Synthesis, structural characterization and biological studies of copper complexes with 2-aminobenzothiazole derivatives

Article abstract of DOI:10.1016/j.molstruc.2014.01.028

Novel copper complexes of 2-aminobenzothiazole derivatives were synthesized by the condensation of Knoevenagel condensate acetoacetanilide (obtained from substituted benzaldehydes and acetoacetanilide) and 2-aminobenzothiazole. They were thoroughly charac

Full text of DOI:10.1016/j.molstruc.2014.01.028

Journal of Molecular Structure 1063 (2014) 160–169
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, structural characterization and biological studies of copper
complexes with 2-aminobenzothiazole derivatives
⇑
J. Joseph , G. Boomadevi Janaki
Department of Chemistry, Noorul Islam Centre for Higher Education, Kumaracoil 629180, Tamil Nadu, India
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
Novel copper complexes of 2-aminobenzothiazole derivatives were synthesized by the condensation of
knoevenagal condensate acetoacetanilide (obtained from substituted benzaldehydes and acetoacetani-
lide) and 2-aminobenzothiazole. They were thoroughly characterized by elemental analysis, IR, 1H
NMR, UV–Vis., molar conductance, magnetic moment and electrochemical studies.
ꢀ
ꢀ
ꢀ
A series of novel copper complexes of
2-aminobanzothiazole derivatives
were synthesized.
A potent lead compound by selecting
suitably substituted Knoevenagal
moiety.
Six compounds with high potency
and better antioxidant agents.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 October 2013
Received in revised form 9 January 2014
Accepted 10 January 2014
Available online 28 January 2014
Novel copper complexes of 2-aminobenzothiazole derivatives were synthesized by the condensation of
Knoevenagel condensate acetoacetanilide (obtained from substituted benzaldehydes and acetoacetani-
lide) and 2-aminobenzothiazole. They were thoroughly characterized by elemental analysis, IR, 1H
NMR, UV–Vis., MS Spectra, molar conductance, magnetic moment and electrochemical studies. These
spectral studies suggested that distorted square planar geometry for all the complexes. Molar conduc-
tance data and magnetic susceptibility measurements provide evidence for monomeric and neutral nat-
ure of the complexes. The electrochemical behaviour of the ligand and complexes in DMSO at 298 K was
studied. The present ligand systems stabilize the unusual oxidation states of copper ion during electrol-
ysis. Antibacterial screening of the ligands and their complexes reveal that all the complexes show higher
activities than the free ligands.
Keywords:
2-aminobenzothiazole
Characterization
Pharmacological and biological
Ó 2014 Elsevier B.V. All rights reserved.
1. Introduction
activities from a key part of research in the pharmaceutical
field. Bring about modifications by manipulating the parent
Innovations/Inventions of newer, cheaper and more potent
analogs of molecules with already well recognized biological
structures serves to enhance the activity of the potent analogs
and eliminates adverse effects or toxicity associated with the
parent drug. Particularly, 2-aminobenzothiazole/beta-diketone
and its derivatives are known for their variety of clinical
applications [1–3].
⇑
Corresponding author. Tel.: +91 9629474150.
E-mail address: Chem_joseph@yahoo.co.in (J. Joseph).
http://dx.doi.org/10.1016/j.molstruc.2014.01.028
0022-2860/Ó 2014 Elsevier B.V. All rights reserved.

J. Joseph, G. Boomadevi Janaki / Journal of Molecular Structure 1063 (2014) 160–169
161
In this present study, we have focused on the structural modi-
fications on 2-aminobenzothiazole. In this perspective, low molec-
ular weight transition metal complexes with organic ligands have
been and are still viewed as promising pharmaceutical agents with
antioxidant/free radical scavenging properties, owing to their abil-
ity to interact and/or react with reactive oxygen or nitrogen species
and counterbalance excessive endogenous free radical generation
in biological systems. It is hope that metal complexes may be be-
haved as therapeutics.
The b-diketones such as curcumin, phlorectin and structurally
related phytopolyphenols have well described neuroprotective
properties against toxicity induced by hydrogen peroxide in a cel-
lular model of oxidative stress [4]. Among them curcumin has cru-
cial features of a neuroprotective drug since it acts as a powerful
scavenger of superoxide anions so it has both neuroprotective
and anti-aging effects. Thus, the curcumin based analogs have
great potential for the prevention of multiple neurological condi-
tions than the current therapeutics [5]. Condensation of the active
methylene group of the b-diketone with an aldehydic group will
give a non-enolisable Knoevenagel condensate, which can effec-
tively react with amines to form Schiff bases. Schiff bases have
been reported to show a variety of biological activities like antibac-
terial, antifungal, herbicidal and clinical activities by virtue of the
azomethine linkage [6].
pronounced biological and pharmacological activities. As a conse-
quence, it is essential to understand the relationship between li-
gand and the copper ion in biological systems. We have
undertaken intensive efforts to synthesize and present them as a
potential candidate for neuronal diseases. The aim of the present
study is to prepare the desired Schiff bases which are based on
the condensation of a Knoevenagel condensate of acetoacetanilide
precursor with 2-aminobanzothiazole and to investigate their ef-
fect on pathogenic strains of Gram-positive and Gram-negative
bacteria. Further, in vitro free radical scavenging activities of the li-
gands and their copper complexes were evaluated by DPPH assay
method. The DNA binding efficiency of copper complexes has also
been determined using electrochemical and electronic absorption
techniques.
2. Experimental
2.1. Material
All chemicals and solvents were reagent grade and were pur-
chased from Merck. All supporting electrolyte solutions were pre-
pared using analytical grade reagents and doubly distilled water.
Calf thymus DNA purchased from Genei Biolab, Bangalore, India.
Benzothiazoles are bicyclic ring system with multiple applica-
tions. Among benzothiazoles, 2-aryl benzothiazole has received
much attention due to unique structure and an important pharma-
cophore in a number of diagnostic and therapeutic agents which
was studied at 1950s. It is used as radioactive amyloid imagining
agents [7] and anticancer agents [8] and reported cytotoxic on can-
cer cells [9]. Polyfunctional ligands system of 2-aminobenzothiaz-
oles has been studied as central muscle relaxants and are found to
interfere with glutamate neurotransmission in biochemical, elec-
trophysiological and behavioural experiments and reported as
neuroprotectors [10]. Some of these drugs exhibit increased anti-
cancer activity when administered as metal complexes [11,12].
Metal complexes of N and S chelating ligands have attracted con-
siderable attention because of their interesting physicochemical
properties and pronounced biological and pharmacological activi-
ties. The N and S atoms play a key role in the coordination of met-
als at the active sites of various metallobiomolecules [13,14].
Copper is an important biometal which is essential for normal
human metabolism and its imbalance leads to deficiency or excess
diseases. Cu(II) complexes are preferred candidates for various
pharmacological studies due to the presence of its biorelevent li-
gands [15]. These complexes have multiple roles in medicinal pro-
ceedings such as antimicrobial, antiviral, anti-inflammatory,
antitumor agents, enzyme inhibitors, or chemical nucleases with
reduced side effects and it has distinct superoxide-dismutase-
(SOD-)mimetic activity [16,17]. DNA is a potent target of cytostatic
drugs, the effect of copper compounds on DNA functionality is very
important. The ability of Cu(II) complexes to bind to DNA and ex-
hibit nuclease activity in the presence of reducing agents is well
established [18].
2.2. Instrumentation
Elemental analysis of ligands and their copper complexes were
carried out using Perkin–Elmer elemental analyzer. Molar conduc-
tance of the complexes was measured using a coronation digital
conductivity meter. The 1H NMR spectra of the ligands were re-
corded using TMS as internal standard. Chemical shifts are ex-
pressed in units of parts per million relative to TMS. The IR
spectra of the ligands and their copper complexes were recorded
on a Perkin–Elmer 783 spectrophotometer in 4000–200 cmꢁ1
range using KBr disc. Electronic spectra were recorded in a Systron-
ics 2201 Double beam UV–Vis., spectrophotometer within the
range of 200–800 nm region. Magnetic moments were measured
by Guoy method and corrected for diamagnetism of the compo-
nent using Pascal’s constants. Cyclic voltammetry was performed
on a CHI 604D electrochemical analyzer with three electrode sys-
tem of glassy carbon as the working electrode, a platinum wire
as auxiliary electrode and Ag/AgCl as the reference electrode. Tet-
rabutylammoniumperchlorate (TBAP) was used as the supporting
electrolyte. Solutions were deoxygenated by eradication with N2
previous to measurements. The interactions between metal com-
plexes and DNA were studied using electrochemical and electronic
absorption techniques. The FAB-mass spectra of ligands and their
metal complexes were recorded on a JEOL SX 102/DA-6000 mass
spectrometer/data system using Argon/Xenon (6 kV, 10 A) as the
FAB gas. The Thermogravimetric analyses data were measured
from 0 °C to 1000 °C temperature at a heating rate of 10 °C/min.
The data were obtained by using a Perkin Elmer Diamond TG/
DTA instrument.
Literature review shows that heterocyclic derivatives contain-
ing nitrogen and sulphur atom serve as a unique and versatile scaf-
folds for systematic drug design. These concerns have led to major
research efforts to discover new antibacterial agents that could be
used to combat bacterial infections one of which are the Schiff
bases have highly conjugated Pharmacophoric systems. Based
upon this we synthesized a series of copper complexes from the
Schiff base ligands synthesized by the condensation of Knoevena-
gel condensate acetoacetanilide (obtained from substituted benz-
aldehydes and acetoacetanilide). The synthesized ligand system
is highly conjugated like curcumin (Scheme 1) analog so we are
promising that nitrogen and sulphur containing heterocycles have
2.3. Synthesis of Knoevenagel condensate b-diketones
The reaction was proceeded by Knoevenagel condensation
between equimolar quantity of acetoacetanilide and aromatic
aldehyde(s) such as 4-hydroxy-3-methoxybenzalde (L1)/4-chloro-
benzaldehyde(L2)/3-nitrobenzaldehyde (L3)/2-chlorobenzaldehyde
(L4)/3-chlorobenzaldehyde (L5)/cinnamaldehyde (L6) was refluxed
in the presence of potassium carbonate as the catalyst. The product
was formed with lose of water molecule to provide substituted b-
ketoanilides. The progress of reaction was monitored by TLC. After
completion of reaction, the reaction mixture was poured on

162
J. Joseph, G. Boomadevi Janaki / Journal of Molecular Structure 1063 (2014) 160–169
Scheme 1. Outline of synthesis of copper complexes of 2-aminobenzothiazole derivatives.
crushed ice. The yellow coloured Knoevenagel condensate b-keto-
anilide was obtained. The separated product was filtered washed
with ice cold water and dried.
of CT DNA in 50 mM NaCl/50 mM tris–HCl (pH 7.2) gave the ratio
of the UV absorbance at 260 and 280 nm, A260/A280, of ca. 1.8–1.9,
indicating that the DNA was sufficiently free of protein contamina-
tion. The DNA concentration was determined by the UV absor-
bance at 260 nm after 1:100 dilution. The molar absorption
coefficient was taken as 6600 m2 molꢁ1. Stock solutions were kept
at 4 °C and used safter not more than 4 days. Concentrated stock
solutions of the complexes were prepared by dissolving the com-
plexes in DMSO and diluting suitably with the corresponding buf-
fer to the required concentration for all of the experiments.
2.4. Synthesis of Schiff base ligands
Ethanolic solutions of 2 mol of 2-aminobenzothiazole was
added dropwise to one mole of Knoevenagel condensate b-ketoani-
lide(s) in 40 ml ethanol and anhydrous potassium carbonate used
as a catalyst. The obtained products were set aside in a refrigerator
for 10 h. The progress of reaction was monitored by TLC. After com-
pletion of reaction the solid material was removed by filtration and
recrystallized from ethanol. The better percentage yield (75%) was
obtained by adopting the above procedure.
2.6.1. Absorption titration experiment
Absorption titration experiment was performed by maintaining
a constant concentration of the complex while varying the nucleic
acid concentration. This was achieved by dissolving an appropriate
amount of the copper complex stock solution and by mixing vari-
ous amounts of DNA stock solutions while maintaining the total
volume constant. This resulted in a series of solutions with varying
concentrations of DNA but with a constant concentration of the
complex. The absorbance (A) of the most red-shifted band of com-
plex was recorded after each successive additions of CT DNA. The
intrinsic binding constant, Kb, was determined from the plot of
2.5. Synthesis of copper(II) complexes
Ethanolic solutions of 2-aminobenzothiazole derivatives
(2 mol) and copper acetate (1 mol) were refluxed for about 2 h.
The progress of reaction was monitored by TLC until the product
was formed. Then, it was poured on crushed ice. The solid material
was removed by filtration and recrystallized from ethanol.
The following schematic representation shows the outline of
synthesis of compounds and their complexes.
[DNA]/(ea
DNA in base pairs,
ꢁ
e
f) vs [DNA], where [DNA] is the concentration of
a, the apparent extinction coefficient which is
e
obtained by calculating Aobs/[complex] and ef corresponds to the
extinction coefficient of the complex in its free form. The data were
fitted to the following equation where eb refers to the extinction
coefficient of the complex in the fully bound form.
2.6. DNA binding studies
The binding interactions between metal complexes and DNA
were studied using electrochemical and electronic absorption
methods by using different concentrations of CT-DNA. Solutions
½DNAꢂ=ðea
ꢁ
ef Þ ¼ ½DNAꢂ=ðeb
ꢁ
ef Þ þ 1=Kbðeb
ꢁ
ef
Þ
ð1Þ

J. Joseph, G. Boomadevi Janaki / Journal of Molecular Structure 1063 (2014) 160–169
163
Eachset of data, when fitted tothe above equation, gave a straight
line with a slope of 1/(eb f) and a y-intercept of 1/Kb(eb f). Kb
was determined from the ratio of the slope to intercept.
incubated overnight at 37 °C. Inoculation medium containing
24 h grown culture was added aseptically to the nutrient medium
and mixed thoroughly to get the uniform distribution. This solu-
tion was poured (25 mL in each dish) into petri dishes and then al-
lowed to attain room temperature. Wells (6 mm in diameter) were
cut in the agar plates using proper sterile tubes. Then, wells were
filled up to the surface of agar with 0.1 mL of the test compounds
ꢁ
e
ꢁ
e
2.7. Antioxidant Assay
2.7.1. Superoxide dismutase activity (SOD)
dissolved in DMSO (200 lM/mL). The plates were allowed to stand
The superoxide dismutase activity (SOD) of the copper(II) com-
plexes were evaluated using alkaline DMSO as source of superox-
ide radicals ðOÅ2ꢁÞ generating system in association with nitro
blue tetrazolium chloride (NBT) as a scavenger of superoxide.
Add 2.1 ml of 0.2 M potassium phosphate buffer (8.6 pH) and
for an hour in order to facilitate the diffusion of the drug solution.
Then the plates were incubated at 37 °C for 24 h for bacteria and
48 h for fungi and the diameter of the inhibition zones were read.
Minimum inhibitory concentrations (MICs) were determined by
using serial dilution method. The lowest concentration (lg/mL)
1 ml of 56 ll of NBT solutions to the different concentration of cop-
of compound, which inhibits the growth of bacteria after 24 h incu-
bation at 37 °C. The concentration of DMSO in the medium did not
affect the growth of any of the microorganisms tested.
per complex solution. The mixtures were kept in ice for 15 min and
then 1.5 ml of alkaline DMSO solution was added while stirring.
The absorbance was monitored at 540 nm against a sample pre-
pared under similar condition except NaOH in DMSO.
3. Results and discussion
2.7.2. Hydrogen peroxide assay
A solution of hydrogen peroxide (2.0 Mm) was prepared in
phosphate buffer (0.2 M, 7.4 pH) and its concentration was deter-
mined spectrophotometrically from absorption at 230 nm. The
The ligands and their complexes are stable at room tempera-
ture. Copper complexes are stable at room temperature and do
not undergo any decomposition for a long time. They are sparingly
soluble in common organic solvents but soluble in DMF and DMSO.
The analytical, physical properties and molar conductance data of
the complexes are given in Table 1. The Cu(II) complexes were dis-
solved in DMSO and the molar conductivities of 10ꢁ3 M of their
solution at room temperature were measured. The lower conduc-
complexes of different concentration and Vitamin C (100 lg/ml)
were added to 3.4 ml of phosphate buffer together with hydrogen
peroxide solution (0.6 ml). An identical reaction mixture without
the sample was taken as negative control. The absorbance of
hydrogen peroxide at 230 nm was determined after 10 min against
the blank (phosphate buffer).
tance values (2–5
X
ꢁ1 cm2 molꢁ1) of the complexes support their
non-electrolytic nature. Thus, the present complexes have non-
electrolytic nature as evidenced by the involvement of acetate ions
in coordination. This result was further confirmed from the chem-
ical analysis of CH3COOꢁ ion, not precipitated by addition of FeCl3.
The elemental analysis data of the complexes are in good agree-
ment with theoretical values presented in Table 1. The results ob-
tained from micro analytical measurements, metal estimation,
2.8. Antimicrobial activities
The in vitro antimicrobial activities of the investigated com-
pounds were tested against the bacterial species and fungal spe-
cies. One day prior to the experiment, the bacterial and fungal
cultures were inoculated in broth (inoculation medium) and
Table 1
Physical characterization, analytical, molar conductance and magnetic susceptibility data of the ligands and their complexes.
Compound
Yield (%)
Colour
(Found) calc
(X
ꢁ1 cm2 molꢁ1
)
leff (BM)
Cu
–
C
H
N
L1
62
73
76
54
43
65
56
74
78
44
62
71
Dark brown
Dark brown
Dark brown
Dark brown
Dark Brown
Yellow
68.31
(68.12)
4.66
(4.37)
9.96
(9.88)
–
–
–
–
–
–
3
4
2
4
4
5
–
L2
–
–
–
–
–
67.69
(67.87)
4.03
(3.82)
10.19
(10.06)
–
L3
66.06
(66.12)
4.47
(4.67)
12.43
(12.88)
–
L4
67.69
(67.87)
4.03
(3.82)
10.19
(10.06)
–
L5
67.69
(67.87)
4.03
(3.82)
10.19
(10.06)
–
L6
74.28
(74.06)
4.68
(4.41)
8.69
(8.49)
–
[CuL1(OAc)2]
[CuL2(OAc)2]
[CuL3(OAc)2]
[CuL4(OAc)2]
[CuL5(OAc)2]
[CuL6(OAc)2]
Reddish brown
Pale brown
Black
8.56
(8.43)
58.17
(58.43)
4.21
(4.06)
7.54
(7.45)
1.82
1.80
1.89
1.82
1.82
1.86
8.69
(8.60)
57.44
(57.53)
3.86
(3.92)
7.66
(7.51)
8.41
(8.98)
55.58
(32.73)
3.73
(2.43)
11.2
(6.43)
Pale brown
Pale brown
Light black
8.69
(8.60)
57.44
(57.53)
3.86
(3.92)
7.66
(7.51)
8.69
(8.60)
57.44
(57.53)
3.86
(3.92)
7.66
(7.51)
7.57
64.30
4.32
6.67
(7.42)
(64.43)
(4.16)
(6.87)

164
J. Joseph, G. Boomadevi Janaki / Journal of Molecular Structure 1063 (2014) 160–169
Table 3
conductivity and mass spectral data confirm the stoichiometry of
the copper complex as [CuL(OAc)2]. The magnetic moments of cop-
per(II) in any of its geometry lies around 1.9 B.M. which is very
close to spin-only value i.e. 1.73 B.M. The values which we found
in our case lie in the range, 1.80–1.89 B.M. These values are typical
for mononuclear copper(II) compounds having d9-electronic con-
figuration. The observed magnetic moments of all the complexes
correspond to distorted square planar Cu(II) complexes. However,
the values are slightly higher than the expected spin-only values
due to spin orbit coupling contribution.
Characteristic IR bands of the Schiff base ligands and their copper complexes (in
cmꢁ1).
Compound
m
m
m
m
t
asy(COOꢁ)
t
sy(COOꢁ)
(C@N) (C@N) (MAO) (MAN)
L1
L2
L3
L4
L5
L6
1628
1630
1624
1630
1630
1638
1642
1646
1662
1653
1652
1666
1624
1626
1618
1626
1631
1632
–
–
–
–
–
–
510
509
507
509
510
512
–
–
–
–
–
–
449
451
452
451
453
448
–
–
–
–
–
–
–
–
–
–
–
–
1298
1294
1321
1308
1280
1317
[CuL1(OAc)2] 1612
[CuL2(OAc)2] 1618
[CuL3(OAc)2] 1611
[CuL4(OAc)2] 1618
[CuL5(OAc)2] 1618
[CuL6(OAc)2] 1621
1394
1390
1438
1456
1412
1422
3.1. 1H NMR
The 1H NMR spectra of ligands were recorded in DMSO-d6 Solu-
tion at room temperature. The ligand L1 showed the following
spectral features for Knoevenagel condensate acetoacetanilide
moiety: aromatic protons of acetoacetanilide ring appear as multi-
plet at the region between 6.8–7.4 dppm (m, 5H), the phenyl mul-
tiplet was observed at 7.32–7.7 (m, 3H), methyl protons at
2.25 ppm (s, 3H), AOH at 10.8 (s, H) and AOCH3 at 3.5 (s, 3H). In
addition, peak appeared at 7.3 ppm, which is assigned to free-NH
group of acetoacetanilide moiety. Moreover the multiplets within
the range 7.8–8.2 ppm (m, 8H) were assigned to the aromatic pro-
tons of benzothiazole ring [19]. The peak at 5.4 ppm is attributable
to the AHC@CA group present in the Knoevenagel condensate
moiety. The chemical shifts of all ligands are listed in Table 2. It
was concluded that the absence of amino group of 2-aminobenzo-
thiazole indicated the formation of schiff base ligand system.
The IR Spectral features were reinforced the conclusion drawn
from conductance measurements [22].
3.3. Electronic spectroscopy
The electronic absorption spectra of the Schiff base ligands and
their copper complexes in DMSO as a solvent were recorded at
room temperature and the band positions of the absorption max-
ima; band assignments and the proposed geometry are mentioned
in Table 4. The absorption spectrum for ligand L2 shows band at
329 nm attributed to p–p
* transitions within the Schiff base mole-
cule. The electronic spectrum of the corresponding complex
[CuL2(OAc)2] (Fig. 2) in DMSO reveals a broad band at 429 nm as-
signed to 2B1g ? 2A1g transition which is characteristic of distorted
square planar environment around the copper(II) ion. Similar spec-
tral features were assigned for other complexes [23].
3.2. FT-IR spectroscopy
In order to characterize the binding mode of the Schiff base to
the metal ion in the complexes, the IR spectrum of the free ligand
was compared with the spectra of the copper complexes. The char-
acteristic IR bands for the synthesized ligands and their copper
complexes were listed in Table 3. The IR Spectrum of [CuL2(OAc)2]
complex was shown in Fig. 1 as supplementary material. The spec-
trum of the ligand (L2) showed band at 1646 cmꢁ1 for the imine
Table 4
Electronic spectra of Schiff base ligands and their copper complexes (nm).
Compound
Wavelength(nm) Band
assignments
Geometry
m
(C@N) group which results from the Schiff base condensation of
L1
L2
L3
L4
L5
L6
352
329
344
319
319
332
p
–
pꢄ
–
–
–
–
–
–
p–
pꢄ
2-aminobenzothiazoles and Knoevenagel condensate was shifted
to a lower frequency of 1626 cmꢁ1 after complexation [20]. More-
over, the appearance of new bands at 451 cmꢁ1 and 510 cmꢁ1 cor-
p–
p–
p–
p–
pꢄ
pꢄ
pꢄ
pꢄ
responds to
m(MAN) and m(MAO) [21]. Also the new bands at
1383 cmꢁ1 and 1292 cmꢁ1 corresponds to symmetric and asym-
[CuL1(OAc)2] 427
[CuL2(OAc)2] 429
[CuL3(OAc)2] 426
[CuL4(OAc)2] 424
[CuL5(OAc)2] 432
[CuL6(OAc)2] 430
2B1g
2B1g
2B1g
2B1g
2B1g
2B1g
?
?
?
?
?
?
2A1g
2A1g
2A1g
2A1g
2A1g
2A1g
Distorted square
planar
Distorted square
planar
Distorted square
planar
Distorted square
planar
Distorted square
planar
Distorted square
planar
metric stretching for
m(MAO) which evidenced the participation
of the COOꢁ ion in the complexes. These facts are further supported
by the appearance of bands between 1390–1456 cmꢁ1 and 1280–
1321 cmꢁ1 attributed to
t t
asy(COOꢁ) and sy(COOꢁ) respectively
in all copper complexes. The difference in
and
Dt between t
asy(COOꢁ)
t
sy(COOꢁ) in metal complexes was ꢃ100 cmꢁ1 (110–
135 cmꢁ1) suggests the mode of coordination of carboxylate group
in copper complexes in a monodentate manner. Finally it was re-
ported that the copper complexes were behave as bidentate and
coordinate through azomethine nitrogen atoms and acetate ions.
Table 2
1H NMR chemical shifts d (ppm) of ligands L1–L6.
Compound
ACH3
ANH
Acetoacetanilide (aromatic)
Phenyl (aromatic)
Benzothiazole (aromatic)
Functional group
L1
L2
L3
L4
L5
L6
2.25
2.23
2.27
2.22
2.24
2.26
7.3
6.8–7.4
7.32–7.7
7.8–8.2
10.8 (–OH)
3.5 (OCH3)
–
–
–
–
7.35
7.38
7.34
7.36
7.33
6.84–7.43
6.87–7.45
6.83–7.45
6.82–7.42
6.86–7.44
7.33–7.73
7.36–7.81
7.34–7.74
7.35–7.73
7.35–7.77
7.83–8.24
7.86–8.27
7.82–8.24
7.84–8.23
7.85–8.25

J. Joseph, G. Boomadevi Janaki / Journal of Molecular Structure 1063 (2014) 160–169
165
Fig. 2. Electronic absorption spectra of [CuL2(OAc)2] complex.
3.4. EPR spectra
EPR spectrum of the copper complex was recorded in DMSO at
300 and 77 K. The spectrum at 300 K shows an intense absorption
band at high field, which is isotropic due to tumbling motion of the
molecules. This complex in the frozen state shows four well re-
solved peaks with low intensities in low field region. This fact
was evident from the absence of half field signal, observed in the
spectrum at 1600G due to the
Dms = 2 transitions, rulling out
any Cu–Cu interaction [24] and the synthesized compounds mono-
meric in nature [25]. The observed trend of copper complex of L1 is,
g||(2.24) > g\(2.05) > ge(2.0023) describes the axial symmetry with
the unpaired electron residing in the dx2
orbital [26]. Molecular
ꢁy2
r
orbital coefficients a2 (covalent inplane
-bonding), b2 (covalent
in-plane
p
-bonding) and
c
2 (out-plane
p-bonding) were calculated
using the following Eqs. (2)–(4).
a2 ¼ ðA =0:036Þ þ ðg ꢁ 2:0027Þ þ 3=7ðg? ꢁ 2:0023Þ þ 0:04
ð2Þ
ð3Þ
ð4Þ
k
k
b2 ¼ ðgk ꢁ 2:0027ÞE= ꢁ 8ka2
c2 ¼ ðgk ꢁ 2:0027ÞE= ꢁ 2ka2
For the present complex, the observed order K||(0.93) > K\(0.68)
implies a greater contribution from out-of plane -bonding than
from in in-plane -bonding in metal–ligand bonding. The A||
p
p
p
and A\ values in the order: A|| (146) > A\ (51) also indicate that
the complex has square planar geometry. The empirical factor
f = g||/A|| cmꢁ1 is an index of tetragonal distortion. Values of this
factor may vary from 105 to 135 for small to extreme distortions
in square planar complexes and it depends on the nature of the
coordinated atoms. The f values of copper complexes are 153,
151, 146, 148, 144 and 149, indicating significant distortion from
planarity.
3.5. Mass spectra
The FAB mass spectra of the Schiff bases and their correspond-
ing copper complexes were recorded and compared their stoichi-
ometry compositions (Scheme 2). The [CuL1(OAc)2] complex
shows the molecular ion peak at m/z 757. This molecular ion fur-
ther by losing two acetate ions gave a fragment ion peak at m/z
638 and these undergo demetallation to form the species [L]+ gave
fragment ion peak at m/z 575. Cu complexes of [CuL2(OAc)2],
[CuL4(OAc)2], [CuL5(OAc)2] shows molecular ion peak (M+) at
m/z = 745, 745, 745 respectively. Further, the fragmentation of
two acetate ions was observed at m/z = 626, 626, 626. After losing
their metal, the corresponding ligands ([L]+) shows molecular ions
peaks at m/z = 564, 564, 564.
Scheme 2. Mass fragmentation of copper complex of L3.
2-aminobenzothiazole with molecular ion peak at m/z = 638,
resulting from the elimination of metal results ion peak ([L]+) at
m/z = 574. The mass fragmentation pattern of copper complex of
L3 was shown in Scheme 2.
In case of [CuL6(OAc)2] complex, the molecular ion peak ob-
served at m/z = 737. This molecular ion further by losing two ace-
tate atoms gave a fragment ion peak at m/z = 618 and these
demetallation to form the species [L]+ gave fragment ion peak at
m/z = 555. Elemental analysis values are in close agreement with
the values calculated from molecular formula of these complexes,
The mass spectrum of Cu(II) complex of [CuL3(OAc)2] shows a
molecular ion peak (M+) at m/z = 756. The second fragmentation
of two acetate ions leads to the formation of ligand moiety of

166
J. Joseph, G. Boomadevi Janaki / Journal of Molecular Structure 1063 (2014) 160–169
which is further supported by the FAB-mass studies of representa-
tive complexes.
25.00
20.00
15.00
10.00
5.00
5.500
5.000
4.500
4.000
3.500
3.000
2.500
2.000
1.500
1.000
0.500
3.6. Thermogravimetric analysis
From thermal analysis, nature of intermediates and final prod-
ucts of the thermal decomposition of coordination compounds
can be obtained. From TGA curves, the weight loss was calculated
for the different steps and compared with those theoretically cal-
culated for the suggested formulae based on the results of elemen-
tal analyses and mass spectra together with the molar conductance
measurements. The TGA confirms the formation of CuO as the end
products from which the copper content could be calculated and
compared with that obtained from the analytical determination.
Thermogravimetric analyses of the copper complexes were re-
corded. By this Thermogravimetric analysis, we determine the
compositional differences as well as to ascertain the nature of asso-
ciated water molecules. From the thermal investigation (TG/DTG)
it is possible to observe that the decomposition occurs for the cop-
per complexes in three ways. All complexes start decomposition at
190–240 °C, suggesting the loss of acetate ions. However, the
decomposition at 330–420 °C corresponds to the decomposition
of ligands. Above 530–650 °C, copper complexes resulting in CuO
as main residue after decomposition steps. The differential ther-
mo-gravimetry (DTG) curve of the representative Cu(II) complex
shows three decomposition steps, the first decomposition step in
the range 320–410 °C corresponds to loss of acetate molecules,
the second decomposition range 580–640 °C range corresponds
to loss of 2-aminobenzothiazole moiety, further leaving behind
the metal oxide residue above 740–800 °C range.
0.00
-5.00
-10.00
100 200 300 400 500 600 700 800 900 1000
Temp Cel
Fig. 3. TGA curve for [CuL2(OAc)2].
The results showed that Cu(II) complex of L2 decompose mainly
in three steps. The Cu(II) complex 2 exhibits thermal stability up to
200 °C, which confirms that this complex is free from any types of
water molecules. In the first step, two acetate molecules are
evolved at 210–230 °C. The complex further decomposes in the
second step in the range of 250–410 °C associated with the partial
loss of ligand L2. In the final decomposition step appeared in the
range 460–580 °C corresponding to the complete thermal decom-
position of the complexes and the loss of their organic portion re-
sults in the formation of CuO as final products. In DTA analysis, An
intense exothermic decomposition peaks were observed for
[CuL2(OAc)2] at 330 °C, 620 °C, 780 °C shown in Fig. 3. All other
copper complexes showed similar thermogram.
Fig. 4. Cyclic voltammogram of [CuL6(OAc)2] complex.
The percentage of copper content was calculated from the
weight of the ash obtained and compared with those values with
the results of atomic absorption spectra (AAS). The copper content
in all the complexes was done by elemental analysis agrees well
with the thermal studies.
3.7. DNA binding experiments
3.7.1. Cyclic voltammetric studies
Cyclic voltammogram of [CuL6(OAc)2] in the absence of DNA
showed two segments of cathodic and anodic peaks were shown
in Fig. 4. The first segment, cathodic and anodic peaks were ob-
served at ꢁ0.530 V and ꢁ0.390 V, respectively. This showed reduc-
tion from +2 to +1 form sat a cathodic peak potential. Also, the
second segments of cathodic peaks and anodic peaks Epc2 and
Fig. 5. Cyclic voltammogram of [CuL6(OAc)2] in the presence and absence of
different concentrations of DNA.
Epa2 at ꢁ1.522 V and ꢁ1.342 V which corresponds to ligand oxida-
tion and reduction behaviour, respectively.
The cyclic voltammogram of [CuL6(OAc)2] in the presence of dif-
ferent concentration of DNA in the solution of same concentration
of the complex causes a considerable decrease in the voltammetric
current. In addition, the peak potentials, both Epa and Epc as well as
E1/2 have a shift to negative potential which is shown in Fig. 5. The
decrease extents of the peak currents observed for metal complex
upon addition of CT-DNA may indicate that the binding affinity of
copper complex and thus copper complex interacts with CT-DNA
through intercalation binding mode [27]. The electrochemical
parameters of the Cu(II) complexes are shown in Table 5. It was
concluded that the present ligand systems stabilize the unusual

J. Joseph, G. Boomadevi Janaki / Journal of Molecular Structure 1063 (2014) 160–169
167
Table 5
drugs. Lower IC50 value, greater the hydrogen donating ability.
Copper complex of L6 showed greater antioxidant activity. Copper
complex of L1 also showed a good antioxidant activity is due to the
presence of OH group (efficient hydrogen donors to stabilize the
unpaired electrons and there by scavenging free radicals). The
introduction of ANO2 group in the ligand system markedly in-
creases the antioxidant efficiency of the complexes with careful
selection of the substituents on the ligands, the antioxidant behav-
iour of the complexes can be improved.
The synthesized complexes show same antimicrobial and anti-
oxidant activities. The activity was found in the order of [CuL6
(OAc)2] < [CuL1(OAc)2] < [CuL3(OAc)2] < [CuL2(OAc)2] < [CuL4(OAc)2]
< [CuL5(OAc)2].
Electrochemical parameters for the interaction of DNA with copper complexes.
Compound
Redox couple E1/2 (V)
DEp (V)
ipa/ipc
Free
Bound
Free
Bound
[CuL1(OAc)2] Cu(II) ? Cu(I) ꢁ0.140 ꢁ0.517 ꢁ0.46
ꢁ0.215 1.19
[CuL2(OAc)2] Cu(II) ? Cu(I) ꢁ1.432 ꢁ1.475 ꢁ0. 184 ꢁ0.250 1.22
[CuL3(OAc)2] Cu(II) ? Cu(I) ꢁ0.383 ꢁ0.460 ꢁ0.144
[CuL4(OAc)2] Cu(II) ? Cu(I) ꢁ1.521 ꢁ1.615 ꢁ0.144
[CuL5(OAc)2] Cu(II) ? Cu(I) ꢁ1.405 ꢁ1.418 ꢁ0.144
[CuL6(OAc)2] Cu(II) ? Cu(I) ꢁ0.215 ꢁ0.350 ꢁ0.144
ꢁ0.144 1.15
ꢁ0.210 1.12
ꢁ0.180 1.21
ꢁ0.173 1.25
oxidation states of copper ion during electrolysis. Other copper
complexes were also showed similar electrochemical behaviour.
3.8.1. Superoxide dismutase activity
SODs are metalloenzymes that catalyze the dismutation of the
superoxide radical ðOÅ2ꢁÞ into hydrogen peroxide (H2O2) and molec-
ular oxygen (O2), providing an important defense against oxidative
damage. SOD catalyzes the dismutation of superoxide through a so
called ‘‘Ping-Pong mechanism’’. First, the metal cation (Mn+) is re-
duced to M(nꢁ1)+ and reoxidized back to Mn+. Then, superoxide an-
3.7.2. Absorption spectral titrations
Electronic absorption spectroscopy is one of the most useful
techniques for DNA binding studies of metal complexes. The bind-
ing of copper(II) complexes to DNA helix has been characterized
through absorption spectral titrations, by following changes in
absorbance and shift in wavelength. The experiments were per-
formed by maintaining a constant concentration of the complex
while varying the DNA concentration.
ion coverts the tetrazolium salt NBT to NBT-diformazan,
a
formazan dye. Absorbance is measured at 540 nm using a standard
spectrophotometer. Addition of SOD to this reaction reduces super-
oxide ion levels, thereby lowering the rate of NBT-diformazan for-
mation. SOD activity in the experimental sample is measured as
the percent inhibition of the rate of NBT-diformazan formation.
The superoxide dismutase activity (SOD) of the complexes was
investigated by the NBT assay method [29]. The chromophore con-
centration value required to yield 50% inhibition of the reduction of
NBT (IC50). The IC50 of present copper complexes was found at the
In the UV region, the Cu(II) complex of L1 exhibits a band at ca.
444 nm. With increasing DNA concentration, the absorption bands
of the complexes were affected, resulting in a hypochromism ten-
dency and slight shifts to longer wavelengths, which indicates that
the Cu(II) complex can interact with DNA (Fig. 6). The observed
hypochromism and bathochromism for the Cu(II) complex are
large compared to those observed for potential intercalators. The
intrinsic binding constant (Kb) was obtained by monitoring the
change in absorbance with increasing concentrations of DNA for
the Cu(II) complexes. The intrinsic binding constant (Kb) values
of copper complexes of L1–L6 are 1.6 ꢅ 106, 2.3 ꢅ 106, 1.6 ꢅ 106,
1.9 ꢅ 106, 3.2 ꢅ 106 and 2.8 ꢅ 106, respectively and compared with
classical intercalator (ethidium bromide-DNA) was found to be
1.4 ꢅ 107 Mꢁ1. The prepared copper complexes are less binding
strength than classical intercalator.
range of 32–45
ited by the native enzyme (IC50 = 0.04
l
mol dmꢁ3 which are higher than the value exhib-
mol dmꢁ3). All the tested
l
compounds show SOD activity. Similar values obtained for all com-
pounds. The SOD values of Cu(II) complexes were listed in Table 6
and graphically presented in Fig. 7.
In the present study, the higher SOD mimetic activity of copper
complexes than that of native enzyme is due to the presence of
easily labile acetate ion and also azomethine containing stabilize
the Cu(I) complex formed during superoxide dismutation reaction
which further reacts with superoxide ion to give hydrogen perox-
ide. The distorted geometry of these complexes may favour the
geometrical change, which is essential for the catalysis as the
geometry of copper in the SOD enzyme also changes from distorted
square planar geometry. The difference in reactivities of the syn-
thesized complexes may be attributed to the coordination environ-
ment asnd the redox potential of the couple CuI/CuII in copper(II)
complexes during the catalytic cycle. The above results also sup-
ported from the ‘‘f’’ factor obtained from EPR spectra. The proposed
mechanism of SOD activity as follows:
½CuL5ðOAcÞ2ꢂ > ½CuL4ðOAcÞ2ꢂ > ½CuðL1ÞðOAcÞ2ꢂ > ½CuL3ðOAcÞ2ꢂ
> ½CuL2ðOAcÞ2ꢂ > ½CuL6ðOAcÞ2ꢂ
These data implies that the compounds interact with CT-DNA
by appreciable intercalation binding mode [28]. A similar spectral
behaviour was obtained for all other complexes.
3.8. Antioxidant assay
Compounds with antioxidant properties could be expected to
offer protection in inflammation and lead to potentially effective
CuII þ Oꢁ2 ! CuI þ O2
ð5Þ
ð6Þ
CuI þ O2ꢁ þ 2Hþ ! CuII þ H2O2
Table 6
Antioxidant activity of Schiff base copper complexes in (l
mol dmꢁ3).
Compound
IC50
(l
mol dmꢁ3
)
IC50
O2ꢁ
(l
mol dmꢁ3
)
OHꢁ
[CuL1(OAc)2]
31
56
33
62
52
25
33
35
38
32
32
30
[CuL2(OAc)2]
[CuL3(OAc)2]
[CuL4(OAc)2]
[CuL5(OAc)2]
[CuL6(OAc)2]
Sodium ascorbate
Bovin Erythrocyte
14.2
2.1
14.2
2.1
Fig. 6. UV Absorption spectrum for [CuL1(OAc)2] in increasing concentration of CT-
DNA.

168
J. Joseph, G. Boomadevi Janaki / Journal of Molecular Structure 1063 (2014) 160–169
SOD ACTIVITY ANTIOXIDANT ACTIVITY
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
0
20
40
60
80
100
120
0
10
20
30
40
50
60
70
80
90
CONCENTRATION mg/ml
CONCENTRATION
[CuL1(OAc)2]
[CuL6(OAc)2]
[CuL2(OAc)2]
[CuL3(OAc)2]
[CuL4(OAc)2]
[CuL5(OAc)2]
[CuL1(OAc)2]
[CuL6(OAc)2]
[CuL2(OAc)2]
[CuL3(OAc)2]
[CuL4(OAc)2]
[CuL5(OAc)2]
Fig. 7. Superoxide dismutase activity of Cu(II) complexes in (l
mol dmꢁ3).
Fig. 8. Anti oxidant activity of Cu(II) complexes in (l
mol dmꢁ3).
It has been proposed that electron transfer between Cu(II) and
Table 7
MIC values of synthesized compounds and their complexes (in
superoxide anion radicals occurs through direct binding. As a con-
sequence of this interaction, these ions undergo rapid reduction to
Cu(I) with the release of O2 molecule. It is assumed that electron
transfer between the central metal and OÅ2ꢁ occurs by direct binding
[30]. The fast exchange of axial solvent molecules and a limited
steric hindrance to the approach of the OÅ2ꢁ in that complexes allow
a better SOD mimic.
l
g/ml).
Compound
Staphylococcus Escherichia Klebsiella
Pseudomonas Proteus
aureus
coli
pneumaniae aeruginosa
vulgaris
L1
L2
L3
L4
L5
L6
16.3
24.6
21.7
24.6
24.6
15.7
23.8
25.8
17.8
25.8
25.8
17.8
7.8
7.3
7.3
7.3
7.3
24.1
28.9
25.9
28.9
28.9
16.9
7.9
8.1
8
8.1
8.1
23.5
26.5
19.5
26.5
26.5
18.5
7.4
7.6
7.5
7.6
7.6
20.2
25.8
22.3
25.8
25.8
17.2
8.5
7.3
7.3
7.3
7.3
3.8.2. H2O2 scavenging assay
[CuL1(OAc)2] 7.3
[CuL2(OAc)2]
The synthesized compounds scavenged the radical in
a
8
concentration dependent manner by causing oxidative damage to
biological targets mediated through Fenton type reaction or
Haber–Weiss reaction and produce OHÅ at the site. With increase
production of OHÅ, vigorously damage DNA (with multiple hit ef-
fect) and convert them into highly reactive radicals. However it
causes damage to the cell even at a very low concentration
[CuL3(OAc)2] 7.4
[CuL4(OAc)2]
[CuL5(OAc)2]
8
8
[CuL6(OAc)2] 6.2
Streptomycin 1.7
6
1.8
6.4
2.3
6.7
1.9
6
1.8
(20 ll) because they liberally soluble in aqueous solution and eas-
indicate that all the compounds tested exhibit moderate to strong
antimicrobial activity on the tested microorganisms. It was ob-
served that increased activity was found in the order of
ily penetrate through biological membrane. Results of percentage
of free radical scavenging activity are shown in Fig. 8 and the val-
ues are tabulated in the Table 6.
½CuL6ðOAcÞ2ꢂ < ½CuL3ðOAcÞ2ꢂ
< ½CuL2ðOAcÞ2ꢂ-½CuL4ðOAcÞ2ꢂ-½CuL5ðOAcÞ2ꢂ
< ½CuL1ðOAcÞ2ꢂ
3.9. Antimicrobial activity
The in vitro antimicrobial activities of the investigated com-
pounds were tested against the bacterial species, Staphylococcus
aureus, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, and
Pseudomonas aeruginosa by disc diffusion method [31,32]. The inhi-
bitions around the antibiotic discs were measured after incubation
and Streptomycin was used as standard drug. It was stated that the
synthesized copper complexes of 2-aminobenzothiazole deriva-
tives showed more activity than its free ligands.
The results with reference to in vitro antimicrobial activities of
the various copper complexes are listed in Table 7. All the com-
pounds tested revealed moderate to strong antimicrobial activity.
Of all the test compounds attempted, [CuL6(OAc)2] and [CuL3
(OAc)2] showed slightly higher activities against most Gram posi-
tive than Gram negative bacteria, but all compounds show strong
activity on the yeast cultures when compared with standard drug
Streptomycin. The significant activity of the Schiff base ligand
may arise from the two imine groups which import in elucidating
the mechanism of transformation reaction in biological system. All
the metal complexes are found to have higher antibacterial activity
against Schiff base ligands. The antibacterial results evidently show
that the activity of the Schiff base compounds becomes more
pronounced when coordinated to the copper ion. The MIC values
Copper toxicity has been largely attributed to its redox-proper-
ties. It can catalyze the production of highly reactive hydroxyl rad-
icals which can subsequently damage lipids, proteins, DNA and
other biomolecules. Therefore, it is possible that copper complexes
of highly conjugated curcumin analogs can cause significant dis-
ruption in cell membrane (enabling more copper to get through
the fungal membrane) leads to extensive damage within the cell.
4. Conclusion
Novel Cu(II) complexes with Schiff bases derived from 2-amino-
benzothiazole and Knoevenagel condensate of b-ketoanilides have
been synthesized and characterized on the basis of elemental anal-
ysis, molar conductance, magnetic moment and spectral data. The
Schiff bases act as bidentate ligand coordinating through two azo-
methine nitrogen atoms. Two acetate ions also coordinated to the
copper ion. The thermal studies indicate that the metal complexes
are thermally more stable compared to the ligand. On the basis of
spectral data, copper complexes showed square planar geometry.
Antibacterial studies of the ligand and complexes have also been

J. Joseph, G. Boomadevi Janaki / Journal of Molecular Structure 1063 (2014) 160–169
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