In-vitro antibacterial activity of Ni(II), Cu(II), and Zn(II) complexes incorporating new azo-azomethine ligand possessing excellent antioxidant, anti-inflammatory activity and protective effect of free radicals against plasmid DNA

Article abstract of DOI:10.1080/00397911.2019.1663213

Azo Schiff base ligand 2-hydroxy-3-methoxy-5-(tolyldiazenyl)benzaldehyde oxime (HL¹) and 2-hydroxy-3-methoxy-5-(methoxyphenyl)benzaldehyde oxime (HL²) were prepared along with their transition metal complexes of Ni(II), Cu(II), and Z

Full text of DOI:10.1080/00397911.2019.1663213

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
In-vitro antibacterial activity of Ni(II), Cu(II),
and Zn(II) complexes incorporating new azo-
azomethine ligand possessing excellent
antioxidant, anti-inflammatory activity and
protective effect of free radicals against plasmid
DNA
Mangesh S. Kasare, Pratik P. Dhavan, Bhaskar L. Jadhav & Suresh D. Pawar
To cite this article: Mangesh S. Kasare, Pratik P. Dhavan, Bhaskar L. Jadhav & Suresh D.
Pawar (2019): In-vitro antibacterial activity of Ni(II), Cu(II), and Zn(II) complexes incorporating
new azo-azomethine ligand possessing excellent antioxidant, anti-inflammatory activity and
protective effect of free radicals against plasmid DNA, Synthetic Communications, DOI:
10.1080/00397911.2019.1663213
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1663213
In-vitro antibacterial activity of Ni(II), Cu(II), and Zn(II)
complexes incorporating new azo-azomethine ligand
possessing excellent antioxidant, anti-inflammatory activity
and protective effect of free radicals against plasmid DNA
Mangesh S. Kasarea, Pratik P. Dhavanb, Bhaskar L. Jadhavb, and Suresh D. Pawara
b
aDepartment of Chemistry, University of Mumbai, Mumbai, India; Department of Life Sciences,
University of Mumbai, Mumbai, India
ABSTRACT
ARTICLE HISTORY
Received 15 June 2019
Azo Schiff base ligand 2-hydroxy-3-methoxy-5-(tolyldiazenyl)benzalde-
hyde oxime (HL1) and 2-hydroxy-3-methoxy-5-(methoxyphenyl)benzal-
dehyde oxime (HL2) were prepared along with their transition metal
complexes of Ni(II), Cu(II), and Zn(II). Ligands and their metal com-
plexes were characterized by several analysis techniques. In- vitro anti-
bacterial, antioxidant and anti-inflammatory activities of synthesized
ligands and their metal complexes have been studied. Biological study
showed that amongst all the synthesized compounds, Cu(II) complexes
possessed excellent antibacterial activity than standard antibiotic
Chloramphenicol. Ligands (HL1) and (HL2) showed excellent antioxi-
dant as well as anti-inflammatory activity. Both the ligands were tested
for their protective effect of free radicals against plasmid DNA and it
was found that both the ligands showed good DNA nicking activity.
KEYWORDS
Antibacterial; anti-
inflammatory; antioxidant;
azo-Schiff base; DNA
fragmentation;
metal complexes
GRAPHICAL ABSTRACT
CONTACT Suresh D. Pawar
sureshpawar2004@gmail.com, sureshpawar@chemistry.mu.ac.in
Department of
Chemistry, University of Mumbai, Santacruz (E), Mumbai 400098, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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M. S. KASARE ET AL.
Introduction
The tendency of azo-compounds as active biological agents allowed them to be used in
the treatment of diseases such as antitumor, antibacterial, antiseptics, and antineoplas-
tics.[1] Azo compounds are versatile and have received much attention in the field of
fundamental and applicative research.[2] Azo-azomethine dyes are being increasingly
used in the textile, leather, and plastic industries.[3] Esin et al. synthesized series of azo-
linked salicylidenic Schiff bases and their metal complexes which has importance in the
field of medicinal chemistry.[4]
Furthermore, azo compounds also showed a variety of biological activities including
antifungal,[5] pesticidal,[6] antiviral and anti-inflammatory activities.[7] In addition,
Schiff base derivatives along with biological activities also showed a variety of pharma-
cological activities such as antidepressant,[8] cytotoxic,[9] analgesic,[10] anti-HIV,[11] anti-
convulsant[12] and anticancer.[13] Siham et al. synthesized azo and imidazole containing
ligand that showed optical as well as antifungal and antioxidant properties.[14]
Over the years, various metal-containing compounds significantly used in various
biological applications, especially anticancer and antimalarial therapy. However, less
attention has been given to the synthesis of metal-based antibacterial drugs.[15,16]
Hence, research and development for metal-containing antibacterial compounds are
required as it is expected that metal-containing drugs may be helpful to overcome the
development of antibiotic resistance.[15,17] However, d-block metals have been used for
synthesis of novel metal-based drugs.[17] For example, Cu complexes have been reported
to be effective anticancer agents.[18–25]
Present work deals with, synthesis of new azo Schiff base ligands and their Ni(II),
Cu(II), and Zn(II) metal complexes. These compounds were then tested for their
In-vitro antibacterial, antioxidant, anti-inflammatory activity and protective effect of free
radicals against plasmid DNA of bacteria have been studied.
Results and discussion
Azo-Schiff base ligands (HL1 and HL2) and their Cu(II), Ni(II), and Zn(II) metal com-
plexes were synthesized through the following route.
IR data
IR spectral study of ligands HL1 and HL2 along with their metal complexes were done
in the range of 400–4000 cmꢀ1 to determine the characteristic vibration bands for the
different functional groups present in the molecule. All IR spectra were shown com-
paratively in Figures S1 and S2. In the spectra of ligands (HL1 and HL2) the phenolic
m(O–H) stretching was observed between the range of 3440–3351 cmꢀ1 as broadband.
In the range of 2974–2836 cmꢀ1 aliphatic m(C–H) vibrations were observed for both the
ligands. The azo group m(N¼N) stretching were observed at 1455–1453 cmꢀ1 for the
ligands. The sharp peak in the range of 1579–1578 cmꢀ1 of the m(C¼N) bond vibrations
was observed for both the ligands.[26]

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For the metal complexes phenolic m(O–H) stretching was disappeared due to deprotona-
tion of hydroxyl hydrogen and binding of oxygen atom with metal ion. Whereas (N–OH)
bond frequency in the metal complexes of Ni(II), Cu(II), and Zn(II) shifted to higher value
than their respective ligands as shown in Table S1. Aliphatic m(C–H) vibrations were
observed in the range of 2991–2912cmꢀ1 for all the metal complexes. Azo group m(N¼N)
stretching for all the complexes as compared to ligands were shifted to lower values in the
range of 1420–1404cmꢀ1. Also the m(C¼N) bond vibrations for metal complexes shifted to
higher frequencies 1649–1641cmꢀ1compared to ligands as shown in Table S1.[27] The
metal-oxygen bonds are observed in the range of 560–500 cmꢀ1, whereas metal-nitrogen
bonds were observed in the range of 440–400 cmꢀ1.[28]
TGA analysis
Thermogravimetric analysis of ligands and their metal complexes was done in an inert
atmosphere of nitrogen at 20–1000 ꢁC temperature range. The ligand HL1 and HL2 start
to degrade in the temperature range of 180–190 ꢁC and continues to decompose at
310–330 ꢁC. From the thermogram it was observed that Ni(II), Cu(II) and Zn(II) metal
complexes have more thermal stability than the free ligands, as shown in Table S2. In
the thermogram no peak was observed for the loss of water molecule up to 210 ꢁC, it
means that there is no water in the coordination sphere of the metal complexes. After
decomposition of metal complexes at higher temperature metal oxides remains as final
residue.[29] All the thermogram were shown in Figures S3 and S4.
UV-Visible study
All the UV-Visible spectra of synthesized ligands and their metal complexes were
recorded in DMSO solvent (1025 M). Due to the presence of azo group in the com-
1
2
ꢂ
pounds band at 373–384 nm for HL and HL was observed and it corresponds to p–p
transition.[30,31] The broad absorption band due to the keto-amine transformation of
these compounds in the range 490–495 nm was observed. The absorption in the higher
energy region confirms the keto-imine form of the compound whereas the one in the
lower energy region suggests the enol-imine form. This behavior was expected for com-
pounds having azo and azomethine groups, in which hydroxyl group present at ortho
position to the C¼N bond on the aromatic ring.[32, 33]
Single broadband in the 412–458 nm range was observed for Ni(HL1)2, Cu(HL1)2,
Zn(HL1)2, Ni(HL2)2, Cu(HL2)2 and Zn(HL2)2 metal complexes as shown in Figures 1
and 2.[32] For ligands two broad peaks were obtained whereas for metal complexes those
two peaks get merged and only one broad peak was obtained due to delocalization of metal
electrons with the donor atoms of the ligands. Spectral data were compiled in Table S3.
Molar conductivity
Molar conductivities of all metal complexes were taken in DMSO due to partial solubil-
ity in common organic solvents, to find out electrolytic nature of the complexes.

4
M. S. KASARE ET AL.
Figure 1. UV-Vis spectrum for HL1 and its metal complexes.
Figure 2. UV-Vis spectrum for HL2 and its metal complexes.
The conductance of metal complexes at 20 lS (10ꢀ3 M) in DMSO was in the range
69–79 Xꢀ1 cm2 molꢀ1, as shown in Table 1. This proves nonelectrolyte behavior of all
the metal complexes and it is evident for absence of acetate ions or water molecules in
coordination sphere of the complexes.[34,35] Therefore it is proposed that complex
formed is in the ratio of 2:1 (ligand:metal) as shown in Scheme 1.[36]

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Table 1. Molar conductivities of all synthesized metal complexes in DMSO at
10ꢀ3 M concentration.
Sr. No.
Compound (10ꢀ3 M) in DMSO
Molar conductance (Xꢀ1cm2 molꢀ1
)
1
2
3
4
5
6
Ni(HL1)2
Cu(HL1)2
Zn(HL1)2
Ni(HL2)2
Cu(HL2)2
Zn(HL2)2
77.60
79.13
73.39
69.71
73.56
71.59
Scheme 1. Route of synthesis.
Figure 3. ESR spectra for Cu(HL1)2.

6
M. S. KASARE ET AL.
Figure 4. ESR spectra for Cu(HL2)2.
Table 2. ESR spectral data of Cu(II) complexes.
Complex
Cu(HL1)2
g
g
?
gav
G
A (G)
a2
meff (B.M.)
jj
jj
2.12
2.11
2.03
2.02
2.07
2.06
4.25
6.08
143.29
287.32
0.170
0.155
1.79
1.78
Cu(HL2)2
ESR spectra
The X-band ESR spectra of Cu(HL1)2 and Cu(HL2)2 were recorded at room temperature
(300 K) in solid-state as shown in Figures 3 and 4, which provide information about the
environment around metal ion in the complex. Intense absorption band was obtained
for Cu(II) complexes of both the ligands in the higher magnetic field. Isotropic spectra
were obtained in both the cases due to tumbling motion of the molecule.[27] The cova-
lency parameter a2 can be calculated to confirm the type of bonding (covalent or ionic)
between metal and ligand by using Eq. (1).
a2 ¼ ꢀðA =0:036Þ þ ðg ꢀ 2:002Þ þ 3/7 ðg ꢀ 2:002Þ þ 0:04
(1)
(2)
Cu
?
k
k
2
2
leff ¼ 3= ðg Þ
4
av
The trend in g value (g > g > 2.0023) for Cu(HL1)2 and Cu(HL2)2 complexes indi-
jj
?
2
2
cate that the unpaired electron is present in the dx ꢀ y orbital and square planar
geometry was expected for both the Cu(II) complexes.[37] The values of G parameter for
Cu(II) complexes found to be greater than 4, which suggests that the Cu–Cu ion inter-
action is negligible in the molecule and complex formed was mononuclear hence 1:2
metal-ligand ratio was confirmed.[38] The effective magnetic moment can be calculated by

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Table 3. Antibacterial activity of ligands and their metal complexes showing MIC.
Minimum inhibitory concentration (MIC) in mM/mL
(Gþ) bacteria (Gꢀ) bacteria
Staphylococcus aureus
Compound
Bacillus subtilis
Escherichia coli
Salmonella typhi
HL1
62.5
62.5
125
125
62.5
62.5
125
62.5
62.5
31.25
62.5
31.25
15.62
31.25
15.62
31.25
Ni(HL1)2
Zn(HL1)2
HL2
62.5
62.5
62.5
31.25
31.25
31.25
62.5
31.25
31.25
31.25
31.25
Ni(HL2)2
Zn(HL2)2
Chloramphenicol
31.25
Table 4. Comparative study of azo Schiff base Cu(II) complexes with MIC values.
Sr. No.
1
(Gþ) Bacteria
(Gꢀ) Bacteria
MIC
References
[40]
S. mutan
P. aeruginosa
S. typhi
25–35 mg/mL
S. Pyoenes
ꢂ
MRSA
E. coli
[41]
2
S. faecalis
B. cereus
S. aureus
S. aureus
B. subtilis
S. aureus
B. subtilis
P. aeruginosa
S. flexineri
E. coli
E. coli
P. aeruginosa
E. coli
2.5–10 mg/mL
[42]
3
4
ꢂ
10–25 mg/mL
9.87–39.50 mg/mL (15.62–62.5 mM/mL)
Present work
S. typhi
MRSA: Methicillin resistant Staphylococcus aureus (taken as positive control).
S. mutans: Streptococcus mutans; S. pyogenes: Streptococcus pyogenes; S. faecalis: Streptococcus faecalis; B. cereus: Bacillus
cereus; S. aureus: Staphylococcus aureus; B. subtilis: Bacillus subtilis; P. aeruginosa: Pseudomonas aeruginosa; S. typhi:
Salmonella typhi; E. coli: Escherichia coli; S. flexneri: Shigella flexneri.
using Eq. (2), and it was found to be 1.79 and 1.78 B.M. for Cu(HL1)2 and Cu(HL2)2
complexes, respectively, as shown in Table 2.[39]
Antibacterial activity
Minumum inhibitory concentration (MIC)
The synthesized azo Schiff base ligands and their transition metal complexes were
screened for In-vitro antibacterial activity. Four different types of bacterial strains (two
gram-positive and two gram-negative) were used for this study. Table 3 shows min-
imum inhibitory concentration (MIC) in mM/mL for all the compounds and standard.
It was found that all the compounds possessed good antibacterial activity, but Cu(II)
complexes of both the ligands spectrum drug Chloramphenicol. MIC values for the
Cu(II) complexes were obtained in the range of 15.62–62.5 mM/mL which are far better
than previously reported work (Table 4). Pictures of microtitre plate are shown in
Figures S5–S8. Error bar graph for antibacterial study was shown in Figure S9.
Antioxidant study
Screening of synthesized ligands and their Ni(II), Cu(II) and Zn(II) complexes for
in-vitro antioxidant activity was done by using DPPH free radical scavenging method.
UV-Visible spectrophotometer was used to examine the antioxidant activity by means

8
M. S. KASARE ET AL.
Table 5. Antioxidant activity of Ligands and their metal complexes showing IC50 values in mM/mL.
Compound !
IC50 mM/mL fi
L1
C1
C2
C3
L2
C4
C5
C6
STD
68.44
3926
2677
4726
52.78
938
3312
3999
72.69
The values in bold indicates best IC50 value amongst the tested samples.
Table 6. Comparative study of antioxidant activity of azo Schiff base ligands and their
metal complexes.
Sr. No.
IC50 Value
% I
References
[14]
1
2
3
94.48–116.39 mg/mL
[43]
17.51–56.47%
21.48–96.33%
15.88 19.57 mg/mL (52.78–68.44 mM/mL)
Present work
Table 7. Protein denaturation assay of Ligands and their metal complexes showing IC50 values in
mM/mL.
Compound !
IC50 mM/mL fi
L1
C1
C2
C3
L2
C4
C5
C6
STD
46.76
1101
1928
1498
55.77
672
942
1119
62.02
The values in bold indicates best IC50 value amongst the tested samples.
of absorption at 517 nm. Ascorbic acid was used as standard antioxidant. Table 5 shows
IC50 values for all the tested samples along with the standard. The study found that
ligands (HL1 and HL2) act as excellent antioxidants such as ascorbic acid and have
much better free radical scavenging activity compared to imidazole and azo-Schiff bases
ligands (Table 6). Error bar graph of the study is shown in Figure S10 and free radical
scavenging ability along with standard deviation is shown in Table S4.
Anti-inflammatory activity
The synthesized compounds were also screened for an anti-inflammatory activity to check
the protection of protein against denaturation. In-vitro protein denaturation screening of
ligands and their Ni(II), Cu(II) and Zn(II) metal complexes revealed that ligand HL1 and
HL2 displayed protecting nature against BSA (Bovin serum albumin). From this we can
conclude that both the ligands possessed superior anti-inflammatory activity (lowest IC50
value) as compared to standard anti-inflammatory drug Diclofenac sodium as shown in
Table 7. Figure S11 represents error bar graph for the anti-inflammatory study and
Table S5 shows percentage inhibition with standard deviation.
DNA fragmentation study of ligands
Metal-free ligand HL1 and HL2 shows excellent antioxidant and anti-inflammatory
activity, therefore we performed their DNA fragmentation study. The incubation of
plasmid DNA (pBR322) with ligands HL1 and HL2 did not show any strand break in
DNA as observed in Lane 1, Lane 2 and Lane 3 (Figure 5).
This confirms that ligands do not show any damage to plasmid DNA. Incubation of
Methyl glyoxyl (MG), lysine along with FeCl3 helps to generate free radicals which in
turn cause DNA strand breaks in pBR322 (Lane 5) Figure 5. Ligands HL1 and HL2

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Figure 5. DNA interaction assay for HL1 and HL2. Lanes 1 and 4 for Control containing pBR322, Lane
2 for pBR322þ HL1, Lane 3 for pBR322þ HL2, Lane 5 for pBR322 þ MG þ Lysine þ FeCl3, Lane 6 for
pBR322 þ MG þ Lysine þ FeCl3 þ HL1, and Lane 7 for pBR322þ MG þ Lysine þ FeCl3 þ HL2.
protects pBR322 by scavenging free radicals generated by MG, lysine and FeCl3 Lanes 6
and 7 (Figure 5).
Experimental
General information
Chemicals and reagents were purchased from S D Fine (Mumbai, India) and Sigma
Aldrich chemical companies (USA). NMR (1H and 13C) spectra of (HL1) and (HL2)
were recorded in d6-DMSO solvent using Bruker Avance II (300 MHz) NMR spectrom-
eter and TMS was taken as internal standard. A mass spectrum was recorded using AB
SCIEX 3200 Q TRAP LC/MS/MS spectrometer. Elemental analysis (C, H, N) were done
by using EA-3000 euro vector Italy elemental analyzer. The melting point of the Schiff
bases and their metal complexes were confirmed by using Analab melting point appar-
atus. IR spectra of (HL1), (HL2), as well as their metal complexes, were also done by
using Perkin Elmer, Frontier equipment with diamond tip. UV-Vis absorption for all
the samples was recorded in DMSO on Shimadzu UV 2450 UV-Vis spectrophotometer.
Molar Conductivity of all samples was measured on EQ-660B mp based conductivity
meter (Equiptronics). ESR of the Cu(HL1)2 and Cu(HL2)2 in solid state at room tem-
perature were done for X band on JES-FA200 ESR spectrometer with X and Q band.
DNA fragmentation study was done using horizontal gel electrophoresis apparatus
(Atto Corp., Yushima, Bunkyo, Tokyo, Japan).
General procedure for the synthesis of azo-Schiff base ligand (HL1)
2-hydroxy-3-methoxy-5-(tolyldiazenyl)benzaldehyde (1a) (0.2 g, 0.75 mm) and hydrox-
ylamine hydrochloride (0.052 g, 0.75 mm) were taken in 100 mL round bottom flask,

10
M. S. KASARE ET AL.
to this 10–12 mL dry methanol was added and pH was adjusted to 7.0 by adding 1 M
NaOH solution, the reaction was refluxed for 3–4 h.[44] Reaction was monitored by
TLC. After completion of reaction the reaction mixture was allowed to cool at room
temperature. Solid appeared after cooling was filtered and crystallized by using etha-
nol. Brown Colored crystals of ligand (HL1) were obtained. Ligand (HL2) was also
synthesized by following the above procedure, and structures of azo-Schiff base
ligands were represented in Scheme 1. For NMR spectra and mass spectra of
the compounds.
Spectral data for ligand (HL1)
2-hydroxy-3-methoxy-5-(p-tolyldiazenyl)benzaldehyde oxime (HL1) M.W. ¼ 285.30 g/
mol. M.P. ¼ 207–209 ꢁC, Yield ¼ 77.68% (0.164 g), Color¼Brown. Elemental analysis
for HL1 (C15H15N3O3) theoretical¼C 63.15, H 5.30, N 14.73; found¼C 63.37, H 5.19, N
14.51. LC-MS: (M þ Hþ) values are calculated for HL1: m/z calcd. 285.30, found 286.10.
1H-NMR (300 MHz, DMSO-d6) d (ppm) ¼ 11.524 (s, Ar-OH), d¼10.424 (s, N–OH),
d¼8.428 (s, 1H, C–H), d¼7.776–7.352 (m, 6H, Aromatic), d¼3.905 (s, 3H, –OCH3),
d¼2.386 (s, 3H, –CH3). 13C-NMR (75 MHz, DMSO-d6) d (ppm) ¼ 151.31(a), 148.95(b),
148.82(c), 147.73(d), 144.41(e), 129.52(f), 128.06(g), 121.48(h), 119.87(i), 116.26(j),
102.24(k), 55.10(l).
Conclusions
All the compounds were successfully synthesized and characterized by various analysis
techniques. Screening of ligands and their respective metal complexes for In-vitro anti-
bacterial activity against gram-positive and gram-negative bacteria was done and result
showed that Cu(II) complexes possessed excellent antibacterial activity as compared to
Ni(II) and Zn(II) metal complexes as well as their parent ligands. Ligand HL1 and HL2
showed excellent antioxidant and anti-inflammatory activity as compared to standards,
whereas metal complexes do not show such activity. DNA fragmentation study was car-
ried out for ligands and it showed good protective effect of free radicals against plasmid
DNA of bacteria. On the basis of overall study we can conclude that ligand HL1 and
HL2 along with their Cu(II) complexes possess excellent biological activity.
Data compiled in supporting information includes experimental procedure, theoret-
ical data, spectra of all compounds, images and bar graph of biological studies.
Acknowledgments
One of the authors (Mangesh Kasare) is thankful to DST-PURSE, New Delhi for the award of
research fellowship. All authors are also thankful to Microanalytical Laboratory, Department of
Chemistry, University of Mumbai for providing characterization facilities and IIT Bombay SAIF
for ESR facility.
Disclosure statement
No potential conflict of interest was reported by the authors.

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