Spectroscopic characterization and molecular docking studies of acetyl ferrocene-derived Schiff base ligand with phenanthroline and some transition metal ions

Article abstract of DOI:10.1007/s10973-017-6735-0

As a part of systematic investigation of the reactivity of a novel ferrocene-based Schiff base ligand, HL ligand was synthesized by condensation of 2-acetylferrocene with 2-aminophenol and mixed with 1,10-phenanthroline to give new mixed chelates. Series of transition metal ions Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) complexes were synthesized. The structures of the ligand and mixed ligand complexes were confirmed by elemental analysis, spectroscopic studies [IR, ¹H NMR, UV–Vis, mass spectrometry, SEM] and thermal analysis (TG/DTG). The molar conductance measurements of the complexes in DMF determine electrolytic and non-electronic nature of the complexes. Significant applications have been done to ensure the biological importance of the new mixed metal complexes like antimicrobial activities (four bacterial organisms and four fungal organisms), anticancer activities (MCF7 breast cancer cell line) and Molecular Operating Environment studies with the crystal structure of acetylcholinesterase (PDB: 1B41), the synthetic DNA dodecamer (PDB: 1BNA) and virus protein U (Vpu) of human immune deficiency virus (HIV-1) (PDB: 2N28).

Full text of DOI:10.1007/s10973-017-6735-0

J Therm Anal Calorim
DOI 10.1007/s10973-017-6735-0
Spectroscopic characterization and molecular docking studies
of acetyl ferrocene-derived Schiff base ligand with phenanthroline
and some transition metal ions
1
1
1,2
W. H. Mahmoud
•
N. F. Mahmoud
•
G. G. Mohamed
Received: 18 June 2017 / Accepted: 23 September 2017
Ó Akad e´ miai Kiad o´ , Budapest, Hungary 2017
Abstract As a part of systematic investigation of the
reactivity of a novel ferrocene-based Schiff base ligand,
HL ligand was synthesized by condensation of 2-acetyl-
ferrocene with 2-aminophenol and mixed with 1,10-
phenanthroline to give new mixed chelates. Series of
transition metal ions Cr(III), Mn(II), Fe(III), Co(II), Ni(II),
Cu(II), Zn(II) and Cd(II) complexes were synthesized. The
structures of the ligand and mixed ligand complexes were
confirmed by elemental analysis, spectroscopic studies [IR,
Introduction
Interest in coordination chemistry is increasing continu-
ously with the preparation of inorganic ligands containing a
variety of donor groups, and it is multiplied manifold when
the ligands have biological importance [1]. Schiff base
complexes of transition metals are of particular interest to
inorganic chemists because their structural, spectral and
chemical properties are often strongly dependent on the
nature of the ligand structure [2]. A large number of Schiff
bases and their complexes have been studied for their
interesting and important properties, e.g., their ability to
reversibly bind oxygen, catalytic activity in hydrogenation
of olefins, transfer of an amino group, photochromic
properties and complexing ability toward some toxic met-
als [3]. Schiff bases are also superior reagents in biological,
pharmacological, clinical and analytical applications [4].
Metal complexes of these ligands possess a wide spectrum
of medicinal properties. Schiff bases and their metal
complexes have played important roles in the development
of chemical industries through catalysis, substrate carriers
and dyes [5–7]. These ligands are widely studied because
of their pronounced coordinating properties and stability
[8, 9]. A number of symmetrical Schiff bases and chelates
have been reported [10–13], while comparatively little is
known on synthesis and physicochemical properties of
Schiff base ligands and metal complexes [14–19].
1
H NMR, UV–Vis, mass spectrometry, SEM] and thermal
analysis (TG/DTG). The molar conductance measurements
of the complexes in DMF determine electrolytic and non-
electronic nature of the complexes. Significant applications
have been done to ensure the biological importance of the
new mixed metal complexes like antimicrobial activities
(
four bacterial organisms and four fungal organisms),
anticancer activities (MCF7 breast cancer cell line) and
Molecular Operating Environment studies with the crystal
structure of acetylcholinesterase (PDB: 1B41), the syn-
thetic DNA dodecamer (PDB: 1BNA) and virus protein U
(
Vpu) of human immune deficiency virus (HIV-1) (PDB:
N28).
2
Keywords Mixed ligand chelates Á IR Á Molar
conductance Á Antimicrobial Á Breast cancer Á Molecular
Operating Environment
So, the aim of this work is to synthesize and characterize
Schiff base HL ligand (Fig. 1) and its mixed ligand che-
lates with 1,10-phenanthroline with eight transition metal
ions: Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II)
and Cd(II), in order to study the effect of the mixed ligand
systems on physicochemical properties and their biological
applications.
&
G. G. Mohamed
ggenidy@hotmail.com
1
2
Chemistry Department, Faculty of Science, Cairo University,
Giza 12613, Egypt
Egypt Nanotechnology Center, Cairo University,
El-Sheikh Zayed, 6th October City, Giza 12588, Egypt
123

W. H. Mahmoud et al.
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 (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 nor-
mal saline and was used for viability counting. 10% Fetal
bovine serum (FBS) (heat inactivated at 56 °C for 30 min),
N
HO
Fe
Fig. 1 Structure of ferrocene Schiff base ligand (HL)
Experimental
-1
-1
1
00 units mL penicillin and 2 mg mL streptomycin
were supplied from Sigma Chemical Co., St. Louis, Mo,
USA, and were used for the supplementation of RPMI-
Material and reagent
1640 medium prior to use. 0.025% (w/v) trypsin (Sigma
All chemicals used were of the analytical reagent grade
Chemical Co., St. Louis, Mo, USA) was used for the har-
vesting of cells. 1% (v/v) Acetic acid (Sigma Chemical
Co., St. Louis, Mo, USA) was used for dissolving the
unbound SRB dye. 0.4% Sulforhodamine-B (SRB) (Sigma
Chemical Co., St. Louis, Mo, USA) dissolved in 1% acetic
acid was used as a protein dye. A stock solution of tri-
chloroacetic acid (TCA, 50%, Sigma Chemical Co., St.
Louis, Mo, USA) was prepared and stored. 50 lL of the
stock was added to 200 lL RPMI-1640 medium/well to
yield a final concentration of 10% used for protein pre-
cipitation. 100% Isopropanol and 70% ethanol were used.
Tris base 10 mM (pH 10.5) was used for SRB dye solu-
bilization. 121.1 g of Tris base was dissolved in 1000 mL
of distilled water, and pH was adjusted by HCl acid (2 M).
(
AR) and of highest purity available. The chemicals used
included 2-acetylferrocene which was supplied from Strem
Chemicals Inc., CrCl Á6H O and MnCl Á2H O (Sigma-
3
2
2
2
Aldrich), NiCl Á6H O, CoCl Á6H O, CuCl Á2H O and
2
2
2
2
2
2
ZnCl Á2H O (BDH), FeCl Á6H O (Prolabo), CdCl Á2H O
2
2
3
2
2
2
(
Merck), 1,10-phenanthroline and 2-aminophenol (Merck).
Organic solvents were spectroscopic pure from BDH-in-
cluded ethanol, diethylether and dimethylformamide.
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 Collection.
The tumor cell line (MCF7) was maintained in the National
Cancer Institute, Cairo, Egypt, by serial subculturing.
Measurements
Solutions
Microanalyses of carbon, hydrogen and nitrogen were
carried out at the Microanalytical Center, Cairo University,
Egypt, using CHNS-932 (LECO) Vario Elemental Ana-
lyzer. Analyses of the metals followed the dissolution of
-
A fresh stock solution of 1 9 10 M of 2-acetylferrocene
3
-
1
2 g L ) was prepared in the appropriate volume of
(
absolute ethanol. Solutions of the Schiff base ligand and its
-
5
metal complexes (1 9 10 M) were prepared by dilution
of the previous prepared stock solutions for measuring their
UV–Vis spectra.
the solid complex in concentrated HNO , neutralizing the
3
diluted aqueous solutions with ammonia and titrating the
metal solutions with EDTA. FT-IR spectra were recorded
-
1
on a PerkinElmer 1650 spectrometer (4000–400 cm ) in
KBr disks. Electronic spectra were recorded at room tem-
perature on a Shimadzu 3101pc spectrophotometer as
Solution of anticancer study
-
A fresh stock solution of 1 9 10 M of Schiff base ligand
3
1
solutions in DMF. H NMR spectra, as a solution in
-
1
0.0016 g L ) was prepared in the appropriate volume of
(
DMSO-d , were recorded on a 300-MHz Varian-Oxford
6
ethanol (95%; Sigma Chemical Co., St. Louis, Mo, USA):
It was used in cryopreservation 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 sodium bicarbonate, com-
pleted 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 lm). The
prepared medium was kept in a refrigerator (4 °C) and
Mercury at room temperature using TMS as an internal
standard. A saturated solution of the metal compound
which consisted of approximately 3 mg of compound dis-
solved in 1 mL of D O was made in an NMR tube. NMR
2
studies that included 37 °C incubation were done in the
following fashion. The initial NMR of a 37 °C incubation
study was done at room temperature before the tube was
placed in the incubator at 37 °C. The NMR tube was then
incubated for 20 min before it was removed from the oven
and analyzed. There was about 15 min of time at room
temperature to slow down the reaction for monitoring
1
23

Spectroscopic characterization and molecular docking studies of acetyl ferrocene-derived…
during analysis. The NMR tube was then returned to the
oven for additional incubation. The times on the 37 °C
NMR studies actually refer to the total amount of time the
tube was incubated in the oven. For example, a 40-min
incubated sample would actually take about 70 min real
time.
Antimicrobial activity
The in vitro antibacterial and antifungal activity tests were
performed through the well diffusion method [22] using
ampicillin as positive control for Gram (?) bacteria, gen-
tamicin for Gram (-) bacteria and amphotericin for the
four fungi, respectively. The bacterial organisms used are
Gram (?) bacteria: Streptococcus pneumoniae and Bacil-
lus subtilis, Gram (-) bacteria: Pseudomonas aeruginosa
and Escherichia coli and fungi like: Aspergillus fumigatus,
Syncephalastrum racemosum, Geotricum candidum and
Candida albicans. Stock solution (0.001 mol) was pre-
pared by dissolving the compounds in DMSO. The nutrient
agar medium for antibacterial was (0.5% peptone, 0.1%
beef extract, 0.2% yeast extract, 0.5% NaCl and 1.5%
agar–agar) 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 mL) after dis-
-
3
Molar conductivities of 10 M solutions of the solid
complexes in DMF solvent were measured using Jenway
4
010 conductivity meter. The thermogravimetric analyses
TG and DTG) of the solid complexes were carried out
from room temperature to 1000 °C using a Shimadzu TG-
0H thermal analyzer. The anticancer activity was per-
(
5
formed at the National Cancer Institute, Cancer Biology
Department, Pharmacology Department, Cairo University.
The optical density (O.D.) of each well was measured
spectrophotometrically at 564 nm with an ELIZA micro-
plate reader (Meter tech. R 960, USA). The molecular
structure of the investigated ligand was optimized by DFT-
based B3LYP method along with the LANL2DZ basis set.
The molecule was built with the PerkinElmer ChemBio
Draw and optimized using PerkinElmer ChemBio3D soft-
ware [20, 21]. The scanning electron microscopic (SEM)
image of the complexes was recorded by a (Quanta
FEG250) SEM, National Research Center, Egypt.
-
3
solving in DMSO at 1.0 9 10 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
inhibition zones was measured in millimeters. Antimicro-
bial activities were performed in triplicate, and the average
was taken as the final reading [23].
Synthesis of ferrocene Schiff base ligand HL
The new ferrocene Schiff base ligand was prepared by
mixing 30 mL of hot saturated ethanolic solution of the
2
-acetylferrocene (10 g, mmol) and 30 mL of hot ethanolic
solution of 2-aminophenol (4.79 g, mmol). The mixture
was refluxed for 3 h, and 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 chloride. The yield was 85%.
Anticancer activity
Potential cytotoxicity of the compounds was tested using
the method of Skehan and Storeng [24]. 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
Synthesis of metal complexes
compounds under investigation (0, 5, 12.5, 25, 50 and
-1
The transition metal complexes were prepared by mixing
equal amounts (0.00125 mol) of hot saturated DMF solu-
tion of the HL Schiff base ligand and 1,10-phenanthroline,
with the same ratio of metal chloride (1 M:1HL:1Phen
molar ratio). The mixture was refluxed for 3 h. The
resulting complexes were filtered and washed several times
with hot ethanol until the filtrates become clear. The solid
complexes then dried in desiccator over anhydrous calcium
chloride. The yield ranged from 69 to 95%.
1
00 lg 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
4
8 h at 37 °C and in 5% CO atmosphere. After 48 h, cells
2
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 absorbance was automatically subtracted, and
mean values of each drug concentration were calculated.
The relation between surviving fraction and drug concen-
tration is plotted to get the survival curve of breast tumor
cell line for each compound.
Spectrophotometric studies
The absorption spectra of HL ligand and its metal com-
plexes under study were scanned within the wavelength
range from 200 to 700 nm.
123

W. H. Mahmoud et al.
Calculation:
(OH) stretching mode of the phenolic hydroxyl group, a
-
medium band at 1147 cm assigned for (C–N) bending
1
The percentage of cell survival was calculated as fol-
lows (Eq. 1):
-
1
mode and a medium band at 1109 cm
assigned for
(
C–O) stretching.
1
Survival fraction ¼ O:D: ðtreated cellsÞ=O:D: ðcontrol cellsÞ
ð1Þ
The IC50 values (the concentrations of the ferrocene
Schiff base ligand or complexes required to produce 50%
inhibition of cell growth). The experiment was repeated 3
times.
H NMR spectrum of HL ligand showed that the chemical
shift of the proton signal of the OH phenolic proton was
found at 8.87 ppm. The protons of the phenyl signals were
assigned at 6.38–6.65 ppm, and due to their interference, it
was not possible to separate them. The chemical shifts of the
protons of the ferrocene rings were assigned at
4.24–4.77 ppm, while the band at 3.32 ppm can be assigned
Molecular docking
to methyl protons. Electronic spectral data of the Schiff base
HL ligand were recorded in DMF solution. The electronic
spectra of the ligand exhibited three bands at 270, 326 and
428 nm. The first and second bands corresponded to p ? p*
and p–p* transitions of the benzene ring and C=N group,
respectively [27]. The third band corresponded to inter-
molecular charge transfer transitions [28].
Molecular Operating Environment (MOE) 2008 (MOE
source: Chemical Computing Group Inc., Quebec, Canada,
2
008) program was used in molecular docking studies.
Firstly, a Gaussian contact surface around the binding site
was sketched; Finally, docking studies were done to assess
the binding free energy of the inhibitor inside the macro-
molecule. Autorotatable bonds were allowed; the best ten
binding poses were directed to analyze for achieving the
best score to compare the docking poses to the ligand in the
co-crystallized structure [25].
Mass spectrum of HL ligand showed m/z peak at 318.65
?
17FeNO) . The proposed
amu corresponds to (C18
H
molecular formula of synthesized ligand was confirmed by
comparing molecular formula weight 318 amu that was in
good agreement with theoretical explanation.
In order to find out the possible binding modes of the
most active compounds against the crystal structure of:
acetylcholinesterase (PDB: 1B41), the synthetic DNA
dodecamer (PDB: 1BNA) and virus protein U (Vpu) of
human immune deficiency virus (HIV-1) (PDB: 2N28),
molecular docking studies were performed using MOE
The thermal analyses (TG and DTG) were used to
confirm the suggested fragmentation patterns and deter-
mine the decomposition temperatures of the ligand. The
TG data for HL Schiff base ligand (Fig. 2) showed two
stages of decomposition. The first stage is within the
temperature range of 125–240 °C, which correlated with
2
008 software and it is a rigid molecular docking software
evaluation of C H N molecule with mass loss of 34.27%
7 9
[
26]. The structure of ligand in PDB file format was created
(calculated mass loss = 33.50%). The second decomposi-
tion stage in the temperature range of 240–505 °C corre-
sponds to complete decomposition of the final part of
by Gaussian03 software. The crystal structure of: acetyl-
cholinesterase (PDB: 1B41), the synthetic DNA dodecamer
(
PDB: 1BNA) and virus protein U (Vpu) of human
ligand (C10H ) with mass loss 40.32% (calculated mass
8
immunodeficiency virus (HIV-1) (PDB: 2N28) was
downloaded from the protein data bank (http://www.rcsb.
org/pdb).
loss = 40.13%). The total mass loss amounted to 74.50%
(calcd. 73.62%) leaving metal oxide (FeO) contaminated
with carbon atom as a residue.
Results and discussion
–1
DTG/mg min
.00
TG/%
00.00
1
1
Characterization of the ferrocene-based Schiff base
ligand (HL)
0.00
8
6
0.00
0.00
The Schiff base HL ligand was prepared by the conden-
sation of 2-acetylferrocene with 2-aminophenol in molar
ratio of 1:1. The structure was identified by elemental
–
–
1.00
2.00
3.00
1
40.00
0.00
analysis, infrared, UV–visible, H NMR spectra, SEM and
thermogravimetric analysis. From the investigation, the
ligand is shown in Fig. 1. The infrared spectrum was
consistent with the formation of the Schiff base ligand. The
fundamental stretching mode of azomethine (C=N) was
2
–
0
.00
500.00
1000.0
T/°C
-
1
-1
Fig. 2 TG/DTG thermal analysis of HL ligand
found at 1655 cm , broad band at 3374 cm assigned for
1
23

Spectroscopic characterization and molecular docking studies of acetyl ferrocene-derived…
Characterization of the mixed ligand complexes
complexes were of electrolytic and non-electrolytic nature
34]. The Cr(III), Fe(III), Co(II) and Ni(II) complexes were
electrolytic in nature and had molar conductivities of
[
The Schiff base HL ligand was mixed with 1,10-phenan-
throline to give eight mixed ligand chelate in the molar
ratio 1:1:1 (HL–M–Phen). The isolated solid complexes
were subjected to elemental analyses (C, H, N and metal
-
1
-1
2
83.70, 77.50, 58.10 and 57.12 X mol cm , respec-
tively. The Mn(II), Cu(II), Zn(II) and Cd(II) complexes
were nonelectrolytes in nature and had molar conductivi-
1
-1
-1
2
content), IR, H NMR, molar conductance, SEM and
ties of 21.50, 30.00, 32.20 and 2.90 X
mol
cm ,
thermal analysis (TG/DTG) to identify their molecular
structures. The IR peak shifts in (C=N) azomethine group
of the complexes on comparing with that of the free ligand
gave an idea about its coordination to the metal ions
respectively. The complexes had two general formulas: one
for electrolyte complexes and the other for the nonelec-
trolyte complexes, and they expressed as follows [35]:
Electrolytic complexes: [M(L)(Phen)(H O) ]Cl , (where
n
2
2
[
29–31]. The bioefficacy of these complexes has also been
n = 2 for M = Cr(III) and Fe(III) and n = 1 for
M = Co(II) and Ni(II)).
screened against the growth of four bacterial species and
four fungal species in vitro to evaluate their antimicrobial
potential, and other biological applications have been done
in order to throw more light on the effect of chelation on
the ligand activity [32, 33].
Non-electrolytic complexes: [M(L)(Phen)(Cl)(H O)],
2
(M = Mn(II), Cu(II), Zn(II) and Cd(II)).
IR spectra
Elemental analysis and molar conductivity
IR spectrum of the HL ligand exhibited a broad band at
-
1
The elemental analyses results are summarized in Table 1.
These results as well as the obtained mass spectra are in
good agreement with the proposed formula. The complexes
were dark brown or black in color, stable in air and soluble
in different solvents like DMF and DMSO and insoluble in
ethanol, methanol and water. The molar conductance val-
ues of the complexes were found to be in the range from
3374 cm for m(OH) of the phenolic group. This band
shifted in the spectra of the metal complexes to
-
1
3393–3422 cm . For m(C=N) stretching of the azomethine
group, characteristic band of the Schiff base ligand in the
-
1
spectrum of HL ligand appeared at 1655 cm , but in the
spectra of the mixed ligand complexes appeared in the
-
1
range of 1628–1658 cm . This was attributed to the
nitrogen atom of the (C=N) group coordinated to the metal
-
1
-1
2
2
.90 to 83.70 X mol cm , which indicated that the
Table 1 Analytical and physical data of HL ligand and its mixed ligand complexes with 1,10-Phen
-
1
-1
2
Compound
Color
Yield %
Empirical formula
formula weight)
Elemental analysis
Found (calcd%)
m
K /X mol cm
(
C
H
N
M
[
[
[
[
[
[
[
[
Cr(L)(Phen)(H
2
O)
2
]Cl
2
Dark brown
Dark brown
Black
73
81
95
75
94
84
77
69
C
30
C
30
C
30
C
30
C
30
C
30
C
30
C
30
H
H
H
H
H
H
H
H
28Cl
2
CrFeN
3
O
3
2
54.31
4.20
6.12
16.10
83.70
21.50
77.50
58.10
57.12
30.00
32.20
2.90
(
54.79)
59.16
59.36)
56.26
56.28)
57.11
57.28)
56.98
57.32)
58.26
58.54)
58.16
58.39)
54.14
54.23)
(4.26)
3.99
(6.39)
6.71
(16.44)
18.04
Mn(L)(Phen)(Cl)(H
2
O)]
26ClFeMnN
3
O
(
(4.29)
4.06
(6.92)
5.98
(18.30)
16.40
Fe(L)(Phen)(H
2
O)
2
]Cl
2
28Cl
2
Fe
2 3
N O
3
(
(4.23)
4.28
(6.35)
6.38
(16.94)
18.02
Co(L)(Phen)(H
2
O)
2
]Cl
Black
28ClCoFeN
3
O
3
(
(4.45)
4.19
(6.68)
6.57
(18.30)
17.83
Ni(L)(Phen)(H
2
O)
2
]Cl
Dark brown
Black
28ClFeNiNO
3
(
(4.46)
4.11
(6.69)
6.57
(18.23)
19.09
Cu(L)(Phen)(Cl)(H
2
O)]
3 2
26ClCuFeN O
(
(4.22)
3.87
(6.83)
6.56
(19.43)
19.25
Zn(L)(Phen)(Cl)(H
2
O)]
Dark brown
Brown
3 2
26ClFeN O Zn
(
(4.21)
3.83
(6.81)
6.20
(19.63)
25.11
Cd(L)(Phen)(Cl)(H
2
O)]
3 2
26ClCdFeN O
(
(3.92)
(6.32)
(25.37)
123

W. H. Mahmoud et al.
-
1
ions [36–38]. A medium band appeared at 1147 cm was
assigned for (C–N) bending in the free ligand. This band
-
1
was shifted to a range of 1143–1147 cm in the mixed
ligand complexes. Also, another medium band appeared at
-
1
109 cm was assigned to (C–O) stretching in the free
1
-
HL ligand that shifted to a range of 1103–1108 cm in
1
the complexes. New bands appeared in the spectra of
-
metal chelates at 948–979 and 845–856 cm could be
1
assigned to H O stretching of coordinated water. Another
2
-
new two bands appeared at: 563–593 cm which attrib-
1
-
1
uted to M–O stretching and at 530–534 cm
which
attributed to M–O stretching of coordinated water. M–N
-
1
stretching bands appeared at 486–496 cm
[36–38].
Thus, IR data in Table 2 showed that the Schiff base
ligand was coordinated to the metal ions through the two
N atoms of 1,10-phenanthroline: one N atom of azome-
thine group and one oxygen atom of the deprotonated
phenolic O of HL ligand [39].
1
H NMR spectra
1
The H NMR spectrum of the HL Schiff base ligand dis-
played three significant peaks at 8.87, 6.38–6.65 and
4
.24–4.77 ppm with an integration equivalent to the
hydrogen protons corresponding to the (s, 1H, phenolic
proton), (m, 4H, benzene ring) and (m, 9H, ferrocene
rings), respectively [40, 41]. The peak at 8.87 ppm
assigned for phenolic proton was disappeared in the
spectra
of
[Zn(L)(Phen)(Cl)(H O)]
2
and
[
Cd(L)(Phen)(Cl)(H O)] complexes, indicating that the
2
phenolic oxygen was coordinated to the metal ions in the
mixed chelates with proton displacement. The signals
observed at 7.72–8.24 ppm and 7.39–7.72 ppm were
assigned to aromatic ring protons of Zn(II) and Cd(II)
complexes, respectively. The multiplet signals found at
6
.36–6.61 ppm and 6.36–6.79 ppm were attributed to
pyridine rings of Zn(II) and Cd(II) chelates, respectively.
The ferrocene rings gave a group of multiplet signals at
4
.23–4.78 ppm and 4.24–4.78 ppm for Zn(II) and Cd(II)
complexes, respectively [42].
Mass spectral studies
The molecular ion peak of the [Ni(L)(Phen)(H O) ]Cl
2
2
complex was observed in its mass spectrum at 630.22 amu
which confirmed the proposed formula of the complex
(
theoretical molecular weight 630 amu). In the mass
spectrum of [Ni(L)(Phen)(H O) ]Cl complex, a peak
2
2
?
corresponding to [C H FeNO]
18 17
ion appeared as
molecular ion peak at m/z = 318.88 amu. This peak
confirmed the presence of the ferrocene Schiff base ligand
in the proposed structure of the complex. However, the
1
23

Spectroscopic characterization and molecular docking studies of acetyl ferrocene-derived…
base peak of the Ni(II) complex appeared at m/z = 227.94
amu. The peaks appeared at m/z = 572.51, 402.24, 342.06,
complexes gave different curves containing different
decomposition steps. The experimental weight loss values
for the complexes were in good agreement with the cal-
culated values [45].
2
76.01, 184.95, 108.99 and 55.92 amu can correspond to
various fragments in Ni(II) mixed ligand complex [43].
The TG curve of [Cr(L)(Phen)(H O) ]Cl complex
2
2
2
UV–Vis spectral studies
showed three decomposition steps within the temperature
range of 60–545 °C. The first and second decomposition
steps were accompanied by loss of C H Cl N fragment
The electronic spectra of the free HL ligand and its mixed
ligand complexes with 1,10-Phen were recorded in DMF
1
5
17
2 2
in the temperature range of 60–320 °C with an estimated
mass loss of 45.64% (calcd. 45.05%). The third stage of
decomposition showed loss of C H NO fragment at
-
5
-1
solution with 10 mol L concentration at room tem-
perature. Characteristic p ? p* transitions were observed
in the range of 266–271 nm and 320-333 nm which
attributed to transition of the benzene ring and C=N group,
respectively. The bands found in the spectra of the com-
plexes at 431-434 nm can be attributed to intermolecular
charge transfer transitions. The same p ? p* transition
profile was also detected for the free HL ligand at 270 nm
and p ? p* transition observed at 326 nm [44].
9
11
0.5
320–545 °C with an estimated mass loss of 21.21% (calcd.
21.46%). Thereafter, the percentage of the residue corre-
sponds to chromium oxide contaminated with iron(II)
oxide and carbon atoms. The total estimated mass loss was
found to be 66.51% (calcd. 66.84%).
TG curve of the [Mn(L)(Phen)(Cl)(H O)] complex
2
showed three steps of decomposition. The first stage of
decomposition occurred in the 160–390 °C temperature
range, corresponding to the loss of C H Cl N fragment,
Thermal analysis
1
5
17
2 2
and was accompanied by a mass loss of 38.65% (calcd.
38.99%). The second and third stages of decomposition
involved the removal of C H N fragment in the
Thermal properties of the HL ligand and its mixed ligand
complexes with 1,10-Phen were investigated with TG/DTG
under the ambient temperature up to 1000 °C. The thermal
analysis data are summarized in Table 3. All of the
1
2 9
390–490 °C temperature range and were accompanied by
mass loss of 28.17% (calcd. 27.53%). The total mass loss
Table 3 Thermoanalytical results (TG and DTG) of HL ligand and its mixed ligand complexes with 1,10-Phen
Compound
TGA range/
°
T
s
/°C
n* Mass loss%
Total mass
loss %
Found (calcd)
Assignment
Residue
C
Found Calcd.
HL
125–237
38–504
60–320
20–545
O)] 160–390
90–490
205
1
1
2
1
1
2
2
34.27 33.5
40.32 40.13
45.64 45.05
21.21 21.46
38.65 38.99
28.17 27.53
69.28 69.74
74.5
Loss of C
7
H
9
N
FeO ? C
2
471
(73.62)
66.51
(66.84)
66.83
(66.52)
69.28
Loss of C10
H
8
[
[
[
[
[
Cr(L)(Phen)(H
2
O)
2
]Cl
2
109, 281
407, 589
207
Loss of C15
H
17Cl
2
N
2
2 3 ?
1/2 Cr O
FeO ? 6C
3
9
Loss of C H11NO0.5
Mn(L)(Phen)(Cl)(H
2
Loss of C13
Loss of C12
Loss of C26
H
H
H
17ClN
2
MnO ? FeO ? 5C
3
370, 453
162, 458
9
N
Fe(L)(Phen)(H
2
O)
2
]Cl
2
100–530
28Cl
N
2 3
O
0
.
5
2 3 ?
1/2 Fe O
FeO ? 4C
(
69.74)
Co(L)(Phen)(H
2
O)
2
]Cl
120–265
195
1
2
3
2
20.47 19.97
44.96 45.19
31.72 31.61
37.19 37.42
65.16
Loss of C
3
H12ClN
3
CoO ? FeO ? 6C
2
65–830
80–410
10–650
513, 655
(65.43)
69.03
Loss of C21
Loss of C10
Loss of C16
H
H
H
16
O
Ni(L)(Phen)(H
2
O)
2
]Cl
135, 241,
3
15ClN
13NO
2
NiO ? FeO ? 4C
76
4
(69.63)
4
47, 606
[
[
[
Cu(L)(Phen)(Cl)(H
2
O)] 120–240
40–700
O)] 150–470
70–655
O)] 156–330
30–526
186
1
2
2
1
2
1
23.94 23.98
46.27 47.47
40.03 40.63
33.08 32.60
32.17 32.00
34.09 34.19
70.20
Loss of C
6
H
12ClN
2
CuO ? FeO ? 2C
ZnO ? FeO ? C
CdO ? FeO ? 2C
2
554, 507
195, 425
604
(71.46)
73.11
Loss of C22
Loss of C14
Loss of C15
Loss of C11
Loss of C17
H
H
H
H
H
14
N
Zn(L)(Phen)(Cl)(H
2
19ClN
2
2
4
(73.23)
66.26
7
N
Cd(L)(Phen)(Cl)(H
2
197, 312
492
17ClN
3
(66.19)
9
N
n* = number of decomposition steps
123

W. H. Mahmoud et al.
Fig. 3 TG/DTG thermal
analysis of
TG/%
00.00
–1
DTG/mg min
.00
1
[
2
Cu(L)(Phen)(Cl)(H O)]
0
complex. a In case of Cr(III),
Fe(III), Co(II) and Ni(II)
complexes (where n = 2 for
Cr(III) and Fe(III) complexes
and n = 1 for Co(II) and Ni(II)
complexes). b In case of Mn(II),
Cu(II), Zn(II) and Cd(II)
complexes
8
6
0.00
0.00
0.50
4
2
0.00
0.00
0.00
500.0
1000.0
T/°C
amounted to 66.83% (calcd. 66.52%), and manganese
oxide contaminated with iron(II) oxide and carbon atoms
was remained as a residue.
(a)
The [Fe(L)(Phen)(H O) ]Cl chelate exhibited two
2
2
2
decomposition steps. The first and second steps occurred in
the temperature range of 100–530 °C. These steps assigned
to loss of C H Cl N O . fragment with estimated mass
N
N
H O
M
OH2
2
6
28
2 3 0 5
2
loss of 69.28% (calcd. = 69.74%). The overall mass loss
N
.Cln
O
Fe
amounted to 69.28% (calcd. = 69.74%) leaving ‘Fe O ,
2
3
FeO and contaminated carbon as the residue of
decomposition.
The TG curve of [Co(L)(Phen)(H O) ]Cl complex
2
2
showed three decomposition steps within the temperature
range of 120–830 °C. The first decomposition step was
accompanied by loss of C H ClN fragment in the tem-
(b)
3
12
3
perature range of 120–265 °C with an estimated mass loss
of 20.47% (calcd. 19.97%). The second and third stages of
decomposition showed loss of C H O fragment at
N
N
2
1 16
2
4
65–830 °C with an estimated mass loss of 44.96% (calcd.
5.19%). Thereafter, the percentage of the residue corre-
Cl
O
M
OH2
N
sponds to CoO and FeO oxides contaminated with carbon
atoms and the total estimated mass loss was found to be
Fe
6
5.16% (calcd. 65.43%).
TG curve of the [Ni(L)(Phen)(H O) ]Cl complex
2
2
showed five steps of decomposition. The first, second and
third stages of decomposition occurred in the 80–410 °C
temperature range, corresponding to the loss of C H
Fig. 4 Structure of HL Schiff base metal complexes
1
0 15-
[Cu(L)(Phen)(Cl)(H O)] complex (Fig. 3) showed only
2
ClN fragment, and were accompanied by a mass loss of
2
three decomposition steps around 120–700 °C. The first
decomposition step occurred at 120–240 °C with a mass
loss of 23.94% (calcd. 23.98%) corresponding to the loss of
3
1.72% (calcd. 31.61%). The fourth and five stages of
decomposition involved the removal of C H NO frag-
16 13
ment in the 410–650 °C temperature range and were
accompanied by mass loss of 37.19% (calcd. 37.42%). The
total mass loss amounted to 69.03% (calcd. 69.63%) NiO
contaminated with FeO, and carbon atoms were remained
as a residue.
C H ClN fragment. The second and third steps of
6
12
2
decomposition occurred at 240–700 °C with a mass loss of
6.27% (calcd. 47.47%) corresponding to the loss of
C H N fragment. The total mass loss was 70.20% (calcd.
4
22 14
1
23

Spectroscopic characterization and molecular docking studies of acetyl ferrocene-derived…
Fig. 5 SEM image of a HL
ligand and
2 2 2
b [Cr(L)(Phen)(H O) ]Cl
complex
7
1.46%) leaving CuO contaminated with FeO and carbon
corresponds to zinc oxide, iron oxide and carbon atom and
the total estimated mass loss was found to be 73.11%
(calcd. 73.23%).
atoms as a residue.
The TG curve of [Zn(L)(Phen)(Cl)(H O)] complex
2
showed three decomposition steps within the temperature
range of 150–655 °C. The first and second decomposition
steps were accompanied by loss of C H ClN fragment in
The [Cd(L)(Phen)(Cl)(H O)] chelate exhibited three
2
decomposition steps. The first and second steps occurred in
the temperature range of 150–330 °C. These steps assigned
to loss of C H ClN fragment with an estimated mass
1
4
19
2
the temperature range of 150–470 °C with an estimated
mass loss of 40.03% (calcd. 40.63%). The third stage of
decomposition showed loss of C H N fragment at
1
1
17
2
loss of 32.17% (calcd. 32.00%). The third stage of
decomposition showed loss of C H N fragment at
1
5
7
17 9
470–655 °C with an estimated mass loss of 33.08% (calcd.
32.60%). Thereafter, the percentage of the residue
330–530 °C with an estimated mass loss of 34.09% (calcd.
34.19%). The overall mass loss amounted to 66.26%
Aspergillus fumigatus
Syncephalastrum racemosum
Bacillis subtilis
Geotricum candidum
Candida albicans
Escherichia coil
3
3
2
2
1
1
5
0
5
0
5
0
5
0
Streptococcus pneumoniae
Pseudomonas aeruginosa
Sample
Fig. 6 Biological activity of ferrocene Schiff base ligand and its mixed ligand complexes with 1,10-Phen
123

W. H. Mahmoud et al.
1
23

Spectroscopic characterization and molecular docking studies of acetyl ferrocene-derived…
(
a)
Aspergillus fumigatus
Geotricum candidum
Syncephalastrum racemosum
Candida albicans
3
00
50
00
50
00
2
2
1
1
50
0
HL
Cr(III)
Mn(II)
Fe(III)
Co(II)
Ni(II)
Cu(II)
Zn(II)
Cd(II)
(b)
4
4
3
3
2
2
1
1
50
00
50
00
50
00
50
00
Streptococcus pneumoniae
Pseudomonas aeruginosa
Bacillis subtilis
Escherichia coli
50
0
HL
Cr(III)
Mn(II)
Fe(III)
Co(II)
Ni(II)
Cu(II)
Zn(II)
Cd(II)
Fig. 7 Activity index of ferrocene Schiff base ligand and its mixed metal complexes with 1,10-Phen against: a different fungal species and
b different bacterial species
(
calcd. = 66.19%) leaving CdO, FeO and carbon as the
SEM studies
residue of decomposition.
The SEM analysis was carried out to check the surface
morphology of the selected HL ligand and its Cr(III) mixed
ligand complex with 1,10-Phen, and the micrographs
obtained are given in Fig. 5. The micrograph of the Schiff
base ligand given in Fig. 5a showed the presence of well-
defined crystals free from any shadow, and its external
surface had a twisted fiber and grass-like morphology. On
the other hand, the micrograph of chromium(III) complex,
Fig. 5b, showed a rock-like appearance with a numerous
territorial patches. These facts revealed the amorphous
nature of the complex with complicated interpretation due
Structural interpretation
The structures of mixed ligand complexes of HL with 1,10-
Phen and some transition metal ions: Cr(III), Mn(II),
Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) were con-
1
firmed from elemental analyses, IR, H NMR, UV–visible
spectra, molar conductance, SEM and thermal analyses
(
TG and DTG) [46–48]. The proposed structural formulae
of the complexes were listed as two types of coordination
as shown in Fig. 4.
123

W. H. Mahmoud et al.
Fig. 8 3D plot of the interaction against receptors of 1B41 with: a ferrocene Schiff base ligand HL, b [Co(L)(Phen)(H
c [Zn(L)(Phen)(Cl)(H O)] and d [Cd(L)(Phen)(Cl)(H O)] complexes
2 2
O) ]Cl,
2
2
to unclear appearance. It was evident from the SEM study
that in the synthesized metal complex, semi-crystals were
found to grow up from just a single molecule to several
molecules in an aggregate distribution with particle sizes of
few nanometers. In addition, different characteristic shape
of metal Schiff base complex was identified and this SEM
image was quite different from that of HL Schiff base. The
average particle size of HL ligand was 37.88 nm, but the
average particle size of the [Cr(L)(Phen)(H O) ]Cl com-
Cu(II), Zn(II) and Cd(II) metal complexes showed poten-
tial antibacterial activity. Ferrocene-based Schiff HL
ligand showed antibacterial activity with inhibition zone
diameters of 13.0–26.0 mm. Either Fe(III) or Cu(II) com-
plexes showed weak activity with inhibition zone diame-
ters of 10.0–12.0 mm. The Co(II), Zn(II) and Cd(II)
complexes showed great activity with inhibition zone
diameters of 10–19 mm that are summarized in Table 4.
This higher antimicrobial activity of the metal complexes
compared with that of Schiff base was perhaps due to the
change in structure due to coordination and chelating tends
to make metal complexes acted as more powerful and
potent bacteriostatic agents, thus inhibiting the growth of
the microorganisms [50, 51].
2
2
2
plex was 26.39 nm [49].
Antimicrobial activity
Antibacterial activity of HL ligand and its mixed ligand
complexes with 1,10-phenanthroline was tested against
different bacterial species: two Gram (?) Streptococcus
pneumoniae and Bacillus subtilis and two Gram (-)
Pseudomonas aeruginosa and Escherichia coli by using
modified agar diffusion method. Their activities were
compared with standards antibiotics such as ampicillin and
gentamicin. The antibacterial results displayed in Fig. 6
suggested that Cr(III), Mn(II), Fe(III), Co(II), Ni(II),
On the other hand, antifungal activity of Schiff base HL
ligand and its mixed ligand complexes also was tested
against different fungal microorganisms: Aspergillus
fumigatus, Syncephalastrum racemosum, Geotricum can-
didum and Candida albicans by using modified agar dif-
fusion method. The antifungal results suggested that metal
complexes showed potential antifungal activity with inhi-
bition zone diameters of 11–25 mm. According to
1
23

Spectroscopic characterization and molecular docking studies of acetyl ferrocene-derived…
Table 5 Energy values obtained in docking calculations of HL and Co(II) complex with the crystal structure of: acetylcholinesterase (PDB:
1
B41), the synthetic DNA dodecamer (PDB: 1BNA) and virus protein U (Vpu) of human immune deficiency virus (HIV-1) (PDB: 2N28)
-
1
˚
Distance/A
Receptor
Ligand moiety
Receptor site
Interaction
E/kcal mol
1
B41
O 36
C 7
O ARG 296
6-ring TRP 286
OP1 DA 18
OP1 DA 18
H-donor
H-Pi
3.06
4.37
2.16
3.84
4.41
2.92
3.06
3.75
- 1.8
- 0.6
- 2.7
- 0.9
- 0.6
- 2.7
- 4.1
- 1.1
1
BNA
Fe 25
C21
Metal
Ionic
0
5
-ring
C4 DA 17
H-Pi
2
N28
O36
C21
C21
O HIS 72
H-donor
Ionic
OE1 GLU 69
OE2 GLU 69
Ionic
-
1
˚
Distance/A
Receptor
Co-complex moiety
Receptor site
Interaction
E/kcal mol
1
B41
N39
N58
O64
N39
N58
O64
Fe24
N39
N39
N39
O64
Fe24
N39
N39
O TYR 341
O SER 293
O TYR 341
OP2 DT 19
OP1 DT 19
OP1 DT 19
OP2 DT 20
OP1 DT 19
OP2 DT 19
OE1 GLU 69
OE2 GLU 69
O HIS 72
H-donor
H-donor
H-donor
H-donor
H-donor
H-donor
Metal
3.50
3.20
2.83
3.28
3.09
2.74
2.33
3.38
3.28
2.88
2.79
2.54
2.88
3.31
- 0.8
- 1.9
- 4.2
- 3.1
- 2.8
- 7.0
- 2.8
- 2.4
- 2.8
- 16.8
- 6.8
- 0.9
- 5.3
- 2.7
1
BNA
Ionic
Ionic
2
N28
H-donor
H-donor
Metal
OE1 GLU 69
OE2 GLU 69
Ionic
Ionic
Overtone’s concept of cell permeability, the lipid mem-
brane that surrounded the cell favored the passage of only
the lipid soluble materials due to which liposolubility was
an important factor, which controlled the antimicrobial
activity. On chelation, the polarity of the metal ion would
be reduced to a greater extent due to the overlap of the
ligand orbital and partial sharing of the positive charge of
the metal ion with donor groups. Further, it increased the
delocalization of p-electrons over the whole chelate ring
and enhanced the lipophilicity of the complexes. This
increased lipophilicity enhanced the penetration of the
complexes into lipid membranes and blocking of the metal
binding sites in the enzymes of microorganisms. These
complexes also disturbed the respiration process of the cell
and thus blocked the synthesis of the proteins that restricted
further growth of the organisms [52].
Activity index ðAÞ
Inhibition Zone of compound ðmmÞ
Inhibition Zone of standard drug ðmmÞ
¼
 100
ð2Þ
From the data, it was concluded that Cd(II) complex had
the highest activity index, while Fe(III) complex had the
lowest activity index, see Fig. 7 [55].
Anticancer activity
The cytotoxic properties of the selected mixed ligand
complexes and their free ferrocene-based Schiff base
ligand (HL) were screened against breast cancer cell line
MCF7. The pharmacological results showed that all the
metal complexes were inactive against MCF7 cell line
except the Mn(II) mixed ligand complex showed great
The activities of the prepared HL ligand and its mixed
ligand complexes were confirmed by calculating the
activity index according to the following relation (Eq. 2)
-
1
cytotoxic activity. It had IC50 of 4.5 lg mL
which
considered as very low concentration of the metal complex
to kill 50% of the breast cancer cell line MCF7. The HL
ligand showed very weak cytotoxic activity and IC50 of
[
53, 54]:
123

W. H. Mahmoud et al.
Table 6 Energy values obtained in docking calculations of Zn(II) and Cd(II) complexes with the crystal structure of: acetylcholinesterase (PDB:
1
B41), the synthetic DNA dodecamer (PDB: 1BNA) and virus protein U (Vpu) of human immune deficiency virus (HIV-1) (PDB: 2N28)
-
1
˚
Distance/A
Receptor
Zn-complex moiety
Receptor site
Interaction
E/kcal mol
1
B41
O64
O66
O66
OD2 ASP 74
OD2 ASP 74
OH TYR 124
N ASP 74
H-donor
H-donor
H-acceptor
Pi-H
2.63
3.03
2.80
4.61
2.77
2.89
2.77
2.71
2.72
2.71
3.79
- 0.8
- 0.7
- 0.8
- 0.9
- 16.6
- 6.0
- 6.2
- 19.1
- 9.0
- 6.7
- 1.0
6
-ring
1
BNA
N28
N39
N64
N39
N39
O64
N39
N39
OP1 DT 19
OP1 DT 19
OP1 DT 19
OE1 GLU 69
OE1 GLU 69
OE1 GLU 69
OE2 GLU 69
H-donor
H-donor
Ionic
2
H-donor
H-donor
Ionic
Ionic
-
1
˚
Distance/A
Receptor
Cd(II)-complex moiety
Receptor site
Interaction
E/kcal mol
1
B41
N58
N58
O64
N58
N58
O64
5-Ring TRP 286
6-Ring TRP 286
6-Ring TRP 286
H-Pi
4.46
3.91
4.28
3.35
3.29
2.80
3.82
2.71
3.74
2.61
3.80
- 1.7
- 1.9
- 0.7
- 1.2
- 5.9
- 3.8
- 0.6
- 19.0
- 0.9
- 5.4
- 1.4
H-Pi
H-Pi
0
1
BNA
O3 DC 11
H-donor
H-donor
H-donor
Pi-H
OP1 DG3 12
OP1 DG3 12
0
6
-ring
C4 DA 17
2
N28
N39
O64
N39
N39
OE1 GLU 69
OE1 GLU 69
OE2 GLU 69
OE2 GLU 69
H-donor
H-donor
Ionic
Ionic
-
1
5
8.0 lg mL that means Mn(II) mixed ligand complex
has great cytotoxic activity than HL ligand itself [56].
developed for treatment of intoxication by nerve agents and
for the design of safer and more effective insecticides by
comparison with the three-dimensional structure of the
insect enzyme [59, 60].
Molecular modeling of HL ligand: Docking Study
Studying the binding of HL and its mixed ligand com-
plexes with crystal structure of acetylcholinesterase (PDB:
1B41) gave the minimum binding energy was found to be
All docked compounds, HL ligand and Co(II), Zn(II) and
Cd(II) mixed ligand complexes, were represented in balls
and stick to clarify suggesting the preferred binding mode
of compounds in the target crystal structure (Figs. 8–10).
Also, the current ligand–receptor interactions were ana-
lyzed on the basis of energy scores as described in Tables 5
and 6 [57].
-
1
- 4.2 kcal mol
for [Co(L)(Phen)(H O) ]Cl complex.
2 2
The minimum energy docked pose revealed that the Co(II)
complex fitted into the curve contour of the targeted protein
in the groove. Moreover, -OH group of the Co(II) com-
plex acted as strong H-bond donors and was engaged in
hydrogen-bonding interactions with oxygen atom of O
TYR 341 of Tyrosine amino acid [61], see Fig. 8 and
Tables 5 and 6.
Acetylcholinesterase (AChE) is among the most effi-
-
1
cient enzymes with a turnover number of [ 104 s . While
the structural and mechanistic origin of its catalytic power
and high reactivity toward organophosphorus inhibitors has
been a subject of interest for several decades, only recently
it has been possible to delineate the unique functional
architecture of the AChE active center. Knowledge of the
structural and functional properties of AChE, in particular
those of human AChE (hAChE), is important for the design
of anti-Alzheimer drugs [58]. Improved procedures were
The crystal structure of the synthetic DNA dodecamer
(CpGpCpGpApApTpTpCpGpCpG) has been refined to a
˚
residual error of R = 17.8% at 1.9-A resolution (two-
rdata). The molecule forms slightly more than one com-
plete turn of right handed double-stranded B helix. The two
ends of the helix overlap and interlock minor grooves with
neighboring molecules up and down a 21 screw axis,
1
23

Spectroscopic characterization and molecular docking studies of acetyl ferrocene-derived…
producing a 190 bend in helix axis over the 11-base-pair
steps of the dodecamer [62]. From the data presented in
Tables 5 and 6, the Zn(II) complex showed highest inter-
From the data summarized in Tables 5 and 6, it was
found that all of the tested compounds were interacted with
the protein receptors through a hydrogen bond, ionic and
metal interaction. The values of interaction energies
revealed that Zn(II) complex had the most stable interac-
tion than the other complexes and free HL ligand with
action
with
minimum
binding
energy
of
-
1
16.6 kcal mol with the crystal structure of the syn-
-
thetic DNA dodecamer (PDB ID: 1BNA), see Fig. 9.
Virus protein U (Vpu) is one of the accessory proteins
encoded by human immunodeficiency HIV-1 virus of
AIDS. Although it is dispensable for viral replication
in vitro, it has multiple biological functions that are crucial
for viral infectivity in vivo. Vpu removes newly synthe-
sized CD4 receptors from the endoplasmic reticulum (ER)
and causes their subsequent degradation. As a result, it
prevents CD4 receptors from binding to the viral envelope
-
1
minimum binding energy of - 19.1 kcal mol , see
Fig. 10.
-
1
The histogram of the binding energy (- E kcal mol
)
between HL ligand and its Co(II), Zn(II) and Cd(II) mixed
ligand chelates with 1,10-phenanthroline with crystal
structures of: acetylcholinesterase (PDB: 1B41), the syn-
thetic DNA dodecamer (PDB: 1BNA) and virus protein U
(Vpu) of human immunodeficiency virus (HIV-1) (PDB:
2N28) is shown in Fig. 11. The histogram showed that the
(
Env) precursor gp160, thereby enhancing viral infectivity.
Vpu also enhances the release of newly formed virus par-
ticles by antagonizing the human immune restriction factor
BST-2/CD317 (tethering), which otherwise prevents their
release. Recently, Vpu has been shown to induce down
modulation of natural killer (NK) cell receptor NK, T cell
and B cell antigen (NTB-A) from the cell surface and
prevent HIV infected cells from degranulation and lysis by
NK cells [63–66].
[Zn(L)(Phen)(Cl)(H O)] had the minimum binding energy
2
-
of - 0.8, - 16.6 and - 19.1 kcal mol with the receptors
1
of 1B41, 1BNA and 2N28, respectively.
Fig. 9 3D plot of the
interaction against receptors of
1BNA with: a ferrocene Schiff
base ligand HL,
b [Co(L)(Phen)(H
2
O)
2
]Cl,
O)] and
O)]
c [Zn(L)(Phen)(Cl)(H
d [Cd(L)(Phen)(Cl)(H
complexes
2
2
123

W. H. Mahmoud et al.
Fig. 10 3D plot of the interaction against receptors of 2N28 with: a ferrocene Schiff base ligand HL, b [Co(L)(Phen)(H
c [Zn(L)(Phen)(Cl)(H O)] and d [Cd(L)(Phen)(Cl)(H O)] complexes
2 2
O) ]Cl,
2
2
2
2
1
1
5
0
5
0
5
0
HL ligand
HL-Co-Phen
HL-Zn-Phen
HL-Cd-Phen
Conclusions
The coordination chemistry of some transition metal ions:
Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and
Cd(II) with ferrocene-based Schiff base ligand HL (as
primary ligand) and 1,10-phenanthroline (as secondary
ligand) was elucidated. The metal complexes were char-
1
acterized by elemental analyses, molar conductance, IR, H
NMR, UV–visible spectral analysis, mass spectroscopy,
SEM and thermal analyses techniques. The HL ligand and
its mixed ligand chelates were subjected to thermal anal-
yses (TG and DTG). The biological activity (antimicrobial
and antibreast cancer activity) of the HL ligand and its
mixed ligand complexes was also screened. Mn(II) com-
1B41
1BNA
Protein receptor
2N28
-
1
plex showed the best IC50 value of 4.5 lg mL . MOE
Molecular Operating Environment) docking studies were
(
Fig. 11 Histogram of the binding energy (- E kcal/mol) between
ferrocene Schiff base ligand HL and its mixed ligand chelates with
different protein receptors (PDB: 1B41, 1BNA and 2N28)
performed using MOE 2008 software which performed
docking calculations to identify the binding orientation or
1
23

Spectroscopic characterization and molecular docking studies of acetyl ferrocene-derived…
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2 2
O donor
different proteins. The [Zn(L)(Phen)(Cl)(H O)] complex
2
showed the best binding ability with minimum binding
energy through ionic, hydrogen acceptor and donor inter-
actions with the tested three crystal structures (PDB) 1B41,
1
1
7. Lashanizadegan M, Boghaei DM. Template synthesis and X-ray
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1
BNA and 2N28.
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