Transition metal complexes of s-triazine derivative: New class of anticonvulsant, anti-inflammatory, and neuroprotective agents

Article abstract of DOI:10.1007/s00044-013-0634-0

A new series of transition metal complexes of 2,4-bis(indolin-3-one-2- ylimino)-6-phenyl-1,3,5-triazine) (BIPTZ) have been synthesized. The structural features of BIPTZ and metal(II) complexes were investigated using elemental analyses, magnetic susceptibility, molar conductance, mass, IR, UV-Vis, ¹H NMR, ¹³C NMR, CV, and ESR spectral studies. Electronic absorption spectra and magnetic susceptibility measurements of the complexes predict their geometry. The redox behavior of the copper(II) complexes has been studied by cyclic voltammetry. All the synthesized compounds may serve as potential photoactive materials as indicated from their characteristic fluorescence spectrum. The Schiff base and its metal complexes were screened for anticonvulsant and anti-inflammatory activities in vivo. The metal(II) complexes are potent agents in treating neurochemical and behavioral abnormalities seen in Parkinson's diseased (PD) mice than free ligand.

Full text of DOI:10.1007/s00044-013-0634-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0634-0
ORIGINAL RESEARCH
Transition metal complexes of s-triazine derivative: new class
of anticonvulsant, anti-inflammatory, and neuroprotective agents
•
•
•
R. Shanmugakala P. Tharmaraj C. D. Sheela
N. Chidambaranathan
Received: 23 January 2013 / Accepted: 20 May 2013
Ó Springer Science+Business Media New York 2013
Abstract A new series of transition metal complexes of
2,4-bis(indolin-3-one-2-ylimino)-6-phenyl-1,3,5-triazine)
(BIPTZ) have been synthesized. The structural features of
BIPTZ and metal(II) complexes were investigated using
elemental analyses, magnetic susceptibility, molar con-
ductance, mass, IR, UV–Vis, 1H NMR, 13C NMR, CV, and
ESR spectral studies. Electronic absorption spectra and
magnetic susceptibility measurements of the complexes
predict their geometry. The redox behavior of the cop-
per(II) complexes has been studied by cyclic voltammetry.
All the synthesized compounds may serve as potential
photoactive materials as indicated from their characteristic
fluorescence spectrum. The Schiff base and its metal
complexes were screened for anticonvulsant and anti-
inflammatory activities in vivo. The metal(II) complexes
are potent agents in treating neurochemical and behavioral
abnormalities seen in Parkinson’s diseased (PD) mice than
free ligand.
Introduction
Medicinal inorganic chemistry is arousing a significant
interest in the design of metal complexes as potential diag-
nostic and therapeutic agents (Cerchiaro and Ferreira, 2006).
A comprehensive list of metal complexes which are already
in use, encourage further studies for new metallodrugs such
as metal-mediated antibiotics, antibacterial, antiviral, and
anticancer compounds. While possessing a unique charac-
teristic esteem in the heterocyclic compounds due to its wide
range of therapeutic activities, s-triazine exhibits a seminal
value in antibacterial (Chohan et al., 2004), antiviral
(Davidson and Boyki, 1978), anti-HIV, and anti-inflamma-
tory activities (Hielman et al., 1980; Sun et al., 2011).
Recently, triazine derivatives have been disclosed as a
potent inhibitor of tyrosine kinase and have demonstrated
antiangiogenic property in vivo (Baindur et al., 2005). A
large number of structurally novel triazine derivatives have
been reported to be a suitable lead compound for the possible
development of new antitumor agents, (Chohan et al., 2010).
Several triazine derivatives are well known in the context of
anticancer drugs (Porter et al., 2002), estrogen receptor
modulators (Henke et al., 2002), inhibitors of sorbitol
dehydrogenase (Mylari et al., 2003), anti-trypanosomal
agent (Klenke et al., 2001), antitrypanosomal drugs, and
antimalarial agents (Katiyar et al., 2005). For instance,
carbamazepine and lamotrigine which are currently used
anticonvulsant drugs contain a triazine ring in their struc-
tures. In harmony with the aforementioned study, we herein
report the synthesis and characterization of Schiff base
derived from condensation of 2,4-diamino-6-phenyl-1,3,5-
triazine and indoline-2,3-dione and its metal complexes.
Furthermore, the synthesized compounds were evaluated for
anticonvulsant activity, anti-inflammatory activity, and
neuroprotectivity on albino mice.
Keywords s-Triazine ꢀ Metal complexes ꢀ
Anticonvulsant ꢀ Anti-inflammatory ꢀ Neuroprotectivity
R. Shanmugakala
Department of Chemistry, C.R. Engineering College,
Madurai, India
P. Tharmaraj (&)
Department of Chemistry, Thiagarajar College, Madurai, India
e-mail: sheelatharmaraj@gmail.com
C. D. Sheela
Department of Chemistry, The American College,
Madurai, India
N. Chidambaranathan
Department of Pharmacology, K.M. College of Pharmacy,
Madurai, India
123

Med Chem Res
Materials and methods
infrared (IR) spectra of Schiff base and its metal(II) com-
plexes were recorded on a Jasco FT-IR spectrophotometer
in KBr disks. 1H NMR spectra of the Schiff base was
recorded in DMSO-d6 on Bruker 300 MHz spectrometer at
room temperature using TMS as an internal reference. 13C
NMR spectrum of the Schiff base was recorded in DMSO-
d6 at room temperature. EI-mass spectrum of the Schiff
base was performed on JEOL-CGC MATE-2 instrument.
Cyclic voltammetry measurements of Cu(II) complexes
were carried out at room temperature in DMSO under N2
atmosphere on BAS-50 voltammograph using a three-
electrode cell containing a reference Ag/AgCl electrode, Pt
wire auxiliary electrode, and glassy carbon working elec-
trode in DMSO with tetrabutylammonium perchlorate
(TBAP) as supporting electrolyte. The electronic absorp-
tion spectra of the complexes were recorded in DMSO on
Materials
All the chemicals used were of reagent grade and used
without further purification.
2,4-Bis(2,4-bis(indolin-3-one-2-ylimino)-6-phenyl-1,3,5-
triazine (BIPTZ)
This compound was prepared by refluxing a mixture of 2,4-
diamino-6-phenyl-1,3,5-triazine (0.01 mol) and indoline-
2,3-dione (0.02 mol) in ethanol for a period of 6 h. The
reaction was monitored by TLC and the resulting solution
was slowly evaporated. The product was obtained as a
reddish brown crystal. Yield: 75 %. m.p.: 185–187 °C. IR
(KBr, cm-1): 1616, 1458 and 3190. H NMR (DMSO-d6
a JASCO V-530 spectrophotometer in the region
1
300 MHz) (ppm): 9.607 (s, 2H, NH), 5.7–7.06 (m, 13H,
Ar–H). 13C NMR (DMSO-d6) (ppm): 117.38–143.24
(aromatic carbon), 155.57 (C=N of triazine ring), 164.42
(C=O), 167.50–172.18 (isatin ring carbon). EI-mass: m/z
445. Analysis Found. C, 67.45; H, 3.33; N, 22.07 %. The
synthesis of BIPTZ is shown in Fig. 1.
200–1100 nm. Fluorescence spectra were recorded on
ELICO SL-174 spectrofluorometer. The ESR spectra of
Cu(II) complexes were recorded in solid state at 300 and
77 K on JEOL 100 ESR spectrometer using DPPH as ‘‘g’’
marker. Magnetic susceptibility of the complexes was
obtained on a Sherwood Magnetic susceptibility balance
Mk1 at room temperature. Effective magnetic moments
Preparation of metal(II) complexes
were calculated using the formula leff = 2.28 (vM T)1/2
where vM is the corrected molar susceptibility. Molar
An ethanolic solution of metal(II) chloride (MCl2, conductivity measurements of the complexes were recor-
,
M=Cu(II), Ni(II), Co(II)) was stirred under reflux with hot
ethanolic solution of the Schiff base in 1:1 and 1:2 M ratios
for 4 h. During refluxation, the metal chelates were sepa-
rated out. The metal chelates thus separated were filtered,
ded on Systronics conductivity bridge type (OSWAL) in
DMSO (10-3 M) at room temperature. The synthesized
Schiff base and its metal complexes were screened for
anticonvulsant, anti-inflammatory, and neuroprotective
washed with ethanol, and dried over CaCl2 in vacuum. All activity in K.M. College of Pharmacy, Madurai.
the complexes obtained are colored and are listed in
Table 1.
Pharmacology
Characterization
Schiff base (BIPTZ) and its metal(II) complexes were
evaluated for in vivo anticonvulsant, anti-inflammatory,
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), neu- and neuroprotective activities. Maximal electroshock
rotoxin was obtained from Sigma Chemicals & Co. All
other chemicals and solvents were purchased from Aldrich
Chemicals & Co. and the solvents were distilled before use
as per the standard procedure. The elemental analyses were
done at Central Drug Research Institute, Lucknow. The
method was used for establishing anticonvulsant activity,
and carrageenan-induced rat paw edema method was used
for evaluating anti-inflammatory activity. Behavioral
parameter, antioxidants like lipid peroxidation, reduced
glutathione and superoxide dismutase, and oxidative stress
Fig. 1 Synthesis of BIPTZ
O
N
N
Ethanol
N
N
+
HN
2
O
NH
N
N
N
Reflux
6 hrs
N
H
H2N
N
NH2
O
O
2,4-diamino-6-phenyl triazine
BIPTZ
Indoline-2,3-dione
123

Med Chem Res
Table 1 Elemental analysis, molar conductance, and magnetic moment measurements
Compound Empirical formula
Color
C % found
(calc)
H % found
(calc)
N % found
(calc)
M % found
(calc)
K Ohm-1
leff
(BM)
cm2mol-1
BIPTZ
(1)
C25H15N7O2
Red
67.45 (67.41) 3.33 (3.37)
51.85 (51.81) 2.53 (2.59)
51.95 (51.99) 2.54 (2.59)
52.13 (52.17) 2.65 (2.60)
58.56 (58.59) 2.96 (2.92)
22.07 (22.02)
–
–
–
[Cu(C25H15N7O2)Cl2] Brown
[Ni(C25H15N7O2)Cl2] Green
[Co(C25H15N7O2)Cl2] Violet
16.90 (16.92) 10.95 (10.92) 10.5
16.90 (16.98) 11.16 (10.57) 5.3
17.09 (17.04) 10.23 (10.26) 8.6
1.94
3.04
4.96
1.82
(2)
(3)
(4)
[Cu(C25H15N7O2)2]Cl2 Dark
blue
19.17 (19.14) 6.24 (6.20)
160
(5)
(6)
[Ni(C25H15N7O2)2]Cl2 Brown
58.70 (58.70) 2.95 (2.93)
58.85 (58.82) 2.93 (2.94)
19.19 (19.17) 5.93 (5.96)
19.24 (19.21) 5.72 5.78)
156
201
2.95
4.75
[Co(C25H15N7O2)2]Cl2 Dark
violet
Fig. 2 Proposed structure of
metal(II) complexes
2+
N
N
HN
NH
N
N
N
O
O
O
O
M
2Cl-
N
N
N
HN
NH
N
N
N
N
HN
NH
N
N
N
O
M
O
Cl
Cl
(1), (2), (3)
(4), (5), (6)
parameters such as nitrite level and myeloperoxidase level
were also measured on albino mice.
stimuli. The time needed for the development of
unequivocal sustained clonic seizure activity involving the
limbs was carefully noted. The onset of a general clonus
was used as the end point. The general clonus was char-
acterized by forelimb clonus followed by full clonus of the
body. The duration of clonic convulsions was also noted.
Seizure-free interval in 1 h was considered as protection.
The number of animals protected in each group was
recorded and percentage protection was calculated.
Anticonvulsant activity
The anticonvulsant activity was studied by Supra maximal
electrical shock method. Healthy male albino wistar mice
weighing from 200–250 g were selected and housed in
separate cages with 12/12 h light/dark cycle at 21 ? 2 °C
and fed with balanced diet, water ad libitum. The animals
were divided into nine groups of six each. The first groups
of animals were served as control, received 10 ml/kg
normal saline. Second group served as standard which
received 25 mg/kg phenytoin sodium. The Schiff base
(BIPTZ) and its metal complexes (1-6) (10 mg/kg) were
administered by IP injection to rest of the seven groups.
The evaluation was started 30 min after administration of
the synthesized compounds and Pinna electrodes with the
intensity of 150 mA current were used to deliver the
Anti-inflammatory activity
The anti-inflammatory activity was studied by carra-
geenan-induced rat paw edema method. Albino mice of
either sex (200-220 g) were selected and kept in animal
house under standard laboratory conditions. The animals
were divided into nine groups of six animals each. Group I
served as control and received 10 ml/kg normal saline.
Group II served as standard and received Diclofenac
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Med Chem Res
Lipid peroxidation
sodium (10 mg/kg) through IP route and the remaining
seven groups served as test groups and received Schiff base
(BIPTZ) and metal(II) complexes (1-6) (10 mg/kg) 30 min
prior to carrageenan injection. The initial left hind paw
volume of the rats was measured using a digital plethys-
mometer. The volume of the left hind paw of the test group,
standard, and control groups were measured at 60, 240, and
360 min after carrageenan injection. Mean increase in paw
volume was measured and percentage of inhibition was
calculated.
MDA level was measured according to the standard
method at room temperature. 200 ll of supernatant was
added to 50 ll of 8.1 % sodium dodecyl sulfate, vortexed,
and incubated for 10 min at room temperature. 375 ll of
thiobarbituric acid (0.6 %) was added and placed in a
boiling water bath for 60 min and then the sample was
allowed to cool to room temperature. A mixture of 1.25 ml
of butanol: pyridine (1.5:1) was added, vortexed, and
centrifuged at 1000 rpm for 5 min. The colored layer
(500 ll) was measured at 532 nm on a ELICO 171 Spec-
trophotometer and the values were expressed in mmoles of
MDA formed per mg protein/min (Ohkawa et al., 1979).
Neuroprotective activity
Male wistar mice weighing from 250–280 g were selected
and kept in animal house under standard laboratory con-
ditions at 25 20 C with light–dark cycles of 12 h. The
animals were acclimatized to laboratory conditions before
the experiment starts. The animals had free access to pellet
diet and water ad libitum. The animals were divided into
nine groups, each consisting of six mice. Group I served as
vehicle control and received equivalent volume of vehicle
of drug for 12 days, Group II received equivalent volume
of vehicle of drugs for 7 days and on 7th day received
intrastriatal injection of MPTP (32 lmol in 2 ll) and
vehicle for further 5 days. Group III–IX received the syn-
thesized Schiff base (BIPTZ) and its metal complexes
(1–6), respectively, for 7 days and on 7th day received
intrastriatal injection of MPTP (32 lmol in 2 ll) and again
treatment for 5 days. At the end of experimental period, the
animals were fasted overnight and sacrificed by cervical
decapitation. The brains were excised immediately and the
brain tissue was homogenized in ice-cold butanol solution
and used for further analysis.
Reduced glutathione
Reduced glutathione levels were measured according to the
standard procedure (Ellman, 1959) at room temperature.
0.75 ml of supernatant was mixed with 0.75 ml of 4 %
sulfosalicylic acid and then centrifuged at 1,200 rpm for
5 min at 4 °C, from this 0.5 ml of supernatant was taken and
added to 4.5 ml of 0.01 M 5,5-dithiobis-(2-nitrobenzoic
acid) (DTNB) and absorbance was measured at 412 nm by
using a ELICO 171 UV–Vis Spectrophotometer.
Statistical analysis
All experimental results are expressed as mean SEM.
Behavioral parameters were analyzed using one-way ANOVA
followed by Newman’s keul’s multiple range tests. The crite-
rion for statistical significance was considered as P\0.01.
Results and discussion
Locomotor activity
All the complexes are colored, stable, and hygroscopic in
nature. The complexes are insoluble in common organic
solvents but soluble in DMF and DMSO. The elemental
analyses (Table 1) support that the Schiff base forms metal
complexes of the type [MLCl2] and [ML2] Cl2. The
geometry of the metal complexes was elucidated using
spectral studies. The proposed structure of the metal
complexes is shown in Fig. 2.
The locomotor activity was measured using Actophotom-
eter. It consists of cage which has 30 9 30 9 30 cm, and
at the bottom six lights and six photocells were placed in
the outer periphery of the bottom in such a way that a
single mouse blocks only one beam. Photocell is activated
when the rays of light falls on photocells. The beam of light
is interrupted as and when animal crosses the light beam,
number of cut interruptions was recorded for 10 min.
Molar conductance measurements
Antioxidant studies
The molar conductivity measurement of metal(II) com-
plexes of [ML] type (1–3) indicates the non-ionic nature of
these complexes (5.3–10.5 X-1cm-1mol-1) and hence they
are considered as non-electrolytes (Sharaby, 2007). Metal
complexes of [ML2] type (4–6) were found to have molar
conductance values in the range of 156–201 X-1cm-1mol-1
Brain tissue was homogenized in 50 mmol phosphate
buffer (pH 7.0) containing 0.1 mmol of ethylenediamine
tetraacetic acid (EDTA) to give 5 % (w/v) homogenate.
The homogenate was centrifuged at 10,000 rpm for 10 min
at 0 °C in cold centrifuge and the resulting supernatant was
used for further studies.
123

Med Chem Res
2
2
2
suggesting their ionic nature and that of the type 1:2 elec-
trolytes (Geary, 1971).
to 2B1 ? A1 (m1), 2B1 ? B2 (m2), and 2B1 ? E (m3)
transitions, respectively; which are characteristic of square
pyramidal geometry. The magnetic moment of (1) is found
to be 1.94 BM, which is interpreted as suggestive of a five-
coordinate square pyramidal geometry around copper(II)
ion (Yamada et al., 2002; Acuria Cueva et al., 2003). The
nickel(II) complex (2) exhibits three d–d bands at 9,756;
14,619; and 20,661 cm-1 and these bands may be tenta-
Infrared spectra
The important infrared spectral data of the Schiff base and its
metal complexes are listed in Table 2. The IR spectra of the
Schiff base exhibited a characteristic high intensity band at
1616 cm-1, assigned to m(C=N). In comparison with the
spectra of the Schiff base, all the complexes exhibited the
band of m(C=N) in the region of 1654–1681 cm-1 indicating
that the ketimine nitrogen atom is coordinated to the metal
ion (Murukan et al., 2007). A characteristic strong band
observed around 1728 cm-1 ascribedto m(C=O)of isatin was
observed at similar positions in the spectra of metal com-
plexes, suggesting the noninvolvement of carbonyl oxygen
in coordination (Akinchan et al., 2002). The Schiff base
exhibits a strong band at 1458 cm-1 which is attributed to
m(C=N) group in s-triazine. This band is shifted to lower
frequency of 1404–1419 cm-1 upon complexation which
indicates that (C=N) of triazine ring is one of the coordi-
nating atoms in the ligand (Solankee and Thakor, 2006). The
band at 3190 cm-1 assigned for m(NH) group was almost
unchanged in the metal complexes, suggesting that this
group is not participating in coordination (Bhusan subudhi
et al., 2007). New bands are found in the spectra of metal
complexes in the region 428–464 cm-1 assigned to m(M–N)
(Kulkarni et al., 2011). Proof of chloride coordination in 1:1
metal complexes is demonstrated by new bands at
328–345 cm-1 assigned to m(M–Cl) (Tharmaraj et al., 2009).
Therefore, from the IR spectra, it is concluded that the Schiff
base behaves as a neutral tridentate coordinating to the metal
ion via the triazine ring nitrogen and ketimine nitrogen.
3
3
3
3
tively assigned to B1(F) ? E(F), B1(F) ? A2(P), and
3
3B1(F) ? E(P) transitions, respectively, suggesting
square pyramidal geometry. The spectra resemble those
spectra reported for five-coordinate square pyramidal
nickel(II) complexes (Khalil, 2003; Yang et al., 2009). The
electronic absorption spectrum of (3) displayed three bands
at 10,050; 15,432; and 20,703 cm-1 which can be assigned
to the transitions 4A2 ? E ? B1, 4A2 ? E ? E(P),
4
4
4
4
4
4
4
and A2 ? E ? A2(P), respectively, which are charac-
teristic of square pyramidal geometry. Thus the electronic
spectral data of (3) are in good agreement with the already
reported square pyramidal complexes (Gupta and Chandra,
2006). The metal complexes (2) and (3) have magnetic
moment values 3.04 and 4.96 BM, respectively, which
further confirms the square pyramidal geometry (Dahl,
1969).
The electronic spectrum of (4) gives two bands at 17,543
and 21,739 cm-1 which are assignable to ligand-to-metal
charge transfer and intra-ligand charge transfer, respectively.
A broad band at 11,061 cm-1 is characteristic of d–d transi-
tion due to 2Eg ? T2g transition (Ram Agarwal et al., 2006).
2
This band strongly favors an octahedral geometry and the
same is further supported by the magnetic moment 1.82 BM
(Thakurta et al., 2009; Hazell et al., 2000). The d9 configu-
ration makes Cu(II) ion susceptible to John–Teller distortion.
As a result, the above complex is found to be tetragonally
distorted which can give rise to three types of electronic
transitions. These may not be resolved into three bands due to
the fact that d orbitals lie closer to each other. The nickel(II)
complex (5) exhibits three d–d bands at 9,881; 12,738; and
NMR spectra
The 1H NMR spectrum of the Schiff base under study
showed the characteristic resonance at 9.6 ppm due to –NH
proton of isatin ring. The sharp multiplet signals of the
phenyl protons are found in the region 5.7–7.06 ppm. 13C
NMR spectrum of Shciff base exhibits singlet at 155 ppm
which is attributed to three equivalent carbon of triazine
ring and aromatic carbons observed in the region
117–172 ppm. The equivalency of C2, C4, and C6 indicates
the symmetric nature of the ligand. Carbonyl carbon is
observed at 164 ppm and isatin ring carbons are observed
in the region 167–172 ppm. Figs. 3, 4, 5.
21,645 cm-1 which are tentatively assigned to 3A2g ? T2g,
3
3A2g ? T1g(F),
and
3A2g ? T1g(P)
transitions,
3
3
Table 2 Important IR frequencies of Schiff base and metal(II)
complexes
Compound m(C=N) ketimine m(C=N) triazine m(NH) m(M–N)
BIPTZ
(1)
1616
1681
1681
1678
1662
1666
1654
1458
1412
1419
1419
1404
1415
1412
3190
3296
3213
3271
3282
3262
3225
–
435
453
464
428
445
438
(2)
Electronic absorption spectral studies and magnetic
susceptibility
(3)
(4)
(5)
The electronic spectrum of copper(II) complex (1) shows
three bands at 10,964; 14,792; and 17,094 cm-1 assignable
(6)
123

Med Chem Res
Fig. 3 EI-mass spectrum of Schiff base
Fig. 4 1H NMR spectrum of
Schiff base
respectively, which arises from octahedral geometry (Chan-
dra et al., 2009). The measured magnetic moment value is
found to be 2.95 BM; this also supports the octahedral
geometry (Emaraa and Abou-Hussen, 2006). The electronic
spectrum of Co(II) complex (6) consists of three absorption
bands at 9,980; 12,437; and 21,186 cm-1 which may be
4.75BM which is an indicative of octahedral geometry (Singh
et al., 2006).
ESR spectral studies
The ESR spectra of Cu(II) complexes (1) and (4) were
recorded in solid state at 300 and 77 K, and the spin
Hamiltonian parameters are listed in Table 3. The ESR
spectrum of (1) exhibits anisotropic signals with
g = 2.227 and g\ = 2.042. The g and g\ values are
4
4
4
4
assigned to T1g(F) ? T2g(F), T1g(F) ? A2g, and
4
4T1g(F) ? T1g(P) transitions, respectively, suggesting that
there is an octahedral geometry around Co(II) ion (Omar and
Mohamed, 2005). The magnetic moment value is found to be
k
k
123

Med Chem Res
Fig. 5 13C NMR spectrum of Schiff base
closer to 2 and g [ g\, suggesting an axially elongated
(Kasumov and Koksal, 2004). The observed value of G is
2.83, characteristic of mononuclear configuration which
also suggests that the exchange coupling is present and
misalignment is appreciable. The a2 value (0.713) pointed
out appreciable in-plane covalency. The calculated value of
g /A (170.3 cm) reveals slightly distorted structure. The
k
square pyramidal geometry (Ray and Kauffman, 1990).
The covalent character of metal–ligand bond is inferred
from the giso value 2.10. The trend, g [ g\ [ ge (2.0023)
k
shows that the unpaired electron lies predominantly in the
dx2–y2 orbital of the copper(II) ion (Gudasi et al., 2006).
The calculated magnetic moment for the copper(II) com-
plex (1.96 BM) as per the relation l2 = 3/4 [g]2 is indic-
ative of an unpaired electron. The a2 value (0.74)
suggestive of in-plane covalency and the poor in-plane
p-bonding in the complex is reflected in their b2 values.
The molecular orbital coefficients a2and b2 were calculated
using the following equations.
k
k
orbital reduction factors such as K and K\ are estimated
k
from the equation K = (g –2.0023) DE/8k, K\
=
k
k
(g\–2.0023) DE/2k and K (0.43) [ K\ (0.15) show poor
k
in-plane p-bonding which is also reflected in b2 values.
Electrochemical behavior
ꢀ
ꢁ
Cyclicvoltammetry is a highly versatile electro-analytical
technique. In recent years, it has become the most popular
technique for studying electrochemical reactions. The
cyclicvoltammogram of Schiff base (BIPTZ) in nitrogen
atmosphere does not show any oxidation or reduction peak.
Controlled potential electrolysis of the copper(II) complex (1)
(Fig. 6a) exhibits well-defined irreversible redox peak corre-
sponding to the formation of CuII ? CuIII with anodic peak at
46.38 mV (Epa), followed by the respective cathodic waves in
the reversible scan at -400 mV (Epc) due to CuIII ? CuII
reduction. The ratio of cathodic to anodic peak currents
a2 ¼ Ajj=p þ gjj ꢁ 2:0023 þ 3=7ðg? ꢁ 2:0023Þ þ 0:04
b2 ¼ gjj ꢁ 2:0023 E =8ka2
ꢀ
ꢁ
The calculated value of g /A is 138.7 cm characteristic
k
of distorted structure. The geometric parameter G is esti-
k
mated from the expression G = (g –2.0023)/(g\–2.0023).
k
The observed value G for the Cu(II) complex is 5.65
suggesting no appreciable coupling (Fouda et al., 2008).
The observed g , g\, and A values for copper(II)
k
k
complex (4) are characteristic of octahedral geometry
123

Med Chem Res
Table 3 ESR spectral data of copper(II) complexes
Complex
g
g\
giso
a2
b2
A X10-4 cm-1
A\X10-4 cm-1
g /A cm
k k
G
k
k
(1)
(4)
2.227
2.265
2.042
2.095
2.10
2.15
0.740
0.713
0.783
1.206
160.5
133.7
112.3
69.5
138.7
170.3
5.65
2.83
Fig. 6 Cyclicvoltammogram of
Cu(II) complexes (1) and (4)
Ipc/Ipa = 1.075corresponds to one-electronprocess. Thepeak
separation between Epa and Epc is 446.38 mV, larger than the
value required for a reversible process (59 mV), which indi-
cates that the electron transfer process is irreversible in nature
(Kannappan et al., 2003). The cyclicvoltammogram of Cu(II)
complex (4) displays one reduction peak at (Epc) -300 mV
with a corresponding anodic peak at (Epa) 4.67 mV (Fig. 6b).
The peak separation DEp = 304.67 mV, which indicates that
the reduction process is irreversible in nature and the ratio
of cathodic to anodic peak currents corresponding to the
chemical change occurs with one-electron transfer as
Cu(II) ? Cu(III) ? Cu(II).
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Med Chem Res
Fluorescence studies
Table 4 Fluorescence data of Schiff base and metal(II) complexes
Compound Excitation wavelength
kmax (nm)
Fluorescence wavelength
kmax (nm)
The fluorescence studies are carried out for Schiff base and
its metal complexes in DMSO. The spectral data are listed
in Table 4 and the overlapping spectrum of the Schiff base
and its metal complexes are presented in Fig. 7. The Schiff
base exhibits a broad emission band with a maximum
wavelength of 560 nm upon photo excitation at 550 nm.
Similarly, all the above complexes were characterized by
the emission bands around 458–575 nm. Significant dif-
ferences in positions of emission maximum of Schiff base
and its complexes establish the complexation process
(Majumder et al., 2006). The excitation and emission
spectra of metal complexes in DMSO at room temperature
are similar and these excitation wavelength match the
absorption spectra of the corresponding metal complexes.
The most increased fluorescence intensity of Schiff base
was observed in cobalt(II) complex (3). The maximum
emission of the nickel(II) complex (2) was observed when
the complex was excited at 558 nm, suggesting that ligand-
to-Ni(II) complex energy transfer is mainly mediated by
the Schiff base. The strong emissions of metal complexes
indicate that the Schiff base is a good chelating agent to
absorb and transfer energy to metal(II) ions. The efficient
energy transfer from Schiff base to metal ion is one of the
key factor to achieve characteristic fluorescence. Among
the six metal complexes, the excitation and emission
intensities of Ni(II) complex (2) are relatively weak and the
fluorescence intensity of Co(II) complex (3) is the strongest
among the complexes. This enhancement of fluorescence
through complexation is of much interest as it opens up the
opportunity for photochemical applications of these
complexes.
BIPTZ
(1)
550
446
558
476
458
445
469
561
458
575
483
469
459
471
(2)
(3)
(4)
(5)
(6)
Fig. 7 Fluorescence spectrum of metal(II) complexes
Pharmacological study
duration when compared to Schiff base. Such increased
activity of the metal complexes is of tremendous impor-
tance in pharmaceutical field. Procedures employed for
evaluation of anticonvulsant and anti-inflammatory activity
were reviewed and approved by the Institutional Animal
Ethical Committee (IAEC).
Anticonvulsant activity
Anticonvulsant activity data of the Schiff base and its metal
complexes are presented in Table 5 and the graphical
representation is shown in Fig. 8. The results were statis-
tically analyzed by one-way ANOVA followed by New-
man keul’s multiple range tests and expressed as
mean SEM (Poojary et al., 2012). The satisfactory
results of the Schiff base and its metal(II) complexes are
quite long and comparable to phenytoin which is used as
the standard anticonvulsant drug. It has been reported that
the existence of a hydrophobic unit, an electron donor
group, and hydrogen bonding domain are essential for
anticonvulsant activity. As evidenced by the active drugs,
such as carbamazepine and lamotrigine, the synthesized
Schiff base fulfills these demands. All the metal(II) com-
plexes showed considerable effect on animals for a longer
Anti-inflammatory activity
Anti-inflammatory activity data of the Schiff base and its
metal complexes were evaluated by carrageenan-induced
rat paw edema method and the results are shown in
Table 6. Injection of carrageenan into the rat paw produces
inflammation resulting from metabolism of arachidonic
acid. From the observation, it is found that the Schiff base
and metal(II) complexes possess higher anti-inflammatory
activity compared to the standard. Among all the metal
complexes, the percentage inhibition shown by the com-
plex (6) was 64 % and it was significant and comparable
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Med Chem Res
Table 5 Anticonvulsant activity data of Schiff base and metal(II)
complexes
Table 6 Anti-inflammatory activity data of Schiff base and its
metal(II) complexes
Compound
Dose
mg/kg
Duration of seizure
mean SEM
% inhibition of
extension phase
Compounds
Dose (mg/ Paw volume
kg)
% inhibition of paw
edema
(ml)
Control
10
10
13.52 2.12
2.22 0.45
–
Control
10
10
5.92 0.96
1.70 0.48
–
Phenytoin
sodium
83.72
Diclofenac
sodium
71.28
BIPTZ
(1)
10
10
10
10
10
10
10
4.56 0.92
4.32 0.88
4.20 0.71
4.22 0.65
4.24 0.90
4.06 0.55
4.34 0.75
66.27
68.04
68.93
68.78
68.63
69.97
68.63
BIPTZ
(1)
10
10
10
10
10
10
10
2.62 0.72
2.47 0.46
2.40 0.40
2.52 0.53
2.50 0.55
2.48 0.45
2.12 0.33
55.74
58.27
59.45
57.43
57.77
58.10
64.18
(2)
(2)
(3)
(3)
(4)
(4)
(5)
(5)
(6)
(6)
Fig. 9 Anti-inflammatory activity of Schiff base and metal(II)
complexes
Fig. 8 Anticonvulsant activity of Schiff base and metal(II)
complexes
possible integrity of cellular interactions in the brain
resulting in undisturbed neural function.
with the standard drug Diclofenac sodium (71 %) (Fig. 9).
The enhanced anti-inflammatory activity of the complexes
may be explained on the basis of enhanced penetration
through cellular membranes due to complexation (Stef-
ancich et al., 1991).
Evaluation of behavioral activity in MPTP-treated mice
The locomotor activity data of the Schiff base and metal
complexes given in (Table 7) reveal that there was no
significant difference between the locomotor activities in
MPTP-treated mice and control group when accessed on
1st and 5th day. The administration of MPTP significantly
decreases the locomotor activity and motor function in
association with a significant oxidative damage induced in
striatal region of the brain on 8th and 12th day. Alcoholic
extract of Schiff base and its metal complexes (1–6) also
display no significant difference in locomotor activity on
1st and 5th day. But it was significantly increased on 8th
and 12th day of treatment with the Schiff base and its metal
complexes (1–6) as compared to MPTP-treated group
(Fig. 10). Thus it is plausible that the administration of
Schiff base and metal complexes (1–6) produces a signif-
icant neuroprotective effect in MPTP-induced striatal
lesions in mice.
Anti-parkinsonian activity
Neurodegeneration refers to a condition of neuronal death
occurring as a result of progressive disease of long term.
Among hundreds of different neurodegenerative disorders,
much attention has been given to Parkinson’s disease.
Parkinson’s disease (PD) is a chronic progressive neuro-
degenerative movement disorder characterized by a pro-
found loss of nigrostriatal dopaminergic neurons.
Neuroprotection is a broad term to cover any therapeutic
strategy to prevent nerve cells called neurons from dying,
and it usually involves an intervention, either a drug or
treatment. The goal of neuroprotection is to limit neuronal
dysfunction after injury and attempt to maintain the
123

Med Chem Res
Table 7 Effect of Schiff base and metal(II) complexes on locomotor activity in MPTP-treated mice
Groups
1st day
5th day
8th day
12th day
Control
MPTP
BIPTZ
(1)
296 10.62
257.66 9.6
259.66 9.27
259.32 3.13
260.83 3.22
257.16 2.18
256.16 2.24
250.40 10.20
248.22 9.30
252.30 9.18
259 3.12
252.16 2.10
136.33 3.56*
263.66 3.49
240.66 2.87
287.33 2.30
245.52 2.97
248.6 8.97
246.5 9.25
232.8 9.24
282 9.77
291.16 11.42
281 10.63
133.16 3.38*
260 2.73
255.66 2.71
258.33 1.4
212.33 2.82
260.05 10.82
226.55 8.60
235.45 9.34
(2)
270 10.63
(3)
277.66 10.11
266.12 9.25
257.22 8.68
260.32 9.57
(4)
(5)
(6)
Values are expressed as mean SEM (n = 6)
* Values were significantly different from control group at P \ 0.01
dismutase (SOD) constitute the major intracellular antiox-
idant protection systems by removing superoxide anion and
hydrogen peroxide. An effect of Schiff base and metal
complexes on level of antioxidants of MPTP-induced mice
is presented in Fig. 11. Glutathione (GSH), a potent anti-
oxidant plays an important role in the dopamine turnover.
It is a well-known fact that there is a reduced level of
Dopamine occurring in dopaminergic neuronal damaged
brain. Dopamine metabolism results in the formation of
cellular oxidant, hydrogen peroxide, and at this stage glu-
tathione peroxidase is not sufficiently enough to alternate
the oxidative alterations. The lowering of reduced gluta-
thione level is observed in MPTP-treated mice (Table 8)
getting restored when treated with Schiff base and metal
complexes which help to preserve the normal cellular
glutathione level.
Fig. 10 Effect of Schiff base and metal(II) complexes on Locomotor
activity
The damaging effects of MPTP are partly due to the
formation of hydroxyl radical during the MPTP metabo-
lism, dopamine and its metabolite. Superoxide dismutase
(SOD) is a class of enzyme which majorly defense against
the oxygen and hydroxyl radical. An effect of Schiff base
and metal(II) complexes on superoxide dismutase in
MPTP-treated mice are studied. From the observation, it is
concluded that there is a significant reduction in the SOD
level in Parkinson’s diseased mice, which shows restora-
tion upon treatment with Schiff base and metal complexes.
Among all the metal complexes, (6) exhibits promising
results.
An effect of Schiff base and metal complexes on level of
lipid peroxides given in Table 8, confirmed that among the
complexes, (2) showed promising increase in lipid perox-
ide level as compared to MPTP-treated mice.
Fig. 11 Effect on SOD level and oxidative stress parameters
The nitrite salt, NaNO2 (sodium nitrite) has the ability to
convert hemoglobin to methemoglobin. This causes
reduction in oxygen carrying capacity of blood, leading to
memory impairment. In the present study, it was observed
that the nitrite levels were significantly increased in mice
Antioxidant studies
Among the most prominent internal antioxidants, the
enzyme glutathione peroxidase (GSH) and superoxide
123

Med Chem Res
Table 8 Effect of Schiff base and metal(II) complexes on antioxidant levels in MPTP-treated mice
Groups
Lipid peroxidation nmol/mg protein
Reduced glutathione lmol/mg protein
Superoxide dismutase
Control
MPTP
BIPTZ
(1)
1.10 0.12
0.056 0.004
32.65 2.36
2.56 0.25a*
1.60 0.16b*
1.54 0.14b*
1.50 0.15b*
1.62 0.18b*
1.54 0.20b*
1.60 0.22b*
1.64 0.26b*
0.020 0.002a*
0.048 0.003b*
0.042 0.003b*
0.040 0.002b*
0.044 0.003b*
0.041 0.005b*
0.045 0.006b*
0.043 0.003b*
8.65 0.92a*
16.85 1.22b*
14.26 1.36b*
15.62 1.58b*
14.24 1.30b*
18.30 1.22b*
13.20 1.32b*
18.35 1.22b*
(2)
(3)
(4)
(5)
(6)
Values are expressed as mean SEM (n = 6)
a*
Values were significantly different from control group at P \ 0.01
b*
Values were significantly different from MPTP-induced group at P \ 0.01
Table 9 Effect of Schiff base and metal(II) complexes on oxidative
stress parameters in MPTP-treated mice
have been synthesized and characterized with the help of
spectral and analytical methods. On the basis of the above
techniques the geometry of the metal(II) complexes were
proposed as square pyramidal for [ML] type and octahedral
for [ML2] type complexes. Schiff base and its metal(II)
complexes are highly fluorescent in nature. They were
found to exhibit promising in vivo anticonvulsant and anti-
inflammatory activity. The synthesized Schiff base and its
metal(II) complexes exert neuroprotective effect by
restoring the neurotransmitters and antioxidants in the
corpus striatum of PD mouse. Our findings suggest that the
newly designed Schiff base and its metal(II) complexes
prevent impairments within the confines of the MPTP
model of Parkinson’s disease. Hence the synthesized
compounds may be utilized for further investigations to be
formulated as an useful drug for Parkinson’s disease.
Groups
Nitrite level
Myeloperoxidase OD/min
Control
MPTP
BIPTZ
(1)
120.4 3.54
205.62 5.30
210.45 7.45a*
148.65 4.23b*
172.25 4.56b*
158.32 4.05b*
162.10 4.52b*
165.16 4.22b*
160.22 4.26b*
165.14 4.42b*
320.24 8.30a*
232.40 5.98b*
245.32 6.25b*
230.15 5.98b*
238.20 6.05b*
242.18 5.65b*
240.28 5.13b*
236.25 5.45b*
(2)
(3)
(4)
(5)
(6)
Values are expressed as mean SEM (n = 6)
a*
Values were significantly different from control group at P \ 0.01
Values were significantly different from MPTP-induced group at
b*
P \ 0.01
challenged with MPTP as compared to control group.
Treatment with Schiff base (BIPTZ) and its metal com-
plexes (1–6) decreases the nitrite level significantly as
compared to MPTP-challenged mice. Myeloperoxidase
(MPO) is an important marker of tissue damage involving
inflammatory cells. Table 9.
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