Synthesis, characterization, and biological evaluation of 4-[(4-hydroxy-7-methyl-1,3-benzothiazol-2-yl) diazenyl]-5-methyl-2-phenyl-2,4-dihydro-3-pyrazol-3-one and its metal complexes

Article abstract of DOI:10.1080/00958972.2020.1787393

New mononuclear Cu(II), Co(II) and Ni(II) complexes of novel azo-dye ligand 4-[(4-hydroxy-7-methyl-1,3-benzothiazol-2-yl)diazenyl]-5-methyl-2-phenyl-2,4-dihydro-3-pyrazol-3-one (L) with O,N-donor site were synthesized and are characterized by various spec

Full text of DOI:10.1080/00958972.2020.1787393

Journal of Coordination Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gcoo20
Synthesis, characterization, and biological
evaluation of 4-[(4-hydroxy-7-methyl-1,3-
benzothiazol-2-yl) diazenyl]-5-methyl-2-phenyl-2,4-
dihydro-3-pyrazol-3-one and its metal complexes
Mallikarjuna Niluvanji Matada , Keshavayya Jathi , Kiptoo Geoffry , Ravi
Berenkere Nagarajappa & Harmesh Chander Tandon
To cite this article: Mallikarjuna Niluvanji Matada , Keshavayya Jathi , Kiptoo Geoffry , Ravi
Berenkere Nagarajappa & Harmesh Chander Tandon (2020): Synthesis, characterization, and
biological evaluation of 4-[(4-hydroxy-7-methyl-1,3-benzothiazol-2-yl) diazenyl]-5-methyl-2-
phenyl-2,4-dihydro-3-pyrazol-3-one and its metal complexes, Journal of Coordination Chemistry,
DOI: 10.1080/00958972.2020.1787393
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JOURNAL OF COORDINATION CHEMISTRY
https://doi.org/10.1080/00958972.2020.1787393
Synthesis, characterization, and biological evaluation of
4
-[(4-hydroxy-7-methyl-1,3-benzothiazol-2-yl) diazenyl]-5-
methyl-2-phenyl-2,4-dihydro-3-pyrazol-3-one and its
metal complexes
a
a
b
Mallikarjuna Niluvanji Matada , Keshavayya Jathi , Kiptoo Geoffry , Ravi
a
c
Berenkere Nagarajappa and Harmesh Chander Tandon
a
Department of PG Studies and Research in Chemistry, School of Chemical Sciences, Jnana Sahyadri,
b
Kuvempu University, Shankaraghatta, Shimoga, Karnataka, India; Department of Chemistry and
Biochemistry, School of Biological and Physical Sciences, Moi University, Eldoret, Kenya; Department
c
of Chemistry, Sri Venkateswara College, Dhula Kuan, New Delhi, India
ABSTRACT
ARTICLE HISTORY
New mononuclear Cu(II), Co(II) and Ni(II) complexes of novel azo-
dye ligand 4-[(4-hydroxy-7-methyl-1,3-benzothiazol-2-yl)diazenyl]-
Received 19 April 2020
Accepted 13 June 2020
5
-methyl-2-phenyl-2,4-dihydro-3-pyrazol-3-one (L) with O,N-donor
KEYWORDS
site were synthesized and are characterized by various spectro-
scopic techniques. The quantum chemical parameters were eval-
uated for all the compounds by ZINDO/1 semi-empirical method
and are compared with the experimental data. Spectral investiga-
tions suggested the octahedral geometry for Co(II) and Ni(II) com-
plexes and distorted tetrahedral geometry for Cu(II) complex. The
antibacterial activity of the compounds was screened against dif-
ferent microbial strains and the results indicated that all the metal
complexes exhibited higher activity than the free ligand. The
interaction of pUC18 DNA with the synthesized compounds was
explored by gel electrophoresis technique. All metal complexes
exhibited significant cleavage activity against supercoiled pUC18
DNA. The anticancer activity of the compounds was studied
against K562, A549, and MDA-MB-231 by MTT assay and all the
metal chelates exhibited good anticancer properties.
Azo dyes; Benzothiazole;
metal complexes; TG-DTA;
DNA cleavage
CONTACT Keshavayya Jathi
jathikeshavayya1959@gmail.com
Department of PG Studies and Research in
Chemistry, School of Chemical Sciences, Jnana Sahyadri, Kuvempu University, Shankaraghatta-577451, Shimoga,
Karnataka, India
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
M. N. MATADA ET AL.
1. Introduction
Azo (-N ¼ N-) dyes are important organic molecules and have attracted attention in
both academic and applied research [1–3]. Therefore, recently several studies have
been carried out on preparation and spectral properties of azo dyes. They are the
most widely used class of dyes due to their versatile applications in various fields and
especially in dying of textile fibers, coloring of different materials (wood, wool, leather,
metal foil, and plastic), biological, and medical investigations [4]. In contrast to azo-
benzene dyes, the azo compounds having hetero atoms in a ring exhibiting brilliant
color and chromophoric strength. Usually, the -N ¼ N- in the azo-dye undergoes
reversible cis-trans isomerization and because of their good thermal stability they can
be used in the design of photo-switches [5, 6].
Substituted benzothiazoles containing azo-group were found to be useful in the
design of optical data storage devices [7], dye-sensitized solar cells [8], and dying of
textile fibers [9–11]. In recent decades, the most important step in the development of
coordination chemistry was the synthesis of new ligands with a unique identity and
novel reactivity. Metal complexes of azo-dyes are reported to be involved in a number
of metabolic reactions such as inhibition of RNA and DNA, protein synthesis, carcino-
genesis and nitrogen fixation. In addition, azo compounds and their metal complexes
are used in analytical chemistry as indicators in acid-base, redox, and complexometric
titrations [12].
In continuation of our work in the field of coordination chemistry of transition
metal (Cu, Co and Ni) chelates with heterocyclic azo dyes and in the light of the fact
that azo metal chelates possess excellent pharmacological properties [13–20]. In the
present work, we have made an attempt to synthesize novel metal complexes of the
azo-dye ligand, 4-[(4-hydroxy-7-methyl-1,3-benzothiazol-2-yl)diazenyl]-5-methyl-2-phe-
nyl-2,4-dihydro-3-pyrazol-3-one (L). The chemical structures of the synthesized com-
pounds were deduced from the analytical and spectroscopic techniques. The
antimicrobial, DNA-cleavage and anticancer studies were carried out to explore the
pharmacological properties of the newly synthesized compounds.

JOURNAL OF COORDINATION CHEMISTRY
3
2. Experimental
2.1. Analysis and physical measurements
Spectral studies were carried out for the ligand and its metal complexes. Elemental
analysis (C, H, and N) was performed on a Vario EL III CHNS analyzer. IR spectra of
the newly synthesized compounds were recorded as KBr pellets on a Perkin-Elmer
ꢀ
1
1
spectrum RX-IFTIR instrument in the region 4000–200 cm . The H NMR spectrum
of the ligand was recorded on a Bruker Avance II, 400 MHz using DMSO-d as a solv-
6
ent. ESI-MS were recorded on a mass spectrometer equipped with electrospray ion-
ization (ESI) source having a mass range 4000 amu in quadruple and 20,000 amu in
Tof. The UV-Vis spectra of the compounds were recorded on an Elico-SL 164 double-
ꢀ
6
beam spectrometer in the range 200–800 nm using 10 M solution in DMSO. The
room temperature ESR spectrum of the Cu(II) complex in the polycrystalline state
was recorded on a BRUKER Bio Spin Gmbh spectrometer at a microwave frequency
8.75–9.65 GHz. The experiment was carried out using diphenylpicrylhydrazyl (DPPH)
as reference with field set at 3000 Gauss. The molar conductivity measurements
ꢀ
6
were recorded on an ELICO CM-180 conductivity bridge in dry DMSO (10 M) solu-
tion using a dip-type conductivity cell fitted with a platinum electrode. The thermal
analysis (TG-DTA) of the complexes were investigated from room temperature to
ꢁ
7
50 C in nitrogen atmosphere on a Perkin Elmer STA 6000 thermal analyzer with
ꢁ
–1
rate of heating of 20 C min and magnetic susceptibility measurements were car-
ried out at room temperature on a vibrating sample magnetometer (VSM) using Ni
as calibrant. Further, the molecular geometries of the azo dye and its complexes
were optimized by quantum chemical method using ZINDO/1 (semi empirical calcu-
lation) method and the quantum chemical parameters were evaluated for all the
studied compounds.
2.2. Reagents and synthetic methods
All chemicals used for the synthesis were of AR grade, purchased commercially. All
solvents were purified by distillation and used. Bromine, potassium thiocyanate,
sodium nitrite, and glacial acetic acid were purchased from Sigma Aldrich chemical
company, India. Melting points of the newly synthesized compounds were deter-
mined by electro-thermal apparatus using open capillary tubes and are uncorrected.
The metal contents of the complexes were determined as per the standard
procedures [21]. The purity of the compounds was checked by thin layer chroma-
tography (TLC) and the spots were observed in iodine vapor. The starting material
2
2
-amino-7-methyl-1,3-benzothiazol-4-ol was prepared by the literature method [22,
3] and 5-methyl-2-phenyl-2, 4-dihydro-3H-pyrazol-3-one was purchased from
Sigma Aldrich.
2.2.1. Synthesis of azo dye ligand (L)
A well stirred solution of 2-amino-7-methyl-1,3-benzothiazol-4-ol (2 mmol) in 6 mL
conc. HCl was cooled in an ice bath and diazotized with the solution of sodium nitrite
ꢁ
(
2.2 mmol) in 2 mL of H SO . The resulting mixture was stirred for 2 h at 0–5 C. The
2
4

4
M. N. MATADA ET AL.
Scheme 1. Synthesis of azo dye ligand (L).
cold diazonium salt solution was added to the well-cooled solution of 5-methyl-2-phe-
nyl-2,4-dihydro-3H-pyrazol-3-one (2 mmol) in acetic acid (10 mL). The reaction mixture
ꢁ
was stirred for another 2 h at 0–5 C maintaining the pH 6 by adding the required vol-
ume of sodium carbonate solution. The crude product was filtered off, washed with
hot water, dried, and recrystallized from ethanol (Scheme 1).
2.2.2. Synthesis of Cu(II), Co(II), and Ni(II) complexes
To the hot solution of (0.2 g, 0.00054 mol) 4-[(7-hydroxy-4-methyl-1,3-benzothiazol-2-
yl)diazenyl]-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (L) in methanol (5 mL) was
added to a hot methanolic solutions of respective metal salts (0.0002 mol) and
refluxed on a water bath for about 5–6 h. The whole reaction mixture was cooled to
room temperature and poured into distilled water. The colored solids separated were
collected by filtration, washed with sufficient quantity of distilled water, and then with
hot ethanol to remove any impurities. It was finally dried over anhydrous CaCl in a
2
vacuum desiccator.
2.3. Pharmacological activity
2.3.1. Antibacterial assay
The antibacterial activity of the synthesized compounds was performed in agar well-
diffusion method explained by Murray and coworkers [24]. Nutrient agar was poured
into the Petri dish and allowed to solidify. Overnight grown bacterial strains Klebsiella

JOURNAL OF COORDINATION CHEMISTRY
5
pneumoniae (13883), Escherichia coli (ATCC 25922), and Bacillus subtilis (ATCC 19659)
were seeded on to petri plates and wells of 6.0 mm diameter were aseptically bored.
–1
Synthesized compounds of 50 lL were dissolved in DMSO of (1.5, 3.0 mg mL ) were
ꢁ
added into the wells. The petri dish plates were kept for incubation for 24 h at 37 C.
The antimicrobial activity was assessed as inhibition zones flanging the wells. Negative
control used was DMSO and tetracycline as positive control.
2.3.1.1. Absorbance-based microtiter plate assay (MPA). Microtiter plate assay was per-
formed as previously described [25, 26]. Sterile growth media of 100 lL was pipetted
into a microtiter plate and to it, 100 lL aliquot of synthesized compounds were then
diluted two-fold in each well. Finally, 100 lL of the culture media of optical density
(0.5) at 600 nm were added to all the wells. Positive controls contained growth media
inoculated with microorganisms. Negative controls contained synthesized compounds
ꢁ
and sterile growth media only. The plates were incubated for 24 h at 37 C and
absorbance was recorded at 600 nm.
2.3.2. DNA-cleavage activity
The cleavage of supercoiled plasmid pUC18 DNA by all the synthesized compounds
was carried out by gel electrophoresis method [27, 28]. This movement is retarded
when they are bound to other molecules. In a typical experiment, 200 mg of agarose
was dissolved in 25 mL of Tris-acetate (TAE) buffer (4.84 g Tris base, pH 8.0, 0.5 M
ꢁ
EDTA) by boiling. When the gel attains approximately 55 C, it was poured into the
gel cassette fitted with a comb. The gel was allowed to solidify and then carefully the
comb was removed. The gel was placed in the electrophoresis chamber flooded with
TAE buffer. The synthesized compounds were dissolved in freshly distilled DMSO
ꢀ
1
(
(
1 mg mL ). The test compounds were added separately to the isolated pUC18 DNA
ꢁ
225 ng) and incubated for 2 h at 37 C. After incubation, 20 mL of DNA sample (mixed
with bromophenol blue dye at 1:1 ratio) was loaded carefully into the wells, along
with standard DNA marker and a constant electricity of 50 V was passed for around
4
5 min. The gel was removed and carefully strained with ethidium bromide (ETBR)
–1
solution (10 mg mL ) for 10–15 min. The bands were observed under UV trans-illumin-
ator (UVP, Germany) and photographed to determine the extent of DNA-cleavage, and
the results were compared with those of a standard DNA marker.
2.3.3. Cytotoxic studies
The cytotoxic study of the newly synthesized metal chelates was investigated by MTT
assay against human mammary tumor cell line (MDA-MB-231), human lung carcinoma
cell line (A549) and human chronic myeloid leukemia cell line (K562) which were pre-
viously procured from the National Centre for Cell Science (NCCS), Pune, India. The
cancer cell lines used in this study were subcultured in Leibovitz’s L-15, Ham’s F-12K
and RPMI 1640 medium, respectively. The antibiotics like 2 mM L-glutamine (Thermo
Fisher Scientific, Inc.; Waltham, MA, USA) containing 10% FBS (Gibco; Grand Island, NY,
USA) and 1% by volume penicillin/streptomycin (Invitrogen Life Technologies;
Carlsbad, CA, USA) were added to the above medium containing cell lines and these
ꢁ
cell were incubated in 5% humidified incubator 37 C. The inhibition effect of the

6
M. N. MATADA ET AL.
Table 1. Physical, analytical, and molar conductance data of azo dye ligand (L) and its
metal complexes.
Elemental analysis
m.p.
ꢁ
2
–1
–1
Ligand/Complexes
Mol. formula
M.W. ( C)
Color
C
H
N
M
D
o
cm X mol
1
1
1
1
L
C
18
C
36
C
36
C
36
H
H
H
H
15
N
5
O
2
S
365.40 267 Orange red 59.16 4.14 19.17
–
–
(
(
(
(
59.22) (4.19) (19.26)
a
b
c
[Cu(L)
[Co(L)
2
]
28CuN10
32CoN10
O
4
S
2
2
792.34 328 Dark blue
823.76 322 Red
54.57 3.56 17.68 8.02
53.31) (3.48) (17.51) (7.98)
52.49 3.92 17.00 7.15
52.34) (3.32) (16.78) (7.13)
52.50 3.92 17.01 7.79
52.41) (3.46) (16.79) (7.66)
25
23
19
2
(H
2
O)
2
]
O
6
S
[Ni(L)
2
(H
2
O)
2
]
32NiN10
O
6
S
2
823.52 325 Brown
–
1
Table 2. Important IR absorption bands of azo dye ligand (L) and its metal complexes (cm ).
Ligand/Complexes
V(H
–
–
3175
3350
2
O) V(OH)phenolic
V(C ¼ O)carbonyl
V(N ¼ N)azo
V(C-O)phenolic
V(M-N) V(M-O)
1
1
1
1
L
3361
–
–
–
1647
1665
1658
1646
1551
1464
1498
1462
1218
1291
1262
1330
–
–
a
b
c
[Cu(L)
2
]
O)
O)
476
471
479
576
564
577
[Co(L)
[Ni(L)
2
(H
(H
2
2
]
]
2
2
2
target compounds was determined by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazo-
lium bromide (MTT) assay as discussed in earlier reports [29, 30]. Cisplatin was used as
a positive control (standard) and DMSO as a negative control. The results of the study
were presented in the form of IC50 values and they are discussed in the Results and
Discussion section.
3. Results and discussion
3.1. Chemistry
The synthetic path employed to obtain the target compounds are depicted in Scheme 1.
The azo dye ligand (L) and its metal complexes have been synthesized and characterized
by physicochemical methods. All the prepared metal complexes are colored solids, non-
ꢁ
hygroscopic, stable at room temperature and possess high melting point (> 300 C). The
metal complexes are freely soluble in DMF and DMSO but insoluble in common other
organic solvents. Elemental analysis and analytical data of the complexes (Table 1) sug-
gest that the metal to ligand ratio (M:L) of the complexes is 1:2 stoichiometry of the type
[
M(L) ] for Cu(II) complex and [M(L) (H O) ] for Co(II) and Ni(II) complexes. The measured
2 2 2 2
molar conductance values of the metal complexes were too low to account for any dis-
ꢀ
1
2
ꢀ1
sociation of the complexes in DMSO (19–25 ohm cm mol ), indicating their non-elec-
trolytic behavior [31].
3.2. IR spectral data
The important IR absorption bands of the ligand and its metal complexes are dis-
ꢀ
1
played in Table 2. In the azo dye ligand (L), the absorption band at 3361 cm is
ꢀ
1
assigned to phenolic OH. A strong band at 1647 cm is due to carbonyl function

JOURNAL OF COORDINATION CHEMISTRY
7
V(C ¼ O). The absorption due to aromatic and aliphatic C-H stretching in the ligand
ꢀ
1
ꢀ1
can be identified by the bands at 3067 cm and 2921 cm , respectively. A band at
1
ꢀ
1
551 cm corresponds to azo (–N ¼ N–) group present in the azo dye [32, 33].
The absorption due to phenolic –OH disappeared in the IR spectra of all the metal
complexes of the ligand, indicating the formation of bonds between metal ion and
phenolic oxygen atom through deprotonation. This was further confirmed by the
enhancement of absorption frequency of the phenolic C-O bond in the region
ꢀ
1
1
291–1330 cm in all the metal complexes, suggesting the bonding of ligand through
-
a deprotonated (C-O) group to the metal ion [34]. In the IR spectra of the metal com-
plexes, medium intensity weak absorption bands observed in the region
ꢀ
1
1
647–1665 cm were due to carbonyl function (C ¼ O), which appeared almost at the
same position as in the case of ligand, thus confirming the non-involvement in coord-
ination. The absorption frequency of azo (N ¼ N) group in all the metal complexes of
ꢀ
1
the ligand shifted to lower frequency by 60–89 cm , indicating the involvement of
nitrogen atom of azo group in complexation with the metal ions. The bonding
between the metal ions and the ligand was further confirmed by the appearance of
ꢀ
1
ꢀ1
new weak intensity bands in the region 564–577 cm and 471–479 cm in all the
complexes, which are assigned to frequencies of m(M-O) and m(M-N) stretching vibra-
ꢀ
1
tions, respectively [35]. The absorption bands at 3175 and 3350 cm
indicate the
presence of coordinated water molecules in the Co(II) and Ni(II) complexes of the lig-
and (L), respectively [36–38].
1
3
.3. H NMR spectral studies
1
The H NMR spectrum of the azo dye ligand (L) was recorded in DMSO-d at room
6
1
temperature. The H NMR spectrum of the ligand exhibited a singlet at 13.50 ppm,
indicating the presence of hydrazone (NH) proton [39, 40]. The signal due to phenolic
-OH proton of the benzothiazole moiety resonated at 11.01 ppm; the signals due to
seven aromatic protons have resonated as multiplets in the region 6.73–9.39 ppm. Six
protons of two methyl groups attached to phenyl and pyrazole ring have resonated as
singlets at 2.35 and 2.41 ppm, respectively.
3.4. ESI-mass spectral data
Azo dye ligand (L) and its metal complexes were studied for their mass spectral stud-
ies. The ESI-mass spectra of all the above compounds exhibited molecular ion peaks
equivalent of their molecular mass along with other fragment ion peaks. The mass
spectrum of the ligand exhibited M þ 1 peak at 366 and 367 (100% and 19%, respect-
ively) which is also a base peak. The mass spectra of Cu(II), Co(II), and Ni(II) complexes
showed peaks attributed to the molecular ions m/z at 790, 822, and 822 correspond-
ing to their molecular weights at 792.34, 823.76, and 823.52, respectively. Hence, the
mass spectral data was found to be in good agreement with the proposed molecular
structures of the compounds.

8
M. N. MATADA ET AL.
Table 3. Electronic spectral data of ligand (L) and its metal complexes.
–1
Ligand/Complexes
Wavenumber (in cm )
Assignment
meff (BM)
Geometry
ꢂ
1
1
L
22321
27624
n!p
–
1.91
–
2
2
a
[Cu(L)
2
]
B
1g ! A1g
Distorted tetrahedral
1
3
9801
1347
4
4
4
1
b
c
[Co(L)
2
(H
2
O)
2
]
22123
6246
29940
0202
T
T
A
A
1g(F) ! T2g(P)(V
3
)
3.98
3.01
Octahedral
Octahedral
4
2
1g(F) ! A2g(F)(V
2
)
3
3
1
[Ni(L)
2
(H
2
O)
2
]
2g ! T1g(P) (V
3
)
)
3
3
2
2g ! T1g(F) (V
2
Table 4. ESR spectral data of Cu (II) complex of azo dye ligand (L).
Complex
g
jj
g
?
g
av
G
1
a
2
[Cu(L) ]
2.341
2.079
2.166
4.31
3.5. Electronic spectral studies
ꢀ
6
The UV-Visible spectra were recorded in DMSO (10 M) at room temperature. The
electronic spectral data of the ligand and its complexes are presented in Table 3. The
electronic spectrum of the Cu(II) complex shows three absorption bands at
ꢀ
1
ꢀ1
ꢀ1
2
2
1
9,801 cm and 27,624 cm and 31,347 cm due to B1g ! A transitions. These
1g
transitions suggest a distorted tetrahedral geometry, which is in agreement with the
literature value [41, 42]. Further, this was confirmed by magnetic susceptibility meas-
urements and it was found to be 1.91 BM, which is in good agreement with the
reported value for distorted tetrahedral environment [43–45]. The electronic spectrum
ꢀ
1
ꢀ1
of Co(II) complex displayed two absorption bands at 22,123 cm and 26,246 cm
.
4
4
4
4
These bands are assigned to T1g (F) ! A (F) (V ) and T (F) ! T (P) (V ) transi-
2g
2
1g
2g
3
tions, respectively. The above transitions suggest an octahedral geometry for Co(II)
complex. The magnetic moment value 3.98 BM corresponds to high spin octahedral
geometry. The Ni(II) complex of the azo dye ligand under present study exhibited two
ꢀ
1
ꢀ1
3
3
bands in the region 20,202 cm and 29,940 cm which are assigned to A2g ! T
1g
3
3
(
F) (V ) and A2g
!
T1g (P) (V ) transitions. The Ni(II) complex has the magnetic
2
3
moment value of 3.01 BM. Thus, the absorption bands and the magnetic moment
value support an octahedral geometry for the Ni(II) complex [46–48].
3.6. ESR spectral study of Cu(II) complex
Room-temperature ESR spectrum of the Cu(II) complex in polycrystalline state was
recorded in DMSO and the spin Hamiltonian parameters of the complex has been cal-
culated and displayed in Table 4. The observed data g (2.341) > g (2.079) > 2.0023
jj
?
suggest the unpaired electron lies in the dx2 – y2 orbital in distorted tetrahedral geom-
etry [42]. The exchange interaction between two Cu(II) centers can be explained using
the Hathaway expression G ¼ (g ꢀ 2)/(g ꢀ 2). If G > 4, the exchange interaction
jj
?
between Cu(II) centers in the solid complex is negligible, while a value of G < 4 a con-
siderable exchange interaction is indicated in the solid complex. In the present study,
the value of G ¼ 4.31 indicates that there is no exchange interaction in the Cu(II) com-
plex of the ligand. Further, the mononuclear nature of the complex was supported by

JOURNAL OF COORDINATION CHEMISTRY
9
Table 5. Thermal data of the metal complexes of the azo dye ligand (L).
%
Weight loss
% Metal oxide
Decomposition
temp. ( C)
Anal.
Calcd
3.78
Anal.
Calcd
ꢁ
Complex No.
Obsd.
3.45
Obsd.
Proposed mode of degradation
[
Cu(L)2]
216
–
–
–
–
Loss due to two methyl groups of
benzothiazole ring
3
20
64
51.87
34.42
50.75
34.12
–
–
Loss due to two moles
of C10
Loss due to two molecules of
benzothiazole moiety (C
CuO
9 4
H N O fragment
4
7 5
H NS)
>712
–
–
10.23
10.03
[
Co(L)
2
(H
2
O)
2
]
110
4.91
4.37
–
–
Loss due to two coordinated
water molecules
3
4
10
87
7.64
26.50
7.29
26.25
–
–
–
–
Loss due to four methyl groups
Loss due to two phenyl groups of
pyrazole moiety and two azo groups
Loss due to two moles
6
96
48.63
48.80
–
–
7 5 3 2
of C H N O S fragment
>
162
739
–
4.29
–
4.37
12.32
–
13.46
–
CoO þ 3C
[
Ni(L)
2
(H
2
O)
2
]
Loss due to two coordinated
water molecules
3
00
23.25
22.37
–
–
Loss due to two phenyl groups of
pyrazole ring and two methyl groups
of benzothiazole moiety
4
5
48
83
38.15
24.23
–
39.14
25.52
–
–
–
–
–
9.06
7 3 3
Loss due to C H N S fragment
Loss due to remaining organic moiety
NiO
>732
10.08
the absence of a band corresponding to the transition DMs ¼ ±2 in the observed ESR
spectrum of the Cu(II) complex [49].
3.7. Thermal studies
The thermal study of the copper, cobalt, and nickel complexes of the ligand (L) was
ꢁ
measured from ambient temperature up to 740 C by thermogravimetric (TG) and dif-
ferential thermal analysis (DTA) in an inert atmosphere at heating temperature
ꢁ
ꢀ1
2
0 C min . The proposed stepwise thermal decomposition of the complexes with
respect to temperature and the formation of respective metal oxides are presented in
Table 5.
From the TG/DTA curve of the Cu(II) complex, the first step of decomposition stage
ꢁ
was observed in the range of 216–320 C with the mass loss of 3.45% (Anal. Calcd
3
.78%). This may be attributed to the loss of two methyl groups of benzothiazole ring.
ꢁ
The DTA curve exhibits an endothermic peak at 291 C (the maximum peak tempera-
ture, Tmax). The second step of decomposition occurs within the temperature range of
ꢁ
3
20–464 C with the practical weight loss of 51.87% (Anal. Calcd 50.75%) which corre-
sponds to the loss of two moles of C H N O fragment. The DTA curve gives an exo-
10 9 4
ꢁ
thermic peak at 334.34 C. Finally, the complex underwent the third step of
decomposition with a weight loss of 34.42% (Anal. Calcd 34.12%) due to loss of two
ꢁ
moles of benzothiazole moiety (C H NS) in the temperature range 464–712 C.
7
5
ꢁ
Thereafter, the complex showed a gradual decomposition up to 712 C and onwards
due to the loss of remaining organic moiety and finally leaving the residue as CuO.

1
0
M. N. MATADA ET AL.
Figure 1. The optimized molecular geometries of the ligand (L) and its complexes.
In the TG/DTA curve of the Co(II) complex, four degradation steps were observed.
The first degradation step with estimated mass loss 4.91% (Anal. Calcd 4.37%) within
ꢁ
the temperature range 25–100 C may be attributed to the loss of two coordinated
ꢁ
water molecules. An endothermic peak in this region with Tmax ¼ 79.27 C on the DTA
ꢁ
curve. The second degradation step occurs within the temperature range 100–310 C
with a practical weight loss of 7.64% (Anal. Calcd 7.29%), corresponding to the loss of
ꢁ
four methyl groups. The DTA curve gives an endothermic peak Tmax ¼ 300.87 C. The
ꢁ
third stage of degradation proceeds within the temperature range 310–487 C with an
estimated mass loss of 26.50% (Anal. Calcd 26.25%); an exothermic peak (T
¼
max
ꢁ
437.12 C) may be attributed to the loss of two moles phenyl groups of the pyrazole
ring along with azo group. The final step of the degradation was observed in the tem-
ꢁ
perature range 487–696 C with a mass loss of 48.63% (Anal. Calcd 48.80%) accompa-
ꢁ
nied by an endothermic peak at Tmax ¼ 532.32 C in DTA. In this step, all other
organic residues (two moles of C H N O S fragment) were removed from the structure
7
5 3 2
leaving three carbon atoms and cobalt oxide (CoO) as the final product.
In the thermogram of the Ni(II) complex, the first stage of decomposition occurs
ꢁ
within the temperature range of 162–300 C with a practical weight loss of 4.29%
(
Anal. Calcd 4.37%) corresponding to the elimination of two coordinated water mole-
ꢁ
cules. The DTA curve gives an endothermic peak at Tmax ¼ 263.68 C. The resultant
complex underwent further decomposition with weight loss of 23.25% (Anal. Calcd
2
2.37%) due to loss of two phenyl groups of the pyrazole moiety and two methyl
ꢁ
groups of benzothiazole ring within the temperature range 300–448 C. An endother-
mic peak in this region with Tmax ¼ 401.25 C on the DTA curve. The third step of
ꢁ

JOURNAL OF COORDINATION CHEMISTRY
11

1
2
M. N. MATADA ET AL.

JOURNAL OF COORDINATION CHEMISTRY
13
Table 7. The quantum chemical parameters evaluated for the azo dye ligand (L) and its
metal complexes.
Electronic parameters
L
[Cu(L)
2
]
2
[Co(L) (H
2
O)
2
]
2 2 2
[Ni(L) (H O) ]
E
E
E
HOMO (eV)
LUMO (eV)
HOMO – ELUMO (eV)
4.58
–5.26
9.84
0.68
–0.68
9.84
0.02
–4.58
5.26
4.15
3.21
–5.00
8.21
1.79
–1.79
8.21
0.19
–3.21
5.00
18.52
4.46
–4.54
9.00
0.04
–0.04
4.50
0.0001
–4.46
4.54
4.19
–4.70
8.89
0.25
–0.25
4.44
0.007
–4.19
4.70
Electronegativity (v)
Chemical potential (a)
Hardness (g)
Electrophilicity index (x)
Ionization potential (A)
Electron affinity (I)
Dipole moment (D)
11.34
11.47
Figure 2. The picture showing the total charge density on the ligand (L) and its complexes.
decomposition with estimated weight loss of 38.15% (Anal. Calcd 39.14%) within the
ꢁ
temperature range of 448–583 C was accompanied by an endothermic peak at T
max
ꢁ
¼
527.41 C in DTA. Further, the complex underwent decomposition within the tem-
perature range 448–583 C with a mass loss of 24.23% (Anal. Calcd 25.52%).
Thereafter, the complex showed a gradual decomposition up to 732 C with a loss of
ꢁ
ꢁ
remaining organic moiety. The final mass of the residue corresponds to the weight
of NiO.
3.8. Geometry optimization
Nowadays, the theoretical modeling used to correlate or to compare the experimen-
tally obtained results becomes more common. This is often more useful in understand-
ing the various structural, optical, thermal, biological, and electrochemical properties
based on the difference between the highly occupied molecular orbital (HOMO) and

1
4
M. N. MATADA ET AL.
–1
Table 8. Minimum inhibitory concentration (MIC, in mg mL ) of ligand (L) and its
metal complexes.
Bacterial strain
Compounds
E. coli
K. pneumoniae
B. subtilis
1
L
19.50
31.25
33.18
41.06
35.06
12.50
15.62
13.25
14.26
9.53
13.00
16.22
12.26
16.06
9.53
1
1
1
a
b
c
[Cu(L)
[Co(L)
[Ni(L)
2
]
(H
(H
2
2
O)
2
]
]
2
2
O)
2
Tetracycline
least unoccupied molecular orbital (LUMO). As from the basic concept of the molecu-
lar orbital theory, if the energy gap between the ground state and exited state or the
difference between HOMO and LUMO is small, the promotion of electron becomes
easy and the molecule can be considered as more reactive and kinetically unstable. If
the energy gap between HOMO and LUMO is higher, the energy required promoting
a valence electron becomes high and thus the molecule becomes kinetically stable
and less reactive [50]. Based on this simple concept and with the help of quantum
chemical approach, one can predict and interpret the structural reactivity of the mole-
cules. As we know from the literature, the structural and chemical variations can sig-
nificantly impact the biological, electrochemical, and optical properties of the
molecules. Therefore, in this study we attempted to correlate the structural properties
with the biological activities. From the preliminary analysis of the theoretical results,
when the molecular system approaches the lowest energy or in other words the mol-
ecule has lowest DE has more affinity to exhibit biochemical properties. If the molecu-
lar system has higher DE value, the excitation of the electron from HOMO to LUMO is
difficult and shows stable or less affinity towards any chemical reaction. Hence, by cal-
culating the DE from this study becomes more useful in understanding the chemical
and biological properties of the newly synthesized molecules. Therefore, the geomet-
rical structures of the synthesized azo dye and its complexes were optimized with the
help of semi empirical method (ZINDO1) using Hyperchem software. The correspond-
ing optimized geometries of the compounds are displayed in Figure 1. Further, the
HOMO and LUMO energy states of each molecule were obtained from the above
method and are also summarized in Table 6. The chemical and biological properties of
the compounds can be studied by the quantum chemical parameters which are
described by the following formulas (1–7) and the obtained values are tabulated in
Table 7. It is clearly indicated that the DE value was considerably decreased as com-
pared to the ligand (DE ¼ 9.84 eV) and all the complexes have the DE values in the
range 8.21–9.00 eV. In all the studied compounds, the copper and nickel exhibited
lower DE values and according to the above discussions these two molecules have
comparatively more reactive and exhibited higher biological activities against tested
pathogens. Further, Figure 2 indicated the electron density located around the metal
ions in the complexes which also supports the above results [51, 52].
Energy gap ðDEÞ ¼ EHOMO ꢀ E
(1)
(2)
LUMO
ðI þ AÞ
Electronegativity ðvÞ ¼
2

JOURNAL OF COORDINATION CHEMISTRY
15
Figure 3. DNA cleavage activity on plasmid pUC18 DNA: M: Standard DNA, C: Control DNA
(untreated pUC 18), 1: azo dye ligand, 1a: Cu(II) complex, 1b: Co(II) complex and 1c: Ni(II) complex.
ðI þ AÞ
Chemical potential ðaÞ ¼
ꢀ
(3)
(4)
(5)
2
ðIꢀAÞ
Hardness ðgÞ ¼
2
a2
Electrophilicity index ðѡÞ ¼
2
g
Electron affinity ðIÞ ¼ ꢀ ELUMO
(6)
(7)
Ionization potential ðAÞ ¼ ꢀ EHOMO
3.9. Pharmacological activity results
3.9.1. Antibacterial activity
The newly synthesized azo dye ligand (L) and its Cu(II), Co(II), and Ni(II) complexes
were evaluated for their antibacterial studies against three bacterial strains, E. coli, K.
pneumoniae, and B. subtilis. The MIC values of the compounds against respective bac-
terial strains along with the standard are given in Table 8. From the results, it is clear
that all the synthesized compounds exhibited promising antibacterial properties
against tested bacterial strains. On comparing the antibacterial activity of the ligand
and its metal complexes, it is inferred that the metal complexes exhibited more inhibi-
tory effect on the growth of all the microorganisms and this may due to the change
in molecular structure due to coordination with the metal ion that tends to make a
metal complex act as more powerful and potent bactericidal agents. Thus, the results
of the antibacterial activity of the synthesized compounds can be summarized as 1c >
1
a > 1b > 1.
In general, the increase in the antibacterial activity of the complexes over the free
ligand could be predicted in the light of “Chelation Theory.” The enhancement in the
bactericidal activity may be rationalized on the basis that ligands mainly possess azo
(
-N ¼ N-) group. Moreover, on coordination, the polarity of the metal ion will be
greatly reduced due to the overlap of ligand orbitals with metal orbitals and partial

1
6
M. N. MATADA ET AL.
Table 9. The results of the cytotoxic activity of the ligand and its metal complexes (IC , in mM)
5
0
by MTT assay.
Compounds
1
K562
A549
MDA-MB-231
L
44.38
24.18
19.31
25.87
8.23
>50
>50
17.77
>50
7.36
>50
>50
>50
>50
11.68
1a
1b
1c
[Cu(L)
[Co(L)
[Ni(L)
2
2
]
(H
(H
2
O)
O)
2
]
2
2
2
]
Cisplatin
sharing of the positive charge of the metal ion with the donor groups present in the
ligand. Thus, lipophilic character of the central metal ion will increase, which favors its
permeation more efficiently through the lipid layer of the microorganism. Further,
these complexes completely disturb the respiration process of the cell and thus block
the protein synthesis, which restricts further growth of the organisms [53].
3.9.2. DNA-Cleavage activity
Although there has been a wide discovery of drugs for treatment of various diseases,
it remained as a challenge that causes most of the human deaths worldwide [54]. This
is mainly due to limitations of the drugs such as high toxicity, serious side effects and
drug resistance [55]. These limitations that render drugs inability could be associated
with their interaction with the DNA. Therefore, DNA-cleavage studies are essential to
understanding the mechanism of toxicity of the drugs with the DNA molecule, where
DNA-cleavage is controlled by relaxation of circular form of pUC18 DNA into nicked
circular form and linear form. When circular plasmid DNA is conducted by electrophor-
esis the faster migration will be observed for the supercoiled form (Form I). If one
strand is cleaved, supercoils will relax to produce a slow moving open circular form
(II). If both strands are cleaved, a linear form (Form III) will be generated that migrates
in between I and II [56].
In the present study, the cleavage ability of the synthesized compounds on DNA
was performed by gel electrophoresis method. The results of the DNA cleavage activ-
ity of the ligand and its metal complexes are as shown in Figure 3. These findings
indicated that Cu(II) and Ni(II) complexes show complete cleavage of all forms of DNA,
whereas ligand and Co(II) complex partially cleaved Form I DNA and completely
cleaved Form II DNA compared to control DNA. Further, it can be noted that the con-
trol DNA alone did not exhibit any apparent cleavage, whereas the ligand and its
metal complexes exhibited cleavage and these could be explained by an important
coordination role of nitrogen and oxygen to the metal ions in these isolated DNA
cleavage reactions. From the rest of the biological studies like antibacterial and cyto-
toxic studies carried out in this work have a good correlation with the cleavage prop-
erties and therefore it can be evident that the metal ion present in an heterocyclic
core can be an efficient pharmacological agent as they exhibited appreciable cleavage
properties. This can be interpreted that these studied complexes cleave the genome
of the respective microorganisms effectively and thereby inhibit the growth and finally
leads to the death of the cells. From these findings, it is apparent that the tested com-
pounds are potential inhibitors for pathogenic microorganisms.

JOURNAL OF COORDINATION CHEMISTRY
17
Figure 4. The proposed molecular geometries for the synthesized metal complexes.
3.9.3. Cytotoxic activity results
The anticancer activity of the novel bioactive metal complexes of azo dye containing
pyrazole moiety was carried out against some selected cancer cell lines, human
chronic myeloid leukemia cell line (K562), human lung carcinoma cell line (A549), and
human mammary tumor cell line (MDA-MB-231) by MTT assay. The results of the activ-
ity in terms of IC50 values (mM) are presented in Table 9. The results indicated that the
metal complexes exhibited lower values of IC50 against K562 cell line and this suggests
that all these metal chelates are proved to be potential anticancer agents.
Furthermore, the moderate activity was exhibited by the compounds against A549
and MDA-MB-231 cell lines. From overall observation, it is concluded that the chela-
tion can enhance the pharmacological properties of the compounds by suppressing
the anomalous behavior of the cells which do not have any particular physiological
functions in the biological system. Also, these types of drugs having metal ions in their
structures can destroy the tumors present in the biological system more effectively as
compared to the simple heterocyclic compounds. This can be attributed to the discov-
ery of platinum-based molecules ruled the whole drug industry by exhibiting excellent
anticancer properties. Therefore, the present compounds can be used in the develop-
ment of metal-based drugs in the future [57, 58].
4. Conclusion
The present work is focused on the synthesis of novel azo dye ligand 4-[(7-hydroxy-4-
methyl-1,3-benzothiazol-2-yl)diazenyl]-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (L)
and its Cu(II), Co(II) and Ni(II) complexes. All the synthesized compounds were character-
ized by analytical and spectroscopic techniques. IR spectral data indicate that the azo-dye
ligand behaves as a monobasic bidentate O,N-donor coordinating via the nitrogen atom
of the azo group and oxygen atom of the deprotonated hydroxyl group of the benzothia-
zole moiety. Magnetic moment and electronic spectra suggest distorted tetrahedral

1
8
M. N. MATADA ET AL.
geometry for Cu(II) complex and octahedral geometry for the Co(II) and Ni(II) complexes.
ESR data showed that the complexes are mononuclear in nature. Based on the analytical
and spectroscopic results, the following structures were proposed for the complexes and
they are presented in Figure 4. The molecular structures of the synthesized compounds
were analyzed by quantum chemical technique (ZINDO/1) and the optimized structures
were used for the interpretation of chemical reactivity. The antibacterial activity results
showed that all the metal complexes exhibited higher activity against different microbial
strains when compared with the free ligand. We have also studied the DNA-cleavage activ-
ity of newly synthesized ligand and its metal complexes by gel electrophoresis. All the
compounds except ligand (L) and its Co(II) complex cleaved completely by the DNA mol-
ecule. From the above observation, it is revealed that the metal chelates of the azo dye lig-
and having pyrazole ring can be considered as significant anticancer agents.
Acknowledgements
Authors are thankful to the Department of Chemistry, Kuvempu University, Shankaraghatta,
Shimoga for providing the laboratory facilities. We are grateful to the SAIF Panjab University,
STIC Cochin University, SAIF IIT Madras for providing spectral and analytical data.
Disclosure statement
No potential conflict of interest was reported by the authors.
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