Synthesis, characterization and biological studies of a sterically hindered symmetrical nitrogen donor ligand and its metal complexes

Article abstract of DOI:10.1016/j.poly.2021.115292

A new sterically hindered Schiff base ligand (SN-NNDMB) was synthesized from meso-1,2-diphenyl ethylenediamine (meso-stien) and 4-N,N′-dimethylaminobenzaldehyde. Its structure was determined by single-crystal X-ray diffraction data. The crystal structure of the organic ligand was found to be triclinic, space group P-1 with a = 6.1407(8) ?, b = 8.8372(12) ?, c = 12.0006(15) ?, α = 103.882(7)°, β = 95.325(8)°, γ = 91.082(7)°, F(0 0 0) = 254, Dc = 1.253 Mg/m³, μ = 0.571 mm^?1, R = 0.0399, and wR = 0.1019. Co, Ni, Cu and Zn complexes of SN-NNDMB were also prepared and characterized by elemental analysis, IR-, mass-, NMR- and electronic- spectra, magnetic moment, molar conductance, powder XRD, and TGA. The obtained results show that the Schiff base ligand acts as a bidentate, coordinated through the azomethine nitrogen atoms. According to the biotest such as Antimicrobial, DNA binding, DNA cleaving, Anti-tubercular, Anticancer, and SOD-like activity, the compounds showed better activity after chelation. The Cu(II)-SN-NNDMB complex showed the highest bioactive potential amonst the analyzed compounds.

Full text of DOI:10.1016/j.poly.2021.115292

Polyhedron 205 (2021) 115292
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Synthesis, characterization and biological studies of a sterically hindered
symmetrical nitrogen donor ligand and its metal complexes
b
c
d
C. Shiju a, , D. Arish , N. Bhuvanesh , S. Kumaresan
⇑
a Synthetic Products Division, Corporate R & D Center, HLL Lifecare Ltd., Akkulam, Trivandrum 695017, India
FunGlass, Alexander Dubcek University of Trencín, Študentská 2, 911 50 Trencín, Slovakia
c Department of Chemistry, Texas A&M University, College Station, TX 77842, USA
d Department of Biotechnology, Manonmaniam Sundaranar University, Tirunelveli-627 012, India
b
ˇ
ˇ
ˇ
a r t i c l e i n f o
a b s t r a c t
Article history:
A new sterically hindered Schiff base ligand (SN-NNDMB) was synthesized from meso-1,2-diphenyl
ethylenediamine (meso-stien) and 4-N,N0-dimethylaminobenzaldehyde. Its structure was determined
by single-crystal X-ray diffraction data. The crystal structure of the organic ligand was found to be tri-
Received 15 March 2021
Accepted 22 May 2021
Available online 27 May 2021
clinic, space group P-1 with a = 6.1407(8) Å, b = 8.8372(12) Å, c = 12.0006(15) Å,
a = 103.882(7)°,
b = 95.325(8)°,
c
= 91.082(7)°, F(0 0 0) = 254, Dc = 1.253 Mg/m3, m = 0.571 mmꢀ1, R = 0.0399, and
Keywords:
wR = 0.1019. Co, Ni, Cu and Zn complexes of SN-NNDMB were also prepared and characterized by ele-
mental analysis, IR-, mass-, NMR- and electronic- spectra, magnetic moment, molar conductance, powder
XRD, and TGA. The obtained results show that the Schiff base ligand acts as a bidentate, coordinated
through the azomethine nitrogen atoms. According to the biotest such as Antimicrobial, DNA binding,
DNA cleaving, Anti-tubercular, Anticancer, and SOD-like activity, the compounds showed better activity
after chelation. The Cu(II)-SN-NNDMB complex showed the highest bioactive potential amonst the ana-
lyzed compounds.
Metal complexes
Antimicrobial
DNA binding
Anti-tubercular
Anticancer
Ó 2021 Elsevier Ltd. All rights reserved.
1. Introduction
[13–16], designing new structures is still of interest, specifically
for biochemical and catalysis applications.
In coordination chemistry, Schiff bases are an essential class of
ligands [1–4]. Especially transition metal complexes prepared from
such ligands serve various purposes in e.g. biological, clinical, ana-
lytical and industrial applications [5–8]. Due to their fascinating
architectures and topologies, Schiff base transition metal com-
plexes employing many different metal–ligand combinations have
been extensively investigated in recent years. For the biological
field in particular, the DNA binding and cleaving ability of a metal
complex can be tuned by changing the ligand environment. These
studies are also crucial in determining the mechanism of metal ion
toxicity [9,10]. It has been reported that a considerable enhance-
ment of the cytotoxicity and a reduction of side the effects of Pt-
based drugs can be achievd by modifying them with sterically hin-
dered ligands [11,12]. Although several metal complexes of the
aforementioned ligands with fine-tuned electronic and steric
structures have been investigated, mostly salen–based complexes
In the present study we report the synthesis and characteriza-
tion of new divalent Co, Ni, Cu, and Zn complexes of a Schiff base
derived from the condensation of meso-1,2-diphenylethane-1,2-
diamine (meso-stien) (SN) and 4-N,N0-dimethylaminobenzalde-
hyde (NNDMB). Biological studies concerning their antimicrobial
performance, DNA binding, DNA cleaving, anti-tubercular, anti-
cancerous, or SOD like activity have also been reported.
2. Experimental
2.1. Materials
N,N0-dimethylaminobenzaldehyde was purchased from Sigma-
aldrich. Ammonium acetate and benzaldehyde were obtained from
Merck. Co, Ni, Cu, and Zn chlorides were Merck samples. The Colon
Cancer Cells (HCT116) and human cervical cancer cell line (HeLa)
were purchased from National Centre for Cell Science (NCCS), Pune.
All the solvents and other reagents were procured from commer-
cial sources and were of analytical grade.
⇑
Corresponding author.
E-mail address: cshiju83@gmail.com (C. Shiju).
https://doi.org/10.1016/j.poly.2021.115292
0277-5387/Ó 2021 Elsevier Ltd. All rights reserved.

C. Shiju, D. Arish, N. Bhuvanesh et al.
Polyhedron 205 (2021) 115292
2.2. Preparation of meso-1,2-Diphenylethylenediamine (meso-stien)
nm, ~1100, 640, 385. meff (BM) = 3.11; Molar conductance (Kc
(Ohmꢀ1 cm2molꢀ1) 12.2.
Ammonium acetate (60.0 g, 0.78 mol) and benzaldehyde
(29.0 mL, 0.29 mol) were heated at reflux for 3 h. After allowing
the mixture to cool, the white N-benzoyl-N0-benzylidine-meso-
1,2-diphenylethylenediamine was filtered, washed with several
portions of ethanol, and dried in a vacuum to achive a yield of
[Cu(SN-NNDMB)2Cl2]
Blue, yield ~ 64% (0.69 g) Anal. Calcd. for C64H68Cl2CuN8: C,
70.93, H, 6.32, N, 10.34, Cl, 6.54, Cu, 5.86; Found: C, 70.42, H,
6.62, N, 10.88, Cl, 6.16, Cu, 6.03. FAB-Mass: m/z 1082 [M + 1]. IR
(KBr, cmꢀ1) m: 1574, 1453, 3194, 463 cmꢀ1. UV–Vis. (CH2Cl2): k/
42%
(12.0
g).
N-benzoyl-N0-benzylidine-meso-1,2
diphenylethylenediamine (5.0 g, 12 mmol) was treated with
60 mL of 70% H2SO4. The mixture immediately turned to a pale
red colour. After refluxing for 1 h, the mixture turned black. The
hot mixture was poured into a 600 mL beaker filled with crushed
ice. After repeated extractions with diethyl ether, the mixture
was made alkaline with NaOH. The resulting solution was
extracted with dichloromethane. The obtained organic layer was
collected, dried over anhydrous magnesium sulfate, and filtered.
Stripping CH2Cl2 from the mix resulted in meso-1,2
diphenylethylenediamine(meso-stien) in the form of a pale yellow
solid. The yield was found to be ~ 60% (1.57 g) [17,18]. IR (KBr,
nm, ~690. meff (BM) = 1.96; Molar conductance (K
c(Ohmꢀ1 cm2-
molꢀ1) 14.4.
[Zn(SN-NNDMB)2Cl2]
Light Yellow, yield ~ 65% (0.70 g) Anal. Calcd. for C64H68Cl2ZnN8:
C, 70.81, H, 6.31, N, 10.32, Cl, 6.53, Zn, 6.02; Found: C, 71.21, H,
6.52, N, 10.44, Cl, 6.34, Zn, 5.87. FAB-Mass: m/z 1083 [M + 1]. IR
(KBr, cmꢀ1) m: 1588, 1438, 3235, 453 cmꢀ1. meff (BM) = Dia; Molar
conductance (K
c(Ohmꢀ1 cm2molꢀ1) 8.2.
cmꢀ1
)
m
: 3337, 3264 (NAH); 1581 (NH2) (out-of-plane), 684. 1H
7.30 (m Ar-CH).
2.5. Physical measurementss
NMR (CDCl3,), d:, 1.34 (s NH2); 3.98 (s CH);
̴
Elemental analysis was performed using a Perkin-Elmer ele-
mental analyzer. The molar conductivity of the complexes was
measured in DMSO (10ꢀ3 M) solutions using a Coronation Digital
Conductivity Meter. The electrospray (ESI) mass spectra were
recorded using a THERMO Finnigan LCQ Advantage max ion trap
2.3. Synthesis of Schiff base ligand (SN-NNDMB)
A mixture of meso-1,2-diphenylethylenediamine (meso-stien)
(5 mmol, 1.06 g) in MeOH (25 mL) was taken in a 100 mL RB flask.
mass spectrometer. Samples of 10 lL dissolved in methanol, chlo-
A
solution of 4-N,N0-dimethylaminobenzaldehyde (10 mmol,
roform or dichloromethane were introduced into the ESI source
using Finnigan surveyor autosampler and FAB mass spectra were
acquired using a JEOL JMS600H mass spectrometer. 1H NMR spec-
tra were obtained using a JEOL GSX 400 FT–NMR spectrometer. IR
spectra were recorded using a JASCO FT/IR-410 spectrometer in the
4000–400 cmꢀ1 region. Electronic spectra were acquired using a
Perkin Elmer Lambda-25 UV–VIS spectrometer. Cyclic voltammet-
ric measurements were acquired using a Bio-Analytical System
(BAS) model CV-50 W electrochemical analyzer. Magnetic mea-
surements were performed on a Guoy balance by making diamag-
netic corrections using Pascal’s constant. The three-electrode cells
contain a Ag/AgCl reference, an auxiliary Pt and working glassy
electrodes. Tetrabutylammonium perchlorate was used as a sup-
porting electrolyte. Thermal analysis was performed using a SDT
Q 600/V8.3 build 101 thermal analyzer with a heating rate of 20
0C/min in a N2 atmosphere. Powder XRD was performed on a
1.49 g) in MeOH (25 mL) was then added slowly. The reaction mix-
ture was vigorously mixed for about 5 h. The formed precipitate
was collected by vacuum filtration and then washed several times
using anhydrous ether and dried using a desiccator containing
anhydrous CaCl2. The purity of the ligand was analyzed by TLC.
The isolated yield of the ligand was found to be ~ 70% (1.66 g).
Light yellow crystals, 1H NMR (CDCl3) d: 7.8 (s CH = N), 2.9 (s, N-
(CH3)2), 6.6–7.5 (m, ArH), 4.6 (s, CH-N). IR (KBr, cm-1)
(C@N), 1367 (CAN), 1444 (N-CH3), 3025 (Ar CH). Anal. calcd for
32H34N4: C 80.98, H 7.22, N 11.80; found: C 81.21, H 6.85, N
m: 1605
C
12.12. UV–vis (CH2Cl2): k/nm 328, 402. Mass: m/z 475.
2.4. Synthesis of metal complexes
The Schiff base (SN-NNDMB) (2 mmol, 0.95 g) in MeOH (20 mL)
was taken in a 100 mL RB flask. A solution of metal(II) chloride
(1 mmol) in MeOH solution (10 mL) was then added dropwise
and the reaction mixture was stirred for 6 h. The volume of the
reaction mixture was reduced to ½ of the starting volume under
reduced pressure. The formed precipitate was filtered out, washed
several times with ether and with a little cold EtOH, followed by
dried in a vacuum over anhydrous CaCl2.
Rigaku Dmax X-ray diffractometer using Cu-Ka radiation.
A BRUKER GADDS X-ray diffractometer was employed for single
crystal screening, unit cell determination, and data collection. The
detailed method of data reduction, structure solution, and refine-
ment was reported in Ref. [19].
2.6. Antimicrobial activities
[Co(SN-NNDMB)2Cl2]
The antimicrobial efficacy of the synthesized compounds was
tested in vitro against the bacterial species Escherichia coli, Pseu-
domonas aeruginosa, Bacillus subtilis, and Staphylococcus aureus as
well as the fungal species Aspergillus niger, Aspergillus flavus, and
Candida albicans using the disc diffusion method. Amikacin, oflox-
acin and ciprofloxacin were used as standards for antibacterial
activity and nystatin was used as a standard for the antifungal
activity. The detailed procedure was reported in Ref. [20].
Green, yield ~ 60% (0.65 g) Anal. Calcd. for C64H68Cl2CoN8: C,
71.23, H, 6.35, N, 10.38, Cl, 6.57, Co, 5.46; Found: C, 70.87, H,
6.07, N, 11.14, Cl, 6.46, Co, 5.35. FAB-Mass: m/z 1078 [M + 1]. IR
(KBr, cmꢀ1) m: 1587, 1445, 3199, 419 cmꢀ1. UV–Vis. (CH2Cl2): k/
nm, 530–655. meff (BM) = 5.04; Molar conductance (K
c(Ohmꢀ1
cm2molꢀ1) 11.8.
[Ni(SN-NNDMB)2Cl2]
2.7. DNA binding studies
Yellow, yield ~ 68% (0.73 g) Anal. Calcd. for C64H68Cl2NiN8: C,
71.25, H, 6.35, N, 10.39, Cl, 6.57, Ni, 5.44; Found: C, 71.82, H,
6.24, N, 10.56, Cl, 6.22, Ni, 5.25. ESI-Mass: m/z 1077 [M + 1]. IR
(KBr, cmꢀ1) m: 1576, 1454, 3173, 414 cmꢀ1. UV–Vis. (CH2Cl2): k/
2.7.1. Absorption titration experiment
Electronic absorption titrations were performed in a Tris-HCl/
NaCl buffer (5 mmolLꢀ1 Tris-HCl/50 mmolLꢀ1 NaCl buffer pH 7.2)
2

C. Shiju, D. Arish, N. Bhuvanesh et al.
Polyhedron 205 (2021) 115292
using a DMF (10%) solution of metal complexes at room tempera-
ture. The concentration of CT-DNA was determined from the
absorption intensity at 260 nm with an
compounds would indicate growth inhibition, the pink would indi-
cate a lack of growth inhibition for M. tuberculosis [23].
e
value of 6600 (molLꢀ1)-
ꢀ1cmꢀ1. Absorption titration experiments were made using differ-
ent concentrations of CT-DNA while keeping the complex
concentration constant. The correction was made for the absor-
bance of the CT-DNA itself. Metal-DNA solutions were allowed to
incubate for 5 min before the absorption spectra were recorded.
For metal(II) complexes, the intrinsic binding constant (Kb) was
determined by monitoring the changes of the absorption in the
MLCT band with increasing concentrations of DNA using the fol-
lowing equation.
2.9. SOD activity
In vitro Superoxide dismutase (SOD) activity was measured
using DMSO as a source of superoxide radicals (O2ꢀ) and nitrob-
luetetrazolium (NBT) as the O2ꢀ scavenger. In the general proce-
dure, a 400 mL sample to be evaluated was added to a solution
of 2.1 mL potassium phosphate buffer (0.2 M, pH 8.6) and 1 mL
of NBT (56 mM). The test tubes were accumulated in an ice tank
for 15 min, and then 1.5 mL of alkaline DMSO solution was added
and stirred well. The absorbance at 540 nm was examined against
a solution prepared under similar conditions without adding NaOH
to the DMSO. A unit of SOD activity is the concentration of a com-
plex or enzyme, which causes a 50% inhibition of the alkaline
dimethylsulphoxide (DMSO) mediated reduction of NBT.
[DNA]/(ea
the concentration of DNA in the base pairs. The apparent absorp-
tion coefficients ea ef and eb correspond to Aobsd/[Complex], the
extinction coefficient of the complex when fully bound to equilib-
rium binding constant in (molLꢀ1 ꢀ1,
respectively. Each sample
-ef) = [DNA]/(eb-ef) + 1/Kb(eb-ef)where [DNA] means
,
)
solution was scanned from 200 to 500 nm.
3. Results and discussion
2.7.2. Viscosity measurements
Viscosity experiments were performed using an Ostwald vis-
cometer immersed in a thermostated water-bath maintained at a
3.1. Characterization of Schiff base ligand (SN-NNDMB)
constant temperature at 30
0.1 °C. DNA samples of approxi-
The Schiff base ligand SN-NNDMB shows a pale yellow and is
soluble in all common organic solvents. The elemental analysis
data presented in Table 1 of the ligand is in good agreement with
those calculated for the suggested formula. In the 1H NMR (CDCl3)
spectrum, the two azomethine protons exhibit a singlet at 7.8 ppm
and the aromatic protons appear in the 6.6–7.5 ppm range. The
four methyl groups in the ligand cause a singlet at 2.9 ppm while
the protons adjacent to the azomethine nitrogen cause one at at
4.6 ppm. The SN-NNDMB mass spectrum shows a well-defined
molecular ion peak at m/z = 475 (relative intensity = 100%), which
coincides with the Schiff base formula weight (Fig. 1). A peak at m/z
432 corresponds to M+Å –(CH3-N-CH3)Å and is presented in
Scheme 1. In the UV spectrum of SN-NNDMB, the absorption bands
mately 0.5 mM were prepared by sonicating to minimize complex-
ities arising from the DNA flexibility. The flow time was monitored
with a digital stopwatch three times for each sample and an aver-
age flow time was calculated. Each experiment was repeated three
times and an average flow time was calculated. The data were rep-
resented as (g/g0) g is the viscosity
1/3 versus binding ratio, where
of DNA in the presence of complex and g0 is the viscosity of the
pure DNA. Viscosity values were calculated after correcting the
flow time with that of the pure buffer (t0),
The testing procedures for DNA cleavage, in vitro anticancer
activity, and MTT assay was followed as reported in the Refs.
[20] and [21].
g
= (t ꢀ t0)/t0.
at 328 and 402 nm can be attributed to the p–p* transitions of the
azomethine chromophore. The IR (KBr) spectrum presented in
2.8. Antimycobacterial activity screening by resazurin microplate
assay (REMA)
Table 2 of the Schiff base ligand SN-NNDMB exhibits a band at
1605 cmꢀ1 due to azomethine group
m(C@N).
The anti-tuberculosis efficacy of the synthesized compounds
was tested by the resazurin microplate assay (REMA) as reported
by Martin et al., [22] with slight modification. The mechanism is
based on a redox dye color change, namely Resazurin, from blue
in the oxidized form to pink in the reduced for resorufin which is
triggered by the presence of viable cells. Mycobacterium tubercu-
losis H37Rv was grown in a Middlebrook 7H9 broth (Difco BBL,
Sparks, MD, USA) with additions of 10% Oleic Acid Albumin Dex-
trose Complex and 0.5% glycerol. The microbial culture optical den-
sity was adjusted to the McFarland 1.0 unit and 50 mL from this
suspension were used as the inoculum. Stock solutions (prepared
compounds) were prepared in dimethylformamide (DMF) and
were added to a fresh medium in the wells of a microplate to
which 50 mL inoculum was added, making the total assay volume
200 mL. The resulting concentrations of the test compounds were
1, 10 and 100 mg/mL. Growth control wells contained the M. tuber-
culosis H37Rv and medium alone. 1.0 mg/mL of Rifampicin was
used as a positive control to inhibit growth, and negative control
wells contained the highest volume of DMF used in test wells with-
out any compound. The test microplate was incubated for 7 days at
37 °C, then 15 mL of 0.01% a resazurin solution in sterile water was
added to the first growth control wells and again incubated for one
day. After the first set of growth controls turned pink, the proce-
dure was repeated, i.e. the dye solution was added to the second
set of growth controls and test wells and incubated for 24 h at
37 °C. If the blue color retained in the wells containing the test
3.2. Crystallographic study
Single-crystal XRD data and structure refinement for the ligand
is shown in Table 3. The organic ligand crystallized in the triclinic
space group P-1 with a = 6.1407(8) Å, b = 8.8372(12) Å, c = 12.0006
(15) Å,
a = 103.882(7)°, b = 95.325(8)°, c = 91.082(7)°, V = 628.91
(14) Å3, Z = 1, F(0 0 0) = 254, Dc = 1.253 Mg/m3, m = 0.571 mmꢀ1
,
R = 0.0399, and wR = 0.1019. Key bond angles and bond lengths
are shown in Tables 4a and 4b and are all within the normal range.
The ORTEP diagram of the ligand molecule SN-NNDMB is shown in
Fig. 2a. The crystal data shows that the two phenyl rings and two
azomethane nitrogens are trans oriented as shown by the torsion
angle values C1–C7–C7a–C1a = 180° and N1–C7–C7a–N1a = 180°.
The packing structures and two-dimensional structures of the
ligand SN-NNDMB are shown in Fig. 2b. The single-crystal X-ray
diffraction study confirmed the formation of the Schiff base SN-
NNDMB.
3.3. Characterization of metal Schiff base complexes
The analytical and physical characterization of the M(II)-SN-
NNDMB complexes are shown in Table 1. The elemental analysis
results show that the metal-to-ligand ratio is 1:2 in all the complex
systems. The composition of the complexes is [M(SN-NNDMB)2-
Cl2]. The low molar conductance values (see Table 2) of the metal
3

C. Shiju, D. Arish, N. Bhuvanesh et al.
Polyhedron 205 (2021) 115292
Table 1
Analytical and physical data of SN-NNDMB and its complexes.
Compound
Empirical formula
Colour
yield
Elemental analysis Found (calcd) %
C
H
N
Cl
M
SN-NNDMB
C
32H34N4
Light Yellow
Green
Yellow
Blue
Light Yellow
75%
60%
68%
64%
65%
81.21 (80.98)
70.87 (71.23)
71.82 (71.25)
70.42 (70.93)
71.21 (70.81)
6.85 (7.22)
6.07 (6.35)
6.24 (6.35)
6.62 (6.32)
6.52 (6.31)
12.12 (11.80)
11.14 (10.38)
10.56 (10.39)
10.88 (10.34)
10.44 (10.32)
–
–
[Co(SN-NNDMB)2Cl2]
[Ni(SN-NNDMB)2Cl2]
[Cu(SN-NNDMB)2Cl2]
[Zn(SN-NNDMB)2Cl2]
C64H68Cl2CoN8
C64H68Cl2NiN8
C64H68Cl2CuN8
C64H68Cl2ZnN8
6.46 (6.57)
6.22 (6.57)
6.16 (6.54)
6.34 (6.53)
5.35 (5.46)
5.25 (5.44)
6.03 (5.86)
5.87 (6.02)
Fig. 1. Mass spectrum of SN-NNDMB.
[Zn(SN-NNDMB)2Cl2] complexes are soluble in methanol, chloro-
form, dichloromethane, DMF, DMSO.
The mass spectra of the [Co(SN-NNDMB)2Cl2], [Ni(SN-
NNDMB)2Cl2], [Cu(SN-NNDMB)2Cl2] and [Zn(SN-NNDMB)2Cl2]
complexes show molecular ion peaks at m/z 1078 (25%), 1077
(100%), 1082 (18%), and 1083 (14%), respectively, which coincide
with the formula weights of the Schiff base complexes.
3.4. IR spectra
Scheme 1. Mass fragmentation.
Selected IR spectral data are stated in Table 2. The band at
1605 cmꢀ1 for the azomethine group of the free ligand was shifted
to a lower frequency in the range from ~1574 to 1588 cmꢀ1 in the
complexes indicating the coordination of the azomethine N atom
to the metal center. There is no broadband near 3400 cmꢀ1, indi-
cating the absence of water molecules. The IR spectra of all the
complexes reveal their non-electrolytic nature. The [Co(SN-
NNDMB)2Cl2], [Ni(SN-NNDMB)2Cl2], [Cu(SN-NNDMB)2Cl2] and
4

C. Shiju, D. Arish, N. Bhuvanesh et al.
Polyhedron 205 (2021) 115292
Table 2
IR, conductance, and magnetic moment and UV data of SN-NNDMB and its complexes.
Compound
IR cmꢀ1
azo.(C@N)
K
c(Ohmꢀ1 cm2molꢀ1
)
meff
UV/Vis nm
328, 402
(B.M)
m
m
(MꢀN)
SN-NNDMB
1605
–
–
Ligand
[Co(SN-NNDMB)2Cl2]
[Ni(SN-NNDMB)2Cl2]
[Cu(SN-NNDMB)2Cl2]
[Zn(SN-NNDMB)2Cl2]
1587
1576
1574
1588
419
414
463
453
11.8
12.2
14.4
8.2
5.04
3.11
1.96
Dia
530–655
~1100, 640, 385
~690
–
Table 3
Table 4b
Crystal data and structure refinement for SN-NNDMB.
Selected Bond Angles (0).
SN-NNDMB
Bond
Bond Angles (0)
CCDC
2020181
C32 H34 N4
474.63
110(2) K
1.54178 Å
Triclinic
C(8)-N(1)-C(7)
C(12)-N(2)-C(15)
C(12)-N(2)-C(16)
C(15)-N(2)-C(16)
C(6)-C(1)-C(2)
C(6)-C(1)-C(7)
C(2)-C(1)-C(7)
C(3)-C(2)-C(1)
C(4)-C(3)-C(2)
C(3)-C(4)-C(5)
C(4)-C(5)-C(6)
C(1)-C(6)-C(5)
N(1)-C(7)-C(1)
N(1)-C(7)-C(7)#1
C(1)-C(7)-C(7)#1
N(1)-C(8)-C(9)
C(14)-C(9)-C(10)
N(2)-C(12)-C(13)
N(2)-C(12)-C(11)
C(3)-C(12)-C(11)
116.58(15)
120.45(15)
120.73(16)
117.62(15)
118.43(17)
121.85(16)
119.65(17)
120.53(19)
120.20(18)
119.89(17)
119.82(19)
121.12(18)
108.33(14)
108.78(17)
113.51(17)
124.31(17)
118.09(16)
121.94(16)
120.61(17)
117.45(16)
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
P-1
Unit cell dimensions
a = 6.1407(8) Å
a = 103.882
(7)°
b = 95.325(8)°
b = 8.8372(12) Å
c = 12.0006(15) Å
628.91(14) Å3
1
1.253 Mg/m3
0.571 mm-1
254
c
= 91.082(7)°
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data
collection
0.06 x 0.03 x 0.02 mm3
3.81 to 59.99°.
Index ranges
-6<=h<=6, -9<=k<=9, -
13<=l<=13
Reflections collected
Independent reflections
Completeness to
5421
1737 [R(int) = 0.0336]
93.2 %
theta = 59.99°
Absorption correction
Semi-empirical from
equivalents
Max. and min. transmission 0.9887 and 0.9665
Refinement method
Full-matrix least-squares on
F2
Data/restraints/parameters
Goodness-of-fit on F2
1737/0/165
1.004
Final R indices [I>2sigma(I)] R1 = 0.0399, wR2 = 0.1019
R indices (all data)
Largest diff. peak and hole
R1 = 0.0556, wR2 = 0.1085
0.155 and -0.189 e.Å-3
Table 4a
Selected bond lengths.
Bond
Bond Lengths
N(1)-C(8)
N(1)-C(7)
N(2)-C(12)
N(2)-C(15)
N(2)-C(16)
C(1)-C(6)
C(1)-C(2)
C(1)-C(7)
C(7)-C(7)#1
C(12)-C(13)
C(13)-C(14)
C(2)-C(3)
C(3)-C(4)
C(4)-C(5)
C(5)-C(6)
C(9)-C(14)
C(9)-C(10)
C(10)-C(11)
C(11)-C(12)
1.277(2)
1.472(2)
1.376(2)
1.442(2)
1.449(2)
1.387(2)
1.395(3)
1.516(2)
1.534(3)
1.402(3)
1.389(3)
1.393(3)
1.377(3)
1.387(3)
1.388(3)
1.390(2)
1.401(3)
1.379(3)
1.411(3)
Fig. 2. a. ORTEP diagram of the Schiff base SN-NNDMB b. Packing Structure of the
Schiff base SN-NNDMB along an axis.
5

C. Shiju, D. Arish, N. Bhuvanesh et al.
Polyhedron 205 (2021) 115292
metal complexes show new bands in the 429–465 cmꢀ1 region,
probably due to MAN bond formation.
mation about electrochemical reactions. The cyclic voltammo-
grams of metal complexes were recorded at 300 K in the DMSO
solution and the potential range from ꢀ1.0 to 1.2 V with a CT scan
rate of 0.1 V/s. The Co(II) complex shows two peaks; one at
Epc = 0.90 V corresponding to a Co(II)/(I) couple and another at
Epc = -0.15 V during the reverse scan corresponding to a Co(II)/
3.5. Electronic spectra and magnetic properties
The electronic spectrum of [Co(SN-NNDMB)2Cl2] complexes
show two absorption bands (see Table 2) in the 530–655 nm
region, which can be assigned to the overlap of 4T1g(F)?4A2g(F)
and 4T1g(F)?4T2g(F) transitions in an octahedral environment
[24]. The electronic spectrum of the [Ni(SN-NNDMB)2Cl2] complex
shows three bands in the regions around 385, 640 and ~1100 nm
attributable to 3A2g(F)?3T1g(P), 3A2g(F)?3T1g(F) and 3A2g
(F)?3T2g(F) transitions, respectively, suggesting an octahedral
geometry around the Ni(II) atom [24]. The [Cu(SN-NNDMB)2Cl2]
complex in its spectrum displays a broadband in the ~ 690 nm
region, which can be assigned to an 2Eg?2T2g transition, indicating
that the complex has a distorted octahedral geometry [24]. The
magnetic susceptibility value is 5.04 BM for [Co(SN-NNDMB)2Cl2]
(the normal range for octahedral Co(II) complexes is 4.3–5.2 BM),
again indicating a octahedral geometry of the complex [25]. The
[Ni(SN-NNDMB)2Cl2] complex reported herein is found to have a
room temperature magnetic moment value of 3.11 BM, which is
in the normal range observed for octahedral Ni(II) complexes (meff
2.9 – 3.3 BM) [25]. The magnetic moment value of the [Cu(SN-
NNDMB)2Cl2] complex is 1.96 BM which is also normal to observe
for octahedral Cu(II) complexes [25].
(III) couple. The peak to peak separation
DE is 0.75 V indicating
the process to be irreversible. The Ni(II) complex shows two irre-
versible peaks, one at Epc = 0.70 V and another at Epc = 0.40 V cor-
responding to a Ni(II)/(I) couple. The Cu(II) complex shows a
cathodic peak at Epc = 0.5 V vs Ag/AgCl corresponding to a Cu(II)/
(III) couple and the associated anode peak at Epa = -0.6 V corre-
sponding to the formation of a Cu(II)/I couple. The peak to peak
separation
DE is 1.10 V confirming the process to be irreversible.
The Zn(II) complex shows a peak at Epc = 0.40 V vs Ag/AgCl and
the associated anode peak at Epa = 0.55 V. The peak to peak sepa-
ration value
process.
DE = 0.15 V corresponds to the quasi reversible
3.8. Powder XRD
Powder XRD patterns of the complexes were recorded over a
range of 2h = 0-80°. The data showed that [Co(SN-NNDMB)2Cl2],
[Ni(SN-NNDMB)2Cl2],
[Cu(SN-NNDMB)2Cl2],
and
[Zn(SN-
NNDMB)2Cl2] complexes cause sharp peaks indicating their crys-
talline nature. The average crystallite sizes of the complexes were
calculated using Scherrer’s formula. The complexes have an aver-
age crystallite size of 26–35 nm. Based on the above studies, the
overall synthetic procedure and structure of the compounds are
shown in Scheme 2.
3.6. Thermal analysis
Table 5 showes the thermal stability data of the complexes. The
[Co(SN-NNDMB)2Cl2], [Ni(SN-NNDMB)2Cl2], [Cu(SN-NNDMB)2Cl2],
and [Zn(SN-NNDMB)2Cl2] complexes undergo the same type of
decomposition. The decomposition step is represented by a com-
plete removal of the organic ligand moiety in the 250–800 °C range
with the formation of a metal oxide as the final product. The TG
curves of the complex [Co(SN-NNDMB)2Cl2] show a weight loss
of 93.45% (calculated ꢀ 93.05%) in the temperature range from
260 to 545 °C which is due to the decomposition of the coordinated
organic ligand. Above this temperature, a horizontal thermal curve
is observed due to the metal oxide formation. The TG curves of the
4. Biological studies
4.1. Antimicrobial activity
The results of the antimicrobial activities are presented in
Table 6. The experiment’s standard error is 0.001 cm and the
experiment was repeated thrice under similar conditions. DMSO
was used as a negative control for the antibacterial studies and
amikacin, ofloxacin and ciprofloxacin were used as positive stan-
dards. Nystatin was used as a reference for antifungal studies.
These compounds exhibit moderate to intense antimicrobial activ-
ity. The copper(II) complex shows a remarkable activity, especially
against Gram-negative bacteria such as E. coli and B. subtilis. The Cu
complex shows better action against E. coli compared to the stan-
dard amikacin. The Zn complex displays a moderate activity
against the bacteria as well as the fungal species C. albicans. The
antimicrobial activity of the synthesized complexes is greater than
that of the metal-free ligand, indicating that the complexation with
metal enhances the activity of SN-NNDMB. This could be elabo-
rated on the basis of the well-known Overtone concept and chela-
tion theory [26]. Chelation tends to make the ligand SN-NNDMB
more powerful and a potent antibacterial agent.
complexes [Ni(SN-NNDMB)2Cl2] show
a weight loss 92.75%
(93.06%) in the temperature range from 300 to 690 °C showing
the elimination of the coordinated organic ligand. Above this tem-
perature, there is no noticeable weight loss. The complexes [Cu
(SN-NNDMB)2Cl2] and [Zn(SN-NNDMB)2Cl2] show similar decom-
position trends. The decomposition in the temperature range from
290 to 700 °C for the [Cu(SN-NNDMB)2Cl2] and 275–800 °C for [Zn
(SN-NNDMB)2Cl2] complexes correspond to the decomposition of
the organic ligand molecule and it is in agreement with the calcu-
lated mass loss. The final residue is qualitatively proved to be com-
posed of anhydrous metal oxides.
3.7. Electrochemical studies
Cyclic voltammetry offers a rapid location of redox potentials of
the electroactive species, especially for acquiring qualitative infor-
Table 5
Thrmogravimetric data of Schiff base metal complexes.
Complex
Temperature range T (oC)
% Weight loss Obs.(calcd)
Process
[Co(SN-NNDMB)2Cl2]
[Ni(SN-NNDMB)2Cl2]
[Cu(SN-NNDMB)2Cl2]
[Zn(SN-NNDMB)2Cl2]
260–545 > 550
300–690 > 700
290–700 > 700
275–800 > 800
93.45 (93.05) 6.95 (6.95)
92.75 (93.06) 7.25 (6.94)
93.10 (92.70) 6.90 (7.3)
93.23 (92.52) 6.77 (7.48)
Loss of organic moiety CoO
Loss of organic moiety NiO
Loss of organic moiety CuO
Loss of organic moiety ZnO
6

C. Shiju, D. Arish, N. Bhuvanesh et al.
Polyhedron 205 (2021) 115292
Scheme 2. The synthetic procedure of SN-NNDMB and its metal complexes.
Table 6
In vitro antimicrobial activity (MIC, mg/mL) of SN-NNDMB, complexes and standard reagents.
Compound
Bacterial species
Fungal species
E. coli
B. subtilis
P. aeruginosa
S. aureus
A. niger
A. flavus
C. albicans
SN-NNDMB
54
>100
28
03
12
05
05
10
–
80
>100
32
07
18
05
05
2.5
–
>100
26
21
14
43
04
05
2.5
–
68
86
31
22
21
05
05
05
–
28
26
43
08
45
–
–
–
06
>100
27
>100
18
>100
–
–
47
19
20
06
09
–
–
–
05
[Co(SN-NNDMB)2Cl2]
[Ni(SN-NNDMB)2Cl2]
[Cu(SN-NNDMB)2Cl2]
[Zn(SN-NNDMB)2Cl2]
Amikacina
Ciprofloxacina
Ofloxacina
–
06
Nystatina
a
Standard.
4.2. DNA binding studies
4.2.1. Absorption titration method
The metal(II) complexes DNA binding ability was investigated
by electronic absorption titration. This is an effective method to
examine the binding mode of DNA to metal complexes. The inter-
calative mode of binding usually results in a hypochromism and
redshift because of the strong stacking interaction between an aro-
matic chromophore and the base pairs of DNA. The extent of the
spectral change is related to the binding strength. The electronic
absorption titration of a Cu complex is shown in Fig. 3. The absorp-
tion band of the Co(II) complex at 368.6 nm exhibits a hypochro-
mism of 7.6% and a bathochromism of 4.1 nm. The absorption
band of the Ni(II) complex at 356.8 nm exhibits a hypochromism
of 13.7% and a bathochromism of 2.3 nm. The absorption band of
Cu complex at 384.8 nm exhibits a hypochromism of 20.01% and
a bathochromism of 4.7 nm. The Zn complex at 372.4 nm shows
a hypochromism of 4.6% and a bathochromism of 2.5 nm. These
results suggest an association of the complexes with DNA and a
interaction with DNA through intercalation. The intrinsic binding
constant (Kb) values were also calculated and found to be
2.5 ꢁ 105, 3.2x 105, 3.5x 105 and 2.6x 105 Mꢀ1 for the respective
complexes Co(II), Ni(II), Cu(II) and Zn(II).
Fig. 3. The electronic absorption spectrum of a) [Cu(SN-NNDMB)2Cl2] in the
absence of CT DNA and b) in the presence of an increasing amount of CT DNA.
7

C. Shiju, D. Arish, N. Bhuvanesh et al.
Polyhedron 205 (2021) 115292
4.2.2. Viscosity measurements
have no significant activity compared to commercial drugs. At
A viscosity study further confirmed the interaction of the metal
complexes with DNA. The viscosity measurement is based on the
flow rate of a DNA solution through a capillary viscosimeter. The
100
This complex starts to impede the development of the organism at
a 100 M concentration.
lM, the Cu complex inhibits the growth of tubercular bacteria.
l
relative viscosity contribution (g) cause by the DNA in the pres-
ence of a binding agent was obtained. A classical intercalation
model usually resulted in lengthening the DNA helix, as base pairs
were separated to accommodate the binding ligand which leads to
an increase of DNA viscosity. The viscosity of CT DNA increases
with an increase in the ratio of complexes to CT DNA (Fig. 4). The
result further suggests an intercalative binding mode of the com-
plexes with CT DNA and, parallelled to the spectroscopic results
above such as hypochromism, a blue-shift of complexes in the
presence of DNA. The viscosity studies provide strong evidence
for intercalation. The viscosity increase of DNA is attributed to
the intercalative binding mode of the drug because this could
cause the effective length of the DNA to increase [27].
4.5. Anticancer activity
In order to test the biological effects of the ligand SN-NNDMB
and its Co(II), Ni(II), Cu(II), and Zn(II) complexes on cancer cells,
the compounds were used to treat HCT116 (Colon Cancer Cells)
and HeLa (Human Cervical Cancer Cells) at concentrations of
6.25, 12.50, 25.00, 50.00, and 100.00
lM for 48 h. Untreated cells
were used as the control group. Cell growth inhibition was ana-
lyzed by MTT assay and the results revealed that the ligand and
complexes exhibited a dose-dependent inhibitory effect on the
proliferation of HCT116 and HeLa cells as shown in the Fig. 6a
and b as well as Table 8. The IC50 values for the complexes Cu(II)
and Zn(II) are very low compared to the other complexes and the
free ligand (SN-NNDMB). This indicates that these compounds
have pronounced anti-proliferative effects on HeLa and HCT116
cancer cells. Higher IC50 values were noticed for the cases of the
Co(II) and Ni(II) complexes and the free ligand (SN-NNDMB) on
both HeLa and HCT116 cancer cells. The IC50 values for Cu(II), Zn
(II), Co(II), Ni(II) complexes for HeLa cancer cells are better than
those for the HCT116 cancer cells. The IC50 values for the metal
complexes prepared here and the unbound ligand against
HCT116 cancer cells show moderate activities compared to the
4.3. DNA cleavage analysis
Gel electrophoresis experiments using CT DNA were performed
with the ligand and its complexes in the presence or absence of the
oxidant H2O2. The obtained results clearly indicate that all the
complexes could interact with CT DNA in the presence of H2O2.
All the complexes cleave DNA completely as shown in Fig. 5. The
metal complexes seem to catalyze the generation of highly reactive
hydroxyl radicals from H2O2. These hydroxyl radicals participate in
the deoxyribose moiety oxidation, followed by the sugar-phos-
phate backbone hydrolytic cleavage. The complexes completely
cleave the DNA by generating the hydroxyl radicals. Most cleavage
cases are caused by the metal ions interacting with H2O2 to pro-
duce diffusible hydroxyl radicals or molecular oxygen, which
may damage DNA through Fenton-type chemistry [28]. The nucle-
ase activity of the complexes was also investigated in the absence
of H2O2 but did not cleave the DNA, confirming the involvement of
hydroxyl radicals in the cleavage process.
IC50 value of clinically used drugs such as etoposide (29.6
lM)
[29]. Furthermore, the activity of the metal complexes and the free
ligand (SN-NNDMB) towards HeLa cancer cells are not very signif-
icant compared to known metal-free anticancer agents such as
estramustine (IC50 ~1.5 to 3.0
[31] or metal-bound anticancer reagents such as cisplatin (IC50
~8 M) [32]. From the IC50 values, the Cu(II) and Zn(II) complexes
lM), [30] noscapine (IC50 ~22 lM),
l
showed better activity on HCT116 cancer cells than on the HeLa
cancer cells.
4.4. Antitubercular activity
4.6. SOD mimetic activity
Resazurin Microtiter Assay (REMA) was used to determin the
antimicobacterial activity. The results presented in Table 7 indicate
that the Schiff base ligand has no inhibition against M. tuberculosis
The SOD mimetic activity values (IC50) of the synthesized com-
plexes are presented in Table 9. The data shows that the activity of
the complexes is low compared to the native enzyme. The Cu com-
plex has a higher activity than other complexes. In various com-
plexes functioning as SOD enzymes, there is either a one-electron
oxidation followed by the reduction of a metal ion or the formation
of a superoxide complex, which then is reduced to a peroxide by
another superoxide ion. In order to explore this mechanism, the
absorption spectrum of complexes was recorded in the presence
and absence of alkaline DMSO (alkaline DMSO acts as a source of
O2ꢀ). The spectrum peaks were suppressed in alkaline DMSO-con-
taining a buffer (pH 8.6). However, adding NBT, which acts as O2ꢀ
scavenger, reverted these peaks to their original position. This indi-
cates that O2ꢀ is initially attached to the metal complex, which is
later reduced by another O2ꢀ ion. The scavenging ability of each
complex gave its final concentration that produced an efficient
quenching of the superoxide anion radical. In the present study,
the Cu complex has a higher SOD mimetic activity than the other
complexes. The IC50 value for the copper complex is lower than
that of the other complexes and the free ligand.
H37Rv growth up to a 100
lM concentration. The reported Schiff
base (SN-NNDMB) and the metal complexes except the Cu complex
5. Conclusion
Schiff base ligands derived from meso-1,2-diphenylethylenedi-
amine (meso-stien) and 4-N,N0-dimethylaminobenzaldehyde (SN-
NNDMB) and its transition complexes were synthesized. The struc-
Fig. 4. Effect of increasing amount of SN-NNDMB and its metal complexes on the
relative viscosity of CT-DNA.
8

C. Shiju, D. Arish, N. Bhuvanesh et al.
Polyhedron 205 (2021) 115292
Fig. 5. DNA cleavage studies M- Marker, C- Control CT DNA (untreated sample), S1 – H2O2 + DNA, S2 – Ligand + H2O2 + DNA, S2 - [Co(SN-NNDMB)2Cl2] + H2O2 + DNA, S3- [Ni
(SN-NNDMB)2Cl2] + H2O2 + DNA, S4 – [Cu(SN-NNDMB)2Cl2] + H2O2 + DNA, S5 – [Zn(SN-NNDMB)2Cl2] + H2O2 + DNA.
Table 7
Antimycobacterial activity of SN-NNDMB and its complexes.
Compound
100
l
g/mL
50
l
g/mL
25
l
g/mL
12.5
l
g/mL
6.25 lg/mL
SN-NNDMB
N
N
N
P
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
[ Co(SN-NNDMB)2Cl2]
[ Ni(SN-NNDMB)2Cl2]
[ Cu(SN-NNDMB)2Cl2]
[ Zn(SN-NNDMB)2Cl2]
N
N = No inhibition.
P = Inhibition
ture of the Schiff base ligand was verified by single-crystal XRD.
From the spectral data, the Schiff base coordination to the metal
atom was found to be through the azomethine nitrogen and the
geometry of the complexes was found to be octahedral. The Cu
(II) complex shows a better activity against Gram-negative bacteria
such as E-coli then the other synthesized complexes. All synthe-
sized complexes cleave DNA completely. From the DNA binding
studies, it can be concluded that the compounds were interacting
with CT-DNA through intercalation. The Cu(II) complex shows a
comparable activity against both tested cancer cells. The Cu(II)
Fig. 6. a. The activity of compounds on HCT116 b. The activity of compounds on HeLa.
9

C. Shiju, D. Arish, N. Bhuvanesh et al.
Polyhedron 205 (2021) 115292
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SN-NNDMB
56.6
28.8
46.3
24.1
26.5
49.1
25.1
36.5
23.2
24.5
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[ Zn(SN-NNDMB)2Cl2]
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CRediT authorship contribution statement
C. Shiju: Conceptualization, Methodology, Formal analysis,
Investigation, Data curation, Writing - original draft, Writing -
review
& editing, Visualization. D. Arish: Conceptualization,
Methodology, Validation, Formal analysis, Writing - original draft,
Writing - review & editing, Visualization. N. Bhuvanesh: Crystal-
lography studies. S. Kumaresan: Validation, Resources, Data cura-
Coord.
Chem.
57
(7)
(2004)
583–589,
https://doi.org/10.1080/
00958970410001697239.
tion, Writing
administration.
-
review
&
editing, Supervision, Project
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meso-N-Heterocyclic Carbene Ligands and Metal Complexes, Chem. Eur. J. 22
(2016) 9667–9675, https://doi.org/10.1002/chem.201601474.
[18] A.R. Khokhar, G.J. Lumett, Synthesis and characterization of
A series of
Declaration of Competing Interest
Platinum(II) and Palladium(II) complexes containing the bidentate ligand
meso-1,2-Diphenylethylenediamine OR meso-1,2-Bis(4- Chlorophenyl)
Ethylenediamine, J. Coord. Chem. 19 (4) (1989) 321–330, https://doi.org/
10.1080/00958978909408835.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
[19] C. Shiju, D. Arish, N. Bhuvanesh, S. Kumaresan, Synthesis, characterization, and
biological evaluation of Schiff base–platinum(II) complexes, Spectrochim. Acta
A
Mol Biomol. Spectrosc. 145 (2015) 213–222, https://doi.org/10.1016/j.
saa.2015.02.030.
Appendix A. Supplementary data
[20] C. Shiju, D. Arish, S. Kumaresan, Novel water soluble Schiff base metal
complexes: Synthesis, characterization, antimicrobial-, DNA cleavage, and
anticancer activity, J. Mol. Struct. 1221 (2020), https://doi.org/10.1016/
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