Novel Cu(II) and Ni(II) complexes of nicotinamide based Mannich base: Synthesis, characterization, DFT calculation, DNA binding, molecular docking, antioxidant, antimicrobial activities

Article abstract of DOI:10.1016/j.molliq.2020.114423

Nicotinamide incorporating Mannich base ligand (L), Cu(II) and Ni (II) complexes of [CuLCl₂].2H₂O (1) and [NiLCl₂].2H₂O (2) were synthesized and characterized by elemental analysis, FT-IR, UV–Visible, ESR and mass spectrometric methods. The square planar geometry of the complexes (1 and 2) were confirmed from analytical and diverse spectroscopic methods. Cyclic votammetric behaviors of complexes (1 and 2) were studied. The optimized geometry of L, complexes (1 and 2) were obtained by Density Functional Theory (DFT) calculations. DNA binding ability of complexes (1 and 2) were studied by electronic absorption and fluorescence techniques. Both the spectroscopic results show that complex 1 (9.64 × 10⁴ M^?1) has good binding affinity than complex 2 (6.07 × 10⁴ M^?1). The interaction of complexes (1 and 2) with CT-DNA was explored by Molecular docking analysis revealed that an efficient interaction of complexes (1 and 2) with the DNA. The results indicate that prepared complexes (1 and 2) have better binding ability with DNA double helix. Antioxidant activities of complexes (1 and 2) have studied by DPPH method and results suggest that prepared complexes (1 and 2) have better radical scavenging ability. Antimicrobial activities of ligand (L) and complexes (1 and 2) were tested against selected bacterial and fungal pathogens results shows that prepared compounds have higher antimicrobial activity against E. coli and A. niger antimicrobial species than others.

Full text of DOI:10.1016/j.molliq.2020.114423

Journal of Molecular Liquids 320 (2020) 114423
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Novel Cu(II) and Ni(II) complexes of nicotinamide based Mannich base:
Synthesis, characterization, DFT calculation, DNA binding, molecular
docking, antioxidant, antimicrobial activities
a,
C. Kalaivanan a,b,c, M. Sankarganesh c, , M. Yosuva Suvaikin , G. Banu Karthi a,b, S. Gurusamy d,
R. Subramanian e, R. Nandini Asha f
⁎
⁎
a
Department of Chemistry, H.H. The Rajah's College (Autonomous), Pudukkottai, Tamil Nadu 622 001, India
Department of Chemistry, Bharathidasan University, Tiruchirappalli, Tamil Nadu 620 024, India
Department of Chemistry, K. Ramakrishnan College of Technology, Samayapuram, Tiruchirapalli, Tamil Nadu 621 112, India
Department of Chemistry, V.O. Chidambaram College, Palayamkottai Road, Thoothukudi, Tamil Nadu 628 008, India
Department of Chemistry, MSU College Govindaperi, Tirunelveli, Tamil Nadu 627 414, India
Department of Chemistry, Pope's College (Autonomous), Sawyerpuram, Thoothukudi, Tamil Nadu 628 251, India
b
c
d
e
f
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 August 2020
Received in revised form 17 September 2020
Accepted 22 September 2020
Available online 28 September 2020
Nicotinamide incorporating Mannich base ligand (L), Cu(II) and Ni (II) complexes of [CuLCl2].2H2O (1) and
[NiLCl2].2H2O (2) were synthesized and characterized by elemental analysis, FT-IR, UV–Visible, ESR and
mass spectrometric methods. The square planar geometry of the complexes (1 and 2) were confirmed
from analytical and diverse spectroscopic methods. Cyclic votammetric behaviors of complexes (1 and 2)
were studied. The optimized geometry of L, complexes (1 and 2) were obtained by Density Functional The-
ory (DFT) calculations. DNA binding ability of complexes (1 and 2) were studied by electronic absorption
and fluorescence techniques. Both the spectroscopic results show that complex 1 (9.64 × 104 M−1) has
good binding affinity than complex 2 (6.07 × 104 M−1). The interaction of complexes (1 and 2) with CT-
DNA was explored by Molecular docking analysis revealed that an efficient interaction of complexes (1
and 2) with the DNA. The results indicate that prepared complexes (1 and 2) have better binding ability
with DNA double helix. Antioxidant activities of complexes (1 and 2) have studied by DPPH method and re-
sults suggest that prepared complexes (1 and 2) have better radical scavenging ability. Antimicrobial activ-
ities of ligand (L) and complexes (1 and 2) were tested against selected bacterial and fungal pathogens
results shows that prepared compounds have higher antimicrobial activity against E. coli and A. niger anti-
microbial species than others.
Keywords:
Mannich base
Metal complexes
DFT
DNA binding
Antioxidant
Antimicrobial
© 2020 Elsevier B.V. All rights reserved.
1. Introduction
and DNA repair [12]. Its deficiency causes the disease pellagra. There
are compounds, to our anxiety, obtained from amides, in general,
For the past decades, researchers are involved in the development of
drugs from transition metal complexes due to their biological activities
[1–4]. These transition metal complexes are derived from Mannich base
ligands [5,6]. Because of these ligands has enormous biological activities
like antimicrobial, antioxidant, anti-inflammatory, DNA binding and an-
ticancer etc. [7–11].
Nicotinamide (pyridine-3-carboxamide) is a precursor in the
synthesis of nicotinamide adenine dinucleotide (NAD+) and also the
(NADP+) which in turn plays an important role in genomic stability
which shows an enhancement of absorption through bio-membranes
[13]. This absorption leads to a vast pharmaceutical applications like an-
tifungal, antibacterial, antioxidant and anti-inflammatory properties
[14–16]. Reports in the available literature gives us a series of methods
for the synthesis of such compounds [17–20]. The novel compound syn-
thesized is found to have a lead structure to design more potent agents
which may be less toxic and may be used in a variety of therapeutic
treatments. The structural framework of the synthesized compound
(amide moiety) gives strong ability to form the metal complexes and
also to increase the penetration through the bio membranes of the dis-
ease causing microorganism [21–26].
⁎
Corresponding authors.
A number of research studies have been done in the recent times. 1-
[morpholino(4-nitrophenyl)methyl]-3-phenylurea synthesized from 4-
E-mail addresses: msankarajan1990@gmail.com (M. Sankarganesh),
yosu77s@gmail.com (M.Y. Suvaikin).
https://doi.org/10.1016/j.molliq.2020.114423
0167-7322/© 2020 Elsevier B.V. All rights reserved.

C. Kalaivanan, M. Sankarganesh, M.Y. Suvaikin et al.
Journal of Molecular Liquids 320 (2020) 114423
nitrobenzaldehyde, morpholine and N-phenylurea and the metal
complexes prepared from it showed good therapeutic properties
[27]. Nicotinamide, Formalin solution and diclofenac combined to-
gether to give 2-[2-[(2,6-dichlorophenyl)nicotinamidomethyl)
amino)phenyl] acetic acid, which a very good anti-inflammatory
agent [28].
reactants are biologically potent then we expect the synthesized
novel compound to show increased efficiency even when given in
lesser amount.
Moreover, Mannich base ligands are important role in the devel-
opment of metal complexes [2,5]. These transition metal complexes,
especially copper and nickel complexes have various biological ac-
tivities like anticancer, antioxidant, antibacterial, antifungal and
DNA interaction activities [2,5,47]. We have reported their synthesis,
characterization, biological activity, DPPH free radical scavenging,
DFT calculation and DNA binding. We also coordinated it with Cu
(II) and Ni(II) metals and analyzed their binding property, antioxi-
dant and antimicrobial activity.
Further
a number of compounds were prepared from
benzothiazepine, and all of them proved to be a good anti - epilep-
tic agents [29]. Being a potent antioxidant or antibacterial agent
will not help any compound to be medically significant. It needs
to prove that it can bind efficiently with the DNA and can effec-
tively kill the disease causing micro-organism. Binding studies of
1-((2,5-dioxopyrrolidin-1-yl)(4-methoxyphenyl)methyl)thiourea
and its metal complexes with calf thymus DNA is reported [30].
A series of compounds were synthesized from 5-substituted
thiazolidine-2,4-dione, acetanilide and aromatic aldehydes [31].
Their molecular docking studies were done and analyzed. Similarly
a series of N-Benzimidazol-1-yl-methyl-Benzamide derivatives
were synthesized and evaluated for in vitro antimicrobial activity
against a number of bacterial and fungal strains [32]. The compounds
were again characterized by spectral and analytical techniques. Mo-
lecular docking studies were also performed to describe the interac-
tion of the compounds with microbial protein. It is found that the
compounds synthesized might be used for designing more effective
antimicrobial agents.
2. Experimental
2.1. Materials and methods
Nicotinamide (99%), formaldehyde (37.8%), morpholine (99%),
CuCl2.2H2O (99%), NiCl2.6H2O (99.9%) were purchased from
Merck and Alfa Aesar Company. The purchased reagents and sol-
vents were Analytical Reagent grade and used as without further
purification. CHN analyses were accomplished using Carlo Erba
1108 CH analyzer and Coleman N analyzer. The molar conductivi-
ties of the metal(II) complexes were measured in DMSO solutions
(10−3 M) at room temperature. FT-IR spectra were recorded on a
Perkin Elmer 337 FT-IR spectrometerin the form of KBr pellets.
UV–Visible spectra were recorded on a Perkin Elmer EZ 301 spec-
trophotometer. The MS spectrometry and ESR spectra were re-
corded on a JEOL GSX-400.
A series of 4-thiazolidinone derivatives were synthesized from
equimolar quantities of various aromatic amines, morpholine and
formaldehyde in the presence of DMF [33]. Their physico-chemical
parameters were analyzed. It is found that the derivatives of
thiazolidinone, obtained from ρ-chloro substituted aldehyde shows
good receptor binding with the selected target and it showed good
biological activity.
2.2. Synthesis of ligand
Newly synthesized benzimidazole derivatives derived from 2-
(pyrazin-2-yl)-1H-benzimidazole, using sulfa drugs, para amino
phenol, para amino salicylic acid and para amino benzoic acid with
formaldehyde in ethanol were subjected to docking studies against
viral protein CFP 10-ESAT6 complex (3FAV) from Mycobacterium tu-
berculosis using Argus lab software [34]. These studies showed that
all the derivatives had potent antitubercular activity than standard
drug Pyrazinamide.
Synthesis of Mannich base ligand from nicotinamide (10 mmol,
1.2212 g), formaldehyde (10 mmol, 0.3031 g) and morpholine
(10 mmol, 0.8712 g) in 10 mL ethanolic solution. And the syn-
thetic procedure was followed by earlier reported literature [48]
(Scheme I).
2.3. Synthesis of metal complexes
Syahri et al. proved that the addition of secondary amine groups
could increase the antimalarial activity by the method of molecular
docking. He studied the interaction of amine groups of the synthesized
compound to the SER111 and SER108 amino acid residues from the
PfDHFR-TS protein [35].
Antimicrobial activity and the interaction of the compound with
the DNA together can make it therapeutic [36–45]. In our current
work we aimed to link an Aldehyde, Nicotinamide and Isatin.
Nicotinamide by its nature is biologically active. The Isatin and its
derivatives also has proven properties like anti-asthmatic activity,
anti-cancer activity, antimalarial activity, MOA-inhibition activity,
antiviral activity and antimicrobial activity [46]. When two of the
Metal(II) complexes were synthesized from prepared Mannich base
ligand in ethanolic medium. The hot ethanolic solution (10 mL) of the
copper(II) and nickel(II) salts were added drop wise to the ethanolic so-
lution (10 mL) of the Mannich base ligand in 1:1 molar ratio with con-
tinuous stirring with magnetic stirrer for 1 h. The metal(II) complexes
were precipitated and washed with petroleum ether dried at vacuum
desiccators.
2.4. DFT calculations
Density functional theory (DFT) calculation were demonstrated
with the hybrid exchange correlation function using the 6-311G (d,
Scheme I. Synthesis of Mannich base ligand.
2

C. Kalaivanan, M. Sankarganesh, M.Y. Suvaikin et al.
Journal of Molecular Liquids 320 (2020) 114423
p) and LANL2DZ basis set by the Gaussian 09 program to understand
the interaction between ligand (L) and its complexes (1 and 2)
[49–53].
2.5. DNA binding
DNA interaction of complexes (1 and 2) in the presence or ab-
sence of DNA in Tris-HCl/NaCl (5 mM/50 mM) buffer solution at
pH 7.4 were studied by using electronic absorption spectral titration
[54].
Competitive binding of complexes (1 and 2) with ethidium bromide
(EB) bound DNA in Tris-HCl buffer solution (pH 7.4) was investigated by
fluorescence techniques [55].
2.6. Molecular docking
Molecular docking of complexes (1 and 2) with CT-DNA investigated
by using AutoDockTool 4.2 Tool.
2.7. Antioxidant activities
Antioxidant activities of complexes (1 and 2) were monitored by
2,2′-Diphenyl-1-picrylhydrazil (DPPH) method. This experiment was
carried by using UV–Visible spectrophotometer. The percentage inhibi-
tion of ligand (L) and complexes (1 and 2) were calculated by using the
following formula [56,57].
Fig. 1. FT-IR spectra of ligand (L) and complexes (1 and 2).
A0−A
A0
Percentage inhibition ¼
ꢀ 100
3.1. Spectroscopic techniques
3.1.1. FT-IR spectroscopy
A0 is the absorbance of DPPH free radical. A is the absorbance of li-
gand (L) and complexes (1 and 2).
FT-IR spectra of ligand (L) and complexes (1 and 2) are shown in
Fig. 1. FT-IR data of ligand (L) and complexes (1 and 2) are described
in Table 2. FT-IR spectrum of ligand shows a peak appeared at
1680 cm−1 due to –C=O stretching frequency [59]. This frequency was
shifted towards lower frequency at 1623 cm−1 and 1668 cm−1 for com-
plexes (1 and 2) indicates that –C=O group was involved in the coordi-
nation of central metal atoms. A peak was appeared at owing to the –C-N
stretching frequency of free ligand (L). This –C-N stretching frequency
was shifted to lower wave numbers at 1319 cm−1 and 1318 cm−1 for
complexes (1 and 2) indicating that coordination of morpholine nitrogen
atom to the central metal atoms. A new peaks was observed at 443 (com-
plex 1) and 448 (complex 2) due to M-N vibrations. In complexes (1 and
2), peaks observed at below 400 cm−1 attributed to the presence of M-Cl
frequencies.
2.8. Antimicrobial activities
Antimicrobial activities of ligand (L) and complexes (1 and 2)
were tested against bacterial species, Escherichia coli (E. coli) and
Klebsiella pneumoniae (K. pneumonia) and fungal species, Aspergillus
niger (A. niger) and Candida albicans (C. albicans) by well diffusion
method [58].
3. Results and discussion
The synthesized ligand (L) was well soluble in ethanol solution.
The prepared complexes (1 and 2) are soluble in DMSO and DMF
solution. The analytical data of ligand (L) and complexes (1 and
2) were shown in Table 1. The result shows that the ligand and
metal stoichiometric ratio is 1:1 and prepared complexes have
[MLX2].2H2O type.
3.1.2. UV–Visible spectroscopy
Electronic absorption spectra of ligand (L) and complexes (1 and 2)
in DMSO solution are shown in Fig. 2. The UV–Visible spectrum of ligand
Table 1
Physicochemical characterization of ligand (L) and complexes (1 and 2).
Compounds
Formula
Colour
Yield (%)
Found (calculated) (%)
C
H
N
M
Ligand (L)
C11H15N3O2
Pale white
Green
78
70
65
59.68
(59.71)
34.11
(34.25)
28.72
6.79
(6.83)
3.31
(3.39)
5.89
18.92
(18.99)
10.82
(10.89)
9.12
–
Complex (1)
Complex (2)
C11H19N3O4Cl2Cu
18.32
(18.38)
12.72
C
11H27N3O8Cl2Ni
Pale green
(28.79)
(5.93)
(9.16)
(12.79)
3

C. Kalaivanan, M. Sankarganesh, M.Y. Suvaikin et al.
Journal of Molecular Liquids 320 (2020) 114423
Table 2
FT-IR spectral data of ligand (L) and complexes (1 and 2).
Compounds -NH stretch -NH bend Aliphatic –CH stretch >C=O C-N stretch Aromatic -C=N -C-O-C- stretch -C-O-C- stret Aromatic-CH-stretch M-N
M-Cl
(cm−1
)
(cm−1
)
(cm−1
)
(cm−1
)
(cm−1
)
(cm−1
)
(asym)
(sym)
(cm−1
)
(cm−1
)
(cm−1
)
(cm−1
)
(cm−1
)
Ligand (L)
Complex (1) 3368
Complex (2) 3368
3365
1595
1598
1596
2785
2781
2283
1680
1623
1668
1339
1319
1318
1422
1423
1423
1201
1204
1203
1027
1025
1023
3161
3159
3158
–
443
448
–
Below 400
Below 400
(L) displays a band at 269 nm (37,174 cm−1) due to intra ligand charge
transition (INCT). In complexes (1 and 2), the INCT band was appeared
at 299 nm (1) and 261 nm (2) confirms that the formation of com-
plexes (1 and 2). In electronic spectra of complexes (1 and 2),
broad bands were observed at 968 nm (10,330 cm−1) and 782 nm
(12,787 cm−1) and the electronic transitions of complexes 1 and 2
complex 1 exhibits a molecular ion peak at 355 m/z which corre-
sponds to the molecular formula of C11H19N3O4Cl2Cu. These results
suggest that the stoichimetric ratio of ligand (L) and complexes (1
and 2) have 1:1 ratio.
3.2. Cyclic voltammetry
2
1
are B1g
→ →
2A1g and A1g 1B1g transitions respectively [5,60] The
obtained result suggests that square planar geometry of synthesized
complexes (1 and 2).
Cyclic voltammetric (CV) diagram of complexes (1 and 2) in DMSO
solution at scan rate 100 mVs−1 were shown in Fig. 6. The CV data of
complexes (1 and 2) are described in Table 3. The complex 1 is involved
in quasi reversible redox process through the couple as Cu(II)/Cu(I) in
which cathodic peak appears at Epc = −0.6234 V and anodic peak ap-
pears at Epa = −0.7500 V. The Quasi reversible cyclic response is ob-
served in the complex 2 with the reduction peaks at Epc = 0.1982 to
the respective oxidation peak at Epa = 0.8189 V respectively for Ni
(II)/Ni(I).
3.1.3. ESR spectroscopy
The X-band ESR spectrum of complex (1) was recorded at liquid ni-
trogen temperature and shown in Fig. 3. The g-tensor values of complex
(1) show g∥ and g⊥ values are 2.35 cm−1 and 2.06 cm−1 respectively. In
the present complex, g∥ value is greater than g⊥ value and ge value
(g∥ > g⊥ > ge (2.00277)) which designates that unpaired electrons pres-
2
2
ent in the dx − dy orbital [61–64]. Moreover, these results confirm that
square planar geometry of the copper complex (1). In addition, ex-
change coupling interaction between Cu(II) ions by Hathaway expres-
sion as follows,
3.3. DFT calculation
The 3D structure of the ligand (L) and complexes (1 and 2) were
optimized using Density Functional Theory (DFT) calculations
were executed via (B3LYP/6-311G(d,p)/LANL2DZ) basis set using
Gaussian 09 program [38–40].The basis set 6-311G(d,p) was used
for the N, O, C and H atoms and LANL2DZ was applied for the com-
plexes respectively. The structural properties of energy minimized
geometries of ligand and its complexes are exposed in Fig. 7. In li-
gand (L), HOMO is particularly spread on the morpholine moiety
and LUMO is spread on the nicotinamide moiety. Whereas, HOMO
and LUMO electron clouds of the complexes (1 and 2) are shown
in (Fig. 8). Besides, the calculated HOMO-LUMO energy gap of
the complexes (1 and 2) was lower than the free ligand. The
g∥−2:00277
G ¼
g⊥−2:00277
The prepared complex 1 has G value is greater than 4 which shows
that exchange coupling interaction between Cu(II) centers in the solid
state is negligible.
3.1.4. Mass spectroscopy
Mass spectra of ligand (L) and complex (1) were depicted in
Figs. 4 & 5. The ligand (L) showed a molecular ion peak at 224 m/z
which corresponds to the molecular formula is C11H15N3O2. The
Fig. 2. Electronic absorption spectra of ligand (L) and complexes (1 and 2).
Fig. 3. ESR spectrum of complex 1 in DMSO solution at LNT.
4

C. Kalaivanan, M. Sankarganesh, M.Y. Suvaikin et al.
Journal of Molecular Liquids 320 (2020) 114423
Fig. 4. Mass spectrum of ligand (L).
order of the energy band gap is L > L-Cu2+ > L-Ni2+. Moreover,
the dipole moment of ligand (L) (5.59 Debye) is highly low com-
of Cu and Ni metals to the ligand (L), resulting in the disruption
of internal charge transfer and that resulted in the changes in
photophysical properties.
pared to the other complexes (Cu2+-14.38 Debye, and Ni2+
-
12.49 Debye). It reveals that ligand (L) is highly polarized by its
complexes (1 and 2) and confirmed higher dipole moment. The
attained results are noticeably indicated that the complexation
Based on the results of analytical, spectral and theoretical stud-
ies, the proposed structure of complexes (1 and 2) shown in
Scheme II.
Fig. 5. Mass spectrum of complex 1.
5

C. Kalaivanan, M. Sankarganesh, M.Y. Suvaikin et al.
Journal of Molecular Liquids 320 (2020) 114423
where, [DNA] is the concentration of DNA in base pairs, the apparent ab-
sorption coefficient εa, εf and εb correspond to Aobs/[M], the extinction
coefficient of the free complexes (1 and 2) and the extinction coefficient
of the complexes (1 and 2) when fully bound to DNA respectively. Plot
of [DNA]/(εa − εf)vs [DNA] gave a straight line with a slope of 1/(εb − εf)
and an intercept of 1/Kb(εb − εf) and Kb was determined from the ratio
of the slope to intercept (Table 4). The observed values of complexes (1
and 2) are 9.64 × 104 M−1 and 6.07 × 104 M−1 respectively. These cal-
culated values are low as compared to ethidium bromide (EB,
1.4 × 106 M−1). Because, prepared complexes (1 and 2) does not have
enough planarity and presence of flexible morpholine skeleton in its
structural arrangement.
3.5. Competitive binding
The binding nature of complexes (1 and 2) was further confirmed by
fluorescence spectroscopic methods. The prepared complexes (1 and 2)
do not show emission in the presence of CT-DNA. Therefore, the binding
nature of complexes (1 and 2) cannot predict directly by the fluores-
cence spectra. The changes in fluorescence spectra were observed in
the presence EB bound DNA. The fluorescence spectra of complexes (1
and 2) with EB bound DNA in Tris-HCl buffer solution are shown in
Fig. 10(a and b). The concentration of complexes (1 and 2) was in-
creases towards the EB bound DNA results the fluorescence intensity
gradually decreases. This results indicates that competitive reaction
takes place. The Stern-Volmer constant (Ksv), quenching constant
(Kq), binding affinity (Kapp), binding constant (Ka) and binding sites
(n) values of prepared complexes (1 and 2) were calculated by follow-
ing equations [67,68] and shown in Table 5.
Fig. 6. Cyclic voltammogram of complexes (1 and 2).
3.4. Biological applications
3.4.1. DNA interaction
3.4.1.1. Electronic absorption spectra. DNA interactions of complexes (1
and 2) with CT-DNA were performed by UV–Visible spectroscopic
methods. The electronic absorbance spectra of complexes (1 and 2)
with CT-DNA are shown in Fig. 9(a and b). The addition of various con-
centration of CT-DNA to the constant concentration of complexes (1 and
2) results the absorption intensity steadily decreases (hypochromism)
and shifted to higher wavelength (red shift). This observation indicates
that prepared complexes (1 and 2) could be interacting with CT-DNA by
the way of groove mode. Furthermore, the binding affinity of prepared
complexes (1 and 2) were calculated by the following equation [65,66],
F0
F
¼ 1 þ Kqτ0½Qꢁ ¼ 1 þ Ksv½Qꢁ
where, KSV = linear Stern-Volmer quenching constant; [Q] = concentra-
tion of complexes (1 and 2); where, F and F0 are fluorescence intensities
in the presence and absence of complexes (1 and 2). τ0is average life-
time of biomolecular with quencher (10−8 s).
F0−F
F
À
Á
À
Á
À
Á
log
¼ log Ka þ nlog½Qꢁ
½DNAꢁ= εa−εf ¼ ½DNAꢁ= εb−εf þ 1=Kb εb−εf
Table 3
CV data of complexes (1 and 2) in DMSO solution.
Complexes
Epc
(V)
Epa
(V)
ΔE
(V)
ΔE1/2
(V)
ipc
(μA)
ipa
(μA)
ipc/ipa
(μA)
1
2
−0.6234
0.1982
−0.7500
0.8189
0.1266
−0.6207
0.0633
−0.3103
0.1464
0.4462
0.2528
0.09723
0.5789
0.5434
Fig. 7. Energy optimized structure of L and its complexes (1 and 2).
6

C. Kalaivanan, M. Sankarganesh, M.Y. Suvaikin et al.
Journal of Molecular Liquids 320 (2020) 114423
Fig. 8. HOMO and LUMO structure of L and its complexes (1 and 2) by DFT/B3LYP method.
The calculated Ksv, Kq and Ka values are higher in complex 1 than
complex 2. Moreover, the calculated n values of complexes (1 and 2)
are near to unity it states that prepared complexes (1 and 2) interact
with CT-DNA through a single class interaction mode.
Amino acid residues such as Cyt13, Gua14, Ade17, Ade18, Cyt11,
Gua12 are binds with the CT-DNA through hydrophobic interac-
tions which is depicted in violet colour dotted lines. A conventional
hydrogen bonding interactions (green colour) are observed in
Ade17, Ade6, Cyt11, Thy8 with the copper complex. Some π-alkyl
interactions are also observed between Thy19, Cyt9 (light violet)
and the aromatic ring. The major π-cation interactions are between
Cyt15, Gua16 (orange colour) with the chlorine atom of the com-
plex. The best binding mode of docked copper complex with the
binding site of CT-DNA is shown in Fig. 11 with the binding affinity
of −8.4 kcal/mol.
The docking site on the protein target was defined by establishing
a grid box with the dimensions of X: 78 Y: 82 Z: 70 Å, with a grid
spacing of 0.473 Å, centered on X: 50.11 Y:0.125 Z: 26.75 Å. Ten
runs with AutoDockVina were performed in all cases per each ligand
structure, and for each run, the best pose was saved. The interactions
of complex with DNA (PDB:355D) protein-ligand conformations, in-
cluding hydrogen bonds and hydrophobic interactions, were ana-
lyzed (Fig. 11b). The Nickel complex was docked into the active
site of CT-DNA binds with various interactions. Amino acid residues
such as Cyt21, Thy20, Thy19, Thy8 are binds with the CT-DNA
through hydrophobic interactions which is depicted in violet colour
dotted lines. A conventional hydrogen bonding interactions (green
colour) are observed in Gua24, Thy7 with the copper complex.
Some π-alkyl interactions are also observed between Gua4, Cyt3,
(light violet) and the aromatic ring. The major π-cation interactions
are between Cyt23, Gua22 (orange colour) with the chlorine atom of
the complex. The best binding mode of docked nickel complex with
the binding site of CT-DNA is shown in Fig. 11 with the binding affin-
ity of −7.9 kcal/mol.
3.6. Molecular docking
The docking site on the protein target was defined by establish-
ing a grid box with the dimensions of X: 65 Y: 68 Z: 73 Å, with a grid
spacing of 0.375 Å, centered on X: 52.84 Y:0.135 Z: 21.80 Å. Ten
runs with AutoDockVina were performed in all cases per each li-
gand structure, and for each run, the best pose was saved. The in-
teractions of complex 1 with DNA (PDB:355D) protein-ligand
conformations, including hydrogen bonds and hydrophobic inter-
actions, were analyzed (Fig. 11a). The Copper complex was docked
into the active site of CT-DNA binds with various interactions.
3.7. Antioxidant activities
Antioxidant activities of rutin, complexes (1 and 2) in DMSO solu-
tion were studied by DPPH method. The free DPPH solution exhibits
deep purple colour and after the addition of complexes (1 and 2) to-
wards DPPH the colour was turns into yellow in colour (Fig. 12). This
Scheme II. Proposed structure of complexes (1 and 2).
7

C. Kalaivanan, M. Sankarganesh, M.Y. Suvaikin et al.
Journal of Molecular Liquids 320 (2020) 114423
Fig. 10. Fluorescence spectra of complexes (1 and 2) with EB bound DNA in Tris-HCl buffer
solution. (a) complex 1 & (b) complex 2. Insert: Plot of F0/F vs [Q].
Fig. 9. Electronic absorption spectra of complexes (1 and 2) in the absence (dotted lines)
and presence (solid line) of CT-DNA in Tris-HCl buffer solution. (a) complex 1 &
(b) complex 2. Insert: Plot of [DNA]/(εa − εf)vs [DNA].
and fungal species (A. niger and C. albicans). Amikacin was used
as a standard drug. The zone of inhibition of prepared compounds
is shown in Fig. 14(a and b). These results suggest that complexes
(1 and 2) have better antibacterial and antifungal activity than li-
gand (L) due their chelation ability. On chelation, the polarity of
the metal ion will be reduced to a superior extent owing to the
overlap of the ligand orbital and partial sharing of positive charge
of metal ion with donor groups. Moreover, it increases the delocal-
ization of π-electrons over the whole chelate ring and enhances
the lipophilicity of the metal(II) complexes. This increased lipo-
philicity enhances the penetration of the complexes into lipid
membrane and blocks the metal binding sites on enzymes of mi-
croorganisms [58,69–75]. Moreover, the prepared complexes
result shows that prepared complexes (1 and 2) possess better anti-
oxidant activity. The percentage inhibitions of complexes (1 and 2)
are shown in Fig. 13. This result was further confirming the better an-
tioxidant properties of prepared complexes (1 and 2) against DPPH
free radical.
3.8. Antimicrobial activity
Antimicrobial activity of ligand (L) and complexes (1 and 2)
were screened against bacterial species (E. coli and K. pneumonia)
Table 4
Electronic absorption spectral data of complexes (1 and 2) with CT-DNA in Tris-HCl/NaCl
buffer solution.
Table 5
The various parameters of the complexes (1 and 2) with EB bound DNA.
Compound
Band position
max (nm)
Red shift
Δλ
Chromism effect
(%)
Binding constant
λ
(Kb), M−1
Compound
Ksv
Kq
Ka
n
Free
Bound
(L mol−1
)
(L mol−1 s−1
)
(L mol−1
)
Complex (1)
Complex (2)
262
261
268
266
6
5
54.65
36.88
9.64 × 104
6.07 × 104
Complex (1)
Complex (2)
1.6 × 105
2.1 × 103
1.6 × 10−3
2.1 × 10−5
1.76 × 106
5.21 × 104
1.51
1.08
8

C. Kalaivanan, M. Sankarganesh, M.Y. Suvaikin et al.
Journal of Molecular Liquids 320 (2020) 114423
Fig. 11. Molecular docking of complexes (1 and 2) with DNA (a) Complex 1; (b) Complex 2.
higher antimicrobial activity against E. coli and A. niger antimicro-
bial species than others.
nitrogen atom are coordinated to central metal atom. Electronic ab-
sorption and mass spectrometric results shows that the proposed
structure of prepared complexes (1 and 2) possess square planar ge-
ometry. DFT calculations of complexes (1 and 2) have been carried
out. DNA binding ability of complexes (1 and 2) have been investi-
gated by spectroscopic methods. The obtained results have been
suggested that complex 1 has highest binding affinity than complex
2. Molecular docking of complexes (1and 2) results supported that
complex 1 has better DNA interaction ability than complex 2. Anti-
microbial and antioxidant results have been established that the
prepared complexes (1 and 2) possess good antimicrobial and radi-
cal scavenging ability.
4. Conclusion
Novel biologically active copper (1) and nickel complexes (2)
were synthesized from nicotinamide based Mannich base ligand
(L). The prepared ligand (L) and complexes (1 and 2) were structur-
ally characterized by analytical and spectroscopic methods. Elemen-
tal and mass spectrometric result shows that the stoichiometric
ratio of metal to ligand is 1:1. FT-IR and 1H NMR spectroscopic re-
sults clearly indicate that carbonyl oxygen atom and morpholine
Fig. 12. Colour changes of complexes (1 and 2) in the presence or absence of DPPH radical.
(a) Complex 1 (i) DPPH; (ii) DPPH + Complex 1. (b) Complex 2 (i) DPPH, (ii) DPPH +
Complex 2.
Fig. 13. Antioxidant activity of Rutin, complexes (1 and 2).
9

C. Kalaivanan, M. Sankarganesh, M.Y. Suvaikin et al.
Journal of Molecular Liquids 320 (2020) 114423
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