Synthesis, physicochemical characterization, geometric structure and molecular docking of new biologically active ferrocene based Schiff base ligand with transition metal ions

Article abstract of DOI:10.1002/aoc.3858

Physicochemical studies were performed to study new ferrocene based Schiff base ligand (HL), (Z)-(4-(1-((2-carboxycyclohexa-2,4-dien-1-yl)imino)ethyl)[bis(η⁵cyclopenta-1,3-dien-1 yl)]iron with some transition metal ions to form a series of ferrocenyl derivatives bearing transition metal complexes of the type [M(L)Cl(H₂O)₃] (M = Ni(II), Cu(II)), [M(L)Cl(H₂O)₃]nH₂O (M = Mn(II) (n = 1), Co(II) (n = 1), Zn(II) (n = 2) and Cd(II) (n = 3)) and [M(L)Cl(H₂O)₃]Cl.nH₂O (M = Cr(III) (n = 2) and Fe(III) (n = 1)). The new ligand and metal ion complexes have been prepared and characterized by IR, UV-Vis, ¹H-NMR, TG/DTA, elemental analysis and mass spectrometry. The TGA/DTG analysis revealed that the ferrocene precursors decompose spontaneously to form iron(II) oxide. The molecular and electronic structure of the ligand (HL) was optimized theoretically and the quantum chemical parameters were calculated. The molecular structure with a variety of functionalities can be used to investigate the coordination sites and the total charge density around each atom. DFT-based molecular orbital energy calculations of the new ligand have been also studied. All of the complexes were screened against a panel of Gram (+) bacteria: Streptococcus pneumoniae and Bacillis subtilis, Gram (?) bacteria: Pseudomonas aeruginosa and Escherichia coli and panel of fungi: Aspergillus fumigatu, Syncephalastrum racemosum, Geotricum candidum and Candida albicans. Anticancer activity screening for the tested compounds using 4 different concentrations of HL ligand against human tumor cells of breast cancer cell line MCF-7 were obtained. Molecular docking was used to predict the binding between HL ligand and human-DNA-Topo I complex (PDB ID: 1SC7), the receptors of breast cancer mutant oxidoreductase (PDB ID: 3HB5), crystal structure of Escherichia coli (PDB ID: 3T88), to identify the binding mode and the crucial functional groups interacting with the three proteins.

Full text of DOI:10.1002/aoc.3858

Received: 21 January 2017
DOI: 10.1002/aoc.3858
Revised: 21 March 2017
Accepted: 23 March 2017
F U L L PA P E R
Synthesis, physicochemical characterization, geometric structure
and molecular docking of new biologically active ferrocene based
Schiff base ligand with transition metal ions
W.H. Mahmoud | N.F. Mahmoud | Gehad G. Mohamed
Chemistry Department, Faculty of Science,
Cairo University, Giza 12613, Egypt
Physicochemical studies were performed to study new ferrocene based Schiff
base ligand (HL), (Z)‐(4‐(1‐((2‐carboxycyclohexa‐2,4‐dien‐1‐yl)imino)ethyl)
[bis(η5cyclopenta‐1,3‐dien‐1 yl)]iron with some transition metal ions to form a
series of ferrocenyl derivatives bearing transition metal complexes of the type
[M(L)Cl(H2O)3] (M = Ni(II), Cu(II)), [M(L)Cl(H2O)3]nH2O (M = Mn(II) (n = 1),
Co(II) (n = 1), Zn(II) (n = 2) and Cd(II) (n = 3)) and [M(L)Cl(H2O)3]Cl.nH2O
(M = Cr(III) (n = 2) and Fe(III) (n = 1)). The new ligand and metal ion complexes
have been prepared and characterized by IR, UV‐Vis, 1H‐NMR, TG/DTA, elemental
analysis and mass spectrometry. The TGA/DTG analysis revealed that the ferrocene
precursors decompose spontaneously to form iron(II) oxide. The molecular and elec-
tronic structure of the ligand (HL) was optimized theoretically and the quantum
chemical parameters were calculated. The molecular structure with a variety of func-
tionalities can be used to investigate the coordination sites and the total charge den-
sity around each atom. DFT‐based molecular orbital energy calculations of the new
ligand have been also studied. All of the complexes were screened against a panel
of Gram (+) bacteria: Streptococcus pneumoniae and Bacillis subtilis, Gram (−) bac-
teria: Pseudomonas aeruginosa and Escherichia coli and panel of fungi: Aspergillus
fumigatu, Syncephalastrum racemosum, Geotricum candidum and Candida
albicans. Anticancer activity screening for the tested compounds using 4 different
concentrations of HL ligand against human tumor cells of breast cancer cell line
MCF‐7 were obtained. Molecular docking was used to predict the binding between
HL ligand and human‐DNA‐Topo I complex (PDB ID: 1SC7), the receptors of breast
cancer mutant oxidoreductase (PDB ID: 3HB5), crystal structure of Escherichia coli
(PDB ID: 3T88), to identify the binding mode and the crucial functional groups
interacting with the three proteins.
Correspondence
Gehad G. Mohamed, Chemistry Department,
Faculty of Science, Cairo University, Giza,
12613, Egypt.
Email: ggenidymohamed@sci.cu.edu.eg
KEYWORDS
bacteria, breast cancer, DFT, Docking, ferrocene Schiff base, physicochemical studies, TGA/DTG
1 | INTRODUCTION
organometallic compound, is of interest for fundamental rea-
sons, such as bonding and structure, and its numerous,
Metal containing or organometallic compounds are much
sought after in recent years.[1,2] Ferrocene, the archetypal
diverse, potential applications.[3] Ferrocene compounds have
interesting redox properties and they are used in catalytic
Appl Organometal Chem. 2017;e3858.
wileyonlinelibrary.com/journal/aoc
Copyright © 2017 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.3858

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MAHMOUD ET AL.
reactions. They have many potential medicinal applications
as therapeutic agents in the new field of bioorganometallics,
including as anti‐cancer, anti tubercular and anti‐fungal
agents among many others.[4] Ferrocene has garnered interest
over the years as the ubiquitous group to append onto other
active molecules in order to favorably modify the properties
of already active compounds. This has been done with great
success in many cases as several important compounds have
been synthesized and tested in such
a
manner.[5]
Acetylferrocene is the organo iron compound with the for-
mula [(C5H5)Fe(C5H4COMe)], (where Me: methyl). It con-
sists of ferrocene substituted by an acetyl group on one of
the cyclopentadienyl rings. It is an orange, air‐stable solid
that is soluble in organic solvents. Acetylferrocene is pre-
pared by Friedel‐Crafts acylation of ferrocene, usually with
acetic anhydride. Acetylferrocene can be converted to many
derivatives, e.g. reduction to the chiral alcohol [(C5H5)
Fe(C5H4CH(OH)Me)] and precursor to vinylferrocene.
The oxidized derivative, acetylferrocenium, is used as a
1e−‐oxidant in the research laboratory.[6] Functionalized fer-
rocenes play diverse roles in modern chemistry, with systems
featuring pendant Lewis basic groups acting as donor ligands
in various complexes exploited in homogenous catalysis, and
those bearing Lewis acidic groups finding applications, for
example, in polymer synthesis and in detection/sensing. The
latter field exploits cathodic shifts in the redox potential of
the Fe(II) centre which can be induced, for example, on coor-
dination of a Lewis base to a transition metal ion.[7–9] Ferro-
cene is a highly redox‐active organometallic substance,
which has been employed as magnetic, optical, and electro-
chemical materials. Also, chemical modification through
organic synthesis enabled the synthesis of various ferrocene
derivatives and ferrocene‐containing polymers[10,11] The
coordination chemistry of the complexes involving Schiff
base ligands having O and N donor atoms and a number of
transition metal ions has become area of much focus due to
the versatility of Schiff base ligands on treating with transi-
tion metal ions produces mono as well as polynuclear com-
plexes, which have been widely employed in material
science and medicine. The Schiff base complexes may incor-
porate planar aromatic or flexible polydentate ligands.[12]
The present study described the coordination behavior of
(Z)‐(4‐(1‐((2‐carboxycyclohexa‐2,4‐dien‐1‐yl)imino)ethyl)‐
[bis(η5cyclopenta‐1,3‐dien‐1‐yl)]iron (HL ligand) (Figure 1)
toward some transition elements. Metal(II)/(III) complexes
of the new HL ligand was focused and its in vitro antibac-
terial, antifungal and anticancer activity were investigated.
The structure of the studied bi‐ and trivalent metal com-
plexes of HL ligand is elucidated using elemental analyses,
FIGURE 1 The optimized structure of HL ligand
base ligand and human‐DNA‐Topo I complex (PDB ID:
1SC7), the receptors of breast cancer mutant oxidoreductase
(PDB ID: 3HB5) and crystal structure of Escherichia coli
(PDB ID: 3 T88). The antimicrobial and anticancer activi-
ties were screened.
2 | EXPERIMENTAL
2.1 | Material and reagent
All chemicals used were of the analytical reagent grade (AR),
and of highest purity available. The chemicals used included
acetyl ferrocene which was supplied from Strem Chemicals
Inc., CrCl3.6H2O and MnCl2.2H2O (Sigma Aldarich),
NiCl2.6H2O, CoCl2.6H2O, CuCl2.2H2O and ZnCl2.2H2O
(BDH), FeCl3.6H2O (Prolabo), CdCl2.2H2O (Merck) and
anthranilic acid (BDH). Organic solvents were spectroscopic
pure from BDH included ethanol, diethyl ether and dimethyl
formamide. Hydrogen peroxide, sodium chloride, sodium
carbonate and sodium hydroxide (A.R.) were used. Human
tumor cell line (Breast cell) was obtained frozen in liquid
nitrogen (−180°C) from the American Type Culture Collec-
tion. The tumor cell line (MCF7) was maintained in the
National Cancer Institute, Cairo, Egypt, by serial sub‐
culturing.
2.2 | Solutions
Afreshstocksolutionof1x10−3 Mofacetylferrocene(0.4g/L)
was prepared in the appropriate volume of absolute etha-
nol and metanol. Dimethylsulphoxide (DMSO) (Sigma
Chemical Co., St. Louis, Mo, USA): It was used in cryo-
preservation of cells. RPMI‐1640 medium (Sigma Chemical
Co., St. Louis, Mo, USA) was used. The medium was used
for culturing and maintenance of the human tumor cell lines.
The medium was supplied in a powder form. It was prepared
as follows: 10.4 g medium was weighed, mixed with 2 g
1
IR, H NMR, mass spectroscopy, molar conductance, mag-
netic susceptibility and thermal analyses measurements.[13]
The molecular docking study was described in order to elu-
cidate the mode of binding between the ferrocene Schiff

MAHMOUD ET AL.
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sodium bicarbonate, completed to 1 l with distilled water and
shook carefully till complete dissolution. The medium was
then sterilized by filtration in a Millipore bacterial filter
(0.22 μm). 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 the supplemented with penicillin/streptomycin and FBS.
Sodium bicarbonate (Sigma Chemical Co., St. Louis, Mo,
USA) was used for the preparation of RPMI‐1640 medium.
0.05% isotonic Trypan blue solution (Sigma Chemical Co.,
St. Louis, Mo, USA) was prepared in normal saline and was
used for viability counting. 10% Fetal Bovine Serum (FBS)
(heat inactivated at 56°C for 30 min), 100 units/ml Penicillin
and 2 mg/ml Streptomycin were supplied from Sigma Chem-
ical Co., St. Louis, MO, USA and were used for the supple-
mentation of RPMI‐1640 medium prior to use. 0.025% (w/v)
Trypsin (Sigma Chemical Co., St. Louis, MO, USA) was used
for the harvesting of cells. 1% (v/v) Acetic acid (Sigma Chem-
ical Co., St. Louis, MO, USA) was used for dissolving the
unbound SRB dye. 0.4% Sulphorhodamine‐B (SRB) (Sigma
Chemical Co., St. Louis, MO, USA) dissolved in 1% acetic
acid was used as a protein dye. A stock solution of trichloro-
acetic acid (TCA, 50%, Sigma Chemical Co., St. Louis,
MO, USA) was prepared and stored. 50 μl of the stock was
added to 200 μl RPMI‐1640 medium/well to yield a final con-
centration of 10% used for protein precipitation. 100%
Isopropanol and 70% ethanol were used. Tris base 10 mM
(pH 10.5) was used for SRB dye solubilization. 121.1 g of tris
base was dissolved in 1000 ml of distilled water and pH was
adjusted by HCl acid (2 M).
50H thermal analyzer. The anticancer activity was performed
at the National Cancer Institute, Cancer Biology Department,
Pharmacology Department, Cairo University. The optical
density (O.D.) of each well was measured spectrophotometri-
cally at 564 nm with an ELIZA microplate reader (Meter
tech. Σ 960, USA). The molecular structure of the investi-
gated ligand was optimized by DFT based B3LYP method
along with the LANL2DZ basis set. The molecule was built
with the Perkin Elmer ChemBio Draw and optimized using
Perkin Elmer ChemBio3D software.[14,15] The biological
activity was carried out in the regional center for mycology
and biotechnology, Al‐Azhar University.
2.4 | Preparation of acetyl ferrocene Schiff
base ligand HL
The new Schiff base ligand was prepared by mixing equal
amounts of hot saturated ethanolic solution of the acetyl fer-
rocene (8 g, mmol) and 2‐aminobenzoic acid (anthranilic
acid, 4.8 g, mmol). The mixture was refluxed for three hours.
The resulting ligand was filtered and washed several times
with hot ethanol until the filtrates become clear. The solid
ligand then dried in desiccator over anhydrous calcium chlo-
ride. The yield was 72%.
Yield 97%; dark brown solid, m.p > 300°C. Anal. Calcd.
for C19H17FeNO2 (%):C, 65.71; H, 4.90; N, 4.03; Fe, 16.14.
Found (%):C, 65.40; H, 4.46; N, 3.74; Fe, 16.04. IR (ν, cm−1):
3426br (OH), 1780 m (C=O), 1615s (C=N), 1590sh (COO)
asym, 1403sh (COO)sym, 1158 m (C‐N). Uv–vis (λmax, nm):
268 (π–π*), 328 (n–π*). The 1H NMR: 11.41 ppm (s,
1H, COOH), 6.47–7.98 ppm (m, 4H, benzene ring) and
4.23–4.77 (m, 9H, ferrocene rings).
2.3 | Measurements
Microanalyses of carbon, hydrogen and nitrogen were carried
out at the microanalytical Center, Cairo University, Egypt,
using CHNS‐932 (LECO) Vario Elemental Analyzer. Analy-
ses of the metals followed the dissolution of the solid com-
plex in concentrated HNO3, neutralizing the diluted
aqueous solutions with ammonia and titrating the metal solu-
tions with EDTA. FT‐IR spectra were recorded on a Perkin‐
Elmer 1650 spectrometer (4000–400 cm−1) in KBr discs.
Electronic spectra were recorded at room temperature on a
Shimadzu 3101pc spectrophotometer as solutions in DMF.
1H NMR spectra, as a solution in DMSO‐d6, were recorded
on a 300 MHz Varian‐Oxford Mercury at room temperature
using TMS as an internal standard.
2.5 | Preparation of metal complexes
The present metal complexes were prepared by mixing equal
amounts of hot saturated ethanolic solution of the Schiff base
ligand (HL; 0.008 mol) with the same ratio of metal chloride
(1 M:1HL molar ratio). The mixture was refluxed for three
hours. The resulting complexes were filtered and washed sev-
eral times with hot ethanol until the filtrates become clear.
The solid complexes then dried in desiccator over anhydrous
calcium chloride. The yield ranged from 66–99%.
[Cr(L)(Cl)(H2O)3]Cl.2H2O
Yield 87%; dark brown solid, m.p 252°C. Anal. Calcd. for
Cr(C19H26Cl2FeNO7) (%):C, 40.79; H, 4.65; N, 2.50; Cl,
12.70; Cr, 9.30. Found (%):C, 40.63; H, 4.26; N, 2.31; Cl,
12.33; Cr, 8.86 IR (ν, cm−1): 3426br (OH), disappear
(C=O), 1648sh (C=N), 1600s (COO)asym, 1425 m (COO)
sym, 1161 m (C‐N), 940 s and 871 m (H2O coordinated
water), 582 s (M‐O), 541 s (M‐O coordinated water), 483 s
(M‐N). Uv–vis (λmax, nm): 269 (π–π*), 391 (n–π*).
Molar conductivities of 10−3 M solutions of the solid
complexes in DMF:DMSO (1:1) were measured using
Jenway 4010 conductivity meter. UV‐vis spectra were
recorded at room temperature on a Shimadzu 3101pc spectro-
photometer as solutions in ethanol. The thermogravimetric
analyses (TG and DTG) of the solid complexes were carried
out from room temperature to 1000°C using a Shimadzu TG‐

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MAHMOUD ET AL.
[Mn(L)(Cl)(H2O)3].H2O
6.62; Zn, 12.12. Found (%): C, 42.40; H, 4.69; N, 2.16; Cl,
6.60; Zn, 11.97. IR (ν, cm−1): 3442br (OH), disappear
Yield 57%; Dark brown solid, m.p 246°C. Anal. Calcd. for
Mn(C19H24ClFeNO6) (%):C, 44.84; H, 4.72; N, 2.75; Cl,
6.98; Mn, 10.82. Found (%): C, 44.62; H, 4.62; N, 2.33; Cl,
6.50; Mn, 10.78. IR (ν, cm−1): 3424br (OH), disappear
(C=O), 1623 m (C=N), disappear (COO)asym, 1428 m
(COO)sym, 1164 m (C‐N), 933 s and 877 m (H2O coordinated
water), 596 s (M‐O), 543 s (M‐O coordinated water), 485 s
(M‐N). Uv–vis (λmax, nm): 289 (π–π*), 318 (n–π*).
(C=O), 1654sh (C=N), 1590s (COO)asym, 1435s (COO)sym
,
1162s (C‐N), 945 s and 877 m (H2O coordinated water),
568 s (M‐O), 547 s (M‐O coordinated water), 473 s (M‐N).
Uv–vis (λmax, nm): 271 (π–π*), disappear (n–π*).
[Cd(L)(Cl)(H2O)3].3H2O
Yield 38%; dark brown solid, m.p 180°C. Anal. Calcd. for
Cd(C19H28ClFeNO8) (%):C, 37.91; H, 4.66; N, 2.33; Cl,
5.90; Cd, 18.62. Found (%): C, 37.69; H, 4.42; N, 2.15; Cl,
5.61; Cd, 18.41. IR (ν, cm−1): 3449br (OH), disappear
[Fe(L)(Cl)(H2O)3]Cl.H2O
Yield 69%; dark brown solid, m.p 184°C. Anal. Calcd. for
Fe(C19H24Cl2FeNO6) (%):C, 41.83; H, 4.40; N, 2.57; Cl,
13.03; Fe, 10.28. Found (%): C, 41.69; H, 4.32; N, 2.48;
Cl, 12.94; Fe, 10.07. IR (ν, cm−1): 3420br (OH), 1720s
(C=O), 1634sh (C=N), 1580s (COO)asym, 1429sh (COO)
sym, 1180 m (C‐N), 951 s and 852 m (H2O coordinated
water), 591 s (M‐O), 545 s (M‐O coordinated water), 487 s
(M‐N). Uv–vis (λmax, nm): 275 (π–π*), 314 (n–π*).
(C=O), 1615s (C=N), 1583s (COO)asym, 1448s (COO)sym
,
1191s (C‐N), 935 s and 876 m (H2O coordinated water),
591 s (M‐O), 537 s (M‐O coordinated water), 481 s (M‐N).
Uv–vis (λmax, nm): 276 (π–π*), disappear (n–π*).
2.6 | Spectrophotometric studies
[Co(L)(Cl)(H2O)3].H2O
The absorption spectra of HL ligand and its metal complexes
under study were scanned within the wavelength range from
200 to 700 nm.
Yield 66%; dark brown solid, m.p > 218°C. Anal. Calcd. for
Co(C19H24ClFeNO6) (%):C, 44.48; H, 4.68; N, 2.73; Cl,
6.93; Co, 11.51 Found (%): C, 44.28; H, 4.52; N, 2.42 Cl,
6.80; Co, 11.93. IR (ν, cm−1): 3424br (OH), diappear
(C=O), 1626 m (C=N), 1560s (COO)asym, 1428 m (COO)
sym, 1160 m (C‐N), 935 s and 875 m (H2O of coordinated
water), 586 s (M‐O), 537 s (M‐O coordinated water), 482 s
(M‐N). Uv–vis (λmax, nm): 268 (π–π*), 381 (n–π*).
2.7 | Antimicrobial activity
The in vitro antibacterial and antifungal activity tests were
performed through the disc diffusion method[16] using
getamicin as positive control for Gram(+) bacteria, ampicillin
for Gram(−) bacteria and amphotericin for the four fungi,
respectively. The bacterial organisms used are Gram (+) bac-
teria: Streptococcus pneumoniae and Bacillis subtilis, Gram
(−) bacteria: Pseudomonas aeruginosa and Escherichia coli
and fungi like: Aspergillus fumigatu, Syncephalastrum
racemosum, Geotricum candidum and Candida albicans.
Stock solution (0.001 mol) was prepared by dissolving the
compounds in DMSO. The nutrient agar medium for antibac-
terial was (0.5% Peptone, 0.1% Beef extract, 0.2% Yeast
extract, 0.5% NaCl and 1.5% Agar‐Agar) was prepared and
then cooled to 47°C and seeded with tested microorganisms.
After solidification 5 mm diameter holes were punched by a
sterile corkborer. The investigated compounds, i.e. ligand and
their complexes, were introduced in Petri‐dishes (only 0.1 m)
after dissolving in DMSO at 1.0x10−3 M. These culture
plates were then incubated at 37°C for 20 h for bacteria.
The activity was determined by measuring the diameter of
the inhibition zone (in mm). The plates were kept for incuba-
tion at 37°C for 24 h and then the plates were examined for
the formation of zone of inhibition. The diameter of the inhi-
bition zone was measured in millimeters. Antimicrobial
activities were performed in triplicate and the average was
taken as the final reading.[17]
[Ni(L)(Cl)(H2O)3]
Yield 99%; dark brown solid, m.p 94°C. Anal. Calcd. for
Ni(C19H22ClFeNO5) (%):C, 46.11; H, 4.45; N, 2.83; Cl,
7.18; Ni, 11.93. Found (%): C, 45.88; H, 4.32; N, 2.63; Cl,
7.02; Ni, 11.81. IR (ν, cm−1): 3309br (OH), 1820s (C=O),
1652sh (C=N), 1581s (COO)asym
, 1435s (COO)sym,
1157 m (C‐N), 950 s and 872 m (H2O coordinated water),
599 s (M‐O), 540 s (M‐O coordinated water), 493 s (M‐N).
Uv–vis (λmax, nm): 275 (π–π*), 350 (n–π*).
[Cu(L)(Cl)(H2O)3]
Yield 57%; dark green solid, m.p 224°C. Anal. Calcd. for
Cu(C19H22ClFeNO5) (%):C, 45.69; H, 4.41; N, 2.81; Cl,
7.11; Cu, 12.73. Found (%): C, 45.36; H, 4.30; N, 2.91; Cl,
6.88; Cu, 12.54. IR (ν, cm−1): 3410br (OH), 1722s (C=O),
1615s (C=N), 1560s (COO)asym, 1436 m (COO)sym, 1183s
(C‐N), 952 s and 876 m (H2O coordinated water), 582 s
(M‐O), 555 s (M‐O coordinated water), 473 s (M‐N). Uv–
vis (λmax, nm): 273 (π–π*), 321 (n–π*).
[Zn(L)(Cl)(H2O)3].2H2O
Yield 69%; dark brown solid, m.p 140°C. Anal. Calcd. for
Zn(C19H26ClFeNO7) (%):C, 42.50; H, 4.85; N, 2.61; Cl,

MAHMOUD ET AL.
5 of 19
co‐crystallized ligands were removed. The structure of ligand
in PDB file format was created by Gaussian03 software. The
crystal structures of the human‐DNA‐Topo I complex (PDB
ID: 1SC7), the receptors of breast cancer mutant 3HB5‐
oxidoreductase (PDB ID: 3HB5) and crystal structure of
Escherichia coli (PDB ID: 3 T88) were downloaded from
the protein data bank (http://www.rcsb.org./pdb).
2.8 | Anticancer activity
Potential cytotoxicity of the compounds was tested using the
method of Skehan and Storeng.[18] Cells were plated in 96‐
multiwell plate (104 cells/well) for 24 h before treatment with
the compounds to allow attachment of cell to the wall of the
plate. Different concentrations of the compounds under
investigation (0, 5, 12.5, 25, 50 and 100 μg/ml) were added
to the cell monolayer and triplicate wells were prepared for
each individual dose. The monolayer cells were incubated
with the compounds for 48 h at 37°C and in 5% CO2 atmo-
sphere. After 48 h, 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 opti-
cal density (O.D.) of each well was measured spectrophoto-
metrically at 564 nm with an ELIZA microplate reader and
the mean background absorbance was automatically
subtracted and mean values of each drug concentration was
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
3.1 | Characterization of Schiff base ligand
The dark brown Schiff base ligand (HL) obtained by the con-
densation reaction between 2‐acetyl ferrocene and anthranilic
acid in hot ethanolic solution as a solvent, was stable in air
and soluble in the most common organic solvents. The data
of C, H and N content of HL referred to a molecular formula
of C19H17FeNO2 were shown in the experimental part.
These data were found to be in good accordance with the
calculated value based on the synthetic and proposed struc-
ture. Formation of the new ligand was evidenced by the pres-
ence of a strong IR band at 1615 cm−1 due to ν(C=N), while
no bands attributable to ν(C=O) of acetyl ferrocene or
ν(NH2) of anthranilic acid have been detected[21] confirming
Calculation:
The percentage of cell survival was calculated as follows:
Survival fraction = O.D. (treated cells)/ O.D. (control cells).
The IC50 values (the concentrations of the HL ligand or
complexes required to produce 50% inhibition of cell
growth). The experiment was repeated 3 times.
1
the formation of the Schiff base ligand. The H NMR spec-
trum was recorded for HL. The proton of carboxylic group
appeared as singlet at 11.41 ppm while the aromatic protons
appeared as a set of multiplet in the region 6.47–7.98 ppm.
The spectrum also revealed signals at 4.23–4.77 ppm
(m, 9H, ferrocene rings), which can assigned to the
cyclopentadiene aromatic ferrocene protons.
The electronic emission spectral data of HL was recorded
in 10−4 M DMF solution. The electronic absorption spectrum
of HL gave first sharp band at 268 nm which is mainly attrib-
uted to the locally excited intraligand π ! π* transitions. The
second band observed at 328 nm can be attributed to n–π*
electronic transition.[22]
The structure of the Schiff base ligand was confirmed
by carrying out mass spectral analysis. The spectrum
showed a peak at 346.87 amu (M‐1) corresponding to the
molecular ion peak of the ligand moiety [(C19H17FeNO2),
atomic mass 347.21 amu]. The observed peak was in good
agreement with the proposed formula as indicated by the
microanalytical data.
Thermogravimetric (TG) curve for HL ligand of the for-
mula [C19H17FeNO2] showed four weight loss events. The
first and second steps of decomposition occurred within the
range of 46‐363°C, with two maximum temperatures at 136
and 315 °C, correspond to the loss of C7H10N fragment with
estimated mass loss of 30.94% (calculated mass loss
=31.12%). The third and fourth steps of decomposition
occurred within the range of 364‐480°C with maximum tem-
peratures at 370 and 405.5°C which correspond to loss of
2.9 | Computational methodology
The electronic structure calculation of HL ligand was carried
out using the Gaussian03 suite of program.[19] They were
fully optimized employing DFT based B3LYP method along
with the LANL2DZ basis set. In order to incorporate the
effect of the solvent around the molecule, the TD‐DFT
method (along with LANL2DZ basic set) was used to calcu-
late the electronic absorption spectra of the ligand. The con-
tribution of molecular orbital on HOMO and LUMO were
also calculated.
2.10 | Molecular docking
In order to find out the possible binding modes of the most
active compounds against DNA of human‐DNA‐Topo I com-
plex (1SC7), the receptors of breast cancer mutant 3HB5‐
oxidoreductase (3HB5), crystal structure of Escherichia coli
(3 T88) molecular docking studies were performed using
MOE 2008 software and it is a rigid molecular docking soft-
ware.[20] Docking is an interactive molecular graphics pro-
gram for calculating and displaying feasible docking modes
of a receptor and ligand and complex molecules. It necessi-
tates the ligand and the receptor as input in PDB format.
The amino acid chain was kept and the water molecules and

6 of 19
MAHMOUD ET AL.
TABLE 1 The different optimized parameters of HL ligand
C10H7O fragment with estimated mass loss of 39.89% (calcu-
lated mass loss =41.21%) leaving metal oxide FeO contami-
nated with two carbon atoms as a residue. The overall weight
loss amounted to 72.83% (calculated mass loss =72.33%).
Bond lengths (Å)
HL
Fe(1)‐C(2)
Fe(1)‐C(3)
Fe(1)‐C(4)
Fe(1)‐C(5)
Fe(1)‐C(6)
Fe(1)‐C(12)
Fe(1)‐C(13)
Fe(1)‐C(14)
Fe(1)‐C(15)
Fe(1)‐C(16)
C(2)‐C(3)
2.1269
2.1261
2.12
3.1.1 | Geometrical optimization of the ligand
2.1178
2.1203
2.1211
2.1309
2.1271
2.1275
2.1067
1.4427
1.443
The selected geometrical structure of the investigated ligand
(HL) is calculated by optimizing their bond lengths and bond
angles presented in Table 1. Both the highest occupied
molecular orbital (HOMO) and lowest unoccupied molecular
orbital (LUMO) are the main orbital takes part in chemical
stability. The HOMO represents the ability to donate an elec-
tron, LUMO as an electron acceptor represents the ability to
obtain an electron. The HOMO and LUMO for ligand (HL)
are shown in Figure 2. The calculated quantum chemical
parameters are given in Table 2. Additional parameters such
as ΔE, absolute electronegativities, χ, chemical potentials,
Pi, absolute hardness, η, absolute softness, σ, global electro-
philicity, ω, global softness, S and additional electronic
C(2)‐C(6)
C(2)‐H(7)
1.0814
1.4428
1.081
C(3)‐C(4)
C(3)‐H(8)
charge, ΔNmax have been calculated according to the follow-
C(4)‐C(5)
1.4423
1.0811
1.4431
1.0811
1.081
[13–15]
ing equations (1–8)
:
C(4)‐H(9)
ΔE ¼ ELUMO−EHOMO
(1)
(2)
C(5)‐C(6)
C(5)‐H(10)
C(6)‐H(11)
C(12)‐C(13)
C(12)‐C(16)
C(12)‐H(17)
C(13)‐C(14)
C(13)‐H(18)
C(14)‐C(15)
C(14)‐H(19)
C(15)‐C(16)
C(15)‐C(21)
C(16)‐H(20)
C(21)‐C(22)
C(21)‐N(26)
C(22)‐H(23)
C(22)‐H(24)
C(22)‐H(25)
N(26)‐C(32)
C(27)‐C(28)
C(27)‐C(32)
C(27)‐H(33)
C(28)‐C(29)
C(28)‐H(34)
−ðEHOMO þ ELUMO
Þ
χ ¼
2
1.4422
1.4341
1.0808
1.4348
1.081
ELUMO−EHOMO
η ¼
(3)
2
1
σ ¼
η
(4)
(5)
(6)
1.4561
1.0774
1.4577
1.4847
1.0798
1.5236
1.3055
1.0919
1.0981
1.0985
1.4144
1.4063
1.4122
1.0847
1.4107
1.0873
Pi ¼ −χ
1
S ¼
2η
Pi2
ω ¼
(7)
(8)
2η
Pi
η
ΔNmax ¼ −
The HOMO–LUMO energy gap, ΔE, which is an impor-
tant stability index, is applied to develop theoretical models
for explaining the structure and conformation barriers in
many molecular.[23,24]
The data calculated were presented in Tables 1, 2 and
reflected the following notes:
(Continues)

MAHMOUD ET AL.
7 of 19
TABLE 1 (Continued)
Bond lengths (Å)
TABLE 1 (Continued)
HL
Bond lengths (Å)
HL
C(29)‐C(30)
1.407
C(13)‐Fe(1)‐C(16)
C(14)‐Fe(1)‐C(16)
Fe(1)‐C(2)‐H(7)
C(3)‐C(2)‐C(6)
66.5511
66.9176
C(29)‐H(35)
1.0872
1.402
C(30)‐C(31)
125.4162
107.9933
126.0891
125.9173
125.839
C(30)‐H(36)
1.0857
1.4264
1.3884
0.9901
C(31)‐C(32)
A(3)‐C(2)‐H(7)
C(31)‐C((37)
A(6)‐C(2)‐H(7)
C(37)‐O(38)
Fe(1)‐C(3)‐H(8)
C(2)‐C(3)‐C(4)
Bond angles (o)
C(2)‐Fe(1)‐C(4)
C(2)‐Fe(1)‐C(5)
C(2)‐Fe(1)‐C(12)
C(2)‐Fe(1)‐C(13)
C(2)‐Fe(1)‐C(14)
C(2)‐Fe(1)‐C(15)
C(2)‐Fe(1)‐C(16)
C(3)‐Fe(1)‐C(5)
C(3)‐Fe(1)‐C(6)
C(3)‐Fe(1)‐C(12)
C(3)‐Fe(1)‐C(13)
C(3)‐Fe(1)‐C(14)
C(3)‐Fe(1)‐C(15)
C(3)‐Fe(1)‐C(16)
C(4)‐Fe(1)‐C(6)
C(4)‐Fe(1)‐C(12)
C(4)‐Fe(1)‐C(13)
C(4)‐Fe(1)‐C(14)
C(4)‐Fe(1)‐C(15)
C(4)‐Fe(1)‐C(16)
C(5)‐Fe(1)‐C(12)
C(5)‐Fe(1)‐C(14)
C(5)‐Fe(1)‐C(15)
C(5)‐Fe(1)‐C(16)
C(6)‐Fe(1)‐C(12)
C(6)‐Fe(1)‐C(13)
C(6)‐Fe(1)‐C(14)
C(6)‐Fe(1)‐C(15)
C(6)‐Fe(1)‐C(16)
C(12)‐Fe(1)‐C(14)
C(12)‐Fe(1)‐C(15)
C(13)‐Fe(1)‐C(15)
108.0092
126.2502
125.739
66.6933
66.7335
C(2)‐C(3)‐H(8)
C(4)‐C(3)‐H(8)
161.3366
158.4536
124.9998
111.0924
126.8877
66.7325
Fe(1)‐C(4)‐H(9)
C(3)‐C(4)‐C(5)
124.8744
108.0038
125.9762
126.0186
124.6237
108.0114
125.9678
126.0162
125.4437
107.9821
126.0472
125.9699
124.9559
107.8712
126.1913
125.9356
125.3493
108.3615
126.0731
125.563
C(3)‐C(4)‐H(9)
C(5)‐C(4)‐H(9)
Fe(1)‐C(5)‐H(10)
C(4)‐C(5)‐C(6)
66.699
C(4)‐C(5)‐H((HH10)
C(6)‐C(5)‐H(10)
Fe(1)‐C(6)‐H(11)
C(2)‐C(6)‐C(5)
156.1993
123.0805
110.9152
127.3711
163.4291
66.8095
C(2)‐C(6)‐H(11)
C(5)‐C(6)‐H(11)
Fe(1)‐C(12)‐H(17)
C(13)‐C(12)‐C(16)
C(13)‐C(12)‐H(17)
C(16)‐C(12)‐H(17)
Fe(1)‐C(13)‐H(18)
C(12)‐C(13)‐C(14)
C(12)‐C(13)‐H(18)
C(14)‐C(13)‐H(18)
Fe(1)‐C(14)‐H(19)
C(13)‐C(14)‐C(15)
C(13)‐C(14)‐H(19)
C(15)‐C(14)‐H(19)
Fe(1)‐C(15)‐C(21)
C(14)‐C(15)‐C(16)
C(14)‐C(15)‐C(21)
C(16)‐C(15)‐C(21)
Fe(1)‐C(16)‐C(20)
C(12)‐C(16)‐C(15)
120.7715
108.3752
125.6812
162.4942
155.2384
107.1205
160.2748
157.0284
121.1491
124.3546
159.8685
159.1674
123.5363
109.0634
66.6185
126.371
108.5005
125.3065
126.1808
130.2923
106.4758
130.0137
123.2258
125.2519
108.7893
67.2027
66.8672
(Continues)
(Continues)

8 of 19
MAHMOUD ET AL.
TABLE 1 (Continued)
Bond lengths (Å)
HL
C(12)‐C(16)‐C(20)
C(15)‐C(16)‐C(20)
C(15)‐C(21)‐C(22)
C(15)‐C(21)‐C(26)
C(22)‐C(21)‐C(26)
C(21)‐C(22)‐H(23)
C(21)‐C(22)‐H(24)
C(21)‐C(22)‐H(25)
H(23)‐C(22)‐H(24)
H(23)‐C(22)‐H(25)
H(24)‐C(22)‐H(25)
C(21)‐N(26)‐C(32)
C(28)‐C(27)‐C(32)
C(28)‐C(27)‐C(33)
C(32)‐C(27)‐H(33)
C(27)‐C(28)‐C(29)
C(27)‐C(28)‐H(34)
C(29)‐C(28)‐H(34)
C(28)‐C(29)‐C(30)
C(28)‐C(29)‐H(35)
C(30)‐C(29)‐H(35)
C(29)‐C(30)‐C(31)
C(29)‐C(30)‐H(36)
C(31)‐C(30)‐H(36)
C(30)‐C(31)‐C(32)
C(30)‐C(31)‐C(37)
C(32)‐C(31)‐C(37)
N(26)‐C(32)‐C(27)
N(26)‐C(32)‐C(31)
C(27)‐C(32)‐C(31)
C(31)‐C(37)‐O(38)
125.3362
125.87
115.532
129.0757
115.2421
109.1395
111.3258
110.8814
109.2108
108.7208
107.5059
131.4356
120.4547
120.163
119.3733
120.1853
119.757
120.0572
120.2606
120.1174
119.6125
119.3279
121.7292
118.9309
121.2402
119.8272
118.9326
127.1277
113.722
FIGURE 2 The different molecular orbitals of ligand (HL), (a)
HOMO, (b) HOMO‐1, (c) HOMO‐2, (d) HOMO‐3, (e) LUMO, (f)
LUMO + 1, (g) LUMO + 2 and (h) LUMO + 3
TABLE 2 The different quantum chemical parameters of HL ligand
The calculated quantum chemical parameters
E (a.u.)
−1062.74
10.15
Dipole moment (Debye)
EHOMO (eV)
ELUMO (eV)
ΔE (eV)
‐0.221
−0.081
0.139
118.4141
107.1679
χ(eV)
0.151
η (eV)
σ (eV)‐1
0.0695
14.38
i The data of HL had a great chance and priority for biolog-
ical activity based on high ω value.
Pi (eV)
S (eV)‐1
−0.151
7.194
ii S and ω were the softness indexes while η is for hardness
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 investigated HL molecule was soft
towards the coordination.
ω (eV)
0.164
ΔNmax
2.171
molecule capable of accepting electrons from the envi-
ronment and its energy must decrease upon accepting
electronic charge. Therefore, the electronic chemical
potential must be negative.[25]
iii The positive electrophilicity index (χ) value and the neg-
ative chemical potential (Pi) value indicated that the HL

MAHMOUD ET AL.
9 of 19
iv The total energy of free ligand was small, which indi-
cated greatly the stability of the isolated Schiff base
ligand.
v The small energy gap can be associated with a high
chemical reactivity, low kinetic stability and reflects to
efficient electronic charge transfer interaction making
the molecule highly polarizable.
and it was represented by green color. These sites gave
information about the regions that can be considered as a
site of electrophilic attack by the metal ions during
complextion process.[29,30]
3.1.3 | Mulliken charge analyses
Mullikan atomic charges for some important atoms were
calculated and the data are listed in Table 3 and shown in
Figure 4. The calculation of atomic charges plays an impor-
tant role in the application of quantum mechanical calcula-
tions to molecular systems.[31] From Table 3, the calculated
charge value for N and O are −0.292 and −0.282 a.u., indi-
cates the high electronegativity around them and high prob-
ability of electron transfer from these atoms to metal center
in the proposed complexes. Oxygen and nitrogen atoms in
HL had more negative charges than the other atoms. The
C21, C32 and C37 atoms had higher positive atomic charges
than the other carbon atoms. This was due to the electro-
negative atoms such as oxygen and nitrogen attached to
3.1.2 | Molecular electrostatic potential (MEP)
The MEP is a plot of electrostatic potential mapped onto
the constant electron density surface. It is also very useful
in research of molecular structure with its physiochemical
property relationship as well as hydrogen bonding interac-
tions.[26–28] The electrostatic potential V(r) at a given point
r (x, y, z) is defined in terms of the interaction energy
between the electrical charge generated from the molecule
electrons, nuclei and proton located at r. Computation of
electrostatic potential is possible for molecules using the
G‐point and multiple k‐points. In this study, 3D plots of
molecular electrostatic potential (MEP) of ligands
Figure 3 has been drawn. The maximum negative region
which is preferred site for electrophilic attack indications
represented as red color, the maximum positive region
which is preferred site for nucleophilic attack symptoms
as blue color. Potential increases in the order red < green
< blue, where blue shows the strongest attraction and red
shows the strongest repulsion. Regions having the negative
potential are over the electronegative atoms while the
regions having the positive potential are over the hydrogen
atoms.[26] The MEP showed that the negative potential site
was situated over carboxylate oxygen and nitrogen atom
and the positive potential site were present around the
hydrogen atoms. The regions over the rings were neutral
TABLE 3 The different Mulliken charges of HL Ligand
HL
Atom
Mulliken charges
Fe
0.151382
0.028469
0.024879
0.023809
0.032548
0.021314
0.026685
0.031283
0.010986
0.254275
‐0.05782
0.045172
‐0.04979
‐0.29154
‐0.0559
C2
C3
C4
C5
C6
C12
C13
C14
C15
C16
C21
C22
N26
C27
C28
C29
C30
C31
C32
C37
O38
O39
0.005229
‐0.00292
‐0.05411
0.016685
0.28217
0.158256
‐0.28225
‐0.01606
FIGURE 3 Molecular electrostatic potential map of HL ligand, The
electron density isosurface is 0.004 a.U

10 of 19
MAHMOUD ET AL.
found at 1615 cm−1. It was noted that the calculated values
were close to the theoretical data of 1650 cm−1, see
Figure 5.
3.2 | Characterization of ligand metal
complexes
The new Schiff base ligand (HL) and its Cr(III), Mn(II),
Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) complexes
were characterized using different spectroscopic techniques,
elemental analyses, magnetic, solid reflectance and thermal
studies.[32] Accordingly, the structure of HL ligand is given in
Figure 1.
FIGURE 4 Mullikan charges for free HL ligand
carbon atoms. Mulliken method was used for predicting the
suitable sites of coordination to the metal ions present in
Schiff base HL ligand, which was also estimated from
MEP analysis.[29–31]
3.2.1 | Elemental analysis
The stoichiometry and formulation of the HL (Figure 1) and
its metal complexes were confirmed by their elemental anal-
ysis. The metal/ligand ratio was found to be 1:1 in all com-
plexes, which have been arrived by estimating the carbon,
hydrogen, nitrogen, chloride and metal contents of the com-
plexes. The elemental analyses of the ligand and its com-
plexes reveal good agreement with the proposed structures.
The ligand and its metal complexes have high melting points,
and they are found to be air stable. The Ligand is soluble in
common organic solvents, and all the complexes are freely
soluble in DMF and DMSO but insoluble in methanol, etha-
nol and water.[33]
3.1.4 | Vibrational properties
Theoretical harmonic vibrational analysis has been also per-
formed based on the optimized geometry. It was well known
that the vibrational frequencies computed at quantum chemi-
cal methods such as DFT levels contain well‐known system-
atic errors. The scaling factor of 0.96 for LanL2DZ level was
used to correct the effects of anharmonicity and neglected
part of electron correlation.[32–34] The FT‐IR and its theoret-
ical corresponding spectra for HL were shown in Figure 5.
The stretching vibration of a free or non‐hydrogen bonded
OH group appeared experimentally at 3453 cm−1 [34]
The
.
OH stretching mode of HL was calculated theoretically at
3469 cm−1. The stretching vibration of C=N group was
3.2.2 | Molar conductivity measurements
The metal (II) and (III) complexes were dissolved in DMF or
DMF:DMSO (1:1) and molar conductivities of the solutions
at room temperature were measured. The conductance data
indicates that some of the metal complexes are having con-
ductivity values in accordance with electrolytes.[34,35]
The results given in Table 4 showed that the Cr(III) and
Fe(III) complexes had molar conductivity values of 80.8 and
85.1 Ω−1 mol−1 cm2, respectively, which indicated the ionic
nature of these complexes and hence their electrolytic nature.
The molar conductivity values of Mn(II), Co(II), Ni(II), Cu(II),
Zn(II) and Cd(II) chelates under investigation (Table 2) were
found to be 31.6, 17.7, 22.5, 11.2, 10.1 and 6.4 Ω−1 mol−1
cm2, respectively. It is obvious from these data that these che-
lates are non‐ionic in nature and hence non‐electrolyte.[36]
3.2.3 | IR spectra
The characteristic peaks of the free Schiff base ligand and its
metal complexes were listed in the experimental part, where
the band assignments of the guide bands (those affected by
coordination) have been given. The characteristic O—H,
C=O and C=N bands were observed in the IR spectrum of
FIGURE
experimental spectrum
5
IR spectra of HL (a) theoretical spectrum, (b)

MAHMOUD ET AL.
11 of 19
TABLE 4 Thermoanalytical results (TG and DTG) of HL ligand and its metal complexes
TGA
range
(°C)
Mass loss%
Total mass
loss% Found
(calcd)
Compound
HL
Ts(°C)
n* Found Calcd.
Assignment
Residue
45–365
365–480
136, 315
370, 405.5
2
2
30.94 31.12
39.89 41.21
70.83
(72.33)
Loss of C7H10
N
FeO + 2C
Loss of C10H7O
[Cr(L)(Cl)(H2O)3]
Cl.2H2O
45–250
250–1000 365, 529, 1000
97, 207
2
3
19.1
54.86 54.11
19.40
73.96
(73.51)
Loss of 4H2O and HCl
Loss of C19H17ClNO0.5
1/2 Cr2O3 + FeO
MnO + FeO
[Mn(L)(Cl)(H2O)3].
H2O
45–255
255–670
118
382, 575
1
2
31.47 30.05
40.34 41.74
71.93
(71.79)
Loss of 4H2O and C5H7N
Loss of C14H9Cl
[Fe(L)(Cl)(H2O)3]Cl.
H2O
45–500
501–740
92, 310
616
2
1
46.22 46.05
24.17 23.85
70.39
(70.0)
Loss of 3H2O and C14H15
Loss of C5H7Cl2O0.5
N
1/2 Fe2O3 + FeO + C
CoO + FeO
[Co(L)(Cl)(H2O)3].
H2O
45–385
385–630
103, 293
519
2
1
29.99 30.21
41.92 41.03
71.91
(71.24)
Loss of 4H2O and C5H9N
Loss of C14H7Cl
[Ni(L)(Cl)(H2O)3]
45–625
118, 347
2
67.94 67.97
67.94
(67.97)
Loss of 3H2O and C18H16ClN
NiO + FeO + C
CuO + FeO + C
ZnO + FeO
[Cu(L)(Cl)(H2O)3]
45–285
285–575
100, 229
356, 575
2
2
26.56 26.65
40.35 40.58
66.91
(67.23)
Loss of 3H2O and C5H5N
Loss of C13H11Cl
[Zn(L)(Cl)
(H2O)3].2H2O
45–520
520–915
125, 347
651
2
1
41.49 41.37
29.14 29.46
70.62
(70.72)
Loss of 5H2O and C9H10
N
Loss of C10H6Cl
[Cd(L)(Cl)
(H2O)3].3H2O
45–380
380–565
134, 329
421, 502
2
2
28.70 28.73
37.38 37.95
66.07
(66.68)
Loss of 6H2O and C4H3N
Loss of C15H14Cl
CdO + FeO
HL ligand at 3453, 1780 and 1615 cm−1, respectively. The IR
spectrum of HL showed broad band of carboxylic acid at
3453 cm−1 which still broad in the range of 3409–3449 cm
DMSO‐d6 and in the deutrated solvent.[38] The H NMR
spectrum of HL showed a peak at 11.41 ppm which was
attributed to proton of the carboxylic acid group.[39] This
peak was disappeared in the spectra of Zn(II) and Cd(II) com-
plexes, indicating that the carboxylic group played important
part in coordination. The aromatic ring protons were
observed as a multiplet, in the range 6.47–7.98 ppm. The
1H NMR spectrum of the ligand revealed signals at 4.23–
4.77 ppm (m, 9H, ferrocene rings), while for Zn(II) and
Cd(II) complexes the signals were at 3.34 and 3.50 ppm
(m, 9H, ferrocene rings), respectively, which can assigned
to the aromatic protons.[40]
1
−1
in the metal ion complexes. The expected azomethene
C=N appears in the ligand at 1615 cm−1 and in its metal
complexes in the range of 1615–1654 cm−1. The absence of
ν(C=O) stretching vibration bands in the spectra of Cr(III),
Co(II), Zn(II) and Cr(II) complexes indicates strongly the
involvement of carboxylic group in the coordination process.
Other characteristic strong bands appearing in the metal ion
complexes around 1560–1600 cm−1 and 1425–1448 cm−1
were attributed to νasym(COO−) and νsym(COO−), respec-
tively. The difference (= ~135 cm−1) between νasym(COO−)
and νsym(COO−) confirms the coordination mode of the car-
boxylate group.[37] The ν(M‐O) stretching vibration of coor-
dinated water was appeared in the range of 537–555 cm−1
in all of the complexes. New band appeared in the range of
473–493 cm−1 indicates the M‐N interaction. From the spec-
tra and the chemical structure of HL ligand proposed in Fig-
ure (1), it can conclude that the Schiff base ligand could be
considered as mononegative bidentate ligand and coordinated
to the metal ions via deporotenated carboxylate oxygen atom
and azomethene nitrogen.
3.2.5 | UV‐visible spectra of ligand and its
metal complexes
The electronic spectral data of Schiff base ligand (HL) and its
transition metal complexes were recorded in 10−4 and
5x10−4 M DMF solution (Figure S6). The electronic absorp-
tion spectrum of HL gave sharp band at 268 nm which was
mainly attributed to the locally excited intraligand π ! π*
transitions.[41] All the complexes apparently displayed a high
intensity band in the 268–289 nm regions, attributable to the
π ! π* intra‐ligand transition and a medium intensity band
in 314–381 nm regions, assigned to n ! π* transition.[42]
Expectedly, Co(II) and Zn(II) complexes displayed a low
intensity broad band in the 537–674 nm regions attributed
to the d‐d transitions.[43]
3.2.4 | 1H NMR spectra
Proof of the type of bonding of HL with the metal ions was
also confirmed by recording their 1H NMR spectra in

12 of 19
MAHMOUD ET AL.
theoretically calculated mass losses are in a good agreement
in accordance of the observed ones. The discrepancies can
be explained by the simultaneously running thermal
processes.[45]
3.2.6 | Mass spectra
The iron complex also exhibited peaks at m/z 495 (calcd. =
545; M‐3H2O), characteristic of the [Fe(L)(Cl)(H2O)3]Cl.
[12]
H2O
(Figure S7). The molecular ion peak undergoes
The thermal properties of HL and its binary metal com-
plexes were investigated using TG and DTG under nitrogen
atmosphere with a heating rate of 10°C min−1 and the data
obtained were listed in Table 4. It was carried out from the
ambient temperature up to 1000°C to investigate the thermal
stabilities of these new metal complexes and to decide whether
the water molecules (if present) were inside or outside the
inner coordination sphere of the central metal ion.[46,47]
The thermogram of [Cr(L)(Cl)(H2O)3]Cl.2H2O com-
plex showed five decomposition steps within the temperature
range of 45–1000°C. The first and second decomposition
steps accompanied by loss of two uncoordinated water, two
coordinated water and HCl molecules in the temperature
range of 45–250°C with an estimated weight loss of
19.10% (calcd. 19.40%). The three final stages of decomposi-
tion showed loss of C19H17ClNO0.5 molecule at 250–1000°C
with an estimated weight loss of 54.86% (calcd. 54.11%).
Thereafter the percentage of the residue corresponds to chro-
mium oxide contaminated with iron(II) oxide and the total
estimated weight loss is found to be 73.96% (calcd.
73.51%).[48,49] TG curve of the [Mn(L)(Cl)(H2O)3].H2O
complex showed three steps of decomposition. The first stage
of decomposition occurred in the 45–255°C temperature
range and corresponds to the loss of one uncoordinated water,
three coordinated water and C5H7N molecules. It is accompa-
nied by a weight loss of 31.47% (calcd. 30.05%). The second
and third stages of decomposition involve the removal of
C14H9Cl molecule in the 479–668°C temperature range,
and were accompanied by a weight loss of 40.34% (calcd.
41.74%). The total weight loss amounts to 71.93% (calcd.
71.79%) leaving manganese oxide as a residue contaminated
with iron(II) oxide. The thermogram of [Fe(L)(Cl)(H2O)3]
Cl.H2O complex loses weight equal to 46.22% (calcd.
46.05%) in the temperature range of 45–500°C. This corre-
sponds to loss of three water molecules and C14H15N mole-
cule in the first two stages of decomposition. In the third
stage, the complex shows removal of C5H7Cl2O0.5 molecule
at 500–740°C with an estimated weight loss of 24.17%
(calcd. 23.85%). The total weight loss amounts to 70.39%
(calcd. 70.0%) leaving ferrous and ferric oxide as a residue
contaminated with carbon. The thermogram of [Co(L)(Cl)
(H2O)3].H2O complex loses weight equal to 29.99% (calcd.
30.21%) in the temperature range of 45–385°C. This corre-
sponds to loss of one uncoordinated water, three coordinated
water and C5H9N molecule in the first and second stages of
decomposition. In the third stage, the complex showed
removal of C14H7Cl molecule at 385–630°C with a practical
weight loss of 41.92% (calcd. 41.03%). The total weight loss
amounts to 71.91% (calcd. 71.24%) leaving cobalt oxide as a
fragmentation and displayed multiple peaks corresponding
to successive degradation of the complex (Scheme 1).[44]
The expected molecular ion peak appeared at m/z
346.87 amu in the mass spectrum of the complex assignable
to the parent ion of HL ligand [C19H17FeNO2] in the complex.
3.2.7 | Thermal analysis of the metal
complexes
The thermal behavior of all metal complexes, Cr(III), Mn(II),
Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II), is generally
similar. A certain difference comes from the loosing of coor-
dinated water molecules, if it is present. Several effects were
observed on the TG and DTG curves, see Table 4. The
SCHEME 1 Suggested mass fragmentation of [Fe(L)(Cl)(H2O)3]Cl.
H2O complex

MAHMOUD ET AL.
13 of 19
residue contaminated with iron(II) oxide. For [Ni(L)(Cl)
(H2O)3] complex, it decomposed in two steps of decomposi-
tion associated with the removal of three coordinated water
and C18H16ClN molecules in the temperature range of 45–
625°C. The estimated total weight loss of 67.94% (calcd.
67.91%) leaving nickel oxide as a residue contaminated with
iron(II) oxide. TG curve of the [Cu(L)(Cl)(H2O)3] complex
showed four steps of decomposition. The first and second
stages of decomposition occurred in the 45–285°C tempera-
ture range, corresponding to the loss of three coordinated
and C5H5N molecule, and is accompanied by a weight loss
of 26.56% (calcd. 26.65%). The third and fourth stages of
decomposition involved the removal of C13H11Cl molecule
in the 285–575°C temperature range, and are accompanied
by a weight loss of 40.35% (calcd. 40.58%). The total weight
loss amounts to 66.91% (calcd. 67.23%) leaving copper oxide
contaminated with ferrous oxide as final residue.
TG curve of the [Zn(L)(Cl)(H2O)3].2H2O complex
showed three steps of decomposition. The first and second
steps of decomposition occurred in the temperature range of
45–520°C are associated with the loss of two uncoordinated
water, three coordinated water and C9H10N molecules with
an estimated weight loss of 41.49% (calcd. 41.37%). The
third step of decomposition occurs in the temperature range
of 520–915°C is associated with the loss of C10H6Cl mole-
cule and with an estimated weight loss of 29.14% (calcd.
30.10%). Thereafter the weight of the residue corresponds
to zinc oxide contaminated with ferrous oxide as a residue
and the total estimated weight loss of 70.62% (calcd.
71.47%). TG curve of the [Cd(L)(Cl)(H2O)3].3H2O com-
plex showed four steps of decomposition. The first and sec-
ond steps of decomposition occurred in the temperature
range of 45–380°C and are associated with the loss of three
hydrated water, three uncoordinated water and C4H3N mole-
cules with an estimated weight loss of 28.70% (calcd.
28.73%). The third and fourth steps of decomposition
occurred in the temperature range of 380–565°C and are
associated with the loss of C15H13Cl molecule and with an
FIGURE 6 The structure of metal complexes. a) In case of Cr(III)
and Fe(III) complexes (where n = 2 for Cr(III) complex and n = 1 for
Fe(III) complex). b) In case of Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and
Cd(II) complexes (where n = 3 for Cd(II) complex, n = 2 for Zn(II)
complex, n = 1 for Mn(II) and Co(II), and n = 0 for Ni(II) and Cu(II))
FIGURE 7 Biological activity of HL ligand and its metal complexes

14 of 19
MAHMOUD ET AL.
TABLE 5 Biological activity of HL ligand and its metal complexes
Inhibition zone diameter (mm/mg sample)
Gram (+) Bacteria
Aspergillus Syncephalastrum Geotricum Candida Streptococcus Bacillis Pseudomonas Escherichia
(Fungi)
Gram (−) Bacteria
Sample
fumigatus
racemosum
candidum albicans pneumoniae subtilis aeruginosa
coli
Standard (1): Amphotericin
Standard (2): Ampicillin
Standard (3): Getamicin
HL
24
‐‐‐‐
‐‐‐‐
0
20
‐‐‐‐
‐‐‐‐
0
29
‐‐‐‐
‐‐‐‐
0
25
‐‐‐‐
‐‐‐‐
13
17
25
14
13
16
18
15
11
‐‐‐‐
24
‐‐‐‐
10
16
24
17
15
17
18
17
13
‐‐‐‐
32
‐‐‐‐
12
18
32
18
16
19
27
18
13
‐‐‐‐
‐‐‐‐
17
13
12
17
13
10
13
19
11
12
‐‐‐‐
‐‐‐‐
20
17
15
20
15
10
14
18
12
11
[Cr(L)(Cl)(H2O)3]Cl.2H2O
[Mn(L)(Cl)(H2O)3].H2O
[Fe(L)(Cl)(H2O)3]Cl.H2O
[Co(L)(Cl)(H2O)3].H2O
[Ni(L)(Cl)(H2O)3]
17
24
0
13
20
12
11
13
17
14
17
19
29
14
17
20
22
18
13
16
17
21
16
19
[Cu(L)(Cl)(H2O)3]
[Zn(L)(Cl)(H2O)3].2H2O
[Cd(L)(Cl)(H2O)3].3H2O
estimated weight loss of 37.38% (calcd. 37.95%). Thereafter
the weight of the residue corresponds to cadmium oxide con-
taminated with iron(II) oxide with total weight loss percent-
age of 66.07% (calcd. 66.68%).
antimicrobial activity of the metal complexes depending on
the following five principal factors[37,50]
(i) the chelate effect, (ii) the nature of coordinated
ligands, (iii) the total charge of the complex, (iv) the nature
:
3.3 | Structural interpretation
On the basis of various physico‐chemical and spectral data
presented and discussed above, the structures of the
complexes have been confirmed and the proposed structural
formulas of the complexes were shown in Figure 6.
3.3.1 | Antimicrobial activities
Antibacterial activity of the Schiff base ligand and its metal
complexes was investigated by a previously reported
modified disc diffusion method,[48] against different bacterial
species, such as: two Gram‐negative, Pseudomonas
aeruginosa and Escherichia coli and two Gram‐positive,
Streptococcus pneumoniae and Bacillis subtilis and against
different
fungi
such
as:
Aspergillus
fumigatu,
Syncephalastrum racemosum, Geotricum candidum and
Candida albicans. The efficiencies of the ligand and the
metal complexes have been tested against two Gram (+ve),
two Gram (−ve) and four different fungi (Figure 7). The
ligand and all complexes have inhibitory action against all
microorganisms (Table 5). The metal complexes exhibit
higher inhibition against all microorganisms tested compared
with free HL ligand.[49] The biological activity of many ferro-
cenes increased after the coordination with metal. The rate of
FIGURE 8 Activity index of HL ligand and its metal complexes
against (a) different fungal species (b) different bacterial species

MAHMOUD ET AL.
15 of 19
of the ion neutralizing the ionic complex, (v) the nuclearity of
the metal center in the complex.
RNA) and Inhibition of enzymes and antimetabolites e.g folic
acid synthesis.
Also according to the overtone concept of all permeabil-
ity, the lipid membrane that surrounds the cell favors the pas-
sage of only lipid soluble materials in which liposolubility is
an important factor that controls the antimicrobial activity.
On chelation the polarity of the metal ion will be reduced to
a greater extent due to overlap of ligand orbital and partial
sharing of the positive charge of the metal ion with donor
groups. Further it increases the delocalization of π‐electrons
over the whole chelate ring and enhances the lipophilicity
of the complexes.[51] This increased lipophilicity enhances
the penetration of the complexes into the lipid membranes
and blocks the metal binding sites in enzymes of microorgan-
isms. Finally, the mechanism of action of chemicals and
antibiotics against bacteria may be one or more of the follow-
ings: Damage of cell wall, inhibition of plasma membrane
functions (permeability and energy generation), inhibition
of protein synthesis, inhibition of nucleic acids (DNA or
The HL–metal complexes of Mn(II), Cu(II) and Ni(II)
showed specific antifungal activity of inhibition zone of
diameter ranged from 13.0 to 29.0 mm.[52] All the complexes
showed definite bacterial growth inhibition for the four organ-
isms with inhibition zone diameter ranged from 10.0 to
32.0 mm. The results of antimicrobial activities are presented
inTable 5. The HL ligand showed activity against the four bac-
terial organisms in the range of 10.0–17.0 mm [53]. The Cr(III),
Mn(II) and Cu(II) complexes showed the best bacterial inhibi-
tion among all the complexes with inhibition zone diameter
ranged from 12.0 to 32.0 mm indicating that the coordination
of the HL ligand to these metal complexes has enhanced its
antimicrobial activity.[36]
The activities of the prepared ferrocene based Schiff
base ligand and its metal complexes were confirmed by
calculating the activity index according to the following
relation:[54,55]
TABLE 6 Antibreastic cancer activity of HL ligand and its metal complexes
Surviving fraction (MCF7)
IC50
Complex
HL
Conc. (μg/ml)
0.0
5
12.5
25
50
(μg/ml)
1
1
1
1
1
1
0.944
0.944
0.819
0.761
0.738
0.904
0.676
0.840
0.561
0.476
0.523
0.690
0.440
0.520
0.441
0.333
0.390
0.333
0.276
0.356
0.142
0.180
0.347
0.214
21.5
27.7
18.7
11.7
14.7
19.0
[Cr(L)(Cl)(H2O)3]Cl.2H2O
[Mn(L)(Cl)(H2O)3].H2O
[Co(L)(Cl)(H2O)3].H2O
[Zn(L)(Cl)(H2O)3].2H2O
[Cd(L)(Cl)(H2O)3].3H2O
FIGURE 9 Antibreastic cancer activity of HL ligand and its metal complexes

16 of 19
MAHMOUD ET AL.
TABLE 7 Energy values obtained in docking calculations of HL with receptors of DNA of human‐DNA‐Topo I complex (1SC7), the receptors of
breast cancer mutant oxidoreductase (3HB5), crystal structure of Escherichia coli (3 T88)
Receptor
Ligand moiety
Receptor site
Interaction
Distance (Aο)
E (kcal mol−1
)
1SC7
O 18
Fe 28
C 23
NZ LYS 493
OD1 ASP 533
OD1 ASP 533
H‐acceptor
metal
H‐acceptor
2.98
2.87
3.86
−3.5
‐0.7
−0.8
3Hb5
3 T88
O 18
Fe 28
N ILE 14
O GLY 92
H‐acceptor
metal
3.08
2.09
−2.6
‐1.9
O 19
Fe 28
O ASP 67
O ASP 32
H‐donor
metal
2.82
2.25
−2.8
‐0.9
Inhibition Zone of compound ðmmÞ
Inhibition Zone of standard drug ðmmÞ
such that the free energy of the overall system was min-
imized. Molecular docking of HL ligand with DNA of
human‐DNA‐Topo I complex (1SC7), the receptors of
breast cancer mutant oxidoreductase (3HB5), crystal
structure of Escherichia coli (3 T88), was performed by
the MOE 2008 program suite. The crystal structures of
the complexes were used as docking protocols. All
hydrogen atoms were added at every inhibitor enzyme
interaction[64] as shown in Figure 8 and the calculated
energy was listed in Table 7. According to the results
obtained, the Schiff base ligand binds to the proteins
with hydrogen bond interactions and decomposed
Activity index ðAÞ ¼
×100
From the data, it is concluded that Mn(II) complex had
the highest activity index, while Fe(III) complex had the low-
est activity index, see Figure 8.[56]
3.3.2 | Anticancer activities
Anticancer activity screening for the tested compounds
utilizing four different human tumor cell lines concentra-
tions of breast cancer cell line MCF‐7 were obtained from
the National Cancer Institute, Cancer Biology Department,
Pharmacology Department, Cairo University. The relation
between both the surviving fraction and HL ligand con-
centration was plotted to get the survival curve for each
cell line after the specified time. The concentration
required for 50% inhibition of cell viability (IC50) was
calculated and the results are given in Table 6 and are
shown in Figure 9.[57] From the results, it is clear that
Cr(III), Mn(II), Co(II), Zn(II) and Cd(II) complexes are
moderately active against breast cancer cells with inhibi-
tion ratio of 60–68% against breast cancer cells. It is clear
that a pattern of activity can be determined using different
ligand concentrations (Table 6 and Figure 9). The IC50
values are found to be 27.7, 18.7, 11.7, 14.7 and
19.0 μg ml−1 for Cr(III), Mn(II), Co(II), Zn(II) and
Cd(II) complexes, respectively. It is clear that the cobalt
(II) complex has an outstanding IC50 value of 11.7 μg
ml−1 and a very low concentration of this complex can
be used to produce 50% inhibition of cell growth.[58]
3.3.3 | Molecular modeling of HL ligand:
Docking study
Molecular docking is a key tool in computer drug
design.[59–63] The focus of molecular docking is to simu-
late the molecular recognition process. Molecular docking
aims to achieve an optimized conformation for both the
protein and drug with relative orientation between them
FIGURE 10 3D plot of the interaction between HL ligand with
receptors of (a) 1Sc7, (b) 3HB5 and (c) 3 T88 and 3D plot of the
interaction between [Mn(L−)(Cl)(H2O)3].H2O complex with receptors
of (d) 1Sc7, (e) 3HB5 and (f) 3 T88

MAHMOUD ET AL.
17 of 19
TABLE 8 Energy values obtained in docking calculations of [Mn(L−)(Cl)(H2O)3].H2O with receptors of DNA of human‐DNA‐Topo I complex
(1SC7), the receptors of breast cancer mutant oxidoreductase (3HB5), crystal structure of Escherichia coli (3 T88)
Receptor
Ligand moiety
Receptor site
Interaction
Distance (Aο)
E (kcal mol−1
)
1SC7
O 18
Fe 28
C 23
NZ LYS 493
OD1 ASP 533
OD1 ASP 533
H‐acceptor
metal
H‐acceptor
2.98
2.87
3.86
−3.5
‐0.7
−0.8
3Hb5
3 T88
O 18
Fe 28
N ILE 14
O GLY 92
H‐acceptor
metal
3.08
2.09
−2.6
‐1.9
O 19
Fe 28
O ASP 67
O ASP 32
H‐donor
metal
2.82
2.25
−2.8
−0.9
interaction energies in kcal mol−1 exist between HL
ligand with 1SC7, 3HB5 and 3 T88 receptors as shown
in Figure 10. Three‐dimensional plot curves of docking
with HL ligand are shown in Figure 10. The Schiff base
ligand shows a stronger interaction with 1SC7 receptor
than the other receptors.
inhibitory activity against breast carcinoma (MCF7 cell line).
In particular, Co(II) and Zn(II) complexes show high antican-
cer activity with low IC50 values of 11.7 and 14.7 μg ml−1
,
respectively. Molecular docking studies of the free Schiff
base ligand and Mn(II) complex with receptors of (PDB ID:
1SC7, 3HB5 and 3 T88) reveal that HL ligand and Mn(II)
complex show highest binding ability (with binding energy
of −3.5 and −3.4 kcal mol−1, respectively) with human‐
DNA‐Topo I complex (1SC7) and crystal structure of
Escherichia coli (3 T88), respectively.
The binding of HL and its Mn(II) complex with DNA
were performed. The minimum binding energies were
found to be −3.5 and −3.4 kcal mol−1 for HL and
[Mn(L)(Cl)(H2O)3].H2O, respectively. The minimum energy
docked pose revealed that the Mn(II) complexs fitted into
the curve contour of the targeted DNA in the groove.
Moreover, −OH group of the Mn(II) complex acted as
strong H‐bond donors or acceptors and were engaged in
hydrogen‐bonding interactions with O THR 117 in the
DNA. The results correlating well with the experiment
express that the more polar a compound located at almost
the same binding area has, the smaller binding energy is.
Molecular docking techniques substantiate the experimental
results reported here and at the same time provide further
evidence of minor groove binding. It was concluded that
the docking study showed a favorable interaction between
the HL and its Mn(II) complex and the receptors (1SC7,
3HB5 and 3 T88) as shown in Figure 10 and the calculated
energy was listed in Tables 7, 8.
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How to cite this article: Mahmoud WH, Mahmoud
NF, Mohamed GG. Synthesis, physicochemical
characterization, geometric structure and molecular
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Schiff base ligand with transition metal ions. Appl
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