Transition metal complexes of Schiff base ligand based on 4,6-diacetyl resorcinol

Article abstract of DOI:10.1002/aoc.5528

Novel Schiff base ligand based on the condensation of 4,6-diacetyl resorcinol with 2-amino-4-methylthiazole in addition to its metal complexes with Cr (III), Mn (II), Fe (III), Co (II), Ni (II), Cu (II), Zn (II) and Cd (II) ions have been synthesized. The structure, electronic properties, and thermal behaviour of Schiff base and its metal complexes have been studied by elemental analysis, mass, ¹H NMR, IR spectra, thermal analysis, and theoretically by density function theory. The ligand acted as mononegative bidentate (NO) ligand and all complexes showed octahedral geometry except Cu (II) showed tetrahedral geometry as indicated from the spectral and magnetic studies. The Cu (II), Zn (II) and Cd (II) complexes were non electrolytes while the rest of the complexes were electrolytes. The antibacterial plus anticancer activities of the parent Schiff base and its metal complexes were screened. In addition, the molecular docking study was performed to explore the possible ways for binding to Crystal Structure of Human Astrovirus capsid protein (5ibv) receptor.

Full text of DOI:10.1002/aoc.5528

Received: 5 July 2019
DOI: 10.1002/aoc.5528
Revised: 3 December 2019
Accepted: 7 January 2020
F U L L P A P E R
Transition metal complexes of Schiff base ligand based on
4,6-diacetyl resorcinol
1
1
1
Walaa H. Mahmoud
| M.M. Omar | Yasmin M. Ahmed
|
1,2
Gehad G. Mohamed
1
Chemistry Department, Faculty of
Science, Cairo University, Giza, 12613,
Egypt
Novel Schiff base ligand based on the condensation of 4,6-diacetyl resorcinol
with 2-amino-4-methylthiazole in addition to its metal complexes with Cr (III),
Mn (II), Fe (III), Co (II), Ni (II), Cu (II), Zn (II) and Cd (II) ions have been syn-
thesized. The structure, electronic properties, and thermal behaviour of Schiff
base and its metal complexes have been studied by elemental analysis, mass,
2
Egypt Nanotechnology Center, Cairo
th
University, El-Sheikh Zayed, 6 October,
1
2588, Egypt
Correspondence
1
H NMR, IR spectra, thermal analysis, and theoretically by density function
Gehad G. Mohamed, Chemistry
Department, Faculty of Science, Cairo
University, Giza, 12613, Egypt.
Email: ggenidymohamed@sci.cu.edu.eg
theory. The ligand acted as mononegative bidentate (NO) ligand and all com-
plexes showed octahedral geometry except Cu (II) showed tetrahedral geome-
try as indicated from the spectral and magnetic studies. The Cu (II), Zn
(II) and Cd (II) complexes were non electrolytes while the rest of the complexes
were electrolytes. The antibacterial plus anticancer activities of the parent
Schiff base and its metal complexes were screened. In addition, the molecular
docking study was performed to explore the possible ways for binding to Crys-
tal Structure of Human Astrovirus capsid protein (5ibv) receptor.
K E Y W O R D S
antibacterial and anticancer activity, density function theory, molecular docking, Schiff Base
1
| INTRODUCTION
In fact, many metal complexes of sulfur-nitrogen
chelating agents have been revealed to display
Coordination chemistry of studying the transition
metal complexes of Schiff bases has been enhanced by
the current advancements in the subjects of medicine
and bioinorganic chemistry. Schiff bases as the con-
densation result of an amine and ketone or aldehyde
approved cytotoxic (anticancer) activities. In the last
twenty five years, a great deal of concern has been
given to the study of metal complexes of sulfur
ligands. Structural characterization and synthesis of
this type of ligands are essential to ligands containing
both hard and soft donor atoms may yield metal com-
plexes with unusual magnetic properties and interest-
ing stereochemistry and some of the ligands and their
metal complexes are estimated to show biological activ-
[1]
with a general formula of R C=NR are well-known
2
organic compounds. Up to now, a broad range of
Schiff bases has been made and used as ligands to pre-
[2]
pare coordination compounds.
[
4]
A lot of researchers had studied the metal complexes
of Schiff base ligands including one aromatic ring. Metal
complexes of Schiff base ligands with two aromatic rings
have been studied the lowest intense, while a new Schiff
base ligands contain three aromatic rings were related by
ity. This work targeted to synthesis new Schiff base
and its metal complex. Different characterization tools
were used for identification of the structures of the
prepared compounds. The in vitro antibacterial and
anti-breast cancer activities had also been screened.
The possible binding of the prepared compounds with
[3]
Binnemans et al., 2002.
Appl Organometal Chem. 2020;e5528.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
1 of 20
https://doi.org/10.1002/aoc.5528

2
of 20
MAHMOUD ET AL.
ꢀ
Crystal Structure of Human Astrovirus capsid protein
5ibv) receptor was demonstrated.
56 C for 30 min), 100 units/mL penicillin and
2 mg/ml streptomycin were used for the supplementa-
tion of RPMI-1640 medium prior to use. Trypsin (0.25
(
−
1
X 10 % w/v) was used for the picking of cells. Acetic
acid (1% v/v) was used for dissolving unbound SRB
dye. SRB (0.40%) dissolved in 1% acetic acid was
used as a protein dye. A stock solution of trichlor-
oacetic acid (50%) was prepared and stored. An
amount of 50 μL of the stock was added to 200 μL of
RPMI-1640 medium per well to yield a final concentra-
tion of 10% used for protein precipitation. Isopropanol
(100%) and ethanol (70%) were used. Tris base
(10 mM; pH =10.50) was used for SRB dye solubiliza-
tion. Tris base (121.10 g) was dissolved in 1000 ml of
distilled water and the pH was attuned using
hydrochloric acid (2 M).
2
| EXPERIMENTAL
All chemicals used were of the analytical reagent grade
AR) and of the maximum purity available. The
(
chemicals used entered 2-amino-4-methylthiazole which
was provided from Strems Chemical Inc., 4,6-diacetyl res-
orcinol (Sigma-Aldrich), CrCl .6H O, MnCl .2H O and
FeCl .6H O (Sigma-Aldrich, Germany), NiCl .6H O,
CoCl .6H O, CuCl .2H O and ZnCl (BDH) and CdCl
2
3
2
2
2
3
2
2
2
2
2
2
2
2
(Merck, Germany). Solvents of organic used were ethyl
alcohol (95%), methyl alcohol and N,N-
dimethylformamide (DMF). Deionized water was com-
monly consumed in all preparations.
2.3 | Instrumentation
2.1 | Solutions
Microanalyses of carbon, hydrogen and nitrogen were
carried out at the Microanalytical Center, Cairo Univer-
sity, Egypt, using a CHNS-932 (LECO) Vario elemental
analyzer. Analyses of the metals were performed by dis-
Stock solutions of the Schiff base ligand (H L) and its
2
−
3
metal complex of1 X 10 M was prepared by dissolving
an exactly weighed amount in DMF. The conductivity, in
that case measured for the metal complexes solutions.
Dilute solutions of the Schiff base ligand and its metal
solving the solid complexes in concentrated HNO , and
3
dissolving the remainder in deionized water. The metal
content was carried out using inductively coupled plasma
atomic absorption spectrometry (ICP-AES), Egyptian
Petroleum Research Institute. Fourier transform infrared
−
4
complexes (1 X 10 M) were prepared by exact dilution
from the before and prepared stock solutions for measur-
ing their UV–Vis spectra.
(
FT-IR) spectra were recorded with a Perkin-Elmer 1650
−
1
1
spectrometer (400–4000 cm ) in KBr pellets. H NMR
2
.2 | Solution of anticancer study
spectra, as solutions in DMSO-d , were chronicled with a
6
300 MHz Varian-Oxford Mercury at room temperature
−
3
A fresh stock solution (1 × 10
M) of Schiff base
using tetra-methylsilane as an interior standard. Mass
spectra were chronicled using the electron ionization
technique at 70 eV with an MS-5988 GS-MS Hewlett-
Packard instrument at the Microanalytical Center,
National Center for Research, Egypt. UV–visible spectra
were acquired with a Shimadzu UVmini-1240 spectro-
photometer. Molar conductivities of 10− M solutions of
the solid complexes in DMF were measured with a
Jenway 4010 conductivity meter. Thermogravimetric
(TG) and differential thermogravimetric (DTG) analyses
of the solid complexes were carried out from room tem-
ligand (0.12 X 10− g L ) was prepared in the suitable
volume of DMF (90%). DMSO was used in cryopreser-
vation of cells. RPMI-1640 medium was used. The
medium was used for culturing and keep of the
human tumor cell line. The medium was contributed
in a powder form. It was gotten ready as follows:
2
−1
3
1
0.4 g of medium was weighed, mixed with 2 g of
sodium bicarbonate, completed to 1 l with distilled
water and shaken prudently until complete dissolution.
The medium was then uncontaminated by filtration in
a Millipore bacterial filter (0.22 ml). The prepared
medium was kept in a refrigerator (4 C) and checked
at methodical intervals for contamination. Before use,
ꢀ
perature to 1000 C using a Shimadzu TG-50H thermal
ꢀ
analyzer. Antimicrobial measurements were carried out
at the Microanalytical Center, Cairo University, Egypt.
Anticancer activity experiments were performed at the
National Cancer Institute, Cancer Biology Department,
Pharmacology Department, Cairo University. The optical
density (OD) of each in good form was measured spectro-
photometrically at 564 nm with an ELIZA microplate
reader (Meter tech. R960, Lewiston, USA).
ꢀ
the medium was warmed at 37 C in a water bath
and supplemented with penicillin–streptomycin and
FBS. Sodium bicarbonate was used for the preparation
of RPMI-1640 medium. Isotonic trypan blue solution
(0.05%) was prepared in normal saline and were used
for feasibility counting. FBS (10%, heat inactivated at

MAHMOUD ET AL.
3 of 20
−
1
2
2.4 | Synthesis of Schiff base ligand
(nm): 252 (π-π*), 311 (n-π*). u : 4.1; Λ (Ω mol−1 cm )
eff
m
60.7
The symmetric Schiff base ligand (H L) was synthe-
2
sized by condensation of 4,6-diacetylresorcinol
2.5.2 | [Mn (HL)(H O) ]Cl.2H O
2 4 2
(4,6-DAR) in addition to 2-amino-4-methylthiazole. A
ꢀ
solution of 2-amino-4-methylthiazole (15.4 mmol,
Yield 86%; m.p. 180 C; yellow solid. Anal. Calcd for
C H ClMnN O S (%): C, 34.44; H, 5.12; N, 5.74; Mn,
1
4
.76 g) dissolved in ethanol was added dropwise to
,6-DAR (15.4 mmol, 3 g) dissolved in DMF. The
14
25
2 9
11.27. Found (%): C, 34.28; H, 4.99; N, 5.60; Mn, 11.19.
−
1
resulting mixture was stirred under reflux for about
FT-IR (cm ): ν (OH) 3434, azomethine ν(C=N) 1574,
ꢀ
4
–5 hr at 100–150 C, during which brown solid com-
carbonyl (C=O) 1630, ν(H O) stretching bands of coordi-
2
pound was separated. It was filtered, washed, rec-
nated water 951 and 897, ν(M-O) 579 and ν(M-N) 480.
rystallized from diethyl ether and desiccated in
λ
(nm): 226 and 252 (π-π*), 321 (n-π*). u : 5.22; Λ
max
−
eff
m
1
−1
2
vacuum (Scheme 1).
H2L
(Ω mol cm ) 56.5.
ꢀ
Yield 90%; m.p. 161 C; orange solid. Anal. Calcd for
2.5.3 | [Fe (HL)(H O) ]Cl .H O
2
4
2
2
C H N O S (%): C, 57.86; H, 4.82; N, 8.27; Found
1
4
14 2 3
−
1
ꢀ
(
(
1
%): C, 56.59; H, 4.39; N, 8.19. FT-IR (cm ): phenolic ν
Yield 85%; m.p. 122 C; orange solid. Anal. Calcd for
C H Cl FeN O S (%): C, 33.18; H, 4.54; N, 5.53; Fe,
11.06. Found (%): C, 32.77; H, 4.49; N, 5.19; Fe, 10.86. FT-
OH) 3421, azomethine ν(C=N) 1588, carbonyl (C=O)
14
23
2
2 8
1
650. H NMR (300 MHz, DMSO-d , δ, ppm): 8.41 (s, 1H,
6
−1
Ar-H (thiazole)), 6.38, 6.06 (s, 2H (benzene)), 12.72 (s,
IR (cm ):l ν (OH) 3429, azomethine ν(C=N) 1534, car-
1
H, OH ), 10.00 (s, 1H, OH ), λ
(nm): 248 (π–π*),
bonyl (C=O) 1635, ν(H O) stretching bands of coordi-
b
a
max
2
3
21 (n–π*).
nated water 940 and 839, ν(M-O) 576 and ν(M-N) 488.
λ
(nm): 252 (π-π*), 320 (n–π*). u : 5.19; Λ
max
−
eff
m
1
−1
2
2.5 | Synthesis of metal complexes
(Ω mol cm ) 105.9.
Complexes of H L in addition to Cr (III), Mn (II), Fe
2.5.4 | [Co (HL)(H O) ]Cl.5H O
2
2
4
2
(III), Co (II), Ni (II), Cu (II), Zn (II) and Cd (II) metal
ꢀ
ions were prepared by the reaction of 1:1 molar mixture
Yield 84%; m.p. >300 C; Greenish yellow solid. Anal.
Calcd for C H ClCoN O S (%): C, 30.78; H, 5.68; N,
ꢀ
of hot ethanolic solution (60 C) of the suitable metal
14
31
2 12
chloride (0.76 mmol) and H L (0.3 g, 0.76 mmol). The
5.13; Co, 10.81. Found (%): C, 30.45; H, 5.40; N, 4.89; Co,
10.29. FT-IR (cm ): ν (OH) 3401, azomethine ν(C=N)
2
−
1
resulting mixture was stirred under reflux for 1 hr where-
upon the complexes precipitated. They were collected by
filtration and purified by washing several times with
diethyl ether.
1560, carbonyl (C=O) 1636, ν(H O) stretching bands of
2
coordinated water 951 and 838, ν(M-O) 577 and ν(M-N)
498. λ
(nm): 251 (π-π*), 320 (n-π*). u : 4.78; Λ
eff
max
m
−
1
mol−1 cm ) 52.5.
2
(Ω
2
.5.1 | [Cr (HL)(H O) Cl]Cl.4H O
2.5.5 | [Ni (HL)(H O) ]Cl.3H O
2 4 2
2
3
2
ꢀ
ꢀ
Yield 84%; m.p. >300 C; yellow solid. Anal. Calcd for
C H Cl CrN O S (%): C, 31.21; H, 5.02; N, 5.20; Cr,
Yield 80%; m.p. 240 C; yellow solid. Anal. Calcd for
C H ClNiN O S (%): C, 32.95; H, 5.30; N, 5.49; Ni,
14
27
2
2
10
14 27
2 10
9
.66. Found (%): C, 31.18; H, 4.84; N, 4.92; Cr, 9.29. FT-IR
12.57. Found (%): C, 32.81; H, 5.07; N, 5.33; Ni, 12.01.
FT-IR (cm ): ν (OH) 3423, azomethine ν(C=N) 1531,
−
1
−1
(cm ): ν (OH) 3428, azomethine ν(C=N) 1532, carbonyl
(
C=O) 1632, ν(H O) stretching bands of coordinated
carbonyl (C=O) 1625, ν(H O) stretching bands of coordi-
2
2
water 967 and 835, ν(M-O) 575 and ν(M-N) 490. λmax
nated water 952 and 838, ν(M-O) 579 and ν(M-N) 450.
λ
(
(nm): 221 and 252 (π-π*), 320 (n-π*). u : 3.17; Λ
eff
max
m
Ω− mol cm ) 53.
1
−1
2
2
.5.6 | [Cu (HL)(H O)Cl].H O
2 2
ꢀ
Yield 84%; m.p. 169 C; brown solid. Anal. Calcd for
C H ClCuN O S (%): C, 39.59; H, 4.01; N, 6.60; Cu,
14
17
2 5
SCHEME 1 Synthesis of Schiff base ligand
14.96. Found (%): C, 39.27; H, 3.73; N, 6.22; Cu, 14.18.

4
of 20
MAHMOUD ET AL.
−1
[5]
FT-IR (cm ): ν (OH) 3407, azomethine ν(C=N) 1567,
method. Briefly, 100 μl of the test bacteria were grown
carbonyl (C=O) 1631. ν(H O) stretching bands of coordi-
nated water 945 and 837, ν(M-O) 575 and ν(M-N) 489.
in 10 ml of fresh media until they reached a count of
2
[
6]
approximately 108 cells/ml for bacteria.
100 μl of
λ
(
(nm): 226, 252 π–π*, 319 n–π*. u : 1.79; Λ
eff
microbial suspension was spread onto agar plates
corresponding to the broth in which they were
maintained. Isolated colonies of each organism that may
be playing a pathogenic part should be selected from pri-
mary agar plates and tested for susceptibility by disc dif-
max
m
Ω− mol cm ) 50.2.
1
−1
2
2
.5.7 | [Zn (HL)(H O) Cl].3H O
2 3 2
[
7]
fusion method. Plates inoculated Gram(+) bacteria as
Staphylococcus aureus and Bacillus subtilis and Gram(−)
bacteria as Escherichia coli and Pseudomonas
ꢀ
Yield 83%; m.p. 167 C; yellow solid. Anal. Calcd for
C H ClZnN O S (%): C, 33.74; H, 5.02; N, 5.62; Zn,
14
25
2 9
ꢀ
1
3.06. Found (%): C, 33.63; H, 4.48; N, 5.40; Zn, 12.87.
aeuroginosa. They were incubated at 35–37 C for
−
1
FT-IR (cm ): ν (OH) 3400, azomethine ν(C=N) dis-
appeared, carbonyl (C=O) 1620, ν(H O) stretching
24–48 hr and then the diameters of the inhibition zones
[
5]
were calculated in millimeters.
Standard discs of
2
bands of coordinated water 950 and 837, ν(M-O)
amikacin (antibacterial agent), served as positive controls
for antimicrobial activity but filter discs impregnated
with 10 μl of solvent (distilled water, chloroform, DMSO)
were used as a negative control. Blank paper disks
(Schleicher & Schuell, Satis Lda, Spain) with a diameter
of 8.0 mm were impregnated with 10 μ of tested concen-
tration of the stock solutions (20 mg/ml).
1
5
73 and ν(M-N) 470. H NMR (300 MHz, DMSO-d , δ,
6
ppm): 8.39 (s, 1H, Ar-H (thiazole)), 6.15, 6.35 (s, 2H
(
benzene)), 12.80 (s, 1H, OH ), disappeared (s, 1H,
b
OH ), λ
(nm): 245 π–π*, 321 n–π*. u : diamag-
eff
a
max
netic; Λm (Ω− mol cm ) 19.5.
1
−1
2
When a filter paper disc impregnated with a tested
chemical is placed on agar, the chemical will diffuse from
the disc into the agar. This diffusion will place the chemi-
cal in the agar only around the disc. The solubility of the
chemical and its molecular size will determine the size of
the area of chemical infiltration around the disc. If an
organism is placed on the agar it will not grow in the area
around the disc if it is susceptible to the chemical. This
area of no growth around the disc is known as a zone of
inhibition or Clear zone. For the disc diffusion, the zone
diameters were measured with slipping calipers of the
National Committee for Clinical Laboratory Standards.
Agar-based methods such as E-test and disk diffusion can
be good alternatives because they are easier and more
2
.5.8 | [CdR(HL)(H O) Cl]
2 3
ꢀ
Yield 85%; m.p. >300 C; yellow solid. Anal. Calcd for
C H ClCdN O S (%): C, 34.20; H, 3.87; N, 5.70; Cd,
14
19
2 6
2
2.88. Found (%): C, 33.85; H, 3.41; N, 5.31; Cd, 22.59.
−1
FT-IR (cm ): ν (OH) 3396, azomethine ν(C=N) 1567,
carbonyl (C=O) 1634, ν(H O) 958 and 836, ν(M-O)
2
1
5
78, ν(M-N) 490. H NMR (300 MHz, DMSO-d , δ,
6
ppm): 8.40 (s, 1H, Ar-H (thiazole)), 6.07, 6.34 (s, 2H
(benzene)), 12.80 (s, 1H, OH ), disappeared (s, 1H,
b
OH ), λ
(nm): 258 π–π*, 321 n–π*. u : diamag-
eff
a
max
netic; Λm (Ω− mol cm ) 7.
1
−1
2
[
8,9]
rapidly than broth-based methods.
All experiments
2
.6 | Spectrophotometric studies
were performed as triplicate and the data plotted where
the mean value.
[
10]
The absorption spHiectra were recorded for 1 × 10−5
M
solutions of the Schiff base ligand and its metal com-
plexes in DMF, except for Cr (III) complex that had a
2.7.2 | Anticancer activity
−4
concentration of 5 × 10 M and Cd (II), Co (II), Zn
−
4
(
II) complexes that had a concentration of 10 M. The
spectra were scanned within the wavelength range from
00 to 700 nm.
Potential cytotoxicity of the compounds was tested via
[
11]
the method of Skehan and Storeng.
Cells were plated
2
in 96-multiwell plate (104 cells/well) for 24 hr before
treatment using the compounds to let attachment of cell
to the wall of the plate altered concentrations of the com-
pounds under investigation (0, 5, 12.5, 25, 50 and
2.7 | Pharmacology
100 μg/ml) were added to the cell monolayer and tripli-
2
.7.1 | Antibacterial activities
cate wells were prepared for each individual dose. The
monolayer cells were keep warm with the compounds for
ꢀ
Antimicrobial activity of the tested samples was deter-
mined by modified Kirby-Bauer disc diffusion
48 hr at 37 C and in 5% CO atmosphere. After 48 hr,
2
a
cells were immobile, washed and stained with SRB stain.

MAHMOUD ET AL.
5 of 20
Excess stain was washed with acetic acid and attached
stain was convalesced with tris-EDTA buffer. The optical
density (O.D.) of each well was measured spectrophoto-
metrically at 564 nm using an ELIZA microplate reader,
the mean background absorbance was automatically sub-
tracted and mean values of each drug concentration was
calculated. The relation between drug concentration and
surviving fraction is plotted to get the survival curve of
breast tumor cell line for each compound.
2.8 | Results and discussion
2.8.1 | Elemental analysis
The synthesized Schiff base ligand was an orange solid
and stable at room temperature. It was soluble in ethanol
and DMF. The results obtained were in good agreement
using those calculated from the suggested formula (see
experimental part). The structure of the Schiff base ligand
under study was shown in Figure 1.
The percentage of cell survival was calculated as
follows:
Metal complexes of H L were synthesized. The meta-
2
l/ligand ratio was found to be 1:1 in all complexes, which
have been arrived by estimating the carbon, hydrogen,
nitrogen and metal contents of the complexes. Its metal
complexes had the composition of MHL type. The results
O:D:ðtreated cellsÞ
Survival fraction =
O:D:ðcontrol cellsÞ:
The IC50 values (the concentrations of the Schiff base
ligand (L) or its metal complexes required to produce
of the experimental elemental analysis of H L and its
2
complexes had closely values to the theoretical
[
12]
5
0% inhibition of cell growth). The experiment was
calculations.
[11,12]
repeated 3 times.
2.8.2 | Mass spectra
2.7.3 | Computational methodology
The mass spectrum of H L ligand exhibited a molecular
2
+
Gaussian03 suite of program was used for the electronic
ion peak at m/z = 290.24 amu corresponding to [M] ,
which confirmed the proposed formula [C H N O S]
+
structure calculations for H L and Cu (II) complex. DFT
2
14 13 2 3
based B3LYP method along using the LANL2DZ basis set
was employed for full optimization. So as to incorporate
the effect of the solvent around the molecule, the TD-
DFT method (along with LANL2DZ basic set) was used
to calculate the electronic absorption spectra of the
ligand and its Cu (II) complex. The contribution of
molecular orbital on HOMO and LUMO were also
calculated.
and in good agreement with the calculated value
(290.36 amu). The intensity of the peaks as the results of
fragmentation was given in Figure 2a.
The mass spectrum of Cu (II) complex revealed a
molecular ion peak at m/z = 424.21 amu which was
coextensive with the calculated weight of 424.36 amu.
This result confirmed the stoichiometry of this complex
as being of [MHL] type. On the other hand, the peak of
the parent ligand in the mass spectrum of the Cu
(
II) complex seemed at m/z 290.97 amu (Figure 2b).
2.7.4 | Molecular docking
So as to find out the achievable binding modes of the best
active compounds against the Crystal structure of Human
Astrovirus capsid protein (PDB ID: 5IBV), molecular
docking studies were performed with MOE2008 software.
It is a rigid molecular docking software and is an interac-
tive molecular graphics program in support of calculating
and displaying feasible docking modes of a receptor and
ligand and complex molecules. It requires the ligand and
the receptor as input in PDB format. The amino acid
chain was kept and the water molecules and co-
crystallized ligands and chloride ions in out sphere were
removed. The structure of ligand in PDB file format was
created using Gaussian09 software. Crystal structure of
Human Astrovirus capsid protein (PDB ID: 5IBV) was
downloaded from the protein data bank (http://www.
rcsb.org./pdb).
2
FIGURE 1 Structure of Schiff base ligand (H L)

6
of 20
MAHMOUD ET AL.
2 2 2
FIGURE 2 Mass spectra of the (a) Schiff base ligand (H L) and (b) [Cu (HL)Cl(H O)]H O complex
2.8.3 | FT-IR spectral study
OH group and H O molecules in the complexes. This
make it difficult to differentiate and hence H NMR was
2
1
The FT-IR spectrum of H L ligand showed a lack of the
carried out to give us and idea about the OH which par-
2
NH stretching band characteristic of 2-amino-4-meth-
ticipated in binding to the metal ions. Two new ν(H O)
2
2
ylthiazole. On the other hand, a new, strong and sharp
bands of coordinated water molecules appeared in the
−1
vibration band appeared at 1588 cm
due to the
FT-IR spectra of the metal complexes at 836–897 and
−
1
azomethine group (C═N), demonstrating the formation
940–967 cm , indicating the binding of water molecules
of the Schiff base product (H L). The band of keto car-
bonyl ν(C═O) group appeared at 1650 cm . The ν
to the metal ions. In consequence, the H L ligand acted
2
2
−
1
as mononegative bidentate chelating agent, bonded to
the metal ions via a nitrogen atom and deprotonated phe-
(
3
OH) stretching frequencies of H L which lies at
2
−
1
[15,16]
421 cm still persist even after the formation of the
nolic oxygen atom of the Schiff base.
[13]
ligand.
The FT-IR spectra of the complexes were compared
with this free ligand to distinguish the coordination sites
of chelation. The band of azomethine ν(C═N) group was
shifted to lower frequency in the spectra of all the com-
1
2.8.4 | H NMR Spectrum
1
H NMR spectral data (δ ppm) of the free ligand in rela-
−
1
plexes in the range 1531–1567 cm , showing the involve-
ment of azomethine nitrogen in the chelation to the
metal ions. The band of keto carbonyl ν(C═O) group was
slightly shifted to lower frequency in the spectra of all the
complexes. The variance observed in these values may be
due to expected H-bonding between the hydrogen atoms
tion to TMS (0 ppm) in DMSO-d6 were obtained to
approve the ligand structure and its purity. The signals
observed at 10.00 and 12.72 ppm may be assigned to two
phenolic OH and OH groups, respectively. The spec-
trum of free ligand (H L) exhibited a signal at 8.41 ppm
region, which may be assigned to thiazole protons (s,
1H). In the aromatic region, two singlet signals observed
a
b
2
[14]
of the –OH group and the keto carbonyl oxygen.
b
[
17,18]
New bands for all complexes appeared in the region
at 6.38 and 6.06 ppm (s, 2H, Ar-H).
50–498 cm− attributed to ν(M─N). The bands in the
1
1
H NMR spectral (δ ppm) of Zn (II) and Cd
(II) complexes showed phenolic –OHb group at
12.80 ppm, which appeared in the same position of the
free ligand. This confirmed its nonparticipation in chelate
formation and this slight shift can assign to hydrogen
4
−1
region 573–579 cm in the spectra of all the complexes
were assigned to ν(M─O) stretching vibration of the bind-
ing of the ligand to the metal ions which was succeeded
via coordination of metal ions with the deprotonated
phenolic oxygen (-OH ). Also, OH stretching vibration
bond formation with the adjacent carbonyl group. But
a
band at 3421 cm− in the free ligand appeared as broad
1
the signal for OH was disappeared in the H NMR spec-
1
a
band in the metal complexes. This can attributed to the
tra of both Zn (II) and Cd (II) complexes. This indicated

MAHMOUD ET AL.
7 of 20
that OH participated in coordination to the metal ions
with proton displacement. In the aromatic region, two
singlet signals were observed at 6.15 and 6.35 for Zn
suggesting the octahedral geometry of the complex. The
magnetic moment was found to be 4.01 B.M. which con-
a
[
22]
firmed octahedral geometry of Cr (III) complex.
The Mn (II) complex showed three spins allowed
(
(
II) complex and at 6.07 and 6.34 ppm for Cd
II) complex. On the other hand the thiazole proton still
−
1
bands at 18020, 22710 and 26150 cm . These bands may
[12]
4
6
4
6
appear in the same position as free ligand.
the H NMR spectra of Schiff base ligand (H L) and its
The data of
be assigned to T1g
!
A , T (G) ! A1g and
1g
2g
1
4
6
T (D) ! A1g transitions suggesting the octahedral
1g
2
mononuclear metal complexes are given in the
experimental part.
geometry of the complex. The magnetic moment was
found to be 5.22 B.M. which confirmed octahedral geom-
[
22,23]
etry of Mn (II) complex.
The Fe (III) complex showed three spins allowed
bands at 21975, 20690 and 17140 cm . These bands may
−
1
2.8.5 | Molar conductance
4
6
4
6
measurements
be assigned to T (G) ! A , T (G) ! A1g and
2g
1g
2g
4 6
T (D) ! A1g transitions indicating the octahedral
1g
The molar conductance values of the complexes were
measured at room temperature and these data showed
that Cu (II), Zn (II) and Cd (II) complexes have no con-
ductance and they were considered as nonelectrolytes. Cr
geometry of the complex. The magnetic moment was
5.19 B.M. which confirmed octahedral geometry of Fe
(III) complex.
Cobalt (II) complex showed three spins allowed bands
−
1
(III), Mn (II), Co (II) and Ni (II) complexes had molar
at 23120, 21010 and 15985 cm . These bands may be
4
4
4
4
conductivity values of 60.7, 56.5, 52.5 and
assigned to T (F) ! T (F), T (F) ! A (F) and
1g
2g
1g
2g
3.0 Ω− mol−1 cm , respectively. These data suggested
that these complexes were ionic in nature and they were
:1 electrolytes. The Fe (III) complex had a molar con-
1
2
4
T (F) ! T (P) transitions suggesting the octahedral
4
5
1g
2g
geometry of the complex. The magnetic moment is 4.78
B.M. which confirmed octahedral geometry of cobalt
(II) complex.
1
−1
−1
2
ductivity value of 105.90 Ω mol cm , which suggested
that this complex was ionic in nature and it was a 1:2
electrolyte.
The Ni (II) complex showed three spins allowed
bands at 27870, 21985 and 12110 cm-1. These bands may
[19,20]
3
3
3
3
3
be assigned to A ! T (P), T (P) ! A and A
2
g
1g
1g
2g
2g
3
(
F) ! T1g (F) transitions indicating the octahedral
2.8.6 | UV–vis absorption studies
geometry of the complex. The magnetic moment was
3
.17 B.M. which confirmed octahedral geometry of Ni
[
23–25]
It is probable to draw up the electronic transitions and
foretell the geometry with the help of magnetic moments
of most metal ions. The main absorption band of the
ligand is at 248 and 321 nm and they were assigned to
π ! π* and n ! π* transitions within the aromatic rings
in the ligand, respectively. The bands in all metal com-
plexes located at 221–258 nm and 311–321 nm region
were assigned to π ! π* and n ! π* transitions, respec-
tively, which can be related to the binding of these coor-
(II) complex.
The Cu (II) complex showed two spins allowed bands
2
2
2
2
at assigned to B1g ! A and B ! B transitions.
1g
1g
2g
Also the magnetic moment value of the copper
(II) complex is 1.30 B.M. This indicated the formation of
tetrahedral geometry of the complex.
[
9,26]
The Zn (II) and Cd (II) complexes were diamagnetic.
According to the empirical formulae, an octahedral
geometry was suggested for the Zn (II) and Cd
(II) complexes.
[21]
dination centres to the central metal ions.
Thermal analysis.
TG and DTG analysis results of H L and its metal
2
ꢀ
2
.8.7 | Electronic spectral study
complexes at a heating rate of 10 C/min in nitrogen
atmosphere over the range from ambient temperature to
1000 C were summarized in Table (1).
The Schiff base ligand with the molecular formula
(C H N O S) was thermally decomposed in two succes-
sive decomposition steps, within the range from 30 to
ꢀ
The diffused reflectance spectra of the mononuclear com-
plexes were carried out within the range 200–1000 nm. It
is probable to draw up the electronic transitions and
detect the geometry through the help of magnetic
moments of most metal ions.
14
14 2 3
ꢀ
900 C via total mass loss of 98.69% (calcd. = 100%). The
The electronic spectrum of Cr (III) complex showed
three spins allowed bands at 19110, 23510 and
first and second stages within the temperature range of
ꢀ
30–900
C
which correlated with evolution of
−
1
4
4
2
5910 cm . These bands may be assigned to A (F) !
C H N O S molecule with a maximum at 215 and
2g
14 14 2 3
4
4
4
4
ꢀ
T (F), A (F) ! T (F) and A (F) ! T (P) transitions
388 C.
2g
2g
1g
2g
1g

8
of 20
MAHMOUD ET AL.

MAHMOUD ET AL.
9 of 20
The [Cr (HL)(H O) Cl]Cl.4H O complex showed
and ½ Cl molecules by mass loss of 23.59% (calculated
2
3
2
2
ꢀ
four decomposition stages within the range from 30 to
mass loss = 22.99%) with a maximum at 195 C. The last
ꢀ
ꢀ
9
00
C
through total mass loss of 73.69%
stage within the temperature range of 250–900 C which
(
calcd. = 74.67%) leaving ½Cr O contaminated by car-
correlated through evolution of C H N O S molecule
2
3
12 13 2 2
bon atoms as residue. The first stage within the tem-
perature range of 30–100 C which correlated by
with mass loss of 45.95% (calculated mass loss = 45.62%)
with maximum at 520 C.
ꢀ
ꢀ
evolution of three uncoordinated water molecules with
The [Ni (HL)(H O) ]Cl.3H O complex showed four
2
4
2
ꢀ
mass loss of 9.48% (calculated mass loss = 10.03%)
decomposition stages within the range from 30 to 900 C
with total mass loss of 85.61% (calcd. = 85.22%) leaving
NiO as residue. The first stage within the temperature
ꢀ
with a maximum at 50 C. The second stage within
ꢀ
the temperature range of 100–220 C which correlated
ꢀ
by evolution of four water molecules and ½ Cl with
range of 30–100 C which correlated through evolution
2
mass loss of 19.73% (calculated mass loss = 19.97%)
of 2H O uncoordinated molecules by mass loss of 7.61%
(calculated mass loss = 7.06%) with a maximum at 75 C.
2
ꢀ
ꢀ
with maximum at 170 C. The last two stages within
ꢀ
the temperature range of 220–900 C which correlated
The last three stages within the temperature range of
ꢀ
through evolution of ½ Cl2 and C H N O S mole-
100–900 C which correlated through evolution of 5H O,
9
13
2
1.5
2
cule with mass loss of 44.48% (calculated mass
loss = 44.67%) with two maximum at 458 and 825 C.
½ Cl and C H N O S molecules with mass loss of
2
14 13 2 2
ꢀ
78.00% (calculated mass loss = 78.16%) with a maximum
ꢀ
The [Mn (HL)(H O) Cl]Cl.2H O complex showed
at 190, 420 and 500 C.
2
4
2
four decomposition stages within the range from 30 to
The [Cu (HL)(H O)Cl].H O complex showed two
2
2
ꢀ
ꢀ
9
00 C through total mass loss of 70.16% (calcd. = 70.61%)
decomposition stages within the range from 30 to 900 C
with total mass loss of 72.11% (calcd. = 72.69%) leaving
CuO and carbon atoms as residue. The first stage within
leaving MnO contaminated by carbon atoms as residue.
The first and second stages within the temperature range
ꢀ
ꢀ
of 30–210 C which correlated by evolution of six water
the temperature range of 30–110 C which correlated
molecules and ½ Cl with mass loss of 30.60% (calculated
mass loss = 29.41%) with a maximum at 50 and 165 C.
through evolution of H O uncoordinated molecules with
2
2
ꢀ
mass loss of 3.98% (calculated mass loss = 4.24%) with a
ꢀ
The last two stages within the temperature range of
maximum at 80 C. The last stage within the temperature
ꢀ
ꢀ
2
10–900 C which correlated through evolution of
range of 110–900 C which correlated through evolution
C H N O S molecule with mass loss of 39.56% (calcu-
of H O, ½ Cl and C H N O S molecules, by mass loss
8
13
2
2
2
2
11 13 2 2
lated mass loss = 41.20%) with two maximum at 300 and
of 68.13% (calculated mass loss = 68.45%) with a maxi-
mum at 210 C.
ꢀ
ꢀ
6
50 C.
The [Fe (HL)(H O) ]Cl H O complex showed four
The [Zn (HL)(H O) Cl]3H O complex showed three
2
4
2.
2
2
3
2
ꢀ
decomposition stages within the range from 30 to
decomposition stages within the range from 30 to 900 C
with total mass loss of 83.44% (calcd. = 83.66%) leaving
ZnO as residue. The first stage within the temperature
ꢀ
9
00 C with total mass loss of 70.10% (calcd. = 69.91%)
leaving ½Fe O contaminated by carbon atoms as resi-
2
3
ꢀ
due. The first and second stages within the tempera-
range of 30–100 C which correlated through evolution
ꢀ
ture range of 30–350 C which correlated through
of 2H O uncoordinated molecules with mass loss of
2
evolution of 5H O and Cl molecules by mass loss of
7.38% (calculated mass loss = 7.23%) with a maximum at
2
2
ꢀ
3
2.00% (calculated mass loss = 31.80%) with a maxi-
50 C. The last two stages within the temperature range
ꢀ
ꢀ
mum at 75 and 300 C. The last two stages within the
of 100–900 C which correlated through evolution of
ꢀ
temperature range of 350–900 C which correlated
4H O, ½ Cl and C H N O S molecules by mass loss of
2
2
14 13 2 2
through evolution of C H N O S with mass loss of
76.06% (calculated mass loss = 76.43%) with a maximum
at 190 and 500 C.
8
13 2 1.5
ꢀ
3
8.10% (calculated mass loss = 38.11%) with two maxi-
ꢀ
mum at 480 and 650 C.
The [Cd (HL)(H O) Cl] complex showed two decom-
2
3
ꢀ
The [Co (HL)(H O) ]Cl.5H O complex showed four
position stages within the range from 30 to 900 C with
total mass loss of 73.25% (calcd. = 73.79%) leaving CdO
2
4
2
ꢀ
decomposition stages within the range from 30 to 900 C
with total mass loss of 83.43% (calcd. = 81.80%) leaving
CoO contaminated by carbon atoms as residue. The first
as residue. Which correlated through evolution of 3H O,
2
½ Cl and C H N O S molecules with a maximum at
2
14 13 2 2
ꢀ
and second stages within the temperature range of
200 and 750 C.
ꢀ
3
0–140 C which correlated through evolution of 4H O
The thermogram of the complexes confirmed their
structure where the presence of uncoordinated water
molecules in all metal complexes except Cd (II) complex
was suggested. and all complexes had octahedral geome-
try except Cu (II) complex tetrahedral geometry.
2
uncoordinated molecules with mass loss of 13,89% (calcu-
lated mass loss = 13.19%) with a maximum at 65 and
ꢀ
1
1
05 C. The third stage within the temperature range of
ꢀ
40–250 C which correlated through evolution of 5H O
2

10 of 20
MAHMOUD ET AL.
2.8.8 | Geometry optimization.
2.8.9 | Molecular electrostatic potential
(MEP)
The completely optimized geometries of the ligand H2L
and its Cu (II) complex were shown in Figure 3. The
values of the certain bond lengths and bond angles calcu-
lated for Cu (II) complex showed distorted tetrahedral
geometry around the Cu (II) ion (Table 2). A slight elon-
gation in bond lengths C10-N1, N1-C27 and C2-O15 was
In order to study the reactions, electrostatic potential V(r)
maps were calculated which are known for the identifica-
tion of the electronic charge distribution around molecu-
lar surface and subsequently to forecast sites for the
reactions. These maps were calculated by using the same
basis set as for optimization. In the present study, 3D
plots of MEP were drawn from the ligand and its Cu
(II) complex. Based on the MEP, one can generally order
the electron-rich area which has red colour on the map
(favour site for electrophilic attack). However, the
electron-poor region has a blue color (favour site for
nucleophilic attack). But the region with green colour
points to the neutral electrostatic potential region. It can
noted in Cu (II) complex as ligand H L coordinated
2
through azomethine nitrogen and deprotonated phenolic
oxygen. The Cu34-O15, Cu34-N1, Cu34-Cl35 and
Cu34-O36 bond lengths were found to be 1.92, 1.99, 2.31
ꢀ
and 2.00 A , respectively. The two positions were occu-
pied by azomethine nitrogen and deprotonated phenolic
oxygen however another two positions were occupied by
chloride ion and oxygen water. The bond angles in the
coordination sphere of Cu (II) complex were indicative of
a distorted tetrahedral geometry, as previously indicated.
The decrease in the metal-chloride angles may be
be seen that the H L is stable having a very nearly uni-
2
form distribution of charge density. However, oxygen and
nitrogen atoms are surrounded by a greater negative
charge surface, making these sites potentially more
[16,26]
accredited to intramolecular hydrogen bond.
FIGURE 3 The optimized structures of
(
2 2 2
a) H L and (b) [Cu (HL)Cl(H O)]H O complex

MAHMOUD ET AL.
11 of 20
TABLE 2 The different optimized and quantum chemical
parameters of H L and its Cu (II) complex
2
favour of the complexation reaction which is further con-
firmed by the electrostatic potential distribution of Cu
(
II) complex, where a greater negative charge is sur-
[
Cu (HL)
rounded to the metal centre (Figure 4b). The Mulliken
electronegativity also indicated the increase of electro-
negativity of oxygen and nitrogen in Cu (II) complex than
Bond lengths (Å)
H
2
L
2 2
Cl(H O)]H O
C(10)-N(1)
1.30
1.39
1.38
1.34
O(15)-C(2)
1.33
1.42
free H L making them the favour site of electrophilic
2
C(27)-N(1) in ligand which
renumbered as C(26)-N(1)
in Cu (II) complex
[
16,26]
attack by metal ion.
O(15)-H(16)
Cu(34)-O(15)
Cu(34)-N(1)
Cu(34)-Cl(35)
Cu(34)-O(36)
0.98
2
.8.10 | Molecular parameters
1.92
1.99
2.31
2.00
Additional parameters such as the highest occupied
molecular orbital energy (EHOMO), the lowest unoccupied
molecular orbital energy (ELUMO), ΔE, absolute electro-
negativities, χ, chemical potentials, Pi, absolute hardness,
η, absolute softness, σ, global electrophilicity, ω, global
softness, S, and additional electronic charge, ΔNmax have
o
Bond angles ( )
O(36)-Cu(34)-Cl(35)
O(36)-Cu(34)-O(15)
N(1)-Cu(34)-O(15)
N(1)-Cu(34)-Cl(35)
84.50
84.34
92.5
been estimated for the H L free ligand and its Cu
2
(
II) complex and registered in Table 2. Electrophilicity
103.26
index (ω) is one of the most essential quantum chemical
descriptors in describing reactivity and the toxicity of var-
ious specific sites. The electrophilicity may quantify the
biological activity of drug receptor interaction. Also, this
index measures the stabilization energy when the system
acquires an extra negative charge from the environment.
η and σ indexes, are the measure of the molecular stabil-
ity and reactivity also, their concepts are related to each
other. The softness indexes are the vice versa image for
global hardness. These parameters are useful in order to
support the suggestion structures. The mentioned quan-
tum chemical parameters were calculated with the help
of the following equations:
The calculated quantum chemical parameters
E (a.u.)
−887.05 −1174.06
Dipole moment (Debye)
1.01
2.43
E
E
HOMO (eV)
LUMO (eV)
−6.26
−2.18
4.08
−6.53
−3.81
2.45
Δ E (eV)
χ (eV)
−4.22
2.04
−5.17
1.23
η (eV)
σ (eV)−1
0.49
0.82
Pi (eV)
S (eV)−
ω (eV)
ΔNmax
4.22
5.17
1
0.25
0.41
4.36
10.87
−4.20
−2.07
ΔE = ELUMO −EHOMO
ð1Þ
ð2Þ
χ = −ðEHOMO + ELUMOÞ=2
propitious for electrophilic attack (red) as shown in
Figure 4.
The aromatic ring appeared neutral in terms of elec-
tron density. Thus the distribution of potential is in
η = ðELUMO – EHOMOÞ=2
σ = 1=η
ð3Þ
ð4Þ
[16]
FIGURE 4 Molecular
electrostatic potential maps of
(
a) H
O complex. The electron density
isosurface is 0.004 a.u
2 2
L and (b) [Cu (HL)Cl(H O)]
H
2

12 of 20
MAHMOUD ET AL.
Pi = −χ
S = 1=2η
ð5Þ
ð6Þ
ð7Þ
ð1Þ
Both the highest occupied molecular orbital (HOMO)
and lowest unoccupied molecular orbital (LUMO) were
the main orbitals that participate in chemical stability.
The HOMO represents the ability to donate an electron,
LUMO as an electron acceptor represents the ability to
obtain an electron. From the attained data (Table 2), it
can assume that:
ω = Pi=2η
ΔNmax = Pi=η
1
2
. The energies of the HOMO and LUMO were negative
The data calculated were presented in Table 2 and
reflected the following notes:
values and more negative than free H L, which
2
showed the stability of isolated complex.
. The EHOMO and ELUMO values of Cu (II) complex were
calculated and showed
i. The data of H L and its Cu (II) complex had a great
2
chance and priority for biological activity based on
high ω value.
a decrease than the free ligand which represents the
strength of M–HL shorter bonds.
ii. S and ω were the softness indexes while η is for hard-
ness indication; a hard molecule had a high stability
due to its high energy difference in-between the
EHOMO and ELUMO than the soft molecule. So, the
soft molecule was the reactive one having flexible
donation towards the metal ions. Accordingly, the
3. The total energy of Cu (II) complex was higher than
free ligand, which indicated greatly the stability of the
isolated solid complex.
4. The small energy gap can be associated with a high
chemical reactivity, low kinetic stability and reflects
to efficient electronic charge transfer interaction mak-
ing the molecule highly polarizable.
investigated H L molecule was soft towards the
2
coordination.
5. The HOMO level was mostly localized on the
azomethine nitrogen and oxygen of the phenol group
in the ligand, which indicated the preferable sites for
iii. The positive electrophilicity index (χ) value and the
negative electronic, chemical potential (μ) value indi-
[16,27]
nucleophilic attack to the central metal atom.
cated that the H L molecule capable of accepting
2
electrons from the environment and its energy must
decrease upon accepting electronic charge. There-
fore, the electronic, chemical potential must be
negative.
2.8.11 | UV–vis spectra
An identification of the photochemistry of transition
metal compounds needs knowledge of the properties of
molecular orbitals and appropriate excited states. Fron-
tier orbitals played a pertinent role in such systems,
iv. The Cu (II) complex showed high values of dipole
moments than the free ligand.
FIGURE 5 a Theoretical
electronic absorption transitions for
H
2
L in ethanol solvent.
b Theoretical electronic absorption
transitions for [Cu (HL)Cl(H O)]
O complex in DMF solvent
2
H
2

MAHMOUD ET AL.
13 of 20
TABLE 3 Main calculated optical transition with composite ion in terms of molecular orbitals
because they rule the electronic excitations and the tran-
sition characters. With the aid of TD-DFT calculations, it
is possible to have comments on the contributions of the
ligand and metal orbitals to molecular orbitals. It is not
practical to analyse all the electronic transitions and the
orbitals; therefore some limits were used. Because it is
high accuracy and low computational cost of TD-DFT, it
has been popularized for theoretical inspection of elec-
tronic spectra of molecules. The present inspection of low
lying excited state of optimized ground state structures of
H L and its Cu (II) complex has been performed at TD-
2
DFT/B3LYP/LANL2DZ level of theory for 30 singlet
state. In Table 5, the experimental and theoretical elec-
tronic spectra were presented. The TD-DFT calculations
TABLE 4 Biological activity of Schiff base ligand and metal complexes
Sample
Inhibition zone diameter (mm/mg sample)
Gram positive)
(
(Gram negative)
bacillus subtilis
0
Staphylococcus aureus
0
Escherichia coli
0
Pseudomonas aeruginosa
0
Control: DMSO
ligand (H
2
L)
Cr (HL)(H O)
Mn (HL)(H
Fe (HL)(H
Co (HL)(H
11 ± 0.041
11 ± 0.031
12 ± 0.035
17 ± 0.026
25 ± 0.033
20 ± 0.019
24 ± 0.016
16 ± 0.018
24 ± 0.029
10 ± 0.032
0
0
0
[
[
[
[
[
[
[
[
2
3
Cl]Cl.4H
]Cl.2H
]Cl .H
]Cl.5H
]Cl.3H
O)Cl].H
O) Cl].3H
O) Cl]
2
O
12 ± 0.027
14 ± 0.024
15 ± 0.041
20 ± 0.018
15 ± 0.018
16 ± 0.019
16 ± 0.021
16 ± 0.022
9 ± 0.035
13 ± 0.041
11 ± 0.027
16 ± 0.030
24 ± 0.026
15 ± 0.022
30 ± 0.031
14 ± 0.022
17 ± 0.024
6 ± 0.029
13 ± 0.033
12 ± 0.031
15 ± 0.026
21 ± 0.028
16 ± 0.024
21 ± 0.030
15 ± 0.022
25 ± 0.026
10 ± 0.027
2
O)
4
2
O
2
O)
O)
O)
4
2
2
O
2
4
2
O
Ni (HL)(H
2
4
2
O
Cu (HL)(H
2
2
O
Zn (HL)(H
2
3
2
O
Cd (HL)(H
2
3
Amikacin

14 of 20
MAHMOUD ET AL.
TABLE 5 Anti-breast cancer activity of Schiff base ligand (H
2
L) and its metal complexes
Surviving fraction (MCF7)
Complex
Ligand H
Concn. (μg/ml)
0.0
1
5.0
12.5
25.0
50.0
IC50 (μg/ml)
2
L
0.686
1.048
1.048
0.81
0.557
0.929
0.952
0.762
0.867
0.943
0.786
0.271
0.757
0.729
0.524
0.714
0.762
0.571
0.271
0.748
0.586
0.429
0.700
0.600
0.410
15
[Mn (HL)(H
[Co (HL)(H
[Ni (HL)(H
[Cu (HL)Cl(H
[Zn (HL)(H O)
[Cd (HL)(H O)
2
O)
O)
O)
4
]Cl.2H
]Cl.5H
]Cl.3H
O)]H
Cl]3H
Cl]
2
O
1
-----
-----
32
2
4
2
O
1
2
4
2
O
1
2
2
O
1
0.952
1.000
0.852
-----
-----
36
2
3
2
O
1
2
3
1
2
TABLE 6 Energy values obtained in docking calculations of H L and its metal complexes with Crystal Structure of Human Astrovirus
capsid protein (5ibv) receptor
Compound
Ligand (H L)
moiety
S28
Receptor site
Interaction
H-donor
H-acceptor
ionic
Distance (Aο)
3.49
3.11
3.78
4.11
4.45
3.43
2.91
3.08
3.65
2.32
3.36
2.57
3.05
2.72
3.05
2.57
2.62
2.78
3.27
3.57
2.62
2.78
3.27
3.54
3.4
E (kcal/mol)
−0.5
2
O THR 329
O24
NZ LYS 273
−5.4
N1
OE1 GLU 103
CA GLY 93
−1.0
5
6
-ring
-ring
pi-H
−2.1
CG2 THR 401
OE1 GLU 335
OG SER 332
OE1 GLU 335
OE1 GLU 335
OE1 GLU 335
OE1 GLU 335
OD1 ASN 261
OD2 ASP 213
OD1 ASP 213
OD2 ASP 213
OD1 ASN 261
OD1 ASP 213
OD2 ASP 213
OD1 ASP 213
OD1 ASP 213
OD1 ASP 213
OD2 ASP 213
OD1 ASP 213
OD2 ASP 213
OD1ASP 213
OD2 ASP 213
OD1 ASP213
OD1 ASP213
pi-H
−0.8
[
Cr (HL)(H
2
O)
3
Cl] Cl.4H
2
O
S27
H-donor
H-donor
ionic
−1.2
O39
N1
−9.3
−4.0
O35
O39
O42
O15
O36
O36
O36
O16
O41
O41
O44
O34
O41
O41
O44
O44
O37
O37
O40
O33
ionic
−1.4
ionic
−11.0
−2.5
ionic
[
[
Mn (HL)(H
2
O)
4
] Cl.2H
2
O
H-donor
H-donor
ionic
−4.2
−9.4
−6.6
ionic
−4.2
Fe (HL)(H
2
O)
4
] Cl
2
.H
2
O
H-donor
H-donor
H-donor
H-donor
ionic
−3.8
−17.2
−9.5
−0.8
−1.6
ionic
−7.5
ionic
−6.1
ionic
−2.9
ionic
−1.7
[
Co (HL)(H
2
O)
4
]Cl.5H
2
O
H-donor
H-donor
H-donor
ionic
−1.5
2.77
2.95
3.89
−25.2
−19.1
−0.7
(
Continues)

MAHMOUD ET AL.
15 of 20
TABLE 6 (Continued)
Compound
moiety
Receptor site
Interaction
Distance (Aο)
E (kcal/mol)
O33
OD2 ASP213
ionic
3.56
−1.7
O37
O37
O40
O40
O33
O42
O33
O33
O39
O39
O42
O42
S27
OD1 ASP213
OD2 ASP213
OD1 ASP213
OD2 ASP213
OD1 ASP 213
OD2 ASP 213
OD1 ASP 213
OD2 ASP 213
OD1 ASP 213
OD2 ASP 213
OD1 ASP 213
OD2 ASP 213
O THR 100
ionic
3.4
−2.3
−6.2
−4.8
−0.9
−15.7
−10.1
−6.6
−1.4
−6.2
−2
ionic
2.77
2.95
3.83
2.72
3
ionic
ionic
[
Ni (HL)(H
2
O)
4
]Cl.3H
2
O
H-donor
H-donor
ionic
2.72
3.65
2.78
3.46
3.57
3
ionic
ionic
ionic
ionic
−1.6
−4.5
−1.8
−27.1
−7.4
−3.4
−4.6
−12.3
−6.1
−5.1
−2.8
−17.8
−0.9
−4.2
ionic
[
Cu (HL)Cl(H
2
O)] H
2
O
H-donor
H-donor
ionic
3.67
2.64
2.64
2.56
2.78
2.91
2.78
2.91
2.82
3.05
3.84
3.05
O36
O36
O16
O35
O35
O35
O35
O16
O41
O38
O41
OE1 GLU 335
OE1 GLU 335
OD1 ASN 261
OD1 ASP 213
OD2 ASP 213
OD1 ASP 213
OD2 ASP 213
O TYR 132
[
Zn (HL)Cl(H
2
O)
3
] 3H
2
O
H-donor
H-donor
H-donor
ionic
ionic
[
Cd (HL)(H
2
O)
3
Cl]
H-donor
H-donor
ionic
OD2 ASP 213
OD2 ASP 213
OD2 ASP 213
ionic
have been evaluated in the N,N-dimethylformamide sol-
vent background and competed with the experimental
data. The transitions between interfrontier orbitals for
wavelengths corresponding to the maximum oscillator
strength of simulated results with recent experimental
observations were presented in Figure (5 a, b). For exam-
charged than the oxygen atom in the isolated metal ion
and so it may account for the coordination of the nitro-
gen atom instead of the oxygen atom, to the metal ion.
Furthermore, these authors have found that in the pres-
ence of the metal ions, the bidentate binding conforma-
tion with both N and O atoms coordinated to the metal
ions was favoured.
ple, the electronic transitions for H L obtained at calcu-
2
lated 247 nm correspond to experimental peak at 248 nm.
This transition have been majorly contributed from
HOMO to LUMO+2 transitions which was primarily
The structures of the Schiff base ligand (H L) with Cr
2
(III), Mn (II), Fe (III), Co (II), Ni (II), Cu (II), Zn (II) and
Cd (II) complexes were characterized via elemental ana-
lyses, molar conductance, magnetic, solid reflectance and
thermal analysis data and the proposed structures of
metal complexes were reported in Figure 6.
*
π ! π in nature. The different transitions and its experi-
mental counterpart of the free ligand and its Cu
[26]
(II) complex have been reviewed in Table 3.
2.8.12 | Structural interpretation
2.8.13 | Biological activity
Theoretical approaches made by Liang and Lipscomb
indicated that the nitrogen atom was more negatively
The greater antibacterial activity of metal complexes than
the free Schiff base ligands can be justified by chelation

16 of 20
MAHMOUD ET AL.
metal ion with donor groups. Chelation increased the
delocalization of π-electrons over the entire chelate ring
and enhanced the penetration of the complexes into lipid
membranes. It also increased the hydrophobic and lipo-
philic nature of the central metal ions, perhaps leading to
liposolubility and permeability through the lipid layer of
cell membranes. Further, lipophilicity, which controls
the rate of entry of molecules into the cell, was modified
by coordination, so the metal complex can become more
[
16,26]
active than the free Schiff base ligand.
Schiff base ligand and its complexes were screened
for antibacterial activities. The results listed in
Table (4) and Figure 7 showed that complexes exhibited
more inhibitory effects than the parent ligand.
Antibacterial activity of H L ligand and Cr (III), Mn
2
(
(
II), Fe (III), Co (II), Ni (II), Cu (II), Zn (II) and Cd
II) complexes were tested against various bacterial spe-
cies: two Gram (+) Staphylococcus aureus and Bacillus
subtilis and two Gram (−) pseudomonas aeruginosa and
Escherichia coli by using the modified agar diffusion
method.
For Bacillus subtilis: the biological activity follows the
order:
H2L = Cr ðIIIÞ < Mn ðIIÞ < Zn ðIIÞ < FeðIIIÞ
<
Ni ðIIÞ < CuðIIÞ = Cd ðIIÞ < CoðIIÞ
FIGURE 6 Structures of metal complexes
For Staphylococcus aureus: the Co (II) complex showed
of the Schiff base with metal ions as metal chelates dis-
play both nonpolar and polar properties. This makes
them suitable for permeation into cells and tissues. The
polarity of the metal ion will be decrease to a greater
extent due to the overlap of the ligand orbital upon chela-
tion, and partial sharing of the positive charge of the
the highest activity.The activity follows the order:
H L < Cr ðIIIÞ < Mn ðIIÞ < FeðIIIÞ = NiðIIÞ
2
<
Zn ðIIÞ = Cu ðIIÞ = Cd ðIIÞ < Co ðIIÞ
FIGURE 7 Biological activity of Schiff base
ligand and its metal complexes against different
organisms

MAHMOUD ET AL.
17 of 20
2
FIGURE 8 Activity index values of H L
and its metal complexes
For pseudomonas aeruginosa: the biological activity
For Escherichia coli: the biological activity follow the
follow the order:
order:
H L < Mn ðIIÞ < CrðIIIÞ < ZnðIIÞ = FeðIIIÞ
2
H L < Mn ðIIÞ < CrðIIIÞ < ZnðIIÞ < NiðIIÞ
2
<
NiðIIÞ < Cu ðIIÞ = Co ðIIÞ < Cd ðIIÞ
< FeðIIIÞ < Cd ðIIÞ < Co ðIIÞ < Cu ðIIÞ
FIGURE 9 Anticancer activity of Schiff
base ligand (H L) and its metal complexes
2

18 of 20
MAHMOUD ET AL.
Inhibition Zone of compound ðmmÞ
Inhibition Zone of standard drug ðmmÞ
Activity index (A) =
100.
×
It can be conducted from this arrangement that the
antimicrobial activity of the complexes is greater than
related ligand. The increased activity of the metal com-
plexes can be rationalized on the basis of chelation the-
[
15]
ory.
Chelation decreases the polarity of the metal ion,
because positive charges of the metal are partially shared
with the donor atoms extent in the ligands and there may
be π-electron delocalization over the whole chelation.
This phenomenon improved the lipophilic character of
the metal chelate and favours its permeation more effi-
ciently through the lipoid layer of the microorganism. As
the results of antimicrobial activity is related to their abil-
ity to make complexes with soluble extracellular proteins
and with the cell wall, for the lipophilic character of
these compounds, which may bring about the rupture of
the cell membrane of microorganisms. In addition, in
bacteria, the permeability of the cell membrane
isassociated with the loss of ions as well as the decrease
FIGURE 10 The relation between the negative lowest
binding energy of the ligand and its metal complexes with 5ibv
receptor
The activities of the prepared Schiff base ligand and its
metal complexes were confirmed via calculating the
activity index according to the following relation and that
[27]
showed in Figure 8.
FIGURE 11 The interaction
between H
2
L and its metal
complexes with receptor 5IBV.
(
(
(
(
2
a) H L, (b) Cr (III), (c) Mn (II),
d) Fe (III), (e) Co (II), (f) Ni (II),
g) Cu (II), (h) Zn (II) and (i) Cd
II) complexes

MAHMOUD ET AL.
19 of 20
of its potential, causing damage that may lead to the
extravasation of macromolecules, resulting in a collapse
of the cellular functions and, consequently, the bacterial
Astrovirus capsid protein (5IBV). Human astrovirus
(HAstV) is a leading cause of viral diarrhoea in infants
and young children worldwide. HAstV is a non-
enveloped virus with a T = 3 capsid and a positive-
sense RNA genome. The lowest binding energies of the
ligand and its metal complexes by 5IBV receptor were
calculated and showed in Figure 10. 3D interaction
[15]
death.
2.8.14 | Anticancer activity
maps showed the binding models of H L and its metal
2
Metal-based anticancer drug discovery is one of the
future areas of pharmaceutical research. The ligand and
its complexes were investigated for their anticancer
activity against human breast cancer cell line MCF-7 via
using 100 μg/ml concentration. It is apparent that Cr
complexes to the Human astrovirus RNA. It was found
that all of the tested compounds were interacted with
the RNA through a hydrogen bond and a p interaction
(Table 6) and Figure 11. The values of interaction ener-
gies revealed that its Cu (II) complex had the most sta-
[
28,29]
(III), Mn (II), Ni (II), Zn (II) and Cd (II) complexes and
ble interaction.
H L ligand were found to be very active against breast
2
cancer cells. Table (5) and Figure 9 showed the effect of
various concentrations i.e. (0, 5, 12, 25 and 50 μg/ml of
each one) of testing compounds on human breast cancer
cell line MCF-7. The IC50 (the concentration of the com-
pound in μg/ml that inhibits proliferation of the cells by
3 | CONCLUSION
The novel complexes of chromium (III), manganese (II),
iron (III), copper (II), nickel (II), cobalt (II), zinc (II) and
5
0% as compared to the untreated control cells) values
cadmium (II) with the bidentate ligand (H L) were syn-
2
of the investigated compounds were listed in Table (5).
The ligand showed IC50 values of 15.00 μg/ml towards
human breast cancer cell lines (MCF-7), while the Ni
thesized by condensation off 4,6-diacetylresorcinol with
2-amino-4-methylthiazole and characterized using spec-
troscopic methods. From the data of elemental analysis,
the complexes had composition of the MHL type with
general formulae [M (HL)(H O) ]Clx.nH O (M = Mn
(
II) and Cd (II) complexes were also exhibited good
anticancer activity with IC50 values of 32.00 and
6.00 μg/ml, respectively. The ligand was prepared and
2
4
2
3
(II), x = 1, n = 2; Fe (III), x = 2, n = 1); Co (II), x = 1,
n = 5; and Ni (II), x = 1, n = 3) and [M (HL)(H O) Cl]
then showed high activity on the cancer cells and
followed the rules with preparation metal complexes to
know how effective they are, but because cancer cells
are not like normal cells, it could be argued that the
rules used to guide the design of metal-based drugs are
entirely valid and should be followed, since the drugs
that have made it into the clinic to date follow these
rules. However, there are numerous examples of com-
pounds which have been studied on advanced pre-
clinical models or are currently undergoing clinical tri-
als, e.g. the arsenic–glutathione prodrugs that target cer-
2
3
Clx.nH O (M = Cr (III), x = 1, n = 4; Zn (II), x = 0,
2
n = 3; and Cd (II) x = 0, n = 0), [Cu (HL)(H O)Cl]
2
H O. The ligand acted as neutral bidentate (NO) ligand
2
and all complexes showed octahedral geometry except
Cu (II) showed tetrahedral geometry. The molar conduc-
tivity data for complexes indicated that Cu (II), Zn
(II) and Cd (II) complexes were considered as nonelectro-
lytes. Cr (III), Mn (II), Co (II) and Ni (II) complexes are
ionic in nature and they are 1:1 electrolytes. The Fe (III)
complex was a 1:2 electrolyte. The antimicrobial test
referred that some complexes had higher antimicrobial
activity in comparison with that of the free Schiff base
ligand. In addition to that, cytotoxicity of Cd (II) complex
indicated higher anticancer activity than the others with
IC50 32 μg/ml that might become a good anticancer agent
in clinical trials or biological agents. The docking study
showed that the Cu (II) complex has the highest activity
[
24]
tain tumours as well as others described previously.
There is clearly a long way to go before saying that cer-
tain classes of metal complexes should be excluded from
medicinal inorganic chemistry and a better understand-
ing of biology and the use of assays other than cytotox-
icity screening are essential to guide metal-based drug
[28]
design in the future.
−
1
with lowest binding energy (−27.1 kcal mol ) with
Human Astrovirus capsid protein.
2
.8.15 | Molecular modelling: Docking
study
ORCID
Walaa H. Mahmoud https://orcid.org/0000-0001-9187-
Molecular docking studies have been carried out in
4325
order to predict the binding modes of the H L ligand
Gehad G. Mohamed https://orcid.org/0000-0002-1525-
2
and its metal complexes to Crystal Structure of Human
5271

20 of 20
MAHMOUD ET AL.
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