Synthesis, structural characterization, antimicrobial and DNA binding studies of homoleptic zinc and copper complexes of NO Schiff bases derived from homoveratrylamine

Article abstract of DOI:10.1016/j.ica.2019.05.028

Four new homoleptic zinc (1 and 2) and copper (3 and 4) complexes of two Schiff base ligands (L¹H and L²H) derived from 2-(3,4-dimethoxyphenyl)ethan-1-amine (5), a dimethyl derivative of dopamine were synthesized. All four complexes

Full text of DOI:10.1016/j.ica.2019.05.028

Accepted Manuscript
Research paper
Synthesis, Structural Characterization, Antimicrobial and DNA binding studies
of homoleptic zinc and copper complexes of NO Schiff bases derived from ho-
moveratrylamine
C.E. Satheesh, P. Raghavendra Kumar, N. Shivakumar, K. Lingaraju, P. Murali
Krishna, H. Rajanaika, Amar Hosamani
PII:
S0020-1693(19)30055-6
https://doi.org/10.1016/j.ica.2019.05.028
ICA 18929
DOI:
Reference:
Inorganica Chimica Acta
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 January 2019
14 April 2019
16 May 2019
Please cite this article as: C.E. Satheesh, P. Raghavendra Kumar, N. Shivakumar, K. Lingaraju, P. Murali Krishna,
H. Rajanaika, A. Hosamani, Synthesis, Structural Characterization, Antimicrobial and DNA binding studies of
homoleptic zinc and copper complexes of NO Schiff bases derived from homoveratrylamine, Inorganica Chimica
Acta (2019), doi: https://doi.org/10.1016/j.ica.2019.05.028
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Synthesis, Structural Characterization, Antimicrobial and DNA binding studies of
homoleptic zinc and copper complexes of NO Schiff bases derived from homoveratrylamine
C. E. Satheesha, P. Raghavendra Kumara*, N. Shivakumarb, K. Lingarajuc, P. Murali Krishnab, H
Rajanaikac, Amar Hosamanid
aDepartment of Studies and Research in Chemistry, UCS, Tumkur University, Tumkur 572 103, Karnataka, India
bDepartment of Chemistry, Ramaiah Institute of Technology, Bangalore 560 054, Karnataka, India
cDepartment of Studies and Research in Environmental Science, UCS, Tumkur University, Tumkur 572 103,
Karnataka, India
dSolid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, Karnataka, India
*Corresponding authors:raghukp1@gmail.com; +91-9901511112
Abstract:
Four new homoleptic zinc (1 and 2) and copper (3 and 4) complexes of two Schiff base ligands
(L1H and L2H) derived from 2-(3,4-dimethoxyphenyl)ethan-1-amine (5), a dimethyl derivative of
dopamine were synthesized. All four complexes were well characterized by elemental analysis, FT-IR and
UV-Vis., spectroscopy. Further, the zinc complexes (1 and 2) were characterized by 1H and 13C{1H} NMR
spectroscopy while the copper complexes (3 and 4) by single crystal X-ray diffraction. The characterization
data of complexes revealed strong coordination via azomethine nitrogen (N) and phenolate oxygen (O) of
deprotonated ligands (L1 and L2) as NO donors of composition [Zn/Cu(L1-2)2] (1-4). The CT-DNA binding
affinity of complexes 1, 2 and 4 was assessed using electronic absorption titration method which showed
avid binding through intercalation mode and the binding constant (Kb) was found in the order of 105 to 106
M-1. The compounds (1-5) were screened for dose dependent antimicrobial activity by agar well diffusion
method against pathogenic antibacterial strains, E. coli, S. aureus and antifungal strain, C. albicans. The
compounds showed significant toxicity to these pathogens.
Key words: Schiff base, Copper, Zinc, DNA binding, Antibacterial activity, Antifungal activity.
1. Introduction:
The discovery of ‘cis-platin’ a simple platinum complex but a potential antitumor drug given
platform for the design and development of metal-based coordination compounds as metallodrugs
[1]. The advantages of metal in metallodrug are: enhancement of biological activity of the organic
ligand through a novel mechanism of metallotherapeutic action in comparison to organic ligands,
reduced the toxic effects of drug or its metabolites produced in the cell [2]. However, not all metal
complexes have been emerged into successful drugs. Because the biological activity of
metallodrugs depends on several of their properties such as nature of the metal ion and its
1

oxidation state(s), number and nature of the ligands, stereochemistry of the metal complex,
thermodynamics and kinetics of ligand exchange reactions in bio-environment, electrochemical
and photophysical properties [3].
Complexes of platinum metals have been found potential metallodrugs for the treatment of life-
threatening diseases such as cancer, inflammatory, tuberculosis, viral, epilepsy, diabetes and
cardiovascular [1a,e,4]. However, platinum metals-chelates bear several limitations: these metals
are costly, less abundant, more toxic due to severe side effects and most of the complexes are
kinetically less-labile, lack of activity for wide range of cancerous cells. Meanwhile biological
activity of most of the non-platinum d-block metals complexes particularly Mn, Fe, Co, Ni, Cu, Zn
have been explored [1g,h,5] due to their inherent advantages like the metals are more abundant,
cost effective and less-toxic, abundant trace essential elements [1g,3c,d,6], these metal ions exhibit
excellent bio-coordination chemistry by providing suitable coordination centers in physiological
conditions.
Ligands play important roles in metal based drugs. Schiff bases are a special class of ligands
because they: can be easily synthesised from low cost raw materials such as aldehydes/ketones and
primary amines, exhibit rich coordination and structural chemistry with most of the transition
metals, form stable and chelated complexes with additional donors [7]. The azomethine nitrogen
play an important role in biological activity hence Schiff bases and their metal complexes have
been largely explored in medicine for the treatment of various diseases [5g,8].
The evidence of drug resistance, evolution of new diseases by unknown bacteria and severe
toxic effects of existing drugs have been continued to put efforts for designing and development of
new, wide spectrum of bio-active and less toxic metal based drugs where the ligands especially
derived from synthetic/natural biologically active compounds is of current interest [9]. Such type
of drugs may show increased biological potency [9]. Recently, few Cu(II) and Zn(II) [8g,o-p,r-
s,10,27a] complexes of Schiff bases especially containing nitrogen (N) and oxygen (O) donors
found to show potential biological activity [9c,10a,14b]. We herein report the synthesis and
characterization of new homoleptic Zn(II) and Cu(II) complexes (1-4) of Schiff bases (L1H and
L2H) derived from 2-(3,4-dimethoxyphenyl)ethan-1-amine (5) also referred to as
homoveratrylamine, which is a dimethyl derivative of dopamine (DA), main structural unit of
many drugs used for the treatment of neurological disorders like Parkinson’s disease, congestive
2

heart failure and others [11]. Also reported the studies on antimicrobial and DNA binding activities
of above new complexes (1-4).
2. Experimental
2.1 Materials
All solvents (EtOH, MeOH, Pet-ether, Hexane, CHCl3 and MDC) and chemicals were of
commercial reagent grade and used as received. 2-(3,4-dimethoxyphenyl)ethan-1-amine (5) (97%),
Zn(OAc)2.2H2O, Cu(OAc)2.H2O and Tris HCl were purchased from Sigma Aldrich, India. 2-
Hydroxy benzaldehyde (99.5%) and 2’-hydroxy acetophenone (99%) were purchased from Merck
Specialities Pvt. Ind. Ltd. NiCl2.6H2O was supplied by S. D. Fine-Chem Ltd., India. The
microorganisms such as Escherichia coli (E. coli) [NCIM-5051] and Staphylococcus aureus (S.
aureus) [NCIM-5022] as pathogenic bacterial strains and Candida albicans (C. albicans) [NCIM-
3100] as pathogenic fungal strains used in this study were purchased from National Chemical
Laboratory (NCL), Pune, India. These strains were maintained on nutrient agar slant at 4°C.
Standard antibiotics Ciprofloxacin and Fluconazole were purchased from Hi Media, Mumbai,
India. Calf-thymus-DNA (CT-DNA) was purchased from Genei, Bangalore, Karnataka, India.
2.2 Analytical methods
Elemental analysis (C, H and N) was performed on a LECO–CHNSO–9320 type elemental
1
13
analyser. H and C{1H} NMR spectra of 1 and 2 were recorded in CDCl3 or DMSO-d6 solution
on a Bruker WM-400 spectrophotometer (400 MHz) using TMS as an internal standard. The FT-
IR spectra of all the compounds were recorded by scan method in the range of 4000–500 cm-1 with
Agilent FT-IR spectrophotometer. UV–Visible (UV–Vis.,) spectra were recorded on UNI-CAM-
UV 2-100 spectrophotometer. Melting points of all new complexes were determined using
Gallenkamp melting point apparatus in an open capillary closed at one end and were reported
uncorrected. Single crystal X-Ray diffraction data of 3 and 4 were collected on a Bruker SMART
APEX CCD-based X-ray diffractometer with Mo/Kα-radiation (λ, 0.71073 Å, at T 193 K). The
molecular structures of 3 and 4 were solved by direct methods and refinement was carried out
using SHELXTL-97 [12] package and empirical absorption correction has been applied
(SADABS). All refinements were made by full-matrix least-squares on F2 with anisotropic
refinement at calculated positions.
3

2.3 Synthesis of zinc complexes, [Zn(L1-2)2] (1-2)
Zn(OAc)2.2H2O (100 mg, 0.45 mmol) was dissolved in methanol (20 mL) and the resulting
solution was stirred for 10 min. A solution of L1H (260 mg, 0.91 mmol)/ L2H (273 mg, 0.91
mmol) made in of methanol (10 mL) was added slowly and drop wise to the above solution under
vigorous stirring during 10 min. The stirring was continued further for 30 min. A white precipitate
was formed, which was filtered, washed with methanol (25 mL X3) and then with diethyl ether (25
mL X3). When the respective precipitates of 1/2 was recrystallized from 1:1 mixture of methylene
dichloride and hexane at room temperature gave white microcrystals of compound 1/2.
[Zn(L1)2] (1): Yield: 490 mg (85%); M.P.: 164-165 °C; Element. Anal. Calcd. (Found) for
C34H36N2ZnO6: C, 60.40 (60.30); H, 5.72 (5.27); N, 4.42 (4.18); FT-IR: (ν, cm-1): 2928, 2835,
1614, 1536, 1516, 1467, 1345, 1284, 1157, 1029, 935, 908, 852, 760, 624, and 560; UV-Vis., (λmax
1
in nm): 275, and 366; H NMR (CDCl3, δ ppm): 8.315 (s, 1H, CH=N), 7.214-7.258 (t, 1H, H4),
7.164-7.187 (d, 1H, H3), 6.756-6.736 (d, 1H, H6), 6.509-6.617 (m, 3H, H11, H14, H15), 6.685-
6.707 (d, 1H, H5), 3.665-3.701 (t, 2H, NCH2), 3.628 (s, 3H, OCH3), 3.562 (s, 3H, OCH3), 2.691-
2.728 (t, 2H, CH2Ar). 13C{1H} NMR (CDCl3, δ ppm): 36.140 (C9), 55.749 (OCH3), 55.931
(OCH3), 61.835 (C8), 112.375 (C5), 112.982 (C11), 114.394 (C14), 118.621 (C4), 120.943 (C10),
122.825 (C15), 131.089 (C1), 134.936 (C6), 136.424 (C3), 147.769 (C13), 149.059 (C12), 170.421
(C2), 172.295 (C7).
[Zn(L2)2] (2): Yield: 483 mg (80%); M.P.: 167-168 °C; Element. Anal. Calcd. (Found) for
C36H40N2ZnO6: C, 65.30 (65.29); H, 6.09 (6.01); N, 4.01 (3.98); FT-IR: (ν, cm-1): 3010, 2932,
2910, 2836, 1615, 1533, 1511, 1466, 1437, 1407, 1318, 1259,1229,1185,1143,1017, 907, 901, 806,
1
751, 598, and 545; UV-Vis., (λmax in nm): 270, and 365; H NMR (CDCl3, δ ppm): 7.211-7.250
(m, 1H, H4), 7.163-7.186 (dd, 1H, H5), 6.734-6.750 (d, 1H, H3), 6.684-6.705 (d, 1H, H6), 6.612-
6.616 (d, 1H, H11), 6.508-6.567 (m, 2H, H15, H14), 3.658-3.701 (t, 2H, NCH2), 3.634 (s, 3H,
OCH3), 3.567 (s, 3H, OCH3), 2.700-2.738 (t, 2H, CH2Ar ), 2.010 (s, 3H, CH3). 13C{1H} NMR
(CDCl3, δ ppm): 14.121 (CH3) 35.818 (C9), 55.208 (OCH3), 55.419 (OCH3), 61.558 (C8), 103.313
(C5), 111.842 (C11), 112.364 (C14), 119.834 (C4), 120.467 (C10), 124.667 (C15), 130.559 (C1),
136.450 (C6), 136.964 (C3), 147.275 (C13), 148.543 (C12), 169.004 (C2), 170.733 (C7).
2.2 Synthesis of copper complexes, [Cu(L1-2)2] (3-4)
4

Cu(OAc)2.H2O (100 mg, 0.5 mmol) was dissolved in 20 mL of methanol and the resulting
solution was stirred for 10 min. A solution of ligand L1H (286 mg, 1.0 mmol)/ L2H (300 mg, 1.0
mmol) made in 10 mL of methanol was added slowly and drop wise to the above solution under
vigorous stirring during 10-15 min. The stirring was continued further for 30 min during which a
greenish-yellow precipitate of 3/4 was formed. The precipitate was filtered, washed with methanol
(25 mL X3) and then with diethyl ether (25 mL X3).The product was recrystallized from 1:1
mixture of methylene dichloride and hexane gave greenish-yellow single crystals of compound
3/4.
[Cu(L1)2] (3): Yield: 571 mg (85%); M.P.: 140-141 °C; Element. Anal. Calcd. (Found) for
C34H36N2O6Cu: C, 64.59 (64.51); H, 5.74 (5.66); N, 4.43 (4.35); FT-IR: (ν, cm-1): 2966, 2925,
2850, 1610, 1507, 1459, 1449, 1322, 1226, 1137, 1017, 904, 901, 835, 808, 753, and 582; UV-Vis.
(λmax in nm): 270,307, 361, and 703.
[Cu(L2)2] (4): Yield: 575 mg (87%); M.P.: 171-172 °C; Element. Anal. Calcd. (Found) for
C36H40N2O6Cu: C, 65.49 (65.45); H, 6.11 (6.07); N, 4.24 (4.21); FT-IR: (ν, cm-1): 2915, 2835,
1585, 1514, 1440, 1323, 1140, 1022, 858, 815, 752, and 646; UV-Vis. (λmax in nm): 270, 310, 358,
and 712.
2.3 DNA binding activity
The DNA binding activity of zinc and copper complexes (1-4) of NO Schiff base ligands (L1H
and L2H) was assessed using UV–Vis., absorption spectroscopy. CT-DNA was used for the
determination of binding capacity of given compounds. The purity of CT-DNA was verified by
taking the ratio of absorbance at λ260 to λ280, 1.90-2.00 in the buffer 5 mM Tris HCl/ 50 mM NaCl
which prepared in double distilled water at pH, 6.90-7.01. A stock solution of CT-DNA was then
prepared and its concentration per nucleotide was determined by measuring the absorbance at λ,
260 nm using the molar absorption coefficient ε, 6600 Lmol-1cm-1 [21]. The stock solution was
stored at 4 ºC and used within 4 days.
Absorption titration experiments for compounds, 1-4 were performed for a fixed concentration
of each compound (25 µM) against increasing (25–300 µM) amount of CT-DNA. The absorption
titration spectra were recorded in the absence and presence with increasing concentration of CT-
DNA (0–350 µM). The spectra recorded each time on incremental addition of DNA to the test
5

solution against blank solution containing same concentration of DNA without the test sample but
containing buffer. In order to assess the binding strength of these compounds (1-4), the intrinsic
binding constant (Kb) was determined from the plot of [DNA]/( - ) versus [DNA] according to
Eq… (1).
=
+
······ (1)
Where, and are the molar extinction coefficients (Aobs/[Conc]) corresponds to the
apparent, compound in fully bound form to DNA and free compound respectively. The slope
[1/( - )] and Y-intercept [1/Kb( - )] were determined from the plot for each compound and
then Kb was calculated from the ratio of the slope to the intercept.
2.4
Antimicrobial activity studies
The new zinc and copper complexes (1-4) of Schiff base ligands (L1H and L2H) and 5 were
screened for antimicrobial activity by agar well diffusion method against a Gram negative (E. coli)
and a Gram positive (S. aureus) bacteria and a fungi (C. albicans). Two analytical solutions of all
compounds, 1, 2, 3, 4 and 5 were prepared by dissolving 500 and 1000 µg in 50 and 100 µL of
DMSO respectively to get 10 µg/µL concentration of each compound in solution and assessed the
dose dependent antimicrobial activity.
Nutrient and potato dextrose broths were used to culture the bacteria and fungi respectively.
Nutrient agar plates were prepared and swabbed using sterile L-shaped glass rod with 100 µL of 24
h mature broth culture of individual bacterial strains. The wells of 6 mm were crated in to each
plate using sterile cork borer. The standard test solutions of compounds (1-5) were now added into
the wells using sterile micropipettes. These plates were incubated at 37 °C for 36 h. After the
incubation period, the zone of inhibition of each well was measured in mm and the values were
noted. The measurements were made in triplicate for each compound and their average values
were reported. Similarly the zone of inhibition was determined for standard antibiotic drug,
ciprofloxacin (5 µg/50 µL) as a positive control.
Antifungal activity of the culture strains of fungi (C. albicans) performed on potato dextrose
agar (PDA) slant at 27 ± 0.2 °C for 48-96 h, till sporulation. Spore of strains were transferred into
6

5 mL of sterile 1% saline solution. 100 µL of each fungal spore suspension was spread on each
sterile PDA plate. Using the sterile cork borer, wells of 6 mm were made in each plate. The
standard test solutions of compounds (1-5) were now added into the wells using sterile
micropipettes. The plates were incubated for 72 h at 27 °C. After the incubation period, the zone of
inhibition of each well was measured in mm and the values were noted. Triplicates were
maintained for each compound and the average values were reported. Similarly the zone of
inhibition was determined for standard antifungal drug, fluconazole (200 µg/50 µL) as a positive
control.
3. Results and Discussion
3.1 Synthesis of ligands (L1H and L2H) and complexes, 1 to 4
The Schiff bases used for the synthesis of homoleptic zinc and copper complexes (Scheme 1) were
prepared as per our reported procedure [13a] via condensation of 2-(3,4-dimethoxyphenyl) ethan-
1-amine (5) with 2-hydroxy benzaldehyde (L1H) and 2’-hydroxy acetophenone (L2H) in dry
ethanol respectively. These four new complexes (1-4) were easily formed at room temperature
under magnetic stirring of methanolic solutions containing 2 molar equivalents of ligand (L1H or
L2H) and 1 molar equivalents of [Zn(OAc)2.2H2O] and [Cu(OAc)2.H2O] as metal ion precursors.
The precipitate then formed after each reaction was filtered and washed thoroughly with methanol
and then recrystallized in 1:1 mixture of methylene dichloride and n-hexane. Zinc complexes were
obtained as white microcrystalline and copper ones as greenish-yellow crystalline solids in high
yields of about 80-85% and high purity.
R
14
OMe
OMe
13
12
15
H N
R
7
OMe
OMe
2
6
8
O
+
1
5
4
N
H
10
9
11
OH
2
O
2-hydroxybenzaldehyde (R = H)
2-(3,4-dimethoxyphenyl)ethanamine
3
R = H;
L1H
2
L H
5
2-hydroxyacetophenone (R = Me)
R = CH3
;
OMe
MeO
MeO
MeO
Zn(oAc)2. 2 H2O/
Methanol
Cu(oAc)2. H2O/
Methanol
R
L1H or
L2H
O
N
O
Cu
N
O
N
Zn
R
N
OMe
R
O
R
OMe
OMe
OMe
R = H;
M = Cu; 3
R = H;
M = Zn; 1
R = CH3; M = Cu; 4
R = CH3; M = Zn; 2
7

Scheme 1 Synthesis of ligands (L1H and L2H) and complexes (1-4)
The solubility of these four new complexes (1-4) was checked in various solvents and found that
they were soluble in MDC, CHCl3, DMSO, DMF and CH3CN but insoluble in methanol, ethanol,
n-hexane, n-heptane and pet-ether.
3.2 Characterisation of complexes, 1 to 4
The composition of the new zinc (1-2) and copper (3-4) complexes of Schiff bases derived
from veratrylamine was determined by elemental analysis (C, H and N) and was in agreement with
their expected molecular formulae [M(L1-2)2]. The complexes were further characterised by FT-IR,
UV-Vis., NMR spectroscopy (Zinc complexes) and single crystal X-Ray diffraction (Copper
complexes).
3.2.1 UV-Vis. spectroscopy
The electronic spectra of zinc (1-2) and copper (3-4) complexes has been recorded for their
solutions of concentration 2.5X10-5 M made in DMSO.
Fig. 1 UV-Vis., spectra of new Zn (1 – 2) and Cu (3 – 4) complexes of NO Schiff base ligands (L1-
2H). (Inset: d-d transition)
8

In the electronic spectra of all complexes, 1-4 represented in Fig. 1, an intense high-energy
band was observed at λmax, ~270 nm which was attributed to π→π* intra-ligand charge transfer
(ILCT) transition. The bands showed blue shift of about 10-15 nm when compared to these bands
in the respective ligands [13a]. A band observed at λmax, 366 3 nm was due to ligand to metal
charge transfer (LMCT) transition [13a]. In the visible domain of absorption spectra, a wide band
centered at λmax, ~713 nm was observed only at higher concentration for copper complexes (3 and
4) and these bands were attributed to the d-d transition (2Eg→2T2g) for a Cu(II) complexes with d9
configuration which undergo tetragonal distortion due to the John-Teller effect [14].
3.2.2 FT-IR spectroscopy
In the IR spectra of ligands, a strong absorption band observed for ν(O-H) bond stretching
at ν, 3400 cm-1 was absent in the spectra of their Zn (1-2) and Cu (3-4) complexes which indicated
the coordination of phenolate oxygen to central metal ion. The ν(C=N) stretching band showed a
red shift of about 15-20 cm-1 in the complexes 1 to 4 in comparison to those bands in the respective
ligands [14] indicated the involvement of azomethine nitrogen in complex formation. The ν(C-O)
vibrational band in the complexes was shifted to a region of higher wave number [15] and
appeared at 1345 and 1330 cm-1 in complexes 1 and 2 respectively which showed blue shift of
about 30-40 cm-1 [13]. In the IR spectra of Cu(II) complexes (3 and 4) the ν(C-O-) stretching
vibrational bands were appeared at 1348 and 1323 cm-1 respectively which were found very
strongly affected on coordination of ligands and they have shown blue shift of about 100 cm-1 in
the complexes when compared to those bands in respective ligands. The strong absorption bands
between 1580 to 1500 cm-1 in all ligands and complexes could be reasonably attributed to the
presence of the ν(C=C) stretching vibration of the aromatic ring backbone. New bands appeared in
the ranges ν, 578-547 cm−1 and at 534 cm−1 in the all complexes were attributed to the ν(M–N) and
ν(M–O) vibrations respectively which they were not present in the spectra of ligands. Coordination
of the azomethine nitrogen and phenolate oxygen to the metal ions in the copper complexes has
been consistent with X-ray diffraction results [13,16a] those of zinc complexes by NMR studies
discussed later in the manuscript. These observations indicated that the coordination of ligands
occurred in complexes through the phenoxide (O-) and imine (C=N) groups to M(II) ions forming
chelated complexes [13,16a].
3.2.3 NMR Spectroscopy
9

The zinc complexes (1 and 2) were characterised by 1H and 13C{1H} NMR spectroscopy. In
the proton NMR spectra of 1 and 2, the azomethine proton has shown a downfield shift of 0.14 and
0.12 ppm when compared to the chemical shifts of these protons in the ligands L1H and L2H
respectively [13a,16]. In 1 and 2, the NCH2 (0.15 ppm) and CH2Ar (0.25 and 0.29 ppm) protons
were found to be shielded than those protons in their respective ligands L1H and L2H. The
methoxy protons were also found to be shielded about 0.3 ppm when compared to proton NMR
shifts in the respective ligands as observed in such dimethoxy compounds [13a]. The signal for
phenolic proton observed in the proton NMR spectra of L1H and L2H was disappeared in the
spectra of both 1 and 2 [13a].
13
In the C NMR spectra of complex 1 the signals for C2 (-C-O-), C3 (ortho to -CO-) and
azomethine (>C=N-) carbons were found deshielded about 5, 7 and 10 ppm respectively. In the 13C
NMR spectra of complex 2 these signals were also found deshielded about 7, 7 and 3 ppm
respectively in comparison to these signals in the respective ligands [13a,16].
The observations from NMR spectra of 1 and 2 once again confirmed the coordinated of
ligands as deprotonated (L1 and L2), monoanionic bidentate (N,O) donors to the central metal ion.
The magnitude of NMR shifts also demonstrated that the ligand L1 was found to be strongly
coordinated to zinc ion in 1 than L2 in 2 due to the steric hindrance of methyl group.
3.2.4 Single crystal X-Ray diffraction
The complexes 1 to 4 were recrystallized in a 1:1 mixture of methylene chloride and n-
hexane. The microcrystals obtained for Zn(II) complexes (1 and 2) were found not suitable for
single crystal X-Ray diffraction studies. The single crystal X-ray diffraction data for Cu(II)
complexes (3 and 4) was collected and their molecular structures in solid state were determined.
The crystal data and structure refinement parameters of 3 and 4 are given in Table 1 and their
selected bond parameters are given in Table 2. The molecular structures of 3 and 4 are given in
Fig. 1 and Fig. 2 respectively.
The Cu-O and Cu-N bond lengths in 3 and 4 were found in the range of 1.878(4) - 1.888(3)
Å and 2.003(4) - 2.044(4) Å respectively. The Cu-N bonds are slightly stretched in 4 due to the
steric hindrance of bulky methyl group than H in 3. These bond lengths are in agreement with
those shown by the copper(II) complexes of similar Schiff base ligands [13b]. The O-Cu-O/ N-Cu-
10

N (180°) and O-Cu-N (90°) bond angles in both 3 and 4 revealed that they have square planar
geometry around central copper ion [13b]. These observations also strongly confirmed the
coordination of ligands L1H and L2H as deprotonated (L1 and L2) bidentate (NO-) donors forming
homoleptic 6-membered chelated complexes.
Further in the crystals of 3 and 4 the molecules were found to held by C-H O type intermolecular
hydrogen bonding (2.50 - 2.59 Å) resulting in supramolecular assemblies as shown in Fig. S9 and
Fig. S10 respectively (ESI). These secondary interactions were slightly weaker than those found in
copper complexes of similar type of ligands [14b].
Fig. 1 Molecular structure of [Cu(L1)2] (3).
11

Fig. 2 Molecular structure of [Cu(L2)2] (4).
Table 1 Crystal data and structure refinement for of [Cu(L1)2](3) and [Cu(L2)2](4).
Complex
Empirical formula
Formula weight
[Cu(L1)2] (3)
C34H36N2O6Cu
632.19
[Cu(L2)2] (4)
C36H40N2O6Cu
660.24
Temperature/K
298(2)
289(2)
Crystal system
Space group
monoclinic
P21/n
monoclinic
P21/c
a/Å
b/Å
c/Å
α/°
21.3711(12)
5.7236(4)
24.8756(16)
90
10.8183(12)
6.2205(7)
23.431(2)
90
β/°
98.172(6)
90
3011.9(4)
4
1.394
0.774
99.609(10)
90
1554.7(3)
2
1.410
0.753
γ/°
Volume/Å3
Z
ρcalc g/cm3
μ/mm-1
F(000)
1324.0
694.0
Crystal size/mm3
Radiation
0.24 × 0.23 × 0.15
MoKα (λ = 0.71073)
5.062 to 50.046
-25 ≤ h ≤ 25,
-6 ≤ k ≤ 4,
-22 ≤ l ≤ 29
10956
0.23 × 0.22 × 0.21
MoKα (λ = 0.71073)
5.614 to 49.994
-12 ≤ h ≤ 5,
-4 ≤ k ≤ 7,
-25 ≤ l ≤ 27
5468
2Θ range for data collection/°
Index ranges
Reflections collected
Independent reflections
5310 [Rint = 0.0632,
2745 [Rint = 0.0816,
12

Rsigma = 0.0909]
5310/0/392
1.041
Rsigma = 0.1285]
2745/0/208
0.968
Data/restraints/parameters
Goodness-of-fit on F2
R1 = 0.0621,
wR2 = 0.1557
R1 = 0.0947,
wR2 = 0.1897
0.30/-0.43
R1 = 0.0690,
wR2 = 0.1478
R1 = 0.1116,
wR2 = 0.1757
0.55/-0.42
Final R indexes [I>=2σ (I)]
Final R indexes [all data]
Largest diff. peak/hole / e Å-3
CCDC No.
1569503
1569610
Table 2 Selected bond lengths and bond angles of [Cu (L1)2] (3) and [Cu (L2)2] (4).
3
Cu(1)-O(3) 1.888(3) O(3)-Cu(1)-N(1)
Cu(1)-O(6) 1.878(4) O(3)-Cu(1)-N(2)
Cu(1)-N(1) 2.003(4) N(1)-Cu(1)-N(2)
Cu(1)-N(2) 2.004(4) O(6)-Cu(1)-O(3)
N(1)-C(11) 1.301(6) O(6)-Cu(1)-N(1)
N(2)-C(28) 1.298(6) O(6)-Cu(1)-N(2)
N(2)-C(27) 1.481(6)
91.80(15)
88.09(15)
177.81(15)
176.9(2)
88.10(16)
92.13(16)
N(1)-C(10) 1.479(5)
4
Cu(1)-O(3)1 1.878(4) O(3)1-Cu(1)-O(3)
Cu(1)-O(3) 1.878(4) O(3)1Cu(1)N(1)
Cu(1)-N(1) 2.044(4) O(3)-Cu(1)-N(1)
180.0
89.17(16)
90.83(16)
Cu(1)-N(1)1 2.044(4) O(3)1-Cu(1)-N(1)1 90.83(16)
N(1)-C(11) 1.310(6) O(3)-Cu(1)-N(1)1
N(1)-C(10) 1.490(6) N(1)-Cu(1)-N(1)1
11-x,1-y,-z;
89.17(16)
180.0
Table 3 C-H O secondary interactions in [Cu(L1)2] (3) and [Cu(L2)2] (4)
D-H…A
C(15)-H(15) O(2)i
C(32)-H(32) O(5)ii
d(D-H)/Å
0.93
d(H-A)/Å d(D-A)/Å
D-H-A/°
162
3
2.58
2.50
3.4745
3.3750
0.93
156
13

4
C(9)-H(9A) O(2)iii
C(18)-H(18C) O(3)iv
0.97
0.96
2.56
2.59
3.4772
3.4637
157
151
i = 1/2+x, 3/2-y, 1/2+z; ii = -1/2+x, 1/2-y, -1/2+z; iii=1-x,-1/2+y,1/2-z; iv= x,1+y,z
3.2.5 DNA binding activity
The UV–Vis., spectroscopy has been a widely used technique to study the nature of interaction
and binding ability of ligands and their metal complexes with DNA [18,19]. In the present study,
the DNA binding interaction of each compound (1, 2, and 4) was determined by performing
electronic absorption titration experiments using the protein free calf thymus-DNA (CT-DNA)
[20]. The compound 3 was precipitated on addition of buffer hence, its absorption titration spectra
was not recorded.
The changes in absorbance at λmax, 270 and 310 nm was monitored for a fixed concentration
(25 µM) of metal complexes (1, 2 and 4) against the increasing concentration (0-350 µM) of CT-
DNA. The resulted absorption titration spectra are shown in Fig. 5 to Fig. 7 respectively.
The results of absorption titration experiments of new complexes 1 and 4 showed
hyperchromism whereas that of 2 showed hypochromism along with minor blue shift or no shift
[22]. The DNA binding affinity of the above compounds with CT-DNA was determined
quantitatively from the calculation of the intrinsic binding constant, Kb using Eq. (1) [23]. The
extent of hyperchromism or hypochromism and Kb values obtained are given in Table 4.
Table 4 Effect of concentration of CT-DNA on the absorbance bands and binding constant of 1, 2
and 4
λ max (nm)
Δλmax
(nm)
Kb
b
H(%) a,
Sl. No. Compound
(M-1)
Free
249
244
236
Bound
1
248
1
1
1
1.075
-1.189
2.330
24x105
2x105
39x105
1
2
243
2
3
235
4
H(%)a = [ɛfree – ɛbound/ɛfree]x100, b ‘-’ Hypochromism and ‘+’ Hyperchromism
14

The high intrinsic binding constant (Kb, 105 - 106 M−1) of 1, 2 and 4 suggested their strong
binding affinity for CT-DNA. The compounds were expected to bind with the CT-DNA bases
through non-covalent π–π stacking interaction [23b] as the complexes contain planar aromatic
rings. The results demonstrated that the complexes of salicylaldehyde Schiff base bind stronger
than 2-hydroxy acetophenone and further the copper complex exhibited strong binding capacity
than zinc as shown by their binding constants. These findings are due to the steric hindrance of 2-
hydroxy acetophenone Schiff base and the geometry of copper complexes is square planar whereas
the zinc complexes is tetrahedral.
2
1
0
140
120
100
80
60
40
14
16
18
[DNA]x10
20
22
200
300
400
500
-7
Wave length in(nm)
Fig. 5 (a) Electronic absorption spectra of [Zn(L1)2] (1) in 5 mM Tris HCl/50 mM NaCl buffer at
pH 6.90-7.01 in the absence (- - -) and presence (—) of increasing amount of DNA. The [1] =25
μM; [DNA] = 0 - 350 μM. The incubation period is 10 min at room temperature; (b) Plot of
[DNA]/(εa–εf) versus [DNA].
15

4
3
2
1
0
2
1
0
200
300
400
3.0
3.5
4.0
[DNA]x10
4.5
5.0
-7
Wavelength in(nm)
Fig. 6 (a) Electronic absorption spectra of [Zn(L2)2] (2) in 5 mM Tris HCl/50 mM NaCl buffer at
pH 6.90-7.01 in the absence (- - -) and presence (—) of increasing amount of DNA. The [2] =25
μM; [DNA] = 0 - 350 μM. The incubation period is 10 min at room temperature; (b) Plot of
[DNA]/(εa–εf) versus [DNA].
3
1.5
2
1.0
1
0.5
0.0
200
0
300
400
500
5
10
15
-7
[DNA]x10
Wavelength in (nm)
Fig. 7 (a) Electronic absorption spectra of [Cu(L2)2] (4) in 5 mM Tris HCl/50 mM NaCl buffer at
pH 6.90-7.01 in the absence (- - -) and presence (—) of increasing amount of DNA. The [4] = 25
μM; [DNA] = 0 - 350 μM. The incubation period is 10 min at room temperature; (b) Plot of
[DNA]/(εa–εf) versus [DNA].
3.2.6 Antimicrobial activity
16

The antimicrobial activity of new homoleptic zinc (1-2) and copper (3-4) complexes of NO donor
Schiff base ligands (L1H and L2H), and their precursor dimethyl derivative of dopamine (5) was
investigated by agar well diffusion method [24,8n] against the selected bacteria like E. coli (Gram
negative) and S. aureus (Gram positive) and fungi such as C. albicans. Nutrient and potato
dextrose agars were used to culture the bacteria and fungi respectively. The experimental details
and zone of antimicrobial inhibition in respect of both antibacterial and antifungal activity of
compounds (1-5) against the above pathogenic microbial strains are given in Table 5 and Table 6
respectively. The results of antimicrobial activity of 1-5 are also represented diagrammatically in
Fig. 8 and Fig. 9 respectively. Effectiveness of an antimicrobial agent will be evaluated based on
their respective zones of inhibition.
The results of antimicrobial activity studies demonstrated that the synthesized complexes have got
the capacity to inhibit the metabolic growth of the investigated bacteria and the toxicity increases
with dosage of any of the above tested compounds. The complexes found superior antibacterial
and antifungal agents than the corresponding Schiff base ligands [13a] as well as dimethyl
derivative of dopamine (5) under identical experimental conditions. The enhanced biological
activity of the chelated metal complexes is due to the presence of the metal ion. This can be
explained according to the Tweedy's chelation theory, which states that chelation reduces the
polarity of the central metal atom because of partial sharing of its positive charge with the ligand
which favors the permeation of the complexes through the lipid layer of cell membranes [24g].
Among the selected antibacterial pathogens, these complexes showed more toxicity towards E. coli
than S. aureus. Among the complexes the copper complexes showed higher antimicrobial activity
than zinc and which is due to difference in geometrical structures of complexes as revealed by the
literature reports [24].
17

Fig. 8 Antibacterial activity of standard Ciprofloxacin and new compounds: 1, 2, 3, 4 and 5
Table 5 Antibacterial activity of standard Ciprofloxacin and new compounds: 1, 2, 3, 4 and 5
E. coli
S. aureus
Sample
Treatment
(Mean±SE) (Mean±SE)
5 µg/50 µL
13.67±0.03 14.00±0.00
Ciprofloxacin
1
500 µg/50 µL
3.17±0.17
1.17±0.17
3.33±0.33
2.67±0.33
4.33±0.33
1.30±0.06
2.50±0.29
2.67±0.33
4.33±0.33
0.53±0.00
1.17±0.29
1000 µg/100 µL 5.83±0.33
500 µg/50 µL 0.67±0.33
1000 µg/100 µL 2.33±0.33
500 µg/50 µL 2.17±0.17
1000 µg/100 µL 3.67±0.03
500 µg/50 µL 5.67±0.3
1000 µg/100 µL 8.33±0.33
500 µg/50 µL 0.67±0.33
1000 µg/100 µL 1.50±0.29
2
3
4
5
Values are the mean ± SE of inhibition zone in mm.
18

Fig. 9 Antifungal activity of fluconazole and new compounds: 1, 2, 3, 4 and 5
Table 6 Antifungal activity of fluconazole, and new compounds: 1, 2, 3, 4 and 5
C. albicans
(Mean±SE)
Sample
Treatment
(200 µg/50 µL)
(500 µg/50 µL)
(1000 µg/100 µL)
(500 µg/50 µL)
(1000 µg/100 µL)
(500 µg/50 µL)
(1000 µg/100 µL)
(500 µg/50 µL)
(1000 µg/100 µL)
(500 µg/50 µL)
(1000 µg/100 µL)
11.50±0.06
1.00±0.00
2.17±0.00
1.33±0.33
2.67±0.33
1.53±0.03
2.17±0.03
2.00±0.58
3.67±0.33
0.67±0.33
1.67±0.17
Fluconazole
1
2
3
4
5
Conclusions
In conclusion, this paper contributed to the synthesis, characterization, CT-DNA binding affinity
and antimicrobial activity of four new zinc (1 and 2) and copper (3 and 4) complexes of two Schiff base
ligands (L1H and L2H) of homoveratrylamine (5). The composition and structural characteristics of 1-4
were confirmed by elemental analysis, FT-IR and UV-Vis., spectra. The zinc complexes (1 and 2) showed
1
13
characteristic H and C{1H} NMR spectra. The molecular structures of copper complexes (3 and 4) was
confirmed by single crystal X-ray diffraction studies. In all the complexes the deprotonated ligands (L1 and
L2) coordinated as monobasic, bidentate NO donor systems resulting in homoleptic tetracoordinate
19

complexes. The results of CT-DNA binding affinity studies assessed using electronic absorption titrations
demonstrated that they bind via π-π stacking mode and exhibited strong binding capacity as revealed by
their binding constant (Kb) values found in the order of 105 to 106 M-1. The compounds (1-5) also found to
act as potential antimicrobial agents and the activity increases with increasing dosage of the respective
compounds.
Acknowledgements
P. Raghavendra Kumar thanks Council of Scientific and Industrial Research (CSIR), New Delhi,
India for financial support through the project No. 01(2701)/12/EMR-II. We also thank Prof. T. N.
Guru Row for providing single crystal X-Ray diffraction facility at Solid State and Structural
Chemistry Unit, Indian Institute of Science, Bangalore, India.
Appendix A. Supplementary Information (SI)
CCDC Nos.1569503 and1569610 contain the supplementary crystallographic data for 3 and 4.
These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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Synthesis, Structural Characterization, Antimicrobial and DNA binding studies of homoleptic zinc
and copper complexes of NO Schiff bases derived from homoveratrylamine
C. E. Satheesha, P. Raghavendra Kumara*, N. Shivakumarb, K. Lingarajuc, P. Murali Krishnab, H
Rajanaikac, A. Hosamanid
aDepartment of Studies and Research in Chemistry, UCS, Tumkur University, Tumkur 572 103, Karnataka, India
bDepartment of Chemistry, Ramaiah Institute of Technology, Bangalore 560 054, Karnataka, India
cDepartment of Studies and Research in Environmental Science, UCS, Tumkur University, Tumkur 572 103,
Karnataka, India
dSolid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, Karnataka, India
*Corresponding authors:raghukp1@gmail.com; +91-9901511112
Graphical Abstract:
OMe
1.5
OMe
CH3
1.0
0.5
N
N
0.0
200
400
Wavelenth in (nm)
Zn
O
OH
O
N
H2N
OMe
OMe
N
O
Cu
OH
O
N
N
CH3
OMe
OMe
DNA binding and antimicrobial studies of zinc and copper complexes of NO Schiff bases
25

Synthesis, Structural Characterization, Antimicrobial and DNA binding studies of
homoleptic zinc and copper complexes of NO Schiff bases derived from homoveratrylamine
C. E. Satheesha, P. Raghavendra Kumara*, N. Shivakumarb, K. Lingarajuc, P. Murali Krishnab, H
Rajanaikac, A. Hosamanid
aDepartment of Studies and Research in Chemistry, UCS, Tumkur University, Tumkur 572 103, Karnataka, India
bDepartment of Chemistry, Ramaiah Institute of Technology, Bangalore 560 054, Karnataka, India
cDepartment of Studies and Research in Environmental Science, UCS, Tumkur University, Tumkur 572 103,
Karnataka, India
dSolid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, Karnataka, India
*Corresponding authors:raghukp1@gmail.com; +91-9901511112
Highlights:
 Synthesized and characterised homoleptic Zn and Cu complexes of Schiff bases of
homoveratrylamine.
 Single crystal structures of two Cu complexes were solved which contain C-H…O secondary
interactions.
 The complexes showed significant antimicrobial activity and strong DNA binding capacity.
26