± 3.76 22.67 ± 7.14 21.5 ± 7.54 21.33 ± 1.56
complex 19.67± 1.18 28.67± 0.86 31.83 ± 1.72 * P<0.001 * P<0.001 * P<0.001 * P<0.001
10 mg/Kg ** P<0.001 ** P<0.001 ** P<0.001 ** P<0.05
cooper(II) 32.50 ± 0.95 31.33 ± 7.78 30.67 ± 9.96 22.50 ± 0.08
complex 18.83 ± 0.78 25.83 ± 0.47 26.50 ± 0.80 * NS * P< 0.05 * P< 0.001 * NS
5 mg/Kg ** NS ** NS ** NS ** NS
* P values compared with control group
** P values compared with the group receiving Schiff bis base

CONCLUSIONS The copper ions enhanced the anti-

Our study on the anti-inflammatory ac-
tivity of a new Schiff bis base and of its
cooper(II) complex combination showed
that the Schiff bis base exhibited signifi-
cant anti-inflammatory action in acute
experimental inflammation when compared
to the control group.
inflammatory effect of the Schiff bis base
in its complex combination, the effect be-
ing stronger at doses of 10 mg/kg
cooper(II) complex.
The Schiff bis bases and its cooper(II)
complex had an anti-inflammatory effect
comparable to that of indomethacin.

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NOUTĂȚI
NEWS

INFLAMMATION AND HEART DISEASES: ROLE OF TOLL-LIKE

RECEPTOR SIGNALING

Myocardial inflammation is a common theme of a group of diseases that include severe sep-
sis, ischemic myocardial injury and acute myocarditis, and contributes to their pathogenesis.
Under these critical conditions, foreign pathogens (e.g., bacteria or virus) or endogenous
danger molecules (e.g., heat shock proteins [HSPs] or RNA) released from injured tissues
induce local and systemic innate immune responses that lead to myocardial inflammation.
Such innate immune responses could be both detrimental and beneficial in nature. Toll -like
receptors (TLRs) are a critical part of human innate immune system. TLRs recognize path o-
gens via pathogen-associated molecular pattern (PAMP) (1) and endogenous danger mole-
cules via danger-associated molecular pattern (DAMP) (2). TLRs also contribute to the d e-
velopment of inflammation in atherosclerosis that leads to myocardial ischemic injury and
acute coronary syndromes. By mediating the complex cardiac inflammatory signaling, either
beneficial or deleterious in nature, TLRs play a pivotal role in the development of t hese car-
diac diseases. Several important future directions should be considered. While numerous
studies have indicated the contributory role of TLRs in the development of septic cardiom y-
opathy, ischemic myocardial injury and myocarditis, there are many unanswered questions
(including TLRs involvement in polymicrobial sepsis) that are critical for our ultimate u n-
derstanding of the role of TLR signaling (Wei Chao. Inflammation and heart diseases: role
of toll- like receptor signaling. J Anesth Perioper Med 2014; 1: 104-17).

Doina Butcovan

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