Co(II), Ni(II), Cu(II) and Zn(II) complexes of aminothiazole-derived Schiff base ligands: Synthesis, characterization, antibacterial and cytotoxicity evaluation, bovine serum albumin binding and density functional theory studies

Article abstract of DOI:10.1002/aoc.4098

Transition metal complexes of type M(L)₂(H₂O)_x were synthesized, where L is deprotonated Schiff base 2,4-dihalo-6-(substituted thiazol-2-ylimino)methylphenol derived from the condensation of aminothiazole or its derivative

Full text of DOI:10.1002/aoc.4098

Received: 27 June 2017
DOI: 10.1002/aoc.4098
Revised: 10 August 2017
Accepted: 11 August 2017
F U L L P A P E R
Co(II), Ni(II), Cu(II) and Zn(II) complexes of aminothiazole‐
derived Schiff base ligands: Synthesis, characterization,
antibacterial and cytotoxicity evaluation, bovine serum
albumin binding and density functional theory studies
A. Prakash | R. Malhotra
Guru Jambheshwar University of Science
Transition metal complexes of type M(L)2(H2O)x were synthesized, where L is
deprotonated Schiff base 2,4‐dihalo‐6‐(substituted thiazol‐2‐ylimino)methyl-
phenol derived from the condensation of aminothiazole or its derivatives with
2‐hydroxy‐3‐halobenzaldehyde and M = Co2+, Ni2+, Cu2+ and Zn2+ (x = 0 for
Cu2+ and Zn2+; x = 2 for Co2+ and Ni2+). The synthesized Schiff bases and their
and Technology Hissar, 125001, Haryana,
India
Correspondence
R. Malhotra, Guru Jambheshwar
University of Science and Technology
Hissar, 125001, Haryana, India.
Email: malhotra_ksrk@yahoo.co.in
1
metal complexes were thoroughly characterized using infrared, H NMR, elec-
tronic and electron paramagnetic resonance spectroscopies, elemental analysis,
molar conductance and magnetic susceptibility measurements, thermogravi-
metric analysis and scanning electron microscopy. The results reveal that the
bidentate ligands form complexes having octahedral geometry around Co2+
and Ni2+ metal ions while the geometry around Cu2+ and Zn2+ metal ions is
four‐coordinated. The geometries of newly synthesized Schiff bases and their
metal complexes were fully optimized in Gaussian 09 using 6–31 + g(d,p) basis
set. Fluorescence quenching data reveal that Zn(II) and Cu(II) complexes bind
more strongly to bovine serum albumin in comparison to Co(II) and Ni(II)
complexes. The ligands and their complexes were evaluated for in vitro
antibacterial activity against Escherichia coli ATCC 25922 (Gram negative)
and Staphylococcus aureus ATCC 29213 (Gram positive) and cytotoxicity
against lever hepatocellular cell line HepG2.
Funding information
Council of Science and Industrial
Research, Grant/Award Number: 09/752/
(0045)/2012‐EMR‐1
KEYWORDS
antibacterial activity, BSA binding, Co(II), Ni(II), Cu(II) and Zn(II) complexes, cytotoxicity evaluation,
DFT studies, Schiff base, spectroscopic studies
1 | INTRODUCTION
Schiff base ligands, existing in keto and enolic form,
which are of particular interest due to their wide range
Schiff bases are compounds synthesized in high yields by
conventional or microwave condensation between
equivalent amounts of primary amines and aldehyde or
ketones.[1–3] Aminothiazoles, which act as oestrogen
receptors and a novel class of adenosine receptor antago-
nists, when condensed with carbonyl compounds form
of applications as antimicrobial,[4] anticancer,[5–7] anti-
platelet activity[8] and anti‐inflammatory[9] agents and
for Alzheimer's disease treatment.[10] These Schiff base
ligands have strong coordinative ability due to their syn-
thetic flexibility, selectivity and sensitivity towards metal
ions. The activity of these complexes of Schiff base ligands
Appl Organometal Chem. 2017;e4098.
wileyonlinelibrary.com/journal/aoc
Copyright © 2017 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4098

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PRAKASH AND MALHOTRA
in biological systems depends on the ease of cleavage of
bonds between ligands and metal ions.
The biological importance of the thiazole ring is very
well known and reported in the literature. Penicillin, the
2.2 | General procedure for synthesis of
ligands HL1–HL3
Ligand HL1 was synthesized by refluxing equimolar
amounts of 5‐methyl‐2‐aminothiazole (1.14 g, 0.01 mol)
and 2‐hydroxy‐3,5‐dichlorobenzaldehyde (1.91 g, 0.01 mol)
in 50 ml of methanol for 2 h (Scheme 1). The progress of
the reaction was monitored by TLC and, after completion
of the reaction, the solution was left overnight at room tem-
perature. The solid product separated out, which was fil-
tered, washed and recrystallized from ethanol. The same
procedure was usedfor the synthesisof ligandsHL2 and HL3.
The structures of the synthesized Schiff bases were
characterized using infrared (IR), 1H NMR and mass spec-
trometry and analytical data.
very first known antibiotic, also contains
a
tetrahydrothiazole in its skeleton. Thiazolamines are key
intermediates for synthesizing many pharmaceuticals.[11]
A literature survey revealed that compounds with a thia-
zole ring show enhanced biological activity.[12]
Aminothiazoles are known to be ligands of the oestrogen
receptor and as a novel class of adenosine receptor
antagonists.[13]
It has been reported that many compounds show a
marked enhancement in pharmacological and toxicologi-
cal properties when combined with metal ions.[14–16] In
continuation of our research work[17–20] on the study of
the chelation effect on biologically active molecules, we
herein report some new Schiff base ligands derived from
the condensation of aminothiazole and salicylaldehyde
derivatives and their metal complexes to study their anti-
bacterial and cytotoxic properties.
2.2.1 | 2,4‐Dichloro‐6‐(((5‐methylthiazol‐2‐
yl)imino)methyl)phenol (HL1)
Yield: 78%; colour: yellow; m.p. 152 °C. IR (KBr, cm−1):
1660 ν(HC¼N), 3068 ν(―OH). 1H NMR (400 MHz;
CDCl3; δ, ppm): 2.50 (s, 5–CH3), 7.34 (d, 6′–H), 7.36 (s,
4–H), 7.48 (d, 4′–H), 9.08 (s, N¼CH), 13.04 (s, −OH).
MS (ESI): [M + H]+ = 287.88.
2 | EXPERIMENTAL
2.2.2 | 2‐Bromo‐4‐chloro‐6‐(((5‐
methylthiazol‐2‐yl)imino)methyl)phenol
(HL2)
2.1 | Materials and methods
All chemicals used were of AnalaR grade and obtained
from Sigma‐Aldrich and Fluka. Metal salts were pur-
chased from E. Merck and were used as received.
Yield: 83%; colour: orange; m.p. 136 °C. IR (KBr, cm−1):
1672 ν(HC¼N), 3080 ν(―OH). 1H NMR (400 MHz;
SCHEME 1 Synthesis of Schiff base ligands and metal complexes

PRAKASH AND MALHOTRA
3 of 14
CDCl3; δ, ppm): 2.49 (s, 5–CH3), 7.35 (s, 4–H), 7.37 (d, 6′–
H), 7.63 (d, 4′–H), 9.05 (s, N¼CH), 13.18 (s, −OH). MS
(ESI): [M + H]+ = 330.71.
(0.56 g, 2 mmol) with an ethanolic solution (20 ml) of salt
of Co(II) (0.238 g, 1 mmol), Ni(II) (0.238 g, 1 mmol),
Cu(II) (0.170 g, 1 mmol) or Zn(II) (0.136 g, 1 mmol).
The reaction mixture was stirred for 1 h followed by
refluxing for 4–18 h. The solvent was reduced to half
and the reaction mixture was kept overnight. The product
separated out, which was filtered off, washed with cold
ethanol and ether and dried under vacuum over P4O10.
The Co(II), Ni(II), Cu(II) and Zn(II) complexes (5–12)
of ligands HL2 and HL3 were prepared using a similar pro-
cedure. Physical, analytical and spectral data of ligands
and metal complexes are given in Table 1.
2.2.3 | 2,4‐Dichloro‐6‐((thiazol‐2‐ylimino)
methyl)phenol (HL3)
Yield: 69%; colour: pale yellow; m.p. 168 °C. IR (KBr, cm
1
−1): 1653 ν(HC¼N), 3051 ν(―OH). H NMR (400 MHz;
CDCl3; δ, ppm): 7.34 (d, 4–H), 7.37 (d, 6′–H), 7.50 (d, 4′–
H), 7.70 (d, 5–H) 9.18 (s, N¼CH), 13.02 (s, −OH). MS
(ESI): [M + H]+ = 272.92.
2.3 | General procedure for synthesis of
metal complexes 1–12
2.4 | Analysis
1H NMR spectra were recorded with a Bruker 400 MHz
NMR spectrometer and the chemical shifts were reported
in ppm relative to tetramethylsilane as an internal
The metal complexes (1–4) of ligand HL1 were prepared
by mixing a hot ethanolic solution (20 ml) of HL1
TABLE 1 Physical measurements and analytical data of ligands (HL1–HL3) and metal complexes(1–12)
Elemental analysis: found (calcd)
Molecular mass/
Compound molecular formula
Melting
Yield (%) point (°C) C (%)
m/z
H (%)
N (%)
M (%)a
HL1
HL2
HL3
1
C11H8Cl2N2OS
C11H8BrClN2OS
C10H6Cl2N2OS
287.18 78
330.71 83
272.92 69
665.64 62
152
136
46.13 (46.01) 2.84 (2.81)
9.62 (9.76)
—
39.86 (39.84) 2.39 (2.43)
8.45 (8.52)
—
168
43.83 (43.97) 2.20 (2.21) 10.32 (10.26)
—
Co(L1)2(H2O)2
C22H18Cl4CoN4O4S2
>260
39.42 (39.60) 2.59 (2.72)
39.53 (39.61) 2.70 (2.72)
41.68 (41.56) 2.26 (2.22)
41.36 (41.44) 2.17 (2.21)
35.14 (34.94) 2.47 (2.40)
34.86 (34.95) 2.44 (2.40)
37.05 (36.46) 2.08 (1.95)
36.43 (36.37) 1.98 (1.94)
37.81 (37.58) 2.27 (2.21)
37.60 (37.59) 2.34 (2.21)
39.46 (39.52) 1.69 (1.66)
39.47 (39.40) 1.68 (1.65)
8.43 (8.40)
8.49 (8.40)
8.78 (8.81)
8.78 (8.79)
7.58 (7.41)
7.60 (7.41)
7.61 (7.73)
7.64 (7.71)
8.76 (8.76)
8.92 (8.77)
9.37 (9.22)
9.16 (9.19)
9.12 (8.83)
2
Ni(L1)2(H2O)2
C22H18Cl4N4NiO4S2
664.02 58
633.92 67
634.64 65
753.21 56
752.84 57
721.72 75
722.29 79
637.11 82
637.01 72
605.32 67
606.12 63
>260
>260
>260
>260
>260
>260
>260
>260
>260
>260
>260
9.02 (8.80)
9.91 (9.99)
10.41 (10.25)
7.68 (7.79)
7.91 (7.76)
8.84 (8.77)
9.07 (9.00)
9.36 (9.22)
9.14 (9.19)
10.67 (10.45)
10.86 (10.72)
3
Cu(L1)2
C22H14Cl4CuN4O2S2
4
Zn(L1)2
C22H14Cl4N4O2S2Zn
5
Co(L2)2(H2O)2
C22H18Br2Cl2CoN4O4S2
6
Ni(L2)2(H2O)2
C22H18Br2Cl2N4NiO4S2
7
Cu(L2)2
C22H14Br2Cl2CuN4O2S2
8
Zn(L2)2
C22H14Br2Cl2N4O2S2Zn
9
Co(L3)2(H2O)2
C20H14Cl4CoN4O4S2
10
11
12
Ni(L3)2(H2O)2
C20H14Cl4N4NiO4S2
Cu(L3)2
C20H10Cl4CuN4O2S2
Zn(L3)2
C20H10Cl4N4O2S2Zn
aM = Co(II), Ni(II), Cu(II), Zn(II).

4 of 14
PRAKASH AND MALHOTRA
standard. IR spectra were recorded with a Shimadzu IR
affinity‐I 8000 FT‐IR spectrometer using KBr discs.
Electrospray ionization (ESI) mass spectra were obtained
using a VG Biotech Quattrro mass spectrometer equipped
with an ESI source in the mass range m/z 100 to 1000. UV
spectra were recorded in dimethylsulfoxide (DMSO) with
a Varian Cary‐5000 spectrometer. Electron paramagnetic
resonance (EPR) spectra of the Cu(II) complexes were
recorded using a JES FA200 ESR X‐band spectrometer
using tetracyanoethylene as the internal reference. Ele-
mental analysis was carried out with a PerkinElmer
2400. Thermogravimetric analysis (TGA) of samples was
carried out using an SDT‐Q600 simultaneous TGA/DSC
instrument at a heating rate of 10 °C min−1. Magnetic
moments at room temperature of the complexes were cal-
culated by Gouy's method, using Hg[Co(SCN)4] as the
CO2 incubator. Cells were treated with either vehicle
(1% DMSO) or serially diluted test compounds (30 μg ml−1)
or doxorubicin (10 μM as positive control) or 0.1% Triton
(reference control) in a final volume of 200 μl per well
and incubated at 37 °C in a CO2 incubator for 72 h. Fol-
lowing incubation, cells were treated with 100 μg of
MTT and incubated at 37 °C for 4 h. Supernatants were
removed carefully (without disturbing the formazan crys-
tals formed) and 70 μl of DMSO was added to each well.
The plate was kept on a plate shaker until the crystals
were dissolved and the absorbance was read at 540 nm.
The absorbance values from test compound wells were
compared to that for the control wells to calculate the per-
centage inhibition. Inhibition was calculated with respect
to 0.1% Triton (100% inhibition) and 1% DMSO (0%
inhibition).
calibrant. Molar conductance measurements of 10−3
M
solutions of metal complexes in dimethylformamide
(DMF) were conducted using a Systronics model 306 con-
ductivity bridge.
2.7 | Protein binding studies
Fluorescence study of metal complex binding with bovine
serum albumin (BSA) was performed using a spectrofluo-
rimeter (FS920, Edinburgh Instruments, UK) with stan-
dard 3.5 ml quartz cell. The excitation source was a
xenon lamp (450 W) and the sample chamber was
equipped with a Peltier accessory. Scanning parameters
for all measurements were optimized with slit width of
4.0 nm for excitation and emission, dwell time of 0.2 s
and wavelength step of 1 nm. The emission spectra were
recorded in the wavelength range 310–450 nm at a scan
2.5 | Antibacterial activity
Escherichia coli ATCC 25922 (Gram negative) and Staph-
ylococcus aureus ATCC 29213 (Gram positive) were cul-
tured according to ATCC recommendations (American
Type Culture Collection, Manassas, USA). Colonies were
isolated from freshly streaked Mueller–Hinton agar plate.
A bacterial inoculum of 5 × 105 CFU ml−1 was prepared
after adjusting to McFarland's standard following CLSI
guidelines. Ampicillin was used as reference drug and
DMSO as a negative control. Stocks for test compounds
and ampicillin were appropriately diluted (total 11 dilu-
tions in duplicate) to achieve a final concentration range
of 64 to 0.0625 μg ml−1 with 100% DMSO. Diluted com-
pounds were added into cation‐adjusted Mueller–Hinton
Broth (CAMHB) and bacterial suspension was finally
added to it. Plates were placed in a 37 °C air incubator
and incubated for 18–20 h followed by turbidity measure-
ment at 600 nm (Spectra Max M5, Molecular Devices).
Minimum inhibitory concentration (MIC) was interpreted
as the lowest concentration of antimicrobial agent that
completely inhibited growth of an organism.
rate of 100 nm min−1
.
2.8 | Density functional theory (DFT)
calculations
DFT calculations were performed with the Gaussian 09 W
program using the 6–31 + g(d,p) basis set.[21] The geome-
tries with respect to energy were fully optimized using the
B3LYP three‐parameter density functional, which
includes Becke's gradient exchange correction,[22] the
Lee, Yang, Parr correlation functional[23] and the Vosko,
Wilk, Nusair correlation functional.[24]
3 | RESULTS AND DISCUSSION
2.6 | Cytotoxicity assessment
Schiff bases (HL1–HL3) are obtained by the nucleophilic
addition of the ―NH2 group of 2‐aminothiazoles to the
carbonyl group of substituted aromatic hydroxyaldehydes
as shown in Scheme 1.
The crystalline solids so obtained have different
shades of yellow or orange colour due to the presence of
chromophoric group (HC¼N) in the molecule. All the
metal complexes were prepared by direct reaction
Effects of compounds on the viability of human cancer
(hepatocellular) cell lines were determined by colorimet-
ric assay using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl-
tetrazolium bromide (MTT). HepG2 cells were procured
from ATCC and cultured according to ATCC instructions.
Around 8500 cells per well were plated in a 96‐well plate
24 h prior to the experiment and incubated at 37 °C in a

PRAKASH AND MALHOTRA
5 of 14
between Schiff base and corresponding metal salt. The
synthesized complexes are crystalline solids and stable
in air at room temperature. The melting points of the
metal complexes are much higher than those of the
ligands, which indicates that these complexes are much
more stable as compared to the ligands. The complexes
in 10−3 M DMF solution have low molar conductance
values (8.5–12.8 Ω−1 cm2 mol−1) indicating their non‐
electrolyte nature.[25]
of ―OH proton during metal complexation. A slight
downfield shift (9.27 ppm) was observed for azomethine
proton as compared to the ligands suggesting the coordi-
nation of azomethine nitrogen to Zn(II) ion, while the rest
of the signals due to aromatic and thiazolyl protons
remain almost unaltered. A comparison of the H NMR
spectra of HL3 and Zn(L3)2 complex is shown in
Figure 1.
1
3.2 | Mass spectra
3.1 | 1H NMR spectra
In the ESI mass spectrum of ligand HL1, a peak corre-
sponding to [M + H]+ ion appears as molecular ion peak
at m/z = 287.88 amu. The molecular ion peak confirms
the proposed formula (C11H8Cl2N2OS). Peaks correspond-
ing to various fragments of HL1 appear at 287.18, 203.98,
180.81, 179.68, 177.95, 101.98 and 73.99 amu. Similarly,
for ligands HL2 and HL3, the molecular ion peak appears
at 330.71 and 272.92 amu, respectively. The m/z values for
metal complexes 1–12 are given in Table 1.
The 1H NMR spectra of the ligands and their Zn(II) com-
plexes were recorded in CDCl3 containing a small amount
of DMSO‐d6 with tetramethylsilane as internal reference
to confirm the structure of the ligands and the mode of
bonding in Zn(II) complexes. The presence of azomethine
proton of all the aldimines was confirmed by observing
one proton singlet at 9.03–9.18 ppm. Two doublets corre-
sponding to one proton each assigned to CH¼CH of
thiazolyl group was observed at 7.5 ppm in the case of
HL3. One proton singlet assigned to phenolic proton was
observed at 13.02–13.18 ppm for all the ligands. Signals
due to aromatic protons were observed at 7.3–7.7 ppm.
A comparison of 1H NMR spectra of the ligands and their
Zn(II) complexes gives a clue to the mode of binding of
ligand to zinc metal. The one‐proton singlet in the range
13.02–13.18 ppm in the spectra of HL1–HL3, which corre-
sponds to ―OH proton, completely disappeared after
complex formation. The disappearance of the singlet due
to OH group of the free ligand indicates the deprotonation
3.3 | IR spectra
To understand the binding mode of the ligands to the cor-
responding metal ions, IR spectral data of HL1–HL3 and
their metal complexes are compared. The coordination
of the ligand to the corresponding metal ion was con-
firmed on the basis of shifts in absorption bands of various
groups and absence of certain absorptions (Table 2). In
the IR spectra of the ligands, the bands originally attrib-
uted to ν(C¼O) of aldehyde and ν(NH2) of aminothiazole
1
FIGURE 1 Comparison of H NMR spectra of HL3 and Zn(L3)2

6 of 14
PRAKASH AND MALHOTRA
TABLE 2 Important IR spectral bands (cm−1) and assignments
Compound
ν(C¼N)
1660
ν(OH)
ν(M―O)
ν(M―N)
HL1
3068
—
—
1
1638
1639
1641
1642
1672
1657
1651
1653
1654
1653
1639
1633
1631
1633
—
555
567
562
551
—
418
422
424
436
—
2
—
3
—
4
—
HL2
5
3080
—
542
547
561
549
—
427
439
459
449
—
6
—
7
—
8
—
HL3
9
3051
—
FIGURE 2 EPR spectra of Cu(L2)2 (RT, room temperature; LNT,
liquid nitrogen temperature)
534
567
563
557
416
432
428
441
10
11
12
—
—
—
at 1750, 3320 and 3460 cm−1, respectively, of the starting
materials were absent. Instead, a new band appeared at
1653–1672 cm−1, assigned to ν(HC¼N) vibration, which
confirms the formation of Schiff base.[26] Comparison of
the IR spectral data of the ligands and the metal complexes
reveals that the band corresponding to ν(HC¼N) vibration
shifts in frequency by 20–25 cm−1 for all the metal com-
plexes, which indicates the involvement of nitrogen of
azomethine in metal complexation.[27] This is further sup-
ported by the appearance of a new band at 416–459 cm−1
due to ν(M―N) stretching vibrations.[28] A band at 3051–
3080 cm−1 in the IR spectra of ligands is due to ν(―OH)
stretching vibration and the low value may be due to
hydrogen bonding between OH and nitrogen of
azomethine. The absence of this band in the IR spectra of
metal complexes indicates the deprotonation of phenolic
OH on metal complexation and coordination through phe-
nolic oxygen. This was further confirmed by the appear-
ance of a weak low‐frequency band at 534–567 cm−1 due
to ν(M―O).[29] The presence of coordinated water
molecule in complexes of Co2+ and Ni2+ metal ions was
confirmed by the presence of a broad band observed in
the range 3273–3454 cm−1 [30]
while no such band was
,
observed in the spectra of the Cu2+ and Zn2+ complexes.
TABLE 3 EPR data for Cu(II) complexes
Complex
g||
g⊥
gav
G
λ
α2
Cu(L1)2
2.22
2.08
2.13
2.80
−501
0.62
Cu(L2)2
Cu(L3)2
2.24
2.23
2.08
2.09
2.13
2.14
3.05
2.60
−509
−534
0.69
0.66
FIGURE 3 Scanning electron microscopy images of (a) HL3 and
(b) Cu(L3)2

PRAKASH AND MALHOTRA
7 of 14
3
3
3
3
assigned to A2g(F) → T2g(F), A2g(F) → T1g(F) and
3.4 | Conductance and magnetic
susceptibility measurements
3
3A2g(F) → T1g(P), respectively, indicating octahedral
geometry around Ni2+ complexes.[31]
The molar conductance values of metal complexes 1–12
were obtained in DMF as a solvent at room temperature.
The molar conductance of the metal complexes in DMF
showed values (8.5–12.8 Ω−1 cm2 mol−1) indicating that
complexes 1–12 are non‐electrolytes.[25]
The magnetic moment values of all the metal com-
plexes at room temperature were recorded. The magnetic
moment values of Co(II) complexes were found to be in
the range 4.94–5.02 BM, suggesting the Co(II) complexes
in an octahedral environment.[29] Ni(II) complexes have
magnetic moment values in range 2.93–2.97 BM corre-
sponding to two unpaired electrons, indicating a triplet
ground state having octahedral geometry around the
metal ion.[29] Cu(II) complexes show magnetic moment
values of 1.69–1.74 BM, which indicate a square planar
arrangement around the Cu(II) ion.
The electronic spectra of Cu(II) complexes show two
2
low‐energy weak bands assigned to B1g
→
2A1g and
2B1g
→
2Eg transitions at 15 250–15 670 and 20 000–
20 500 cm−1, respectively.[31] A strong high‐energy band
at 30 100–30 900 cm−1 is assigned to metal–ligand
charge transfer.
3.6 | EPR spectra
The solid‐state X‐band EPR spectra of Cu(II) polycrystal-
line solid complexes were recorded in powder form at
room temperature and in DMSO at 77 K. The EPR spec-
trum of Cu(L1)2 at room temperature displayed an isotro-
pic signal having axially symmetric line shape with two g
values, i.e. g|| = 2.22 and g⊥ = 2.08, and gav was computed
3.5 | Electronic spectra
The electronic spectra of Co(II) complexes derived from
ligands HL1 and HL2 show two bands in the region
15 200–16 900 and 21 000–22 000 cm−1 assigned to 4T1g(F)
4
4
→
4A2g(F) (ν2) and T1g(F) → T1g(P) (ν3) transitions,
respectively, while the complex obtained from ligand HL3
gives three bands in the region 9700–10 000 (ν1), 15 000–
16 000 (ν2) and 22 400–23 100 cm−1 (ν3) which are in accor-
dance with octahedral geometry around the Co2+ ion.[27]
The high‐energy band at 29 000–30 000 cm−1 for all the
complexes is assigned to metal–ligand charge transfer band.
The Ni(II) complexes show three bands in the regions
10 300–10 700, 16 200–17 200 and 24 700–25 300 cm−1
FIGURE 4 Numbering schemes of (a) ligand HL1 and (b) metal
complexes 1–4
TABLE 4 Thermal analysis data for metal complexes 1–4
Mass loss (%)
Molecular
formula
Possible evolved
species
Residual
species
Complex
1
Stage
Temp. (°C)
Found
Calcd
Co(L1)2(H2O)2
C22H18Cl4CoN4O4S2
1
2
3
120–160
160–390
390–800
2H2O
C8H10N2S2
Remaining moiety
CoO
5.43
29.72
53.51
11.34
5.41
29.67
53.68
11.24
2
Ni(L1)2(H2O)2
C22H18Cl4N4NiO4S2
1
2
3
140–190
190–410
370–800
2H2O
C5H5NS
Remaining moiety
NiO
5.51
15.11
67.93
11.45
5.26
14.90
68.7
11.14
3
4
Cu(L1)2
C22H14Cl4CuN4O2S2
1
2
110–380
380–800
C10H10N2S2Cl4
Remaining moiety
CuO
ZnO
56.89
30.22
12.87
57.18
30.44
12.48
Zn(L1)2
C22H14Cl4N4O2S2Zn
1
2
120–360
390–670
C10H10N2S2
Organic moiety
34.94
52.14
12.92
35.01
52.38
12.61

8 of 14
PRAKASH AND MALHOTRA
using the relation gav = 1/3(g|| + 2g⊥). From the observed
values it is clear that g|| > g⊥ > 2.0023, and these parame-
ters are well consistent with related systems which suggest
a square planer geometry around Cu(II) metal ion, with an
(0.62–0.69) of the Cu(II) complexes indicate that these are
fairly covalent. The EPR spectra of Cu(L2)2 complex is
displayed in Figure 2.
2
2
unpaired electron lying predominantly in the dx −y orbital
giving 2B1g as the ground state. The value of g|| also helps in
predicting the ionic and covalent environment in metal–
ligand bonding. The g|| values being less than 2.3 is an
indication of significant covalent bonding in Cu(II)
complexes.[32] The value of exchange interaction term G
calculated using G = (g|| − 2.0023)/(g⊥ − 2.0023) gives an
idea about exchange interactions between Cu(II) centres.
The value of G < 4.0 indicates negligible exchange
interactions of Cu–Cu in the complex. The spin–orbital
coupling constant λ values (−534 to −501 cm−1) calcu-
lated using the relation gav = 2(1–2λ/10Dq) are less than
that for the free Cu2+ ion (−828 cm−1) which supports
the covalent character of metal–ligand bond in these com-
plexes. The fraction of unpaired electron density located
on Cu2+ ion, i.e. the value of in‐plane σ‐bonding parame-
ter α2 was calculated using the expression α2 = −(A||/
0.036) + (g|| − 2.0023) + 3/7(g⊥ − 2.0023) + 0.04
(Table 3). From the value of α2, we can predict the ionic
or covalent character in metal complexes: a value of α2 of
0.5 indicates covalent bonding, while a value of 1.0 sug-
gests complete ionic bonding. The calculated values of α2
3.7 | Scanning electron microscopy
On comparison of the scanning electron microscopy
images of free ligand (HL3) and metal complex ([Cu(L3)2])
(Figure 3), it is clear that a crystalline image of the com-
plex was obtained after the complexation process. These
complexes have agglomerated morphological structures.
Cu(II) complexes have needle‐like structure while the
other complexes have broken stone‐like structure. Efforts
made to isolate single crystal of these complexes were not
successful. So to understand better the electronic and
molecular structures of the synthesized ligands and metal
complexes, DFT calculation was performed.
3.8 | Thermogravimetric analysis
Thermal behaviour of complexes was investigated using
the TGA technique. TGA of metal complexes 1–4 was car-
ried out with temperature ranging from room temperature
to 800 °C. The TGA curves show that metal complexes 1–4
decompose in three steps. The first step in the TGA curve
(110–260 °C) of Ni(H2O)2(L1)2/Co(H2O)2(L1)2 corresponds
FIGURE 5 Optimized structures of (a) ligand HL1, (b) [Co(L1)2(H2O)2], (c) [Ni(L1)2(H2O)2], (d) [Cu(L1)2] and (e) [Zn(L1)2]

PRAKASH AND MALHOTRA
9 of 14
to the loss of coordinated water molecules in the complex,
while no such loss of weight is observed in the case of
Zn(L1)2/Cu(L1)2 complex in the same temperature range,
eliminating the possibility of coordinated water present
in the complex. The second and third steps correspond
to the loss of organic moiety leaving metal oxide as the
final residue. Based on the thermograms, decomposition
stages, temperature ranges, decomposition product as
well as weight loss percentages of the complexes were cal-
culated (Table 4).
FIGURE 6 Proposed structures of metal complexes
TABLE 5 Optimized geometry of ligand HL1 and metal complexes 1–4 (bond lengths in angstroms; bond angles in degrees)
Parametera
Ligand HL1
Complex 1
Complex 2
Complex 3
Complex 4
C1–O1
1.370
1.563
1.561
1.545
1.536
C1–C2
1.403
1.390
1.394
1.386
1.413
1.432
1.459
1.334
1.427
1.376
1.385
1.390
1.832
1.839
—
1.437
1.398
1.401
1.389
1.409
1.491
1.478
1.293
1.487
1.381
1.396
1.401
1.813
1.890
2.109
2.116
2.048
2.046
2.067
2.082
91.57
82.56
86.23
89.23
82.14
87.12
173.20
171.27
174.12
1.456
1.392
1.410
1.398
1.411
1.524
1.491
1.320
1.501
1.383
1.402
1.407
1.875
1.934
2.007
2.019
2.134
2.098
2.012
2.101
83.12
79.34
87.72
82.38
81.23
78.92
170.12
177.20
170.45
1.491
1.391
1.427
1.401
1.436
1.591
1.501
1.318
1.543
1.395
1.409
1.401
1.892
1.949
2.190
2.212
2.378
2.421
—
1.458
1.403
1.415
1.393
1.428
1.528
1.494
1321
1.508
1.381
1.404
1.405
1.888
1.921
2.098
2.124
2.097
2.103
—
C2–C3
C3–C4
C4–C5
C5–C6
C1–C6
C6–C7
C7–N1
N1–C8
C8–N2
N2–C9
C9–C10
C10–S1
C8–S1
M–O1
M–O1’
—
M–N1
—
M–N1’
—
M–X1
—
M–X2
—
—
—
∠O1MX1
∠O1MN1
∠N1MX2
∠X2MO1’
∠O1’MN1’
∠N1’MX1
∠O1MO1’
∠X1MX2
∠N1MN1’
—
—
—
—
99.12
—
107.10
—
—
—
—
—
—
101.24
—
108.23
—
—
—
172.12
—
101.12
—
—
—
175.34
103.13
aSee Figure 4 for numbering.

10 of 14
PRAKASH AND MALHOTRA
computed bond lengths for the ligand and the metal
complexes are given in Table 5.
3.9 | Geometry optimization
Ligand HL1 and metal complexes 1–4 were fully opti-
mized in the gas phase with respect to energy using
B3LYP functional and 6–31 + g(d,p) basis set in Gaussian
09 W software. The numbering scheme used to compute
bond lengths and bond angles for ligand HL1 and com-
plexes is shown in Figure 4, and the structures of the
fully optimized geometries are shown in Figure 5. Ligand
HL1 coordinates through azomethine nitrogen and
deprotonated hydroxyl oxygen to Co(II) ion in (ML1)2
type complex 1 in an octahedral fashion. The other two
positions are occupied by water molecules. The opti-
mized structure shows that the geometry around the
metal centre is distorted octahedral and the computed
bond lengths around the metal centre are slightly elon-
gated when compared with free ligand. This might be
possible because of the electron transfer from ligand to
metal. The ligand which has a planar structure loses its
planarity after metal complexation. The two chlorine
atoms move out of the plane in opposite directions. The
After metal coordination, slight deformation was
noticed in complex 1 in the ligand moiety. Because of
this deformation the bond lengths C1–O1, C1–C1, C1–C6,
C7–N1 and N1–C2 elongate slightly. The bond length
C1–O1 which was 1.370 Å in free ligand elongates to
1.563, 1.561, 1545 and 1.536 Å, respectively, in metal
complexes 1–4. A similar trend was observed for other
bond length values. A slight difference in bond length
values causes a deviation of bond angle from regular
90° around the metal centre. Bond angles ∠O1MX1,
∠O1MN1, ∠N1MX2, ∠X2MO1’, ∠O1’MN1’ and ∠N1’MX1
were found to be 91.57°, 82.56°, 86.23°, 89.23°, 82.14°
and 87.12°, respectively. No appreciable change was
observed in bond length and bond angle values in ben-
zene and thiazole moiety.
The Ni(II) complex (2) also showed distorted octahe-
dral geometry as observed from the computed parameters.
Complex 3 which is Cu(II) complex stabilized in square
planar geometry and Zn(II) complex which is complex 4
TABLE 6 Cytotoxicity activity of ligands HL1–HL3 and metal complexes 1–12
Optical density at 540 nm
Compound
Concentration (μg ml−1
)
n1
n2
Average
Inhibition (%)
HL1
30
0.4976
0.513
0.505
8
HL2
30
30
30
30
30
30
30
30
30
30
30
30
30
30
0.5508
0.2489
0.4255
0.219
0.5559
0.2635
0.427
0.553
0.256
0.426
0.227
0.542
0.326
0.525
0.504
0.601
0.563
0.456
0.565
0.570
0.547
0
59
24
65
1
HL3
Co(L1)2(H2O)2
Ni(L1)2(H2O)2
Cu(L1)2
0.234
0.5457
0.324
0.5387
0.3286
0.5294
0.5004
0.591
Zn(L1)2
45
4
Co(L2)2(H2O)2
Ni(L2)2(H2O)2
Cu(L2)2
0.5221
0.5068
0.6109
0.5627
0.437
9
−11
−4
18
−4
−5
0
Zn(L2)2
0.5633
0.474
Co(L3)2(H2O)2
Ni(L3) (H2O)22
Cu(L3)2
0.561
0.568
0.5576
0.5463
0.5832
0.547
Zn(L3)2
Plate 1
(1%) DMSO control
Doxorubicin(10 μM)
(0.1%) Triton
0.546
0.110
0.0542
0.545
0.110
0.0553
0.545
0.110
0.055
0
89
100
Plate 2
Plate 3
(1%) DMSO control
Doxorubicin (10 μM)
(0.1%) Triton
0.556
0.112
0.0554
0.552
0.109
0.0552
0.554
0.111
0.055
0
89
100
(1%) DMSO control
Doxorubicin (10 μM)
(0.1%) Triton
0.511
0.102
0.0541
0.523
0.105
0.0553
0.517
0.104
0.055
0
89
100

PRAKASH AND MALHOTRA
11 of 14
display tetrahedral geometry with a similar trend in com-
puted parameters. The computed bond lengths and bond
angles of complexes 1–4 are given Table 5.
We also conducted charge analysis for metal
complexes 1–4 and the results show that, in complex 1,
groups, which may involve hydrogen bonding with active
centres of specific cell enzymes, thereby resulting in inter-
ference with normal cell processes. But the results unex-
pectedly showed that all the ligands and many of the
metal complexes of these ligands exhibit inhibition (MIC
> 64 μg ml−1) towards the tested microorganisms under
similar experimental conditions. In the case of metal com-
plex Cu(L1)2 (MIC > 16 μg ml−1) an enhancement was
observed in antimicrobial activity of the ligand on coordi-
nation to metal ion against S. aureus (Gram positive)
under similar experimental conditions. This increase in
the activity on complexation as compared to free ligand
is explained on the basis of chelation theory. The positive
charge on metal ion is decreased upon coordination
through donor atoms of the ligand and thus reducing
the polarity of the metal ion due to which π‐electron delo-
calization occurs within the whole chelate ring system.
This process increases the lipophilic nature of the metal
atom which favours its penetration through the lipid layer
of the membrane wall of the microorganism thus
destroying it more effectively.
the
electronic
configuration
of
Co(II)
is:
[core]4s0.023d6.814p0.725s0.185p0.01, plus 18 core electrons,
7.74 valence electrons and 0.026 Rydberg electrons for a
total of 25.766 electrons and is in agreement with the cal-
culated natural charge on Co(II) (+01.233e). Similar
results are found for complexes 2–4 and the results are
in agreement with the charges found on metal ion. On
the basis of these above calculated results, structures can
be anticipated for the synthesized metal complexes, as
shown in Figure 6.
3.10 | Antibacterial activity
All the compounds were tested against two bacteria:
Gram‐negative E.coli and Gram‐positive S. aureus. The
results were compared with those for the standard drug
ampicillin. It has been reported that the nitrogen of
azomethine group having a lone pair of electrons has con-
siderable biological importance. The activity of the ligand
therefore may be expected to be due to the presence of
toxophorically important azomethine and thiazolyl
3.11 | Cytotoxicity bioassay
From the cytotoxicity data it may be concluded that
ligands HL1 and HL3 obtained by the condensation of
FIGURE 7 Dose–response curve of HL3
FIGURE 8 Dose–response curve of
Ni(L3)2(H2O)2

12 of 14
PRAKASH AND MALHOTRA
aminothiazole or methyl‐substituted aminothiazole with
3,5‐dichlorosalicylaldehyde are active against human
cancer cell line HepG2, while ligand HL2 being a conden-
sation product of methylaminothiazole and 3‐
bromo‐5‐chlorosalicylaldehyde exhibits no inhibition
towards cancer cells under the experimental conditions
(Table 6). Among these ligands, HL3 exhibits maximum
percentage inhibition as aminothiazole is sterically more
demanding (R = R1 = H). Therefore a dose–response
curve of ligand HL3 (Figure 7) compared to standard
drugs was obtained with concentration ranging from 30
to 0.2 μg ml−1. Complexes derived from ligand HL1, i.e.
[Co(L1)2(H2O)2], [Ni(L1)2(H2O)2] and [Zn(L1)2], show a
several‐fold increase in activity as compared to the free
ligand. One of the complexes, [Ni(L1)2(H2O)2], exhibited
promising activity, and therefore a dose–response curve
of the complex (Figure 8) was obtained in a similar man-
ner as discussed earlier. Other metal complexes exhibit
moderate or no inhibition and none of the ligands and
complexes was better than the standard used.
3.12 | Protein binding studies
Intermolecular interactions that occur due to various pro-
cesses such as excited‐state reactions, molecular rear-
rangements, energy transfer, ground‐state complex
formation and collision quenching can be easily studied
using the fluorescence quenching mechanism.[33] The
fluorescence spectra of metal complexes 1–4 in the pres-
ence of BSA have a strong emission band (λem) at
327 nm, which corresponds to tryptophan residues of
BSA. It was expected that metal complexes would interact
with the tryptophan residues of BSA. To investigate this,
fluorescence quenching was studied taking a fixed con-
centration of BSA and varying concentrations of metal
complexes (6.62–33.2 μΜ) to evaluate the binding con-
stant of 1–4 with BSA. The results clearly show that keep-
ing BSA concentration constant and increasing the
concentration of metal complexes leads to a considerable
decrease in the fluorescence intensity of BSA. This might
be possible because of the complexation of BSA with
metal complexes. A similar change in the intensity of
BSA fluorescence after metal complexation has been
reported in the literature.[34]
For metal complex 1, the red shift observed was
because of the increase in polarity of the microenviron-
ment around the tryptophan residue after metal complex-
ation. Probably, the loss of compact structure in the
hydrophobic subdomain II where tryptophan‐214 is
placed caused this shift.[35] Similarly, on addition of nickel
complex 2 and copper complex 3 in varying concentra-
tions to BSA causes a red shift from 327 to 337 nm for 2,
FIGURE 9 Fluorescence quenching spectra and Stern–Volmer
plots of BSA for various concentrations of complexes: (a) 1, (b) 2,
(c) 3, (d) 4; [BSA] = 15 μM; [1–4] = 6.62–32.2 μM

PRAKASH AND MALHOTRA
13 of 14
TABLE 8 Binding constants and number of binding sites for
metal complexes 1–4
while for 3 a shift from 327 to 334 nm was observed. How-
ever, the addition of zinc complex 4 to BSA in varying
amounts caused a blue shift of 8 nm. Some studies in
the literature reveal that interactions between molecules,
i.e. PAAB, vitamin B12 and colchicines, with BSA cause
a blue shift of around 5–8.5 nm in the emission spectra.[36]
Possibly this blue shift is observed because of an increase
in hydrophobicity and decrease in polarity around the
tryptophan residue.
Complex
1
Kb
2.99 × 103
n
R2
0.987
0.945
2
3
4
2.86 × 103
3.13 × 103
6.41 × 103
0.991
0.999
1.04
0.923
0.931
0.967
To investigate further the fluorescence data were
analysed using the Stern–Volmer equation: F0/
F = 1 + Ksv[Q], where Ksv is the Stern–Volmer quenching
constant, F0 is the fluorescence intensity of BSA in the
absence of quencher molecule, F is the fluorescence
intensity of BSA in the presence of quencher molecule
and [Q] is the concentration of the quencher metal com-
plex. Figure 9 displays the Stern–Volmer plots of metal
complexes 1–4 with BSA. Bimolecular quenching rate
constant (Kq) was calculated using the following relation:
4 | CONCLUSIONS
Schiff bases obtained by the condensation of
aminothiazole and substituted salicylaldehyde are con-
firmed using spectral techniques. The synthesized Schiff
bases act as uni‐negative bidentate ligands and coordinate
through azomethine nitrogen and deprotonated phenolic
oxygen. Based on the results obtained through various
spectroscopic techniques, Co(II) and Ni(II) complexes
show octahedral geometry, while Cu(II) and Zn(II) com-
plexes show four‐coordinated geometry. The presence of
coordinated water molecules in metal complexes was con-
firmed from IR and TGA data. All the synthesized com-
pounds have been investigated for in vitro antibacterial
activity and cytotoxicity against HepG2 (liver hepatocellu-
lar) cell line. Some of the complexes showed enhanced
activity as compared to the parent ligand.
F0
¼ 1 þ Ksv½Qꢀ ¼ 1 þ Kqτ0½Qꢀ
F
where Kq is the bimolecular quenching rate constant, τ0 is
the lifetime of BSA in the absence of quencher and Ksv is
the Stern–Volmer constant. The calculated values of Ksv
and Kq for metal complexes 1–4 are given in Table 7.
The number of binding sites was also calculated using
the fluorescence quenching data with the following
equation:
ACKNOWLEDGEMENTS
One of the authors (A.P.) is grateful to CSIR (Council of
Science and Industrial Research) New Delhi for providing
JRF fellowship wide letter no. 09/752/(0045)/2012‐EMR‐
1. The authors are also grateful to TCG Life Sciences
(Biology Section), Kolkata for antibacterial and cytotoxic
studies of compounds reported herein.
F0− F
log
¼ logKb þ n log½Qꢀ
F
where Kb and n are the binding constant and number of
binding sites for metal complexes 1–4. The value of Kb
indicates that Cu and Zn complexes bind strongly to
BSA in comparison to Co and Ni complexes. For Cu and
Zn complexes, the value of n calculated is near to 1, indi-
cating the high affinity of binding sites of albumins. The
binding constant and number of binding sites are given in
Table 8.
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How to cite this article: Prakash A, Malhotra R.
Co(II), Ni(II), Cu(II) and Zn(II) complexes of
aminothiazole‐derived Schiff base ligands:
Synthesis, characterization, antibacterial and
cytotoxicity evaluation, bovine serum albumin
binding and density functional theory studies. Appl
Organometal Chem. 2017;e4098. https://doi.org/
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