Transition metal complexes of nano bidentate organometallic Schiff base: Preparation, structure characterization, biological activity, DFT and molecular docking studies

Article abstract of DOI:10.1002/aoc.4556

An organometallic NO-bidentate Schiff base, (2-(1-((1-carboxyethyl)imino)ethyl) cyclopenta-2,4-dien-1-yl)(cyclopenta-2,4-dien-1-yl) iron (HL) was synthesized by condensation of 2-acetylferrocene with amino acid alanine. Then its octahedral Cr (III), Mn (I

Full text of DOI:10.1002/aoc.4556

Received: 6 May 2018
DOI: 10.1002/aoc.4556
Revised: 7 July 2018
Accepted: 17 July 2018
F U L L P A P E R
Transition metal complexes of nano bidentate
organometallic Schiff base: Preparation, structure
characterization, biological activity, DFT and molecular
docking studies
Walaa H. Mahmoud1
Gehad G. Mohamed1,2
| Reem G. Deghadi1 | Maher M.I. El Desssouky1 |
1 Chemistry Department, Faculty of
Science, Cairo University, Giza 12613,
Egypt
2 Egypt Nanotechnology Center, Cairo
University, El‐Sheikh Zayed, 6th October
An organometallic NO‐bidentate Schiff base, (2‐(1‐((1‐carboxyethyl)imino)
ethyl) cyclopenta‐2,4‐dien‐1‐yl)(cyclopenta‐2,4‐dien‐1‐yl) iron (HL) was syn-
thesized by condensation of 2‐acetylferrocene with amino acid alanine. Then
its octahedral Cr (III), Mn (II), Fe (III), Co (II), Ni (II), Cu (II), Zn (II) and
Cd (II) complexes were synthesized. All compounds were characterized on
the basis of elemental analysis (C, H, N and M), molar conductivity, FT‐IR,
UV–Vis, 1H‐NMR, SEM, mass analysis and thermal studies. Furthermore, com-
putational studies of HL ligand have been carried out by DFT/B3LYP method.
HOMO and LUMO energy values, chemical hardness‐softness, electronegativ-
ity, electrophilic index and other parameters were calculated. SEM micro-
graphs of HL ligand and its [Cd (HL)(H2O)2Cl2].2H2O complex, showed that
they were prepared in nano‐structure forms with particle size 54 and 41 nm,
respectively. Antifungal and antibacterial activities of HL ligand and its metal
complexes have been screened in vitro against different species such as Asper-
gillus fumigatus, Candida albicans, Bacillus subtilis, Staphylococcus aureus,
Escherichia coli and Salmonella typhimurium. The synthesized compounds
were evaluated for their anticancer activities against breast cancer cell line
(MCF‐7) and normal melanocytes cell line (HFB‐4). It was found that [Co
(HL)(H2O)2Cl2].3H2O complex had the lowest IC50 value (10.9 μg/ml) and
hence was the most active one. Finally, the optimized structures of the Schiff
base and its Co (II) complex have been used to accomplish molecular docking
studies with receptors of 3HB5, 3MIW, 5IBV and 4WM8 to determine the most
preferred mode of interaction.
City, Giza 12588, Egypt
Correspondence
Gehad G. Mohamed, Chemistry
Department, Faculty of Science, Cairo
University, Giza, 12613, Egypt.
Email: ggenidymohamed@sci.cu.edu.eg
KEYWORDS
antibacterial activities, computational studies, molecular docking, Organometallic Schiff base
Appl Organometal Chem. 2018;e4556.
wileyonlinelibrary.com/journal/aoc
© 2018 John Wiley & Sons, Ltd.
1 of 21
https://doi.org/10.1002/aoc.4556

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MAHMOUD ET AL.
2‐acetylferrocene, alanine, CrCl3.6H2O, MnCl2.2H2O,
FeCl3.6H2O, CoCl2.6H2O, NiCl2.6H2O, CuCl2.2H2O,
ZnCl2 and CdCl2 and they were supplied from Strem
Chemicals Inc., Sigma‐Aldrich, BDH, and Merck, respec-
tively. Organic solvents used were ethyl alcohol (95%),
methyl alcohol and N,N‐dimethylformamide (DMF).
Deionized water was usually used in all preparations.
1 | INTRODUCTION
Cancer is considered as a large family of diseases which
involves abnormal cell growth that may be spread to
other parts of the body. Nowadays, a lot of drugs that
are used for cancer treatment are cytotoxic which affected
by one way or more with the function of DNA in the
cells. As a result, the most important challenge these days
is to develop novel anticancer drugs with high efficacy
and low toxicity.[1] Schiff bases are compounds that have
azomethine functional group which have been synthe-
sized by the condensation of primary amines with active
carbonyls (aldehyde or ketone).[2] These Schiff bases are
very important in the synthesis of many potential and
effective anticancer drugs. Also, they have a broad spec-
trum of biological activities such as antibacterial, antifun-
gal, antimalarial and anti‐inflammatory activities.[3] The
biological activities of Schiff bases can be increased upon
complexation with different transition metal ions.[4–6]
Organometallic Schiff bases and their transition metal
complexes are considered as very essential compounds
because of their electrochemic‐analysis, biochemical syn-
thesis, anticancer, antimicrobial, antifungal as well as cat-
alytic activities.[7] Due to their very important functions
in different fields, ferrocenyl Schiff bases and their transi-
tion metal complexes were prepared. These prepared
compounds can be used in catalysis, crystal engineering,
material science and bio‐organometallic chemistry.[8,9]
Some drugs were very effective by presence of ferrocene
group in their structures such as ferrocene aspirin, anti-
cancer drug ferrocifen, antimalarial drug ferrocene quine,
ferrchloroquine and ferrocene hydroxytamoxifen.[10]
In the light of these important functions of ferrocene
organometallic Schiff bases, preparation of new
ferrocenyl Schiff base ligand that derived from 2‐
acetylferrocene and alanine was the main target of inter-
est. Then its metal complexes of Cr (III), Mn (II), Fe (III),
Co (II), Ni (II), Cu (II), Zn (II) and Cd (II) were also pre-
pared. All compounds were then characterized using dif-
ferent spectroscopic techniques. For better understanding
the structure of ligand, DFT calculations were performed.
The biological and anticancer activities of these com-
pounds were also investigated. Finally, molecular
docking was studied to determine the probable binding
mode of the ligand and its Co (II) complex with the active
site of 3HB5, 3MIW, 51BV and 4WM8 receptors.
2.2 | Solutions
Stock solutions of the ferrocene Schiff base ligand and its
metal complexes of 1 X 10−3 M were prepared by dissolv-
ing an accurately weighed amount in N,N‐
dimethylformamide for Cr (III), Ni (II) and Cu (II) com-
plexes and in ethanol for HL ligand, Mn (II), Fe (III),
Co (II), Zn (II) and Cd (II) complexes. The conductivity
then measured for the 1 X 10−3 M solution of metal com-
plexes. Dilute solutions of the Schiff base ligand and its
metal complexes (1 X 10−4 M) were prepared by accurate
dilution from the previous prepared stock solutions for
measuring their UV–Vis spectra.
2.3 | Solution of anticancer study
A fresh stock solution (1 × 10−3 M) of organometallic
Schiff base ligand (0.12 X 10−2 g l−1) was prepared in
the appropriate volume of ethanol (90%). DMSO was used
in cryopreservation of cells. RPMI‐1640 medium was
used. The medium was used for culturing and mainte-
nance of the human tumor cell line. The medium was
supplied in a powder form. It was prepared as follows:
10.40 g of medium was weighed, mixed with 2 g of
sodium bicarbonate, completed to 1 l with distilled water
and shaken carefully until complete dissolution. The
medium was then sterilized by filtration in a Millipore
bacterial filter (0.22 ml). The prepared medium was kept
in a refrigerator (4°C) and checked at regular intervals for
contamination. Before use, 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
was used for viability counting. FBS (10%, heat
inactivated at 56°C for 30 min), 100 units/ml penicillin
and 2 mg/ml streptomycin were used for the supplemen-
tation of RPMI‐1640 medium prior to use. Trypsin (0.25 X
10−1% w/v) was used for the harvesting 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 pro-
tein dye. A stock solution of trichloroacetic 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 concentration of 10% used for protein
2 | EXPERIMENTAL
2.1 | Materials and reagents
All chemicals used were of the analytical reagent grade
(AR) and of highest purity. The chemicals used included

MAHMOUD ET AL.
3 of 21
precipitation. Isopropanol (100%) and ethanol (70%) were
used. Tris base (10 mM; pH = 10.50) was used for SRB
dye solubilization. Tris base (121.10 g) was dissolved in
1000 ml of distilled water and the pH was adjusted using
hydrochloric acid (2 M).
dissolved in methanol as shown in Scheme (1). The
resulting mixture was stirred under reflux for about 2 h
at 100–150 °C, during which an orange solid compound
was separated. It was filtered, recrystallized, washed with
diethylether and dried in vacuum.
(2‐(1‐((1‐carboxyethyl)imino)ethyl)cyclopenta‐2,4‐
dien‐1‐yl)(cyclopenta‐2,4‐dien‐1‐yl) iron (HL). Yield 92%;
m.p. 85 °C; orange solid. Anal. Calc. for C15H17NO2Fe
(%): C, 60.20; H, 5.69; N, 4.68; Fe, 18.73. Found (%): C,
60.10; H, 5.21; N, 4.51; Fe, 19.01. FT‐IR (ν, cm−1):
hydroxyl (OH) 3453br, carbonyl (C=O) 1744s,
azomethine (C=N) 1659sh, ν (COO)asy 1454sh, ν (COO)
2.4 | Instrumentation
Microanalyses of carbon, hydrogen and nitrogen were
carried out at the Microanalytical Center, Cairo Univer-
sity, Egypt, using a CHNS‐932 (LECO) Vario elemental
analyser. Analyses of the metals were conducted by dis-
solving the solid complexes in concentrated HNO3, and
dissolving the residue in deionized water. The metal con-
tent was carried out using inductively coupled plasma
atomic absorption spectrometry (ICP‐AES), Egyptian
Petroleum Research Institute. Fourier transform infrared
(FT‐IR) spectra were recorded with a PerkinElmer 1650
1366sh. 1H NMR (300 MHz, DMSO‐d6, δ, ppm):
sym
4.24–4.78 (m, 9H, ferrocene ring), 6.42–6.44 (m, 1H, CH
group), 3.29 (s, 1H, carboxylic group), 1.22 (s, 3H, methyl
group of ferrocene), 2.35 (d, 3H, methyl group of amine).
UV–Vis (λmax, nm): 224, 269 (π–π* of ferrocene) and 334
(n–π* of azomethine).
spectrometer (400–4000 cm−1) in KBr pellets. H‐NMR
1
spectra, as solutions in DMSO‐d6, were recorded with a
300 MHz Varian‐Oxford Mercury at room temperature
using tetra‐methylsilane as an internal standard. Mass
spectra were recorded using the electron ionization tech-
nique at 70 eV with an MS‐5988 GS‐MS Hewlett‐Packard
instrument at the Microanalytical Center, National Cen-
ter for Research, Egypt. UV–visible spectra were obtained
with a Shimadzu UVmini‐1240 spectrophotometer. Molar
conductivities of 10−3 M solutions of the solid complexes
in DMF were measured using a Jenway 4010 conductivity
meter. Thermogravimetric (TG) and differential thermo-
gravimetric (DTG) analyses of the solid complexes were
carried out from room temperature to 1000°C using a
Shimadzu TG‐50H thermal analyzer. Antimicrobial mea-
surements 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 well was
measured spectrophotometrically at 564 nm with an
ELIZA microplate reader (Meter tech. R960, USA). The
scanning electron microscope (SEM) image of the com-
plexes was recorded by using SEM Model Quanta 250
FEG (Field Emission Gun) attached with EDX unit
(Energy Dispersive X‐ray Analyses), with accelerating
voltage 30 K.V., magnification 14X up to 1000000 and res-
olution for Gun.1n, National Research Center, Egypt).
2.6 | Synthesis of Schiff base metal
complexes
The Cr (III), Mn (II), Fe (III), Co (II), Ni (II), Cu (II), Zn (II)
and Cd (II) complexes were prepared by a reaction of 1:1
molar mixture of hot ethanolic solution (60°C) of the metal
chloride (1.34 X 10−3 mol) and the ethanolic solution of the
organometallic Schiff base ligand (HL) (0.4 g, 1.34 X
10−3 mol). The resulting mixtures were stirred under
refluxing for 1–2 h, whereupon the complexes precipitated.
They were collected by filtration and purified by washing
several times with diethyl ether. The solid complexes then
dried in desiccator over anhydrous calcium chloride.
2.6.1 | [Cr (HL)(H2O)2Cl2]Cl.2H2O
Yield 81%; m.p. >300°C; dark brown solid. Anal. Calc.
for C15H25Cl3FeCrNO6 (%): C, 33.99; H, 4.72; N, 2.64;
Fe, 16.58; Cr, 9.82. Found (%): C, 33.71; H, 4.63; N, 2.33;
Fe, 16.81; Cr, 9.45. Λm (Ω−1mol−1cm2) = 71; FT‐IR
(ν, cm−1): hydroxyl (OH) 3401br, carbonyl (C=O) disap-
pear, azomethine (C=N) 1623 m, ν (COO)asy 1460 m, ν
(COO)sym 1355s, H2O stretching of coordinated water
900w and 830 s, (M─O) 533w, (M─N) 497w. UV–Vis
(λmax, nm): 265 (π–π*).
2.5 | Synthesis of organometallic Schiff
base ligand (HL)
The organometallic Schiff base (HL) was prepared by
refluxing a mixture of alanine (0.03 mol, 2.76 g) dissolved
in distilled water and 2‐acetylferrocene (0.03 mol, 7 g)
SCHEME 1 Preparation of organometallic Schiff base ligand
(HL)

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MAHMOUD ET AL.
Fe, 10.45; Cu, 11.47. Λm (Ω−1mol−1cm2) = 50; FT‐IR
(ν, cm−1): hydroxyl (OH) 3434br, carbonyl (C=O)
1647sh, azomethine (C=N) 1591s, ν (COO)asy 1452 m,
ν (COO)sym 1372s, H2O stretching of coordinated water
910w and 826 m, (M─O) 535 s, (M─N) 490 s. UV–Vis
(λmax, nm): 265 (π–π*).
2.6.2 | [Mn (HL)(H2O)2Cl2].4H2O
Yield 76%; m.p. 95°C; brown solid. Anal. Calc. for
C15H29Cl2FeMnNO8 (%): C, 33.77; H, 5.44; N, 2.63; Fe,
10.51; Mn, 10.32. Found (%): C, 33.59; H, 5.05; N, 2.40;
Fe, 10.72; Mn, 10.54. Λm (Ω−1mol−1cm2) = 42; FT‐IR
(ν, cm−1): hydroxyl (OH) 3412br, carbonyl (C=O)
1657 m, azomethine (C=N) 1627 m, ν (COO)asy 1458 m,
ν (COO)sym 1353w, H2O stretching of coordinated water
925w and 888w, (M─O) 535 m, (M─N) 500w. UV–Vis
(λmax, nm): 248 (π–π*).
2.6.7 | [Zn (HL)(H2O)2Cl2].5H2O
Yield 85%; m.p. 100°C; brown solid. Anal. Calc. for
C15H31Cl2FeZnNO9 (%): C, 32.09; H, 5.53; N, 2.50; Fe,
9.98; Zn, 11.59. Found (%): C, 31.91; H, 5.22; N, 2.28;
Fe, 9.57; Zn, 11.87. Λm (Ω−1mol−1cm2) = 18; FT‐IR
(ν, cm−1): hydroxyl (OH) 3455br, carbonyl (C=O) disap-
pear, azomethine (C=N) 1648sh, ν (COO)asy 1460sh,
ν (COO)sym 1351w, H2O stretching of coordinated water
922w and 844 m, (M─O) 532w, (M─N) 492 s. UV–Vis
(λmax, nm): 226, 274 (π–π* of ferrocene) and 328 (n–π*
of azomethine).
2.6.3 | [Fe (HL)(H2O)2Cl2]Cl.3H2O
Yield 88%; m.p. >300°C; grey solid. Anal. Calc. for
C15H27Cl3Fe2NO7 (%): C, 32.64; H, 4.90; N, 2.54; Fe,
20.31. Found (%): C, 32.05; H, 4.52; N, 2.19; Fe, 20.85.
Λm (Ω−1mol−1cm2) = 88; FT‐IR (ν, cm−1): hydroxyl
(OH) 3391br, carbonyl (C=O) 1633sh, azomethine
(C=N) 1590w, ν (COO)asy 1474 m, ν (COO)sym 1349w,
H2O stretching of coordinated water 971w and 887w,
(M─O) 570w, (M─N) 488 s. UV–Vis (λmax, nm): 251
(π–π* of ferrocene) and 311 (n–π* of azomethine).
2.6.8 | [Cd (HL)(H2O)2Cl2].2H2O
Yield 90%; m.p. 90°C; brown solid. Anal. Calc. for
C15H25Cl2FeCdNO6 (%): C, 32.49; H, 4.51; N, 2.53; Fe,
10.11; Cd, 20.22. Found (%): C, 32.27; H, 4.39; N, 2.43;
Fe, 10.86; Cd, 20.74. Λm (Ω−1mol−1cm2) = 5; FT‐IR
(ν, cm−1): hydroxyl (OH) 3510br, carbonyl (C=O) disap-
pear, azomethine (C=N) 1623sh, ν (COO)asy 1456 m,
ν (COO)sym 1363s, H2O stretching of coordinated water
2.6.4 | [Co (HL)(H2O)2Cl2].3H2O
Yield 89%; m.p. 105°C; brown solid. Anal. Calc. for
C15H27Cl2FeCoNO7 (%): C, 34.68; H, 5.20; N, 2.70;
Fe, 10.79; Co, 11.37. Found (%): C, 34.47; H, 5.11; N, 2.67;
Fe, 10.33; Co, 11.65. Λm (Ω−1mol−1cm2) = 44; FT‐IR
(ν, cm−1): hydroxyl (OH) 3403br, carbonyl (C=O) 1654sh,
azomethine (C=N) 1620w, ν (COO)asy 1458s, ν (COO)sym
1354w, H2O stretching of coordinated water 891w and
825 m, (M─O) 533 s, (M─N) 495 s. UV–Vis (λmax, nm):
249, 269 (π–π* of ferrocene) and 337 (n–π* of azomethine).
1
920w and 845 m, (M─O) 535 m, (M─N) 491 s. H NMR
(300 MHz, DMSO‐d6, δ, ppm): 4.23–4.77 (m, 9H, ferrocene
ring), 6.46–6.55 (m, 1H, CH group), 3.33 (s, 1H, carboxylic
group), 1.06 (s, 3H, methyl group of ferrocene), 2.35
(d, 3H, methyl group of amine). UV–Vis (λmax, nm): 220,
270 (π–π* of ferrocene) and 331 (n–π* of azomethine).
2.6.5 | [Ni (HL)(H2O)3Cl]Cl.H2O
2.7 | Spectrophotometric studies
The absorption spectra were recorded for 1 X 10−4
solutions of the free organometallic Schiff base ligand
and its metal complexes. The spectra were scanned
within the wavelength range from 200 to 700 nm.
M
Yield 75%; m.p. >300°C; grey solid. Anal. Calc. for
C15H25Cl2FeNiNO6 (%): C, 35.93; H, 4.99; N, 2.79; Fe,
11.18; Ni, 11.78. Found (%): C, 35.53; H, 4.54; N, 2.68;
Fe, 11.35; Ni, 11.56. Λm (Ω−1mol−1cm2) = 75; FT‐IR
(ν, cm−1): hydroxyl (OH) 3412r, carbonyl (C=O) disap-
pear, azomethine (C=N) 1623 m, ν (COO)asy 1437 m,
ν (COO)sym 1354s, H2O stretching of coordinated water
920w and 829 s, (M─O) 535w, (M─N) 495w. UV–Vis
(λmax, nm): 265 (π–π*).
2.8 | Antimicrobial activity
A filter paper disk (5 mm) was transferred into 250 ml
flasks containing 20 ml of working volume of tested solu-
tion (100 mg ml−1). All flasks were autoclaved for 20 min
at 121°C. LB agar media surfaces were inoculated with
four investigated bacteria (Gram‐positive bacteria: Bacil-
lus subtilis and Staphylococcus aureus, Gram‐negative
bacteria: Escherichia coli and Salmonella typhimurium
and two strains of fungi (Aspergillus fumigatus and
2.6.6 | [Cu (HL)(H2O)3Cl]Cl.3H2O
Yield 75%; m.p. >300°C; dark brown solid. Anal. Calc. for
C15H29Cl2FeCuNO8 (%): C, 33.24; H, 5.36; N, 2.89; Fe,
10.34; Cu, 11.73. Found (%): C, 32.89; H, 4.98; N, 2.93;

MAHMOUD ET AL.
5 of 21
Candida albicans) by diffusion agar technique,[11] and
then transferred to a saturated disk with a tested solution
in the center of Petri dish (agar plates). The newly synthe-
sized Schiff base ligand and its metal complexes were
placed at 4 equidistant places at a distance of 2 cm from
the center in the inoculated Petri plates. DMSO served
as control. Finally, all these petri dishes were incubated
at 25°C for 48 hr where clear or inhibition zones were
detected around each disk. Control flask of the experi-
ment was designed to perform under the same condition
described previously for each microorganism but with N,
N‐dimethylformamide solution only and by subtracting
the diameter of inhibition zone resulting with DMF from
that obtained in each case, so antibacterial activity could
be calculated. Gentamycin and ketokonazole were used
as reference compounds for antibacterial and antifungal
activities, respectively. All experiments were performed
as triplicate and data plotted were the mean value.[12]
inhibition of cell growth) were calculated. The experi-
ment was repeated three times for MCF7 cell line.
2.10 | Computational methodology
DFT and molecular modeling theoretical calculations for
organometallic Schiff base ligand (HL) was carried out on
Gaussian03 package,[14] at density functional theory
(DFT) level of theory. The molecular geometry for the
tested ligand was fully optimized using density functional
theory based on B3LYP method along with the LANL2DZ
basis set. The optimized structure of the ligand (HL) was
visualized using Chemcraft version 1.6 package and
GaussView version 5.0.9.[15] Quantum chemical parame-
ters such as the highest occupied molecular orbital energy
(EHOMO), the lowest unoccupied molecular orbital energy
(ELUMO) and HOMO–LUMO energy gap (ΔE) for the
investigated molecule were calculated.
2.11 | Molecular docking
2.9 | Anticancer activity
Molecular docking studies were elaborated using MOE
2008 software and it is rigid molecular docking software.
These studies are very important for predicting the possi-
ble binding modes of the Schiff base ligand and its Co (II)
complex against the receptors of breast cancer mutant
oxidoreductase (PDB ID: 3HB5), crystal structure of Rota-
virus NSP4 (PDB ID: 3MIW), crystal structure of human
Astrovirus capsid protein (PDB ID: 5IBV), crystal struc-
ture of human Enterovirus D68 (PDB ID: 4WM8).[16]
Docking is an interactive molecular graphics program
that can be used to calculate and display feasible docking
modes of the receptors with HL ligand and complex mol-
ecules. It necessitates the ligand, its Co (II) complex and
the receptors as input in PDB format. The water mole-
cules, co‐crystallized ligands and other unsupported ele-
ments (e.g., Na, K, Hg, etc.,) were removed but the
amino acid chain was kept.[17] The structure of the ligand
and it Co (II) complex in PDB file format was created by
Gaussian software. The crystal structures of 3HB5, 3MIW,
5IBV and 4WM8 were downloaded from the protein data
bank (http://www.rcsb.org./pdb).
Potential cytotoxicity of the Schiff base ligand and its
metal complexes were tested using the method of Skehan
and Storeng.[13] Cells were plated in 96‐multiwell plate
(104 cells well‐1) for 24 hr before treatment with the
newly synthesized Schiff base ligand and its metal com-
plexes to allow attachment of cell to the wall of the plate.
Different concentrations of the tested compounds under
investigation (5, 12.5, 25, 50 and 100 μg ml−1) which were
added to the cell monolayer triplicate wells were prepared
for each individual dose. The monolayer cells were incu-
bated with the compounds for 48 hr at 37°C and in 5%
CO2 atmosphere. After 48 hr, cells were fixed, washed
and stained with SRB stain. Excess stain was washed with
acetic acid and attached stain was recovered with tris–
EDTA buffer. The optical density (O.D.) of each well
was measured spectrophotometrically at 564 nm with an
ELIZA microplate reader, the mean background absor-
bance was automatically subtracted and mean values of
each drug concentration were calculated. The relation
between surviving fraction and drug concentration is
plotted to get the survival curve of breast tumor cell line
for each compound.
3 | RESULTS AND DISCUSSION
• Calculation:
• The percentage of cell survival was calculated as
3.1 | Characterization of the
organometallic Schiff base (HL)
follows:
A novel organometallic Schiff base (HL) was synthesized
by condensation of 2‐acetylferrocene with alanine in 1:1
molar ratio. From elemental analysis, the experimental
data showed a good agreement with the calculated values
which confirmed its molecular formula as C15H17NO2 Fe.
Survival fraction = O.D. (treated cells) /O.D. (control
cells).
The IC50 values (the concentrations of the Schiff base
ligand or its metal complexes required to produce 50%

6 of 21
MAHMOUD ET AL.
Also, it showed good physical properties such as: melting
point was about 85°C, its solubility had been performed
in different solvents like ethanol, DMF, DMSO and its
color was orange. The IR spectrum of the prepared Schiff
base ligand showed some important bands that con-
cerned the skeleton of the ligand. The most characteristic
band was appeared at 1659 cm−1 corresponding to
azomethine group which indicated the successful con-
densation of the parent materials.[18] Other two charac-
teristic bands were appeared at 1454 and 1366 cm−1
which were attributed to (COO−)asy and (COO−)sym
respectively.[19] The carbonyl band of the amino acid (ala-
nine) was appeared at 1744 cm
−1 [20] Furthermore, a wide
vibration band of ν (O–H) was situated in the ligand at
3453 cm−1 [21]
To elucidate more structural information
,
.
FIGURE 1 The optimized structure of organometallic Schiff base
ligand (HL)
.
for preparation of the HL ligand, the mass spectrum of
this ligand was recorded. From this spectrum, it was
showed that a molecular ion peak at m/z = 301 a.u was
in agreement with the formula weight of the ligand
C15H17NO2Fe with molecular weight 299 g/mol. 1H‐
NMR spectrum of the synthesized ligand was recorded
in DMSO‐d6. The spectrum showed multiplet signals at
4.24–4.78 ppm which corresponded to ferrocene
group.[22,23] The methyl protons of ferrocene group were
appeared at 1.22 ppm while the methyl protons of alanine
were appeared at 2.35 ppm.[24] Also, proton of (CH group)
of alanine moiety was appeared as multiplet signals in the
range of 6.42–6.44 ppm.[25] Finally, peak at 3.29 ppm was
indicated to proton of the carboxylic acid group. The
shifting of carboxylic proton that appeared may be due
to the intramolecular hydrogen bonding with the sol-
vent.[26] The position of COOH proton was confirmed
ΔE ¼ ELUMO − EHOMO
(1)
(2)
−ðEHOMO þ ELUMO
Þ
χ ¼
2
E
LUMO − EHOMO
η ¼
(3)
2
1
σ ¼
η
(4)
(5)
(6)
Pi ¼ − χ
1
from the H‐NMR spectrum of deuterated solvent.
1
S ¼
2η
3.1.1 | Geometrical optimization of the
organometallic Schiff base ligand
The geometry optimization of the Schiff base ligand was
performed at the DFT level of theory and its optimized
structure with atomic numbering had been given in
Figure (1).[27] The bond lengths and angles of the HL
ligand were calculated and then summarized in Table 1.
The main orbital that take place in chemical stability are
HOMO (highest occupied molecular orbital) and LUMO
(lowest unoccupied molecular orbital). The HOMO repre-
sents the electron donor while LUMO is electron accep-
tor. Additional parameters such as HOMO–LUMO
energy gap, ΔE, absolute electronegativities, χ, chemical
potentials, Pi, absolute hardness, η, absolute softness, σ,
global electrophilicity, ω, global softness, S, and additional
electronic charge, ΔNmax, were calculated using the fol-
lowing equations and then were listed in Table 2:[19,28]
Pi2
ω ¼
(7)
(8)
2η
Pi
η
ΔNmax ¼ −
The energy gap (ΔE) is considered as an important
stability index which uses for explaining the structure
and conformation barriers in many molecular systems.
This energy gap was 4.49 eV. When this energy increases,
the compound becomes more stable. Furthermore, the
value of chemical potential (Pi) was negative, while the
electrophilicity index (χ) had positive value. These

MAHMOUD ET AL.
7 of 21
TABLE 1 The different optimized parameters (bond lengths and bond angles) of organometallic Schiff base ligand (HL)
Bond length (Å)
C(1)‐C(2)
1.4471
1.4517
2.1209
1.4814
1.4366
1.0793
2.1217
1.4447
1.0810
2.1250
1.4391
1.0810
2.1196
1.0806
2.1110
2.1210
2.1184
2.1219
2.1189
2.1213
1.4429
1.4434
1.0812
C(12)‐C(15)
C(12)‐H(16)
C(13)‐C(17)
C(13)‐H(18)
C(15)‐C(17)
C(15)‐H(19)
C(17)‐H(20)
C(21)‐N(22)
C(21)‐C(23)
N(22)‐C(27)
C(23)‐H(24)
C(23)‐H(25)
C(23)‐H(26)
C(27)‐H(28)
C(27)‐C(29)
C(27)‐C(33)
C(29)‐H(30)
C(29)‐H(31)
C(29)‐H(32)
C(33)‐O(34)
C(33)‐O(35)
O(35)‐H(36)
1.4437
1.0811
1.4438
1.0812
1.4422
1.0809
1.0812
1.3009
1.5263
1.4805
1.0920
1.0983
1.0965
1.1004
1.5440
1.5362
1.0949
1.0957
1.0952
1.2411
1.3872
0.9852
C(1)‐C(5)
C(1)‐Fe(10)
C(1)‐C(21)
C(2)‐C(3)
C(2)‐H(6)
C(2)‐Fe(10)
C(3)‐C(4)
C(3)‐H(7)
C(3)‐Fe(10)
C(4)‐C(5)
C(4)‐H(8)
C(4)‐Fe(10)
C(5)‐H(9)
C(5)‐Fe(10)
Fe(10)‐C(11)
Fe(10)‐C(12)
Fe(10)‐C(13)
Fe(10)‐C(15)
Fe(10)‐C(17)
C(11)‐C(12)
C(11)‐C(13)
C(11)‐H(14)
Bond angle (°)
C(2)‐C(1)‐C(5)
C(2)‐C(1)‐C(21)
C(5)‐C(1)‐C(21)
Fe(10)‐C(1)‐C(21)
C(1)‐C(2)‐C(3)
C(1)‐C(2)‐H(6)
C(3)‐C(2)‐H(6)
H(6)‐C(2)‐Fe(10)
C(2)‐C(3)‐C(4)
C(2)‐C(3)‐H(7)
C(4)‐C(3)‐H(7)
H(7)‐C(3)‐Fe(10)
C(3)‐C(4)‐C(5)
C(3)‐C(4)‐H(8)
C(5)‐C(4)‐H(8)
H(8)‐C(4)‐Fe(10)
107.4221
125.4434
127.1344
125.6204
108.2949
124.2104
127.4916
125.8320
108.1489
125.9768
125.8718
125.2072
107.9871
126.1344
125.8784
125.4227
C(12)‐Fe(10)‐C(13)
C(12)‐Fe(10)‐C(17)
C(13)‐Fe(10)‐C(15)
Fe(10)‐C(11)‐H(14)
C(12)‐C(11)‐C(13)
C(12)‐C(11)‐H(14)
C(13)‐C(11)‐H(14)
Fe(10)‐C(12)‐H(16)
C(11)‐C(12)‐C(15)
C(11)‐C(12)‐H(16)
C(15)‐C(12)‐H(16)
Fe(10)‐C(13)‐H(18)
C(11)‐C(13)‐C(17)
C(11)‐C(13)‐H(18)
C(17)‐C(13)‐H(18)
Fe(10)‐C(15)‐H(19)
66.8294
66.8127
66.8394
125.0616
107.9965
125.9997
126.0020
124.7739
108.0264
125.9735
125.9966
125.6066
107.9505
125.9350
126.1140
124.9541
(Continues)

8 of 21
MAHMOUD ET AL.
TABLE 1 (Continued)
Bond angle (°)
C(1)‐C(5)‐C(4)
108.1453
126.3712
125.4801
125.4421
66.8002
C(12)‐C(15)‐C(17)
C(12)‐C(15)‐H(19)
C(17)‐C(15)‐H(19)
Fe(10)‐C(17)‐H(20)
C(13)‐C(17)‐C(15)
C(13)‐C(17)‐H(20)
C(15)‐C(17)‐H(20)
C(1)‐C(21)‐N(22)
C(1)‐C(21)‐C(23)
N(22)‐C(21)‐C(23)
C(21)‐N(22)‐C(27)
C(21)‐C(23)‐H(24)
C(21)‐C(23)‐H(25)
C(21)‐C(23)‐H(26)
H(24)‐C(23)‐H(25)
H(24)‐C(23)‐H(26)
H(25)‐C(23)‐H(26)
N(22)‐C(27)‐H(28)
N(22)‐C(27)‐C(29)
N(22)‐C(27)‐C(33)
H(28)‐C(27)‐C(29)
H(28)‐C(27)‐C(33)
C(29)‐C(27)‐C(33)
C(27)‐C(29)‐H(30)
C(27)‐C(29)‐H(31)
C(27)‐C(29)‐H(32)
H(30)‐C(29)‐H(31)
H(30)‐C(29)‐H(32)
H(31)‐C(29)‐H(32)
C(27)‐C(33)‐O(34)
C(27)‐C(33)‐O(35)
O(34)‐C(33)‐O(35)
C(33)‐O(35)‐H(36)
107.9649
126.0754
125.9581
124.8370
108.0616
126.1620
125.7715
116.7989
115.7348
127.4564
124.0706
113.3569
109.9729
109.7232
108.2080
107.8743
107.5164
104.7462
111.4990
116.8114
107.7429
103.9488
111.2058
110.6923
111.4537
108.9055
107.9762
109.1047
108.6580
126.4634
111.9991
121.4527
110.5527
C(1)‐C(5)‐H(9)
C(4)‐C(5)‐H(9)
H(9)‐C(5)‐Fe(10)
C(1)‐Fe(10)‐C(3)
C(1)‐Fe(10)‐C(4)
C(1)‐Fe(10)‐C(11)
C(1)‐Fe(10)‐C(12)
C(1)‐Fe(10)‐C(13)
C(1)‐Fe(10)‐C(15)
C(1)‐Fe(10)‐C(17)
C(2)‐Fe(10)‐C(4)
C(2)‐Fe(10)‐C(5)
C(2)‐Fe(10)‐C(11)
C(2)‐Fe(10)‐C(12)
C(2)‐Fe(10)‐C(13)
C(2)‐Fe(10)‐C(15)
C(2)‐Fe(10)‐C(17)
C(3)‐Fe(10)‐C(5)
C(3)‐Fe(10)‐C(11)
C(3)‐Fe(10)‐C(12)
C(3)‐Fe(10)‐C(15)
C(3)‐Fe(10)‐C(17)
C(4)‐Fe(10)‐C(11)
C(4)‐Fe(10)‐C(12)
C(4)‐Fe(10)‐C(13)
C(4)‐Fe(10)‐C(15)
C(5)‐Fe(10)‐C(11)
C(5)‐Fe(10)‐C(12)
C(5)‐Fe(10)‐C(13)
C(5)‐Fe(10)‐C(17)
C(11)‐Fe(10)‐C(15)
C(11)‐Fe(10)‐C(17)
67.0104
159.5960
159.3955
124.5512
124.3637
109.7190
66.7487
67.0102
159.0608
123.6675
159.5068
108.7992
124.0001
66.8294
124.0690
108.4616
123.0624
158.4595
109.1340
123.1971
124.8926
158.1523
124.0094
158.6170
109.9280
125.3031
66.8585
66.7937
indicated that the Schiff base ligand might be donated
electron to metal ions.[29]
molecule in addition to determine the presence of inter‐
or intra‐molecular interactions in this molecule.[30] In
these MEP diagrams, different colors such as yellow,
orange, red, green and blue can be used to indicate the
different values of electronic potential that appeared at
the surface of the molecule. Red color represents the elec-
tron‐rich area or a more negative site while blue color
represents a positive site. The MEP diagram of the
3.1.2 | Molecular electrostatic potential
(MEP)
Molecular electrostatic potential (MEP) is useful method
that can be used for determining the reactivity of a

MAHMOUD ET AL.
9 of 21
TABLE 2 The different quantum chemical parameters of organ-
ometallic Schiff base ligand (HL).
The calculated quantum chemical parameters
E (a.u)
−910.33
1.70
Dipole moment (Debye)
EHOMO (eV)
ELUMO (eV)
ΔE (eV)
−5.76
−1.27
4.49
χ(eV)
3.52
η(eV)
2.25
σ(eV)−1
0.45
Pi (eV)
−3.52
0.22
S (eV)−1
ω(eV)
2.75
ΔNmax
1.56
FIGURE 3 IR spectra of organometallic Schiff base ligand (HL)
(a) experimental spectrum and (b) theoretical spectrum
functional groups such as hydroxyl, carboxyl,
azomethine, asymmetric carboxylic and symmetric car-
boxylic groups. The data showed that hydroxyl (OH)
was appeared experimentally at 3453 cm−1, carbonyl
(C=O) at 1744 cm−1, azomethine (C=N) at 1659 cm−1, ν
(COO−)asy at 1454 cm−1 and finally ν (COO−)sym at
1366 cm−1. These bands were recorded by DFT at 3638,
1755, 1673, 1503 and 1370 cm−1, respectively. The agree-
ment between the theoretical and experimental frequen-
cies was very good and indicated to the successful
preparation of the Schiff base ligand and supported the
chemical structure of the ligand. The differences between
theoretical and experimental frequencies may be resulted
from systematic errors (which can be formed from
harmonicity) or from the use of gas phase molecules in
the DFT calculations. So, correlation coefficient was used
as 0.9648 for LanL2DZ in order to overcome these
errors.[34]
FIGURE
2
Molecular electrostatic potential map of
organometallic Schiff base ligand (HL) The electron density
isosurface is 0.004 a.u
organometallic Schiff base was revealed in Figure 2. As a
result, electron‐rich sites were sited on the carboxylic
group of the ligand with red color while ferrocene rings
were surrounded by green color.[31]
3.1.4 | UV–Visible analysis
Three observed bands were appeared in the experimental
UV–Vis absorption spectrum of the Schiff base ligand at
224 and 269 nm which corresponded to π‐π* transitions
of the ferrocene group and at 334 nm which related to
n‐π* transitions in the ‐C=N‐ group.[35]
To confirm the experimental UV–Vis spectrum of the
prepared Schiff base ligand, DFT/B3LYP calculations
were performed. In Table 3, it showed a comparison
between the experimental and the calculated UV–Vis
spectrum bands and also the excitation energies along
with their oscillator strengths that can be obtained from
DFT method. The DFT data showed three absorption
3.1.3 | Vibrational properties
IR spectroscopy is an important technique that used to
identify functional groups in different molecules. So, the
characteristic IR bands of prepared HL ligand were exper-
imentally recorded in the range of 400–4000 cm−1 using
KBr pellet. The theoretical bands of IR spectrum for the
optimized structure of the ligand were determined by
DFT/B3LYP method.[32,33] Then the experimental and
theoretical IR spectra were shown in Figure 3. The free
organometallic Schiff base experimentally had different

10 of 21
MAHMOUD ET AL.
TABLE 3 Main calculated optical transitions with composite ion in terms of molecular orbitals
Compound Transition
Excitation energy (eV) λmax calc. nm (eV) λmax exp. nm (eV) Oscillator strength
Ligand (HL) HOMO → LUMO+4 (65%) 5.31
HOMO‐3 → LUMO (36%) 5.45
HOMO‐4 → LUMO (32%) 5.69
HOMO‐2 → LUMO (30%) 5.39
HOMO → LUMO+3 (55%) 5.30
225 (5.51)
268 (4.62)
307 (4.05)
224 (5.54)
269 (4.61)
334 (3.72)
0.02
0.11
0.03
bands at 225, 268 and 307 nm. The band appeared at
225 nm with an oscillator strength of f = 0.02
corresponded to the transition of HOMO to LUMO+4.
The peak appeared at 268 nm with an oscillator strength
of f = 0.11 arose from the contribution of HOMO‐
4 → LUMO or HOMO‐3 → LUMO or HOMO‐2 → LUMO.
And finally the band at 307 nm with an oscillator strength
of f = 0.03 arose from the contribution of HOMO →
LUMO+3. These transitions were showed in Figure 4.[36]
3.2 | Characterization of Schiff base metal
complexes
3.2.1 | Elemental analysis
Eight transition metal complexes were prepared by
mixing equimolar amounts of the bidentate Schiff base
(HL) with Cr (III), Mn (II), Fe (III), Co (II), Ni (II), Cu
(II), Zn (II) and Cd (II) metal salts in appropriate sol-
vents. The results of elemental analyses with molecular
FIGURE 4 Theoretical electronic
absorption transitions for Schiff base
ligand (HL) in ethanol solvent

MAHMOUD ET AL.
11 of 21
formula, melting points and other physical properties of
all prepared compounds were investigated. They were
stable at room temperature and had high melting point.
All complexes were insoluble in water, highly soluble in
DMF and DMSO solvents and soluble in ethanol except
Cr (III), Ni (II) and Cu (II) complexes.
as neutral bidentate ligand that coordinated to metal ions
via N‐azomethine and O‐carboxylic group.
3.2.4 | UV–Visible spectra of the HL ligand
and its metal complexes
Electronic spectra of the prepared ferrocene‐based Schiff
base ligand and its metal complexes were scanned in
the spectral range 200–700 nm in suitable solvent.[43]
These spectra have important information about metal
complexes with respect to ligand. The UV–Vis spectrum
of the free organometallic ligand showed three absorption
bands at 224, 269 and 334 nm. The first and second bands
corresponded to π‐π* transitions in the cyclopentadienyl
groups and the higher band that was appeared at
334 nm was related to n‐π* transitions in the ‐C=N‐
group.[44,45] The bands that were appeared at 224 and
269 in the spectrum of ligand were shifted in all com-
plexes to lower or higher values in the range of 220–
274 nm. These bands corresponded to π‐π* transitions
of the ferrocene group. Also the band of azomethine
group that was showed in the ligand at 334 nm was
shifted to 311–337 nm that assigned to n‐π* transition.[46]
This data gave good indication in coordination of the
azomethine nitrogen to the metal ions.
3.2.2 | Molar conductivity measurements
Conductivity measurements can be used to determine the
degree of ionization of the metal complexes. The molar
conductivity of Schiff base metal complexes were mea-
sured in different solvents depending upon their solubil-
ities with 1.0 × 10−3 M concentration at 25°C. From the
results, it was very clear that Mn (II), Co (II), Zn (II)
and Cd (II) complexes were non‐electrolytes,[37] while
other metal complexes had electrolytic nature.[38]
3.2.3 | IR spectra
In order to determine the mode of chelation of organome-
tallic Schiff base ligand to metal (II/III) ions, IR spectrum
of free HL ligand was compared with IR spectra of the pre-
pared metal complexes.[39] IR spectrum of the prepared
Schiff base ligand showed five important characteristic
peaks. The most important characteristic peak was
appeared at 1659 cm−1 which corresponded to azomethine
group. These bands were shifted in all metal complexes to
lower wavenumbers in the range of 1590–1648 cm−1. This
shift was indicated to the participation of azomethine
group in coordination.[18] Other two characteristic bands
were appeared in spectrum of ligand at 1454 and
1366 cm−1 which were attributed to (COO−)asy and
(COO−)sym, respectively. These peaks also shifted in all
complexes to lower and higher wavenumber in the range
of 1437–1474 cm−1 and 1349–1372 cm−1, respectively.
These results gave good indication for participating of
the carboxylic group in coordination with metal ions.[40]
The carbonyl band of alanine moiety in HL ligand was
appeared at 1744 cm−1. All metal complexes also showed
peaks at 1633–1657 cm−1 which were corresponded to
(C=O) except Cr (III), Ni (II), Zn (II) and Cd (II) com-
plexes which disappeared from their spectra.[20] Further-
more, a wide vibration band of ν (O–H) situated in the
ligand at 3453 cm−1. This broad band was found in all
3.2.5 | 1H‐NMR spectral studies
The proposed bonding pattern in the prepared complexes
can be also supported by the 1H‐NMR spectral studies. So,
1H‐NMR spectra of the synthesized ligand and its Cd (II)
complex were recorded in DMSO‐d6 and measured their
chemical shift values (ppm).[22] The spectrum of the
ligand exhibited multiplet signals at 4.24–4.78 ppm which
corresponded to ferrocene group. These signals also
appeared in Cd (II) complex at 4.23–4.77 ppm.[23] The
methyl protons of ferrocene group was appeared at
1.22 ppm in the ligand and showed in Cd (II) complex
at 1.06 ppm. Also, the methyl protons of amino acid ala-
nine were appeared at 2.35 ppm which still present in
the complex at the same position.[24] Also, proton of
(CH group) was appeared as multiplet signals in the
range of 6.42–6.44 ppm while was appeared in the Cd
(II) complex at 6.46–6.55 ppm.[25] The proton of carbox-
ylic acid was appeared in the ligand at 3.29 ppm. This sig-
nal was still present in the Cd (II) complex but shifted to
higher value (3.33 ppm). The low value of this proton in
these compounds might be due to the intramolecular
hydrogen bonding with the solvent. The appearance of
this proton signal in Cd (II) complex was respective to
the prevention of deprotonation of carboxylic proton
and the Schiff base behaved as neutral ligand. The
complexes at 3391–3510 cm−1 [21]
The IR spectra of com-
.
plexes showed new two bands which correlated to coordi-
nated water molecule ν (H2O) at 891–971 and 825–888 cm
−1 [41]
.
Also, new two characteristic bands appeared in all
spectra of metal complexes in the range of 532–570 cm−1
and 488–500 cm−1 region, which corresponded to the for-
mation of M‐O and M‐N bonds, respectively.[42] These
data indicated that prepared Schiff base ligand behaved

12 of 21
MAHMOUD ET AL.
shifting occurred in this signal from the ligand indicated
that (COOH) entered in coordination bonds.[26]
plates form. On the other hand, the micrograph of [Cd
(HL)(H2O)2Cl2].2H2O showed clouds or foams structure.
The particle size of HL ligand was 54 nm, while for Cd
(II) complex was 41 nm.[47,48]
3.2.6 | SEM studies
Scanning electron microscope (SEM) has been actually
used in order to determine the particle size and the mor-
phology of the prepared compounds.[2] So, SEM micro-
graphs of the organometallic Schiff base and its Cd (II)
complex were shown in Figure 5. From the data, it was
indicated the successful formation of nanosized particles.
It was showed a noticeable difference between the mor-
phology of the ligand and its complex and also different
in their size. The micrograph of HL ligand represented
3.2.7 | Thermal analysis of Schiff base
ligand and its metal complexes
The DTG and TG results of thermal decomposition of the
HL ligand and its transition metal complexes were car-
ried out within the temperature range from 30 to
1000°C. The temperature ranges, number of stages, stages
of decomposition, decomposition product loss, the calcu-
lated and found weight loss percentage and finally the
residues of all compounds were given in Table 4.
The thermal decomposition process of HL ligand
[C15H17NO2Fe] involved two decomposition steps. The
two decomposition steps started at 100°C and finished
at 1000°C with maximum peaks temperature at 199 and
255°C, which involved the removal of C15H17NO mole-
cule and accompanied by a weight loss of 75.91% (calc.
= 75.92%). Finally FeO remained as residue. The overall
weight loss amounted to 75.91% (calc. = 75.92%).
The [Cr (HL)(H2O)2Cl2]Cl.2H2O complex showed five
weight loss events. The first step of decomposition
occurred within the temperature range of 30–205°C with
a maximum peak temperature at 74°C and correspond to
the loss of two water molecules of hydration and ½Cl2
with estimated mass loss 13.23% (calc. = 13.50%). The
second and third steps of decomposition were carried
out in the range of 205–350°C with maximum peaks tem-
perature at 232 and 339°C and correspond to the loss of
H2O and C4H6 molecules with estimated mass loss
13.23% (calc. = 13.60%). The fourth step of decomposition
occurred in the range of 350–670°C with maximum peak
temperature at 651°C and correspond to the loss of
C2H6NCl molecule with estimated mass loss 15.74% (calc.
= 15.01%). The final step was carried out within the range
of 670–1000°C with maximum peak temperature at 858°C
which correspond to loss of C5H7ClO0.5 fragment with
estimated mass loss of 20.65% (calc. = 20.87%), leaving
behind ferric and chromium oxides contaminated with
carbon as the product of decomposition. The overall
weight loss amounted to 62.85% (calc. = 62.98%).
The [Mn (HL)(H2O)2Cl2].4H2O complex showed three
decomposition stages. The first stage correspond to three
decomposition steps was occurred in the temperature
range of 35–225°C which attributed to the loss of six
water molecules, Cl2 gas and C2H2 molecule
(Found = 38.14% and calc. = 38.48%) with maximum
peaks temperature at 72, 135 and 178°C. The second stage
correspond to two decomposition steps in the tempera-
ture range of 225–480°C which represented to loss of
FIGURE 5 The SEM images of the nanoparticles produced a)
organometallic Schiff base ligand (HL) and b) [Cd(L)
(H2O)2Cl2].2H2O complex

MAHMOUD ET AL.
13 of 21

14 of 21
MAHMOUD ET AL.
C6H6N molecule (Found = 17.15% and calc. = 17.26%)
with two maximum peaks temperature at 312 and
344°C. The final stage correspond to one decomposition
step in the temperature range of 480–1000°C which repre-
sented to loss of C7H9 molecule (Found = 18.26% and
calc. = 17.45%) with maximum peak temperature at
627°C. FeO and MnO remained as residues. The total
found weight loss amounted to 73.55% (calc. = 73.19%).
The [Fe (HL)(H2O)2Cl2]Cl.3H2O thermal curves
showed four decomposition steps. The first step at tem-
perature range of 45–130°C with maximum peak temper-
ature at 80°C which correspond to loss of three hydrated
water molecules (found = 9.48% and calc. = 9.79%). The
second and third steps at temperature range of 130–
340 °C with maximum peaks temperature at 173 and
317°C which related to loss of H2O, Cl2 gas and C2H2
molecule (found = 20.96% and calc. = 20.85%). The final
step at temperature range of 340–1000°C with maximum
peak temperature at 642°C which related to loss of
The first and second steps of decomposition was occurred
within the temperature range 40–190 °C with maximum
peaks temperature at 91 and 163 °C which correspond
to loss of three water molecules of hydration and ½ Cl2
with a mass loss of 16.41% (calc. = 16.53%). The third
and fourth steps of decomposition was occurred in the
temperature range of 190–320 °C with maximum peaks
temperature at 299 and 314 °C and correspond to the
elimination of 3H2O and C6H9Cl molecules with a mass
loss of 31.98% (calc. = 31.49%). The last step of decompo-
sition was occurred within the temperature range of 320–
1000 °C with maximum peak temperature at 568 °C
which correspond to loss C5H8N molecule with a mass
loss of 15.24% (calc. = 15.14%), leaving FeO and CuO
C9H17NO0.5Cl molecule (found
= 33.19%; calc. =
33.09%). After complete decomposition ferrous and ferric
oxides contaminated with carbon remained as residues.
The total found weight loss was 63.63% (calc. = 63.73%).
The [Co (HL)(H2O)2Cl2].3H2O complex thermally
decomposed in three steps. The first step correspond to
a mass loss of 9.76% (calc. 10.41%) within the temperature
range of 30–80 °C with maximum peak temperature at
75 °C which represented the loss of three water molecules
of hydration. The second step pointed to a mass loss of
39.42% (calc. 38.34%) within the temperature range of
80–300 °C with maximum peak temperature at 173 °C
and represented the loss of 2H2O, Cl2 gas and C6H6N
molecule. The final step was occurred within temperature
range of 300–1000 °C with a mass loss of 22.00% (calc.
22.93%) and was reasonably attributed to loss of C9H11
molecule, leaving FeO and CoO as residues. The total
found weight loss was 71.18% (calc. = 71.68%).
The [Ni (HL)(H2O)3Cl]Cl.H2O complex thermally
decomposed in three steps. The first step ascribed to a
mass loss of 19.33% (calc. = 19.56%) within the tempera-
ture range of 30–265 °C with maximum peak temperature
at 78 °C which represented to loss of four water mole-
cules and C2H2 fragment. The second step correspond to
a mass loss of 23.35% (calc. = 23.15%) within the temper-
ature range of 265–555 °C with maximum peak tempera-
ture at 346 °C and represented the loss of Cl2 gas and
C2H7N molecule. The final step was occurred within tem-
perature range of 555–1000 °C with a mass loss of 27.61%
(calc. = 27.94%) and were attributed to loss of C11H8 mol-
ecule, leaving FeO and NiO as residues. The total found
weight loss was 70.27% (calc. = 70.65%).
The thermal decomposition of [Cu (HL)(H2O)3Cl]
Cl.3H2O complex was occurred via five degradation steps.
FIGURE 6 The structure of organometallic Schiff base metal
complexes

MAHMOUD ET AL.
15 of 21
TABLE 5 Biological activity of organometallic Schiff base ligand (HL) and its metal complexes
Inhibition zone diameter (mm/mg sample)
(Gram positive)
(Gram negative)
(fungi)
Bacillus
subtilis
Staphylococcus
aureus
Escherichia
coli
Salmonella
typhimurium
Aspergillus
fumigatus
Candida
albicans
Sample
Control: DMSO
0
0
0
0
0
0
Schiff base ligand (HL)
[Cr (HL)(H2O)2Cl2]Cl.2H2O
[Mn (HL)(H2O)2Cl2].4H2O
[Fe (HL)(H2O)2Cl2]Cl.3H2O
[Co (HL)(H2O)2Cl2].3H2O
[Ni (HL)(H2O)3Cl]Cl.H2O
[Cu (HL)(H2O)3Cl]Cl.3H2O
[Zn (HL)(H2O)2Cl2].5H2O
[Cd (HL)(H2O)2Cl2].2H2O
Gentamycin
NA
NA
NA
14
NA
NA
NA
NA
16
NA
NA
NA
13
NA
NA
NA
12
15
NA
NA
NA
NA
15
NA
NA
NA
20
18
22
20
NA
21
8
NA
20
NA
14
NA
NA
NA
NA
… … ..
17
NA
12
22
22
24
22
21
NA
20
15
21
22
16
26
24
30
17
… … ..
20
Ketokonazole
… … ..
… … ..
… … ..
… … ..
NA: No activity
contaminated with carbon as residues. The total found
weight loss was 63.63% (calc. = 63.16%).
decomposition. The overall weight loss amounted to
63.73% (calc. = 63.91%).
The [Zn (HL)(H2O)2Cl2].5H2O complex lost upon
heating five water molecules of hydration in the first
and second steps of decomposition within the tempera-
ture range of 35–175 °C (maximum peaks temperature
at 64 and 134 °C) with estimated mass loss of 16.00%
(calc. = 16.04%). The third step correspond to loss of
2H2O and C3H6 molecules within the temperature range
of 175–350 °C at maximum peak temperature 316 °C with
estimated mass loss of 14.03% (calc. = 13.90%). The fourth
step correspond to loss of Cl2 gas C12H11N molecule
within the temperature range of 350–1000 °C with maxi-
mum peak temperature at 553 °C with estimated mass
loss of 42.75% (calc. = 42.78%), leaving FeO and ZnO as
residues of decomposition. The overall weight loss
amounted to 72.78% (calc. = 72.72%).
4 | STRUCTURAL INTERPRETATION
The structures of the organometallic Schiff base ligand
(HL) with Cr (III), Mn (II), Fe (III), Co (II), Ni (II), Cu
(II), Zn (II) and Cd (II) complexes were characterized
by elemental analyses, molar conductance, IR, 1H‐
NMR, UV–Vis, mass and thermal analyses then the
The [Cd (HL)(H2O)2Cl2].2H2O complex lost upon
heating four water molecules and C5H7NCl molecule in
the first and second steps of decomposition within the
temperature range of 60–210 °C (maximum peaks tem-
perature at 123 and 167 °C) with estimated mass loss of
34.38% (calc. = 34.03%). The third step correspond to loss
of C6H4Cl molecule within the temperature range of 210–
315 °C at maximum peak temperature 287 °C with esti-
mated mass loss of 20.33% (calc. = 20.13%). The fourth
step correspond to loss of C4H6 molecule within the tem-
perature range of 315–1000 °C with maximum peak tem-
perature at 869 °C with estimated mass loss of 9.02%
(calc. = 9.75%), leaving FeO and CdO as residues of
FIGURE 7 Biological activity of organometallic Schiff base
ligand (HL) and its metal complexes

16 of 21
MAHMOUD ET AL.
ligand was biological inactive against all different bacterial
species. Some metal complexes were also biological inac-
tive such as Cr (III) and Mn (II) complexes. While Co
(II), Cu (II), Zn (II) and Cd (II) complexes showed their
higher activity against all species. The other two com-
plexes had biological activity against only some bacterial
species while were inactive against other species. Further-
more, the activity of the synthesized compounds against
two fungal species showed that HL ligand and its Co (II)
complex had fungal activity values 15 and 20 mm/mg,
respectively, against Aspergillus fumigatus specie. While
Co (II), Cu (II) and Cd (II) complexes had values 15, 12
and 20 mm/mg, respectively, against Candida albicans.
Other metal complexes represented their biological inac-
tive against two different species. These activities may be
due to the destruction that occurred in the synthesis of cell
walls. This leads to alteration in cell permeability charac-
teristics that cause the death of the cell.[50]
FIGURE 8 Activity index of Schiff base ligand (HL) and its metal
complexes against (a) different Gram (+ve) bacteria (b) different
Gram (−ve) bacteria
proposed structures of transition metal complexes were
reported in Figure 6.
5 | ANTIMICROBIAL ACTIVITIES
Antimicrobial activities of the prepared compounds had
been screened against Gram‐positive bacteria: Bacillus
subtilis and Staphylococcus aureus, Gram‐negative bacte-
ria: Escherichia coli and Salmonella typhimurium and
two strains of fungi (Aspergillus fumigatus and Candida
albicans) by using disc‐agar diffusion method.[49] The data
were then given in Table 5 and represented in Figure 7.
The data of antibacterial activities showed that Schiff base
FIGURE 9 Anticancer activity against breast cancer of the Schiff
bases ligand (HL) and its metal complexes
TABLE 6 Anticancer activity against breast cancer of organometallic Schiff base ligand (HL) and its metal complexes
Surviving fraction (MCF7)
IC50
(μg/mL)
Complex
Conc. (μg/mL)
0.0
5.0
12.5
25.0
50.0
Schiff base ligand (HL)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.864
0.800
0.786
0.828
0.753
0.869
0.572
0.765
0.648
0.759
0.772
0.440
0.821
0.545
0.673
0.566
0.712
0.683
0.413
0.566
0.495
0.501
0.284
0.641
0.731
0.307
0.469
0.566
50.2
[Cr (HL)(H2O)2Cl2]Cl.2H2O
[Mn (HL)(H2O)2Cl2].4H2O
[Fe (HL)(H2O)2Cl2]Cl.3H2O
[Co (HL)(H2O)2Cl2].3H2O
[Cu (HL)(H2O)3Cl]Cl.3H2O
[Cd (HL)(H2O)2Cl2].2H2O
30.8
… … ..
… … ..
10.9
42.2
24.8

MAHMOUD ET AL.
17 of 21
The activities of the synthesized Schiff base ligand and
6 | ANTICANCER ACTIVITIES
its metal complexes were confirmed by calculating the
activity index according to the following relation and
then shown in Figure 8.[51–53]
Nowadays, pharmaceutical researches represent the most
advanced area in finding different active drugs for treat-
ment of cancer. Preparation of metal‐based anticancer
drug is considered as one of the most important areas in
this field. So, numerous of transition metal complexes
have been prepared and then investigated for their
anticancer activities.[54] Firstly, all the prepared com-
pounds were screened against breast cancer cell line
(MCF‐7) at concentration 100 μg/ml. It was found that
HL ligand, Cr (III), Mn (II), Fe (III), Co (II), Cu (II) and
Cd (II) complexes had inhibition fraction higher than
Activity index ðAÞ ¼ ½Inhibition Zone of compound ðmmÞ
=Inhibition Zone of standard drug ðmmÞꢀ × 100
From the data of activity index, it showed that HL
ligand, Cr (III) and Mn (II) complexes had no activity
index, while the [Zn (HL)(H2O)2Cl2].5H2O complex
showed higher activity index than others.
FIGURE 10 3D structure of the interaction between Schiff base ligand (HL) with receptors of (a) 3HB5, (c) 3MIW, (e) 5IBV and (g) 4WM8
and 3D plot of the interaction between [Co (L)(H2O)2Cl2].3H2O complex with receptors of (b) 3HB5, (d) 3MIW, (f) 5IBV and (h) 4WM8

18 of 21
MAHMOUD ET AL.
70%. Secondary, IC50 values of these active compounds
were measured by using different concentrations (5,
12.5, 25 and 50 μg/ml). Finally, their results were listed in
Table 6 and shown in Figure 9. The data showed that free
ligand had IC50 value = 50.2 μg/ml. While its Co (II), Cd
(II), Cr (III) and Cu (II) complexes had values of 10.9,
24.8, 30.8 and 42.2 μg/ml, respectively. Furthermore, all
compounds were screened against human normal mela-
nocyte cell line (HFB‐4). It was found that Co (II) com-
plex had the highest surviving fraction with 50%. As a
result, [Co (HL)(H2O)2Cl2].3H2O complex behaved as
the most active and effective complex that can be used
as anticancer drug against breast cancer. The higher
activities of the prepared compounds may be due to the
presence of azomethine group in the macrocyclic chelate
ring. During coordination of metal ions with the nitrogen
of azomethine group in the chelate ring, the polarity of
the metal atoms is reduced. This may be due to partial
sharing of positive charge of the metal ions with the
ligand.[55–57] The higher activity may be attributed to
the increase in π‐electron delocalization in the ligand
moiety on complexation. As a result, penetration of the
complexes can be enhanced and become more efficient
through the lipid layer of cell membranes.[58,59]
TABLE 7 Energy values obtained in docking calculations of organometallic Schiff base (HL) and its [Co (HL)(H2O)2Cl2].3H2O complex
with receptors of breast cancer mutant oxidoreductase (PDB ID: 3HB5), crystal structure of Rotavirus NSP4 (PDB ID: 3MIW), crystal struc-
ture of human Astrovirus capsid protein (PDB ID: 5IBV), crystal structure of human Enterovirus D68 (PDB ID: 4WM8)
Compound
Receptor Ligand moiety Receptor site Interaction Distance (Aο) E (kcal mol−1
)
Ligand (HL)
3HB5
O34
O33
O34
O33
C17
C26
O34
Fe10
O34
O34
O ASN 90
NZ LYS 159
OE1 GLU 105
H‐donor
H‐acceptor
H‐donor
3.05
2.89
3.10
2.93
3.98
3.36
2.98
2.26
2.83
2.94
−2.60
−6.40
−4.40
−1.10
−0.50
−0.70
−0.80
−4.10
−1.40
−1.20
3MIW
NH1 ARG 108 H‐acceptor
NE ARG 108
O VAL 346
N LEU 336
OE1 GLU 335
O GLY 210
N TYR 197
ionic
5IBV
H‐donor
H‐acceptor
metal
H‐donor
H‐acceptor
4WM8
[Co (HL)(H2O)2Cl2].3H2O complex 3HB5
O39
O33
O34
O34
O39
O39
O34
O39
O42
O34
O34
O39
O39
O42
O42
O34
O39
O33
O34
O34
O39
O39
O42
5‐ring
Cl38
O39
O39
O42
O42
OD1 ASP 38
NH2 ARG 67
OD1 ASP 38
OD2 ASP 38
OD1 ASP 38
OD2 ASP 38
OD2 ASP 114
H‐donor
H‐acceptor
ionic
ionic
ionic
2.70
3.26
3.47
2.95
2.70
3.79
2.71
2.74
2.81
3.15
2.71
3.06
2.80
2.81
3.88
2.76
3.01
2.97
2.76
3.19
3.24
3.01
3.02
3.57
3.54
2.91
2.97
2.77
2.77
−26.60
−1.50
−2.00
−4.80
−6.90
−1.00
−27.30
−5.80
−24.70
−3.50
−6.70
−4.10
−6.00
−5.90
−0.70
−16.90
−0.70
−2.50
−6.30
−3.30
−3.00
−4.40
−4.30
−0.70
−0.60
−3.00
−1.20
−24.60
−6.20
ionic
H‐donor
3MIW
OG1 THR 118 H‐donor
OD1 ASP 114
OD1 ASP 114
OD2 ASP 114
OD1 ASP 114
OD2 ASP 114
OD1 ASP 114
OD2 ASP 114
OD1 ASP 213
OD2 ASP 213
ND2 ASN 210
OD1 ASP 213
OD2 ASP 213
OD1 ASP 213
OD2 ASP
H‐donor
ionic
ionic
ionic
ionic
ionic
ionic
H‐donor
H‐donor
H‐acceptor
ionic
5IBV
ionic
ionic
ionic
ionic
OD1 ASP 213
OG SER 133
O GLY 210
O SER 194
O VAL 195
π‐H
4WM8
H‐donor
H‐donor
H‐donor
H‐donor
ionic
OD2 ASP 215
OD2 ASP 215

MAHMOUD ET AL.
19 of 21
characterized by various physicochemical and spectro-
scopic techniques. From elemental analysis, it was indi-
cated that Schiff base ligand reacted with metal ions in
1:1 molar ratio. The spectroscopic data showed that the
HL ligand acted as neutral bidentate ligand and it coordi-
nated to metal ions through azomethine nitrogen and
oxygen atom of the carboxylic group. All the prepared
complexes had octahedral structures and were non elec-
trolyte except Cr (III), Fe (III), Ni (II) and Cu (II) com-
plexes which were monomeric and electrolytes. From
SEM analysis for HL ligand and its [Cd (HL)
(H2O)2Cl2].2H2O complex, it showed that they were pre-
pared in nano‐structure forms with particle size 54 and
41 nm, respectively. The ligand was represented as plates
form while the Cd (II) complex had clouds or foams
structure. By screening the ligand and its metal com-
plexes against breast cancer cell line (MCF‐7) and normal
melanocyte cell line (HFB‐4), it was indicated that the
[Co (HL)(H2O)2Cl2].3H2O complex had the lowest IC50
value of MCF‐7 (10.9 μg/ml) than other compounds. So,
it could be considered as a very important, effective and
active drug against breast cancer. The biological activity
of the prepared ligand and its metal complexes was stud-
ied against two Gram‐negative bacteria, two Gram‐posi-
tive bacteria and two strains of fungi. It showed that
most prepared compounds were biologically inactive
except Fe (III), Co (II), Cu (II), Zn (II) and Cd (II) com-
plexes. From DFT calculations for Schiff base ligand, it
was confirmed the experimental IR and UV–Vis data by
comparing it with the theoretical values which gave good
indication for successful preparation. Molecular docking
studies of the free HL ligand and its Co (II) complex with
receptors of 3HB5, 3MIW, 5IBV and 4WM8 showed that
the lowest binding energy were −6.4, −4.4, −4.1
and −1.4 kcal mol−1 for ligand and −26.6, −27.3, −16.9
and −24.6 kcal mol−1 for Co (II) complex, respectively.
These values indicated that binding energy decreased
upon coordination.
7 | MOLECULAR MODELING OF HL
LIGAND AND ITS [CO (HL)
(H2O)2CL2].3H2O COMPLEX:
DOCKING STUDY
The possible binding sites of the prepared HL ligand and its
[Co (HL)(H2O)2Cl2].3H2O complex with four different
receptors: breast cancer mutant oxidoreductase (PDB ID:
3HB5), crystal structure of Rotavirus NSP4 (PDB ID:
3MIW), crystal structure of human Astrovirus capsid pro-
tein (PDB ID: 5IBV) and crystal structure of human Entero-
virus D68 (PDB ID: 4WM8) were carried out by using
MOE.2008 method for describing and predicting the bind-
ing mode in the pocket of these proteins.[28,60] Three‐
dimensional plots of docking were shown in Figure 10.
Furthermore, the binding energies of the ligand and its
Co (II) complex were calculated and then listed in Table 7.
From experimental anticancer activities data, it indi-
cated that Schiff base ligand had IC50 value = 50.2 μg/
ml against breast cancer cell line and its Co (II) complex
had the lowest IC50 value = 10.9 μg/ml. To confirm this
data, theoretical docking studies were investigated
against breast cancer mutant oxidoreductase (PDB ID:
3HB5). From docking results, it was showed that the low-
est binding energies of HL ligand and its Co (II) complex
were − 6.4 and − 26.6 kcal mol−1, respectively. These
indicated the more active of the complex than its parent
ligand and this large decrease occurred due to the forma-
tion of coordination bonds with Co (II) ion.
Because of the high activities of these compounds,
they were also investigated against three different gastro-
enteritis (inflammation of the stomach and intestines)
which caused by one of many number of viruses such as
Rotavirus, Astrovirus and Enterovirus. The data indicated
that there were high and effective interactions between
these prepared compounds and the three receptors.
The main interaction forces between the compounds
and the active sites were H‐donor, H‐acceptor, ionic, π‐
H and metal. The lowest binding energies of HL ligand
and its Co (II) complex with 3MIW, 5IBV and 4WM8
receptors were − 4.4, −4.1 and − 1.4 kcal mol−1 for ligand
and − 27.3, −16.9 and − 24.6 kcal mol−1 for Co (II) com-
plex, respectively. Also it showed that the binding energy
decreases upon coordination. So, the Co (II) complex was
more active than HL ligand and could be used as very
effective drug against gastroenteritis in the future.[61–64]
ORCID
Walaa H. Mahmoud
http://orcid.org/0000-0001-9187-
4325
Gehad G. Mohamed http://orcid.org/0000-0002-1525-5271
REFERENCES
[1] T. Thirunavukkarasu, H. A. Sparkes, K. Natarajan, V. G.
Gnanasoundari, Inorg. Chim. Acta. 2018. In press
8 | CONCLUSION
[2] S. K. Adavi, A. A. Yadav, R. S. Bendre, J. Mol. Str. 2018, 1152,
223.
Novel Cr (III), Mn (II), Fe (III), Co (II), Ni (II), Cu (II), Zn
(II) and Cd (II) complexes with bidentate organometallic
Schiff base ligand were synthesized and then
[3] Z. H. Chohan, S. H. Sumrra, M. H. Youssoufi, Eur. J. Med.
Chem. 2010, 45, 2739.

20 of 21
MAHMOUD ET AL.
[4] K. Singh, Y. Kumar, P. Puri, M. Kumar, C. Sharma, Eur. J. Med.
Chem. 2012, 52, 313.
[27] H. B. Schlegel, J. Comput. Chem 1982, 3(2), 214.
[28] W. H. Mahmoud, N. F. Mahmoud, G. G. Mohamed, Applied
Organomet. Chem 2017, 31, 1.
[5] A. K. Singh, O. P. Pandey, S. K. Sengupta, Spectrochim. Acta A.
2013, 113, 393.
[29] W. H. Mahmoud, G. G. Mohamed, A. M. Refat, Applied
Organomet. 2017, 31, 1.
[6] M. Shebl, Spectrochim. Acta A 2014, 117, 127.
[7] M. Shabbir, Z. Akhter, I. Ahmad, S. Ahmed, M. Bolte, H.
[30] P. Politzer, D. G. Truhlar, Chemical applications of atomic and
molecular electrostatic potentials: reactivity, structure, scattering,
and energetics of organic, inorganic, and biological systems,
Springer Science & Business Media., New York 1981 472.
Ismail, B. Mirza, Inorg. Chem. Acta. 2017, 463, 102.
[8] P. Hu, K. Q. Zhao, H. B. Xu, Molecules. 2001, 6. M251
[9] A. Togni, R. L. Halterman, Metallocenes 2008, 10, 685.
[31] N. Lotfi, I. Sheikhshoaei, S. Y. Ebrahimipour, H. Krautscheid,
[10] Y. T. Liu, J. Sheng, D. W. Yin, H. Xin, X. M. Yang, Q. Y. Qiao,
J. Mol. Str. 2017, 1149, 432.
Z. J. Yang, J. Organomet. Chem. 2018, 856, 27.
[32] E. Ermiş, J. Mol. Str. 2018, 1156, 91.
[33] Z. Parsaee, J. Mol. Str. 2017, 1146, 644.
[11] A. Albert, Selective Toxicity: Physico‐chemical Basis of Therapy,
6th ed., Wiley, New York 1979.
[12] S. Chandra, D. Jain, A. K. Sharma, P. Sharma, Molecules 2009,
14, 174.
[34] B. Annaraj, S. Pan, M. A. Neelakantan, P. K. Chattaraj,
Comput. Theor. Chem. 2014, 1028, 19.
[13] P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon, D.
Vistica, J. T. Warren, T. Bokesch, S. Kenney, M. R. Boyd,
J. National Cancer Instit. 1990, 82, 1107.
[35] A. Arab, F. Gobal, N. Nahali, M. Nahali, J. Clust. Sci. 2013, 24,
273.
[36] M. Jafari, M. Salehi, M. Kubicki, A. Arab, A. Khaleghian, Inorg.
Chim. Acta 2017, 462, 329.
[14] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, V. G. Zakrzewski, J. A. Montgomery,
R. E. Stratmann, J. C. Burant, S. Dapprich, J. M. Millam,
A. D. Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi,
V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli,
C. Adamo, S. Clifford, J. Ochterski, G. A. Petersson,
P. Y. Ayala, Q. Cui, K. Morokuma, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Ortiz,
A. G. Baboul, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz,
I. Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T. Keith,
M. A. Al‐Laham, C. Y. Peng, A. Nanayakkara, C. Gonzalez,
M. Challacombe, P. M. W. Gill, B. G. Johnson, W. Chen,
M. W. Wong, J. L. Andres, M. Head‐Gordon, E. S. Replogle,
J. A. Pople, GAUSSIAN 03 (Revision A.9), Gaussian, Inc.,
Pittsburgh, 2003.
[37] W. Rehman, R. Yasmeen, F. Rahim, M. Waseem, C. Y. Guo, Z.
Hassan, U. Rashid, K. Ayub, J. Photochem. & Photobio. B. 2016,
164, 65.
[38] A. A. M. Belal, I. M. El‐Deen, N. Y. Farid, R. Zakaria, M. S.
Refat, Spectrochim. Acta A. 2015, 149, 771.
[39] P. Subbaraj, A. Ramu, N. Raman, J. Dharmaraja, J. Saudi
Chem. Soc. 2015, 19, 207.
[40] W. H. Mahmoud, R. G. Deghadi, G. G. Mohamed, J. Therm.
Anal. Calorim. 2017, 127, 2149.
[41] W. H. Mahmoud, G. G. Mohamed, S. Y. A. Mohamedin,
J. Therm. Anal. Calorim. 2017, 130, 2167.
[42] C. Shiju, D. Arish, N. Bhuvanesh, S. Kumaresan, Spectrochim.
Acta A. 2015, 145, 213.
[15] R. Dennington, T. Keith, J. Millam, GaussView, Version 5.0.8, R,
Dennington, Semichem Inc., Shawnee Mission, KS 2009.
[43] M. D. Joksovic, V. Markovic, Z. D. Juranic, T. Stanojkovic, L. S.
Jovanovic, I. S. Damljanovic, K. M. Szecsenyi, N. Todorovic, S.
Trifunovic, R. D. Vukicevic, J. Organomet. Chem. 2009, 694,
3935.
[16] C. J. Dhanaraj, I. U. Hassan, J. Johnson, J. Joseph, R. S.
Joseyphus, J. Photochem. & Photobio. B. 2016, 162, 115.
[17] C. Balakrishnan, L. Subha, M. A. Neelakantan, S. S.
Mariappan, Spectrochim. Acta A. 2015, 150, 671.
[44] A. A. Abou‐Hussein, W. Linert, Spectrochim. Acta A. 2014, 117,
763.
[18] K. Mohammadi, S. S. Azad, A. Amoozegar, Spectrochim. Acta
A. 2015, 146, 221.
[45] M. A. Arafath, F. Adam, M. R. Razali, L. E. A. Hassan, M. B. K.
Ahamed, A. M. Majid, J. Mol. Str. 2017, 1130, 791.
[19] W. H. Mahmoud, R. G. Deghadi, G. G. Mohamed, J. Therm.
Anal. Calorim. 2016, 127(3), 2149.
[46] W. H. Mahmoud, N. F. Mahmoud, G. G. Mohamed, J. Coord.
Chem 2017, 70, 3552.
[20] S. M. Emam, J. Mol. Str. 2017, 1134, 444.
[21] J. Vanco, J. Marek, Z. Travnicek, E. Racanska, J. Muselik, O.
[47] M. Gharagozlou, Z. Baradaran, R. A. Bayati, Ceramics Internat.
2015, 41, 8382.
Svajlenova, J. Inorg. Biochem. 2008, 102, 595.
[22] S. Yadav, R. V. Singh, Spectrochim. Acta A. 2011, 78, 298.
[48] W. H. Mahmoud, N. F. Mahmoud, G. G. Mohamed, J. Therm.
Anal. Calorim. 2017. In press
[23] X. Q. Hao, J. F. Gong, W. T. Song, Y. J. Wu, M. P. Song, Inorg.
Chem. Comm. 2007, 10, 371.
[49] M. Gaber, H. A. El‐Ghamry, S. K. Fathalla, M. A. Mansour,
Mater. Sci. & Eng. C. 2018, 83, 78.
[24] M. Asadi, S. Torabi, K. Mohammadi, Spectrochim. Acta A. 2014,
122, 676.
[50] B. Iftikhar, K. Javed, M. S. U. Khan, Z. Akhter, B. Mirza, V.
Mckee, J. Mol. Str. 2018, 1155, 337.
[25] S. Sujarani, A. Ramu, J. Mol. Str. 2015, 1079, 353.
[26] W. H. Mahmoud, R. G. Deghadi, G. G. Mohamed, Applied
Organomet. Chem 2016, 30, 221.
[51] T. D. Thangadurai, K. Natarajan, Indian J. Chem. A. 2001, 40,
573.

MAHMOUD ET AL.
21 of 21
[52] Z. H. Chohan, H. Pervez, A. Rauf, K. M. Khan, C. T. Supuran,
[61] R. Anita, J. Chacko, G. Jeyakanthan, K. Ueno, C. Sekar, D.
Rao, E. J. Dodson, K. Suguna, R. J. Read, Acta Crystallogr. D.
2012, D68, 57.
J. Enzyme Inhib. Med. Chem. 2004, 19, 417.
[53] W. H. Mahmoud, G. G. Mohamed, O. Y. El‐Sayed, Applied
Organomet. Chem 2017, In press.
[62] Y. Toh, J. Harper, K. A. Dryden, M. Yeager, C. F. Arias, E.
Mendez, Y. J. Tao, J. virology. 2016, 90(20), 9008.
[54] S. Y. Ebrahimipour, I. Sheikhshoaie, J. Castro, W. Haase, M.
Mohamadi, S. Foro, M. Sheikhshoaie, S. E. A. Mahani, Inorg.
Chim. Acta 2015, 430, 245.
[63] Y. Liu, J. Sheng, A. Fokine, G. Meng, W. H. Shin, F. Long, R. J.
Kuhn, D. Kihara, M. G. Rossmann, Sci. 2015, 347, 71.
[55] H. Zafar, A. Kareem, A. Sherwani, O. Mohammad, M. A.
Ansari, H. M. Khan, T. A. Khan, J. Photochem. & Photobio. B.
2014, 142, 8.
[64] J. Zhao, D. Zhang, W. Hua, W. Li, G. Xu, S. Gou, Organometal-
lics. 2018, In press.
[56] T. A. Khan, S. Naseem, R. Hajra, M. Shakir, Inorg. Met.‐Org.
Chem 2010, 40, 861.
How to cite this article: Mahmoud WH,
Deghadi RG, El Desssouky MMI, Mohamed GG.
Transition metal complexes of nano bidentate
organometallic Schiff base: Preparation, structure
characterization, biological activity, DFT and
molecular docking studies. Appl Organometal
Chem. 2018;e4556. https://doi.org/10.1002/aoc.4556
[57] F. A. Cotton, G. Wilkinson, Advanced Inorganic Chemistry, 3rd
ed., Wiley Eastern, New Delhi 1972.
[58] H. A. El‐Boraey, A. A. Serag El‐Din, Spectrochim. Acta A. 2014,
132, 663.
[59] Q. Xiao‐Yang, L. Su‐Zhi, S. An‐Ran, L. Qian‐Qian, Z. Bin, Chi-
nese J. Str. Chem. 2012, 31(4), 555.
[60] W. H. Mahmoud, N. F. Mahmoud, G. G. Mohamed,
J. Organomet. Chem. 2017, 848, 288.