Nano-synthesis and spectral, thermal, modeling, quantitative structure–activity relationship and docking studies of novel bioactive homo-binuclear metal complexes derived from thiazole drug for therapeutic applications

Article abstract of DOI:10.1002/aoc.4352

Seven novel homo-binuclear Cr(III), Fe(III), Cu(II), ZrO(II), Sn(II), Pb(II) and Ce(III) nanosized complexes of a thiazole drug (H₂L) were synthesized for chemotherapeutic applications. H₂L was prepared via a condensation reaction be

Full text of DOI:10.1002/aoc.4352

Received: 11 December 2017
DOI: 10.1002/aoc.4352
Revised: 14 February 2018
Accepted: 22 February 2018
F U L L P A P E R
Nano‐synthesis and spectral, thermal, modeling,
quantitative structure–activity relationship and docking
studies of novel bioactive homo‐binuclear metal complexes
derived from thiazole drug for therapeutic applications
Fawaz A. Saad
Department of Chemistry, Faculty of
Seven novel homo‐binuclear Cr(III), Fe(III), Cu(II), ZrO(II), Sn(II), Pb(II) and
Ce(III) nanosized complexes of a thiazole drug (H2L) were synthesized for
chemotherapeutic applications. H2L was prepared via a condensation reaction
between 2‐(4‐aminobenzenesulfonamido)thiazole and 2‐hydroxybenzaldehyde.
The structures of H2L and its metal complexes were investigated by various
Applied Science, Umm Al‐Qura
University, Makkah, Saudi Arabia
Correspondence
Fawaz A. Saad, Department of Chemistry,
Faculty of Applied Science, Umm Al‐Qura
University, Makkah, Saudi Arabia.
Email: fasaad@uqu.edu.sa
means. These included microanalysis, H NMR, 13C NMR, Fourier transform
1
infrared, UV–visible, electron spin resonance and mass spectroscopies,
transmission electron microscopy (TEM), powder X‐ray diffraction (XRD),
thermogravimetric analysis (TGA) and molar conductivity. The measurements
revealed that H2L coordinates with the metal ions through two chelating centers,
indicating its behavior as a dibasic tetradentate ligand. The first center involves
the nitrogen of azomethine (CH═N) and the α‐hydroxyl oxygen while the other
center is the thiazole nitrogen and the sulfonamide oxygen. From spectroscopic
and analytical data, the Cr(III), Fe(III) and Ce(III) complexes have octahedral
geometries, whereas the Cu(II), ZrO(II), Sn(II) and Pb(II) complexes have
tetrahedral geometries. TEM and XRD measurements unambiguously showed
the nanometric particle sizes of the complexes. The activation thermo‐kinetic
parameters, E*, ΔH*, ΔS* and ΔG*, of the various decomposition steps of the
complexes were determined mathematically from the TGA curves. Gaussian09
and quantitative structure–activity relationship modeling studies were utilized
to verify the biological and structural feature relationships. Docking studies were
performed to throw more light on the biological priority of the proposed drugs,
using microorganism protein receptors. The antitumor and antimicrobial
efficiencies of the H2L drug and its complexes were determined to estimate their
potential therapeutic utility. In general, the complexes showed greater antitumor
and antimicrobial efficiencies than the H2L drug. The Fe(III) complex exhibited
efficient antimicrobial activities against Candida albicans and Staphylococcus
aureus and its efficiency is equivalent to that of standard drugs. The Cu(II)
complex showed the greatest cytotoxic activity towards HEPG2.
KEYWORDS
docking, nanosized metal complexes, QSAR
Appl Organometal Chem. 2018;e4352.
wileyonlinelibrary.com/journal/aoc
Copyright © 2018 John Wiley & Sons, Ltd.
1 of 13
https://doi.org/10.1002/aoc.4352

2 of 13
SAAD
Cu(CH3COO)2⋅H2O, ZrOCl2⋅8H2O, SnCl2⋅2H2O, PbCl2
and Ce(NO3)3⋅6H2O were of high purity and applied as
received.
1 | INTRODUCTION
Sulfa compounds are long‐established as medicaments
used to perform selectively and can act consistently as
preventative and therapeutic agents against various
human diseases.[1] The enormous commercial success of
these curative agents has made the chemistry of sulfa com-
pounds a principal domain of scientific research and a
distinct field in curative sciences.[2] Nitrogen‐, sulfur‐ and
oxygen‐containing coordinative ligands are prevalent
among coordination compounds[3] and are important
components of bioactive complexes.[4] Multinuclear metal-
lic complexes have extensive implementations in material
science and catalysis,[5] alongside their distinctive mag-
netic and spectroscopic attributes.[6,7] Also, multinuclear
metal ion complexes have significant positions in biochem-
ical reactions and biological systems.[8,9] Complex forma-
tion between metal ions and sulfa derivatives, combining
antibacterial activity of sulfa compounds and antifungal
influence of metals, comprises a weighty field of research
due to the strong antimicrobial and pronounced fungicidal
influences of such complexes.[10] Also, metal complexes in
nanotechnology are much explored especially nowadays
where nanometer‐scale materials have attracted signifi-
cant attention due to their range of potential technological
applications and superb functional properties, such as in
biosensors, microelectronics, optics and catalysis.[11]
Hence, it is important to investigate the composition
and biological activity of a novel series of homo‐binuclear
Cr(III), Fe(III), Cu(II), ZrO(II), Sn(II), Pb(II) and Ce(III)
nanoparticle complexes with a thiazole derivative for
prospective therapeutic purposes. The effective coordina-
tion sites in the chelating agent and the geometrical
arrangement of the metallic complexes were investigated
using spectral data assisted by theoretical calculations.
The reported compounds were investigated using various
spectroscopic and analytical techniques. The ligand and
complexes were screened in vitro for their antitumor
and antimicrobial activities to estimate their possible
therapeutic effects. The occurrence of the complexes on
a nanometric scale expedited their absorption by human
cells and displayed a great promise for their utility in
therapy of various human diseases.
Microanalysis (C, H and N contents) was performed
with a 2400 CHN elemental analyzer (PerkinElmer). Mass
spectra of the ligand and metal chelates were obtained with
a Shimadzu GV‐5050 mass spectrometer using the
electrospray ionization technique. The conductance of all
complexes was measured in DMF solvent (10−3 M) at room
temperature using a Jenway (model 4070) conductance
bridge. Fourier transform infrared (FT‐IR) spectra were
obtained with a Bruker Tensor 27 FT‐IR spectrophotometer
as KBr discs within the range 200–4000 cm−1 at the Central
Laboratory, Tanta University, Egypt. A Sherwood magnetic
susceptibility balance was used to obtain magnetic
susceptibilities, at room temperature. UV–visible spectra
were obtained with a Shimadzu spectrometer (model UV‐
3600), applying the Nujol mull technique. NMR spectra
were recorded with a Mercury Oxford NMR 300 Hz spectro-
photometer after dissolving the samples in DMSO‐d6 (Cairo
University). Room temperature X‐band powder electron
spin resonance (ESR) spectra were recorded with a Jeol
JES‐RE1X EPR spectrometer (Alexandria University, ν =
9.435 GHz). A GNR X‐ray diffractometer (APD2000PRO)
was used to record the X‐ray diffraction (XRD) patterns of
the compounds. All patterns were obtained using Cu Kα1
radiation with a graphite monochromator at a scanning rate
of 0.03° min−1 at the Central Laboratory of Tanta
University. Thermogravimetric analysis (TGA) of the
complexes was conducted with a thermal analyzer
(Shimadzu TG‐50), applying N2 as atmosphere with a
heating rate of 10 °C min−1, from ambient temperature up
to 800 °C (Kafr El‐Sheikh University).
2.2 | Synthesis of Thiazole Ligand
The thiazole derivative (H2L) was obtained by condensation
of sulfathiazole (5 mmol, 1.2765 g) with salicylaldehyde
(5 mmol, 0.5236 ml). A 1:1 ratio of the two reactants was
refluxed for 24 h, and then cooled to ambient temperature.
The precipitate was separated immediately (Figure 1),
H
O
H
S
N
N
C
H
S
N
O
O
2 | EXPERIMENTAL
H
O
2.1 | Materials, Solvents and Physical
S
N
N
Measurements
C
S
N
HO
H
O
Sulfathiazole, salicylaldehyde, methanol, ethanol,
triethylamine, dimethylformamide (DMF), dimethyl-
sulfoxide (DMSO), Cr(NO3)3⋅9H2O, Fe(NO3)3⋅9H2O,
FIGURE 1 Structural forms of thiazole drug: keto (top) and enol
(bottom) forms

SAAD
3 of 13
filtered off and recrystallized several times from ethanol to
afford a highly pure ligand. Finally, the obtained compound
was dried over CaSO4 (anhydrous) in a vacuum desiccator.
The ultra‐purity of the obtained ligand was checked by
melting point constancy and TLC.
lines were obtained from the American Type Culture
Collection (Rockville, MD). At 37 °C, the cells were
preserved in a humidified atmosphere with 5% CO2 and
were sub‐cultured two to three times a week. The cells
were plated as a monolayer on RPMI‐1640 medium
supplemented with 10% inactivated fetal calf serum and
50 μg l−1 gentamycin. The monolayers of 10 000 cells
adhered at the bottom of the wells in a 96‐well microtiter
plate (Falcon, NJ, USA) were incubated for 24 h, at 37 °C,
in a moistened incubator with 5% CO2. A sterile phos-
phate‐buffered saline (10 mM, pH = 7.2) was used to
wash the monolayers, and jointly the cells were handled
with 100 μl from different dilutions of tested specimen
in fresh maintenance medium and incubated at 37 °C.
A reference of untreated cells was fabricated in the
absence of the examined material. Three wells were used
from each concentration of the test specimen. Observa-
tions were made using an inverted microscope every
24 h. The exact number of surviving cells was determined
by staining the cells with crystal violet and cell lysing
using 33% glacial CH3COOH. The absorbance (after
thorough mixing) was measured at 590 nm by applying
an ELISA reader. The values of absorbance from
untreated cells were considered as 100% proliferation.
The percentage of variability was calculated as
(1 − (ODT/ODC)) × 100%, where ODC is the average
optical density of uncured cells and ODT refers to the
average optical density of wells with the test specimen.[15]
2.3 | Synthesis of Solid Complexes
The H2L ligand (0.3591 g, 1 mmol) was dissolved in ethanol
(50 ml) and a few drops of DMF were added. Then an
ethanolic solution (2 mmol, 50 ml) of the metal salt
(Cr(NO3)3⋅9H2O (0.8003 g), Fe(NO3)3⋅9H2O (0.8080 g),
Cu(CH3COO)2⋅H2O (0.3993 g), ZrOCl2⋅8H2O (0.6445 g),
SnCl2⋅2H2O, 0.5562 PbCl2 (0.4513 g) or Ce(NO3)3⋅6H2O
(0.8685 g)) was slowly added dropwise to the H2L solution
with constant stirring. The resulting mixture was gently
refluxed for 20 h. A colored precipitate appeared after
adding a few drops of triethylamine as a buffering agent.
The solid products were collected by filtration, washed
several times with ethanol and desiccated over CaSO4
(anhydrous). The obtained complexes were characterized
using various analytical and spectroscopic techniques.
2.4 | Docking Enforcement
Implementing Autodock Tools 4.2 was achieved by
stratifying Gasteiger fractional charges, which were added
to all H2L atoms. The complexes docked to protein receptor
were executed by enforcing integrated hydrogen atoms
(nonpolar) and restriction of rotatable bonds. Addition of
substantial hydrogen atoms alongside Kollman united
atom type charges was the starting step for the program
operation.[12] Autogrid programs were implemented to
acquire the affinity (grid) maps of xx Å grid points beside
0.375 Å spacing.[13] Electrostatic terms and van der Waals
forces were evaluated through Autodock parameter sets
and distance‐dependent dielectric functions, respectively.
Lamarckian genetic algorithm and Solis and Wets local
search method were utilized to achieve the docking
simulations.[14] Torsions, orientation and initial position
of the novel drug were set. Whole rotatable torsions were
freed by applying the docking process. Ten diversified runs
were accomplished to obtain each of the docking
experiments, which were blocked after an ultimate 250
000 energy considerations. The size was set to a constant
value. Torsion steps of 5° and translational and quaternion
steps of 0.2 Å were utilized throughout the present
research.
2.6 | Antimicrobial Studies
The investigated ligand and complexes were separately
examined with plates of Gram‐negative and Gram‐positive
bacteria and fungi. Antimicrobial tests were conducted
using the agar well diffusion method: pathological
bacteria, 1 × 106 CFU ml−1; and fungi, 1 × 104 spores ml
−1
spread on nutrient agar and Sabouraud dextrose agar,
respectively.[16] After the media were solidified by cooling,
a 6 mm (in diameter) well was manufactured in solidified
agar and loaded with 100 μl of a test specimen solution
prepared by dissolving 20 mg of the compound in DMSO.
The vaccinated plates were then incubated for 48 h at
28 °C for fungi and 24 h at 37 °C for bacteria. Negative
references were prepared in a DMSO solvent, which was
used to dissolve the test samples. Amphotericin B (50 μg
ml−1) and ampicillin (50 μg ml−1) were applied as
standards for fungi and bacteria, respectively. After
incubation, antimicrobial efficacy was estimated by
measuring the diameter of inhibition zones (in millime-
ters) for the test organisms compared with the reference
standards. The average inhibition zone was determined
after repeating each experiment three times.
2.5 | Evaluation of Antitumor Activity
The antitumor activity was investigated against HEPG2
liver carcinoma cell lines (Al‐Azhar University). The cell

4 of 13
SAAD
suggested formulae. Mass spectra of [Cr2L(NO3)4(H2O)4]
⋅3H2O, [Fe2L(NO3)4(H2O)4]⋅2H2O, [Cu2L(AcO)2(H2O)2]
⋅H2O, [(ZrO)2LCl2(H2O)2]⋅H2O, [Sn2LCl2(H2O)2]⋅H2O,
[Pb2LCl2(H2O)2] and [Ce2L(NO3)4(H2O)4]⋅2H2O showed
accurate molecular ion peaks at 835.00, 825.00, 656.00,
696.00, 719.00, 878.00 and 993.00, respectively, which are
the same as the suggested molecular weights for complexes
1–7 (Figure 2 and Figures 1S–6S). The multi‐peak patterns
of the mass spectra showed a good indication of the
successive degradation of the compounds with several
peaks assignable to various fragments.[17] The suggested
fragmentation pattern of H2L, as a representative
example, is presented in Scheme 1. In some cases, the
fragmentations led to the figuration of the species [ML]+
which underwent de‐metallization to form [L]+. This is a
widespread occurrence for metal complexes containing
different ligands (ML) which degrade via cleavage of the
metal–ligand bond.[17] This gives evidence supporting the
purities and proposed structures of the complexes.
3 | RESULTS AND DISCUSSION
Depending on information obtained from microanalysis,
1H NMR, UV–visible, FT‐IR, 13C NMR, ESR and mass
spectra, TGA and physical measurements, the Cr(III),
Fe(III), Cu(II), ZrO(II), Sn(II), Pb(II) and Ce(III)
complexes (1–7, respectively0 were assigned to have the
molecular formulae and compositions presented in
Table 1. The data indicated that the Cr(III), Fe(III),
Cu(II), ZrO(II), Sn(II), Pb(II) and Ce(III) ions reacted
with ligand H2L in a metal‐to‐ligand molar ratio of 2:1
for all complexes. Metal complexes 1–7 are stable towards
moisture and air, colored and insoluble in water and most
nonpolar solvents. They, on the other hand, dissolve
freely in coordinating solvents like DMSO and DMF.
The observed molar conductance values of all complexes
lie within the range 8.66–11.28 Ω−1 cm2 mol−1 in DMF
indicative of their non‐electrolytic nature.
3.1 | Mass Spectral Analysis
3.2 | FT‐IR Spectral Analysis
Mass spectra were employed to determine the constituents
and purities of H2L and complexes 1–7. The spectrum of
H2L displayed a molecular ion peak at m/z 359.08 which
is matched with the theoretical molecular weight value.
The molecular ion peaks were utilized to confirm the
The vibrational spectral data for H2L and metal chelates
1–7 are summarized in Table 2 so as to explore the
binding modes in the complexes. By comparing the
spectrum of H2L with those of its complexes, the
following features can be concluded:
TABLE 1 Molecular formulae, empirical formulae, molecular weight, color, molar conductance and microanalysis of H2L and its metal
complexes (1–7)a
Molecular
weight:
found
Microanalysis: found (calcd)
Molecular formula (Empirical
Compound formula)
(calcd)
Color (Λm)
Yellow (—)
C (%)
H (%)
N (%)
M (%)
Ligand
H2L (C16H13N3O3S2)
359.08
53.99
3.36
11.94
— (—)
(359.42)
(53.47)
Faint green (10.32) 22.84
(23.00)
23.19
(23.29)
36.36
(36.58)
27.77
(27.58)
27.04
(26.70)
21.97
(21.87)
19.02
(19.34)
(3.65)
3.45
(3.02)
3.09
(2.81)
3.21
(3.53)
2.75
(2.46)
2.15
(2.38)
2.23
(1.72)
2.09
(2.33)
(11.69)
11.48
(11.73)
12.17
(11.88)
6.93 (6.40) 19.37
(19.36)
6.59 (6.03) 26.39
(26.18)
5.45 (5.84) 33.25
(32.99)
5.16 (4.78) 46.98
(47.16)
9.44 (9.87) 28.61
(28.20)
1
2
3
4
5
6
7
[Cr2L(NO3)4(H2O)4]⋅3H2O
(C16H25Cr2N7O22S2)
835. 00
(835.52)
12.26
(12.45)
13.63
(13.53)
[Fe2L(NO3)4(H2O)4]⋅2H2O
(C16H23Fe2N7O21S2)
825.00
(825.21)
Reddish‐brown
(11.28)
[Cu2L(AcO)2(H2O)2]⋅H2O
(C20H23Cu2N3O10S2)
656.00
(656.63)
Green (10.84)
Brown (9.55)
[(ZrO)2LCl2(H2O)2]⋅H2O
(C16H17Cl2N3O8S2Zr2)
696.00
(696.80)
[Sn2LCl2(H2O)2]⋅H2O
(C16H17Cl2N3O6S2Sn2)
719.00
(719.78)
Creamy yellow
(11.03)
[Pb2LCl2(H2O)2] (C16H15Cl2N3O5Pb2S2) 878.00
(878.74)
Canary yellow
(8.66)
[Ce2L(NO3)4(H2O)4]⋅2H2O
(C16H23Ce2N7O21S2)
993.00
(993.75)
Brown (9.08)
aThe yield for the synthesized complexes was 75.5–78.4%. Molecular weight was obtained from mass spectra. Λm is the molar conductance (Ω−1 cm2 mol−1). All
complexes decompose without melting above 290 °C.

SAAD
5 of 13
FIGURE 2 Mass spectrum of [Ce2L(NO3)4(H2O)4]⋅2H2O (7)
i. The FT‐IR spectrum of H2L showed a medium
intensity band at 3445 cm−1 corresponding to
ν(OH). The presence of coordinated and lattice water
molecules in the structure of complexes 1–7 was
given support by the occurrence of broad bands
within the range 3381–3447 cm−1, attributable to
ν(OH) of water molecules joined with the complexes.
The presence of such water molecules renders
difficult the deprotonation of the OH groups upon
complex formation.[18]
bands changed as evidence for the participation of
sulfonamide oxygen in the interaction with metal
ions.[9]
iv. All the above observations were supported by the
appearance of two new non‐ligand bands within
the ranges 620–656 and 562–594 cm−1, assignable
to ν(M─O) and ν(M─N), respectively, and
confirming the participation of both O and N atoms
in coordination to the metallic centers.[6]
v. For Cr(III), Fe(III) and Ce(III) complexes, the
ii. Azomethine ν(C═N) and thiazole ν(C═N) bands
appeared at 1618 and 1675 cm−1, respectively, in the
spectrum of H2L. These two bands have obvious shifts
upon complexation, indicating the participation of
nitrogen atoms of both azomethine and thiazole ring
in coordination to the chelating metal centers.[9]
iii. In the spectrum of H2L, the three bands observed at
3054, 1364 and 1148 cm−1 were assigned to ν(NH),
manifestation of two new bands at 1321, 1441 cm
;
−1
1320, 1442 cm−1 and 1313, 1454 cm−1
; ,
respectively, with a separation of 120, 122 and
141 cm−1 supported the presence of the terminal
monodentate nitrate.[19] The appearance of νas(OCO)
and νs(OCO) bands at 1658 and 1444 cm−1
,
respectively, confirmed the unidentate mode of the
acetate group[20] for Cu(II) complex (3). New bands
appearing at around 350 cm−1 in the spectra of
complexes 4–6 can be assigned to ν(M─Cl),
supporting the coordination of the chloride ions.[16]
ν
asy(SO2) and νsym(SO2), respectively. For most
complexes, ν(NH) bands disappeared whereas the
positions and shapes of νasy(SO2) and νsym(SO2)
3.3 | Magnetic Moment and Electronic
Spectral Measurements
Electronic spectra of H2L and metal chelates 1–7 were
recorded from 200 to 800 nm. The spectrum of H2L
exhibited two bands at 35 714 and 41 667 cm−1 assigned
to n–π* transition of the CH═N group and high‐energy
1
π–π* transition of La–1A within the aromatic nucleus,
respectively. A third band appeared at 28 090 cm−1
attributed to charge transfer interaction within the whole
molecule. These bands showed obvious changes in the
spectra of complexes 1–7 which can be considered as an
indication for the interaction of constituent atoms of
H2L with the metallic centers.
Cr(III) complex 1 showed a magnetic moment of 3.85
BM in agreement with the presence of three unpaired
SCHEME 1 Proposed fragmentation pathway of thiazole drug
(H2L)

6 of 13
SAAD
TABLE 2 Bands (cm−1) of diagnostic importance in the FT‐IR spectra of free ligand (H2L) and its metal complexes (1–7) and their
assignments
Compound
ν(OH)
ν(C═N), thiazole
ν(C═N), azomethine
ν(M─O)
ν(M─N)
H2L
3445
3423
3382
3447
3386
3386
3446
3381
1675
1653
1647
1658
1628
1618
1618
1619
1618
1614
1621
1612
1597
1577
1571
1578
—
—
Complex 1
Complex 2
Complex 3
Complex 4
Complex 5
Complex 6
Complex 7
656
634
656
641
620
626
620
569
562
566
594
573
576
573
electrons, foreseeable for octahedral chromium
complexes with high spin.[21] Six‐coordinated octahedral
Cr(III) complexes usually display three spin‐allowed
electronic transition bands within the range 18 000–30
000 cm−1. Complex 1 showed three bands in the range
17 182–32 258 cm−1, indicating that it may have either
C4v or D4h symmetry. The bands appearing at 17 182, 25
compound to these vacant metal orbitals. Also, M → N
bonding may happen by partial electron transfer of the
4d and 5d orbitals of Sn(II) and Pb(II) to the vacant
p‐orbitals of nitrogen of organic reagent.[25] As expected,
complexes 4–6 showed diamagnetic properties.
The magnetic moment value Ce(III) complex 7 equals
2.45 BM. The electronic spectrum of complex 7 displayed
a new absorption band at 19 268 cm−1 which may be
related to metal–ligand charge transfer excitations. The
electronic transition and magnetic moment value
indicated a coordination number of six and octahedral
geometry of complex 7 with high‐spin configuration.[26]
4
4
000 and 32 258 cm−1 can be attributed to B1g → Eag,
4
4
4
4B1g → B2g and B1g → Ebg transitions, respectively,
arising from the lifting of the degeneracy of the orbital
triplet (in octahedral symmetry) with increasing energy
and assuming D4h symmetry.[22]
Fe(III) complex 2 exhibited a broad band at 26 596 cm
−1
corresponding to a T2g–π* transition. A shoulder band
3.4 | NMR Spectroscopy
6
appearing at 16 529 cm−1 is assigned to A1g
→
4T2g
transitions. These electronic transitions favor an octahe-
dral symmetry around the Fe(III) ion. Complex 2 exhibited
a magnetic moment of 5.93 BM, indicating five unpaired
electrons and ambiguously supporting high‐spin octahe-
dral configuration. Cu(II) complex 3 showed two new
non‐ligand bands at 24 691 and 15 625 cm−1 corresponding
to 2T2 → 2E2 and charge transfer transitions in tetrahedral
configuration.[23] The abnormal magnetic moment value
of complex 3 (1.91 BM) reveals the Cu–Cu interaction.
The UV–visible spectrum of ZrO(II) complex 4
exhibited only one non‐ligand band at 17 182 cm−1 most
probably attributed to the charge transfer transition. Also,
complex 4 did not show any d–d transitions.
The shifts of ligand bands in the spectra of Sn(II) and
Pb(II) complexes 5 and 6 are a good indication of complex
formation.[24] A band characteristic of charge transfer in
the spectrum of the ligand at 28 090 cm−1 has shifted to
a longer wavelength and appeared at 25 316 and 26
316 cm−1 in the spectra of complexes 5 and 6. It is well
known that a metal is able to form dπ–pπ* bonds with
ligands containing nitrogen as donor atom. Sn(II) and
Pb(II) have their 5d and 6d orbitals completely vacant
and, hence, N → M bonding can occur by the acceptance
of the electron pairs from the nitrogen of the chelating
13C NMR and 1H NMR spectral data are considered one of
the best tools for confirming binding chelation modes. The
ligand spectrum showed significant peaks supporting the
proposed structure (Figure 1). In the spectrum of H2L
(Figure 7S), the NH and phenolic OH hydrogen protons
appeared as singlets at 10.255 and 12.597 ppm,
respectively. The two signals were absent in complexes 4
and 6 spectra, indicating that complex formation occurs
via OH deprotonation.[27] Also, the H2L spectrum
displayed multiple signals at 7.885–7.857 and 7.693–
6.557 ppm due to thiazole‐H and benzene‐H, respectively.
These signals showed downfield shifts to 7.852–7.824 and
7.585–6.452 ppm in the ZrO(II) complex spectrum and
7.856–7.827 and 7.458–6.467 ppm in the Pb(II) complex
spectrum. The downfield shifts are indicative of increased
conjugation upon complex formation, supporting
coordination of ligand to metal centers and giving further
support for the environment of the metals.[28] The signal
for the azomethine proton appeared at 8.953 ppm in the
spectrum of H2L, with obvious shifts and appearing at
8.806 and 8.812 ppm in spectra of complexes 4 and 6. This
is related to the donation of the electron pairs of nitrogen
(CH═N) to interaction with metal ions, resulting in the
formation of a coordinate bond.[28] The 13C NMR signals

SAAD
7 of 13
observed in the free ligand spectrum (Figure 8S) have
obvious shifts in spectra of complexes 4 and 6, which
supports the coordination of H2L to the metallic centers.
The 13C NMR spectrum of H2L displayed a peak at
168.856 ppm attributed to CH═N supporting Schiff base
formation.[29]
(electronic value). This is attributed to spin–orbit interac-
tion with a ground‐state level. The isotropic (go) and
anisotropic (Ao) parameters were computed by applying
go = (g|| + 2g⊥)/3 and Ao = (A|| + 2A⊥)/3. A⊥ and A||
are negative values, whereas K = −(Ao/p) − (ge − go).
From this equation, K (Fermi contact term) is also
determined and found to be 3.573. K is known as a
polarization feature exerted by the uneven apportionment
of d‐electron density on the inner core s‐electron.
3.5 | ESR Spectral Studies
The ESR spectrum of Cu(II) complex 3 was obtained using
2,2‐diphenyl‐1‐picrylhydrazyl standard. Spin Hamiltonian
operators and interaction exchange vector (G) are given in
Table 3, obtained from its spectrum (Figure 9S). The axially
symmetric g tensor parameters show g|| > g⊥ > 2.0023,
3.6 | XRD and TEM Studies
Powder XRD analysis of H2L and complexes 1–7 were
implemented to determine the crystalline character of the
considered compounds. Although single‐crystal X‐ray
crystallography is the greatest rigorous source of
information regarding the framework of a complex, the
difficulty of obtaining suitable crystals in adequate
symmetric form has rendered this method inadequate for
such study. Powder XRD is an extremely beneficial
technique that can give substantial structural information
about compounds under investigation.[32] XRD patterns
were recorded within the 2θ (scattering angle) range from
10° to 90° (Figure 3). Inspecting these XRD patterns, we
notice that the inter‐planar spacing d and relative
intensities (I/I0) of H2L are different compared with those
of each metal complex. The XRD patterns indicate that
H2L and its Sn(II) and Pb(II) complexes are crystalline in
nature, whereas Cr(III), Fe(III), Cu(II), ZrO(II) and Ce(III)
complexes displayed an amorphous nature. This character
is due to the incorporation of water molecules. A
comparative analysis of the patterns points out the
non‐occurrence of smearing or contamination with
starting materials. A shift in the diffraction peaks of the
complexes was predicted, supporting a contribution of
sulfathiazole ligand groups to the metallic sites. All these
observations support the formulation of single‐phase
metal chelates. The inter‐planar distance d (the volume
average of the crystal dimension normal to diffracting
plane) is reckoned from 2θ values by Bragg's law[20]
denoting that dx −y is the ground‐state orbital.[30] G = (g||
− 2.0023)/(g⊥ − 2.0023) = 4 is employed to calculate the
G factor. G > 4 means a modest interchange interaction
between Cu(II) sites; G < 4 indicates a significant Cu–Cu
interaction and coincides directly with calculated mag-
netic moment. The considerably low value (1.586) means
a strong interaction between metallic centers.[16] The g||
value (2.1887) is in agreement with relatively covalent
Cu─O bonds.[31] A decrease of A|| against the g|| increase
indicates tetrahedral distortion (f = g||/A||).[30] Covalence
of in plane π‐bonding (β2) and covalence of in‐plane σ‐
bonding (σ2) were determined applying the following
equations:
2
2
ꢀ
ꢁ
A∥
3
7
α2 ¼
þ g∥−2:0023 þ ðg⊥−2:0023Þ þ 0:04
0:036
ꢀ
ꢁ
g∥−2:0023 E
β2 ¼
−8λα2
where E (15625 cm−1) is the electronic transition
energy while λ (spin–orbital coupling) = −828 cm−1 for
free Cu(II) ion. β2 (0.598) and α2 (0.735) values reveal that
the in‐plane π‐bonding is highly covalent. The dipolar
term such as a displacement vector between charges
inside the complex can be determined from the equation
p = 2γCuβoβN(r−3), where γCu is the magnetic moment of
copper, βo is the Bohr magneton, βN is the nuclear
magneton and r refers to the distance from nucleus to
outer electron shells. The value of p (28.06 × 10−4) does
not deviate much from the well‐documented values. The
deduced g values are totally featured from 2.0023
2d sinθ ¼ nλ
where n is a positive integer and λ is the wavelength
of incident waves.
The values of θ, d and β (the line broadening at half
the maximum intensity (FWHM)) of the most intense
peak, particle size and relative intensity (%) of the
TABLE 3 Spin Hamiltonian parameters for Cu(II) complex (A and p × 10−4
)
Complex
6
g||
g⊥
go
A||
f
A⊥
Ao
G
p
k
α2
β2
2.1887
2.1198
2.1427
165
132.65
62
96.33
1.586
28.06
3.573
0.735
0.598

8 of 13
SAAD
FIGURE 3 XRD pattern of thiazole drug (H2L)
investigated compounds are presented in Table 4. FWHM
of the distinctive peaks is employed to investigate the
crystallite size (from XRD patterns). The particle size
was abstracted applying the highest value of intensity in
comparison with the other peaks. The obtained results
show that Sn(II) and Pb(II) complexes have particles sizes
located within the nanoscale range.
range of prospective technological applications, including
catalysis, optics, microelectronics, chemical sensing and
biological sensing.[34]
3.7 | Thermal Analysis
Investigation of the thermal degradation of metallic com-
pounds is helpful in understanding their coordination
structures. Derivative plots displaying the mass change
rate in relation to temperature or time (derivative
thermogravimetry, DTG) are applied to resolve overlap-
ping processes and to realize the point at which the mass
loss is greatest. Also, it is useful for some methods of cal-
culating the thermodynamic parameters.[35] The thermal
behavior of complexes 1–6 was scrutinized using TGA–
DTG. The results comprise the decomposition stages,
temperature ranges and decomposition products, as well
as the found and calculated mass loss percentages
(Table 1S). The TGA thermograms of complexes 1–6
displayed four successive degradation steps, except for
the Pb(II) complex that showed three degradation steps.
The weight loss at 44–100 °C is assigned to the
abstraction of hydrated water molecules. The weight loss
occurring in the range 100–230 °C corresponds to the
removal of coordinated water. The decomposition step
TEM is considered as a useful technique applied to
illustrate various nanosized metal chelates.[30,33] In this
study, TEM was applied to get straightforward information
about particle size, homogeneity, microstructure, surface
morphology and chemical composition for the ligand and
complexes. The obtained images displayed uniform and
homogeneous surface morphology for all investigated
compounds (Figure 10S). Furthermore, the images indi-
cate the uniformity and similarity among particle forms,
showing the presence of morphological phases and homo-
geneous matrix. The particle diameters were observed to be
in the nanoscale range as follows: H2L, 25.07–44.54; Cr(III)
complex, 19.95–31.54; Fe(III) complex, 25.47–47.14; Cu(II)
complex, 22.93–30.14; ZrO(II) complex, 19.19–28.68; Sn(II)
complex, 13.34–15.12; Pb(II) complex, 21.20–40.11; and
Ce(III) complex, 11.45–24.34 nm. These novel nanome-
ter‐scale compounds usually attract tremendous attention
due to their outstanding functional characteristics and a
TABLE 4 XRD data of H2L and its Sn(II) and Pb(II) complexes (5 and 6)a
Compound
Size of particles (nm)
θ (°)
I/I0 (%)
d (Å)
β (FWHM)
H2L
53.82
60.80
34.38
10.350
11.175
15.040
1323.39
1247.00
945.14
4.2870
3.9921
2.9689
0.1505
0.1336
0.2400
Complex 5
Complex 6
aθ is the scattering angle, I/I0 is the relative intensity, d is the inter‐planar spacing and β (FWHM) is the line broadening at half the maximum intensity.

SAAD
9 of 13
at 165–450 °C is assignable to partial decomposition of
the complex and removal of the coordinative anions.
The last step appeared at 313–700 °C involving complete
decomposition of the organic ligand and forming metallic
oxide polluted with carbon atoms as a final product.[36]
FIGURE 4 Optimized structure of enol form of thiazole drug
3.8 | Thermo‐Kinetic Parameters
molecular orbital) and EHOMO (highest occupied
molecular orbital) energy gap, significant parameters
were determined.[41] Figures 5, 6 and 14S show molecular
orbital images for keto and enol forms of the drug ligand,
LUMO and HOMO levels. The calculated HOMO and
LUMO energies were − 0.22292 and − 0.07775 eV for
keto form, whereas enol form exhibited energies of
HOMO and LUMO equal to −0.18067 and − 0.08735 eV,
respectively. The LUMO observed to be spread over the
whole ligand moiety, whereas the HOMO is centered at
chelation centers (at most) of H2L enriched with heavy
donor atoms. This indicates the lower energy levels of
such atoms shared in a broad spread resonance, confer-
ring on such atoms a plentiful opportunity for dual
nature in ligand‐to‐metal charge transfer process or vice
versa. Also, the thiazole drug exhibits a softness charac-
ter, which augments its flexibility to coordinate with
different metals. Other intrinsic data were gained using
output log files, such as oscillator strength and excitation
energy. Keto and enol forms exhibited excitation energies
equal to 376.25 and 555.45 nm, respectively. Oscillator
strength is considered a good indicator for possible
absorption and emission of radiation by the molecule
depleted in electronic transitions. Its value is between
unity and zero, and that of a strong transition will be
close to 1. The computed values for the oscillator
Mechanistic and non‐mechanistic methods were
employed to calculate the thermodynamic and kinetic
indexes from TGA curves. The mechanism, reaction order
(n), activation energy (E), frequency factor (A), free
energy (ΔG*), enthalpy (ΔH*) and entropy (ΔS*) for
different stages of thermal degradation of complexes 1–6
were reckoned employing the integral method (Figures
11S and 12S). The thermo‐kinetic indexes of various
thermal degradation stages of the complexes are
presented in Table 2S. From the obtained data, the
following remarks are made:
i. The negative ΔH* vales denote that the decomposi-
tion processes are exothermic.
ii. The negative ΔS* values reveal that the reaction
processes are very slow and/or the activated
intermediate complex is highly ordered compared
with the reactants.[37]
iii. ΔG* values increase in a sufficient way for the
subsequent decomposition stages because of the
increase of TΔS* values from one step to another
which override ΔH* values. This means that the rate
of sweeping of the subsequent ligand parts will be
lower than that of the preceding.[38] This is because
of the constitutional rigidity of the rest of the
complex after the loss of one or more ligand parts,
in comparison with the preceding complex, which
needs more energy for its rearrangement before
undergoing any compositional change.
3.9 | Theoretical Studies
FIGURE 5 Frontier molecular orbitals of HOMO for keto form of
thiazole drug (H2L)
3.9.1 | Molecular modeling
The oriented structure of sulfathiazole drug was executed
by Gaussian09 software[39] in the gas phase. DFT/B3LYP
is considered as the most favored tool applied to attain
the optimization employing different base sets. In the
program, visualization screen was used in order to view
the output Gaussian files.[40] The obtained results confirm
the great probability for the existence of both keto and
enol tautomer forms (Figures 4 and 13S). Essential
parameters are acquired depending on the frontier orbital
energy values. Also, using ELUMO (lowest unoccupied
FIGURE 6 Frontier molecular orbitals of LUMO for keto form of
thiazole drug (H2L)

10 of 13
SAAD
strengths were 0.0017 and 0.1882 for keto and enol
tautomers. All bond lengths and significant charge
density over different sites were calculated and are given
in Table 3S, using output files and in combination with
numbering scheme. The atomic charge densities on the
donor atoms (sulfur, oxygen and nitrogen) indicate that
the most negatively charged are the coordinating atoms
(3N, 10O, 16N and 24O), supporting the coordination
character of the ligand. In most cases, the coordinating
atoms of the enol form carry higher atomic charges
compared with the corresponding atoms in the keto form.
This agrees with the coordination of the ligand to metallic
ions in the enol form. It is obvious from the data
presented that the bond lengths are within the normal
ranges.[42] The computational obtained results are in
satisfactory agreement with the experimental ones and
hence strongly support them.
using Polake–Ribiere conjugated gradient algorithm, the
other authentic parameters have been calculated for
optimized structures and are presented in Table 4S. The
computed energies reveal the higher internal energy of
keto form compared with enol form and the greater
chemical reactivity of enol form. These results bolster
the notion of chelating enol form rather than keto one.
3.9.3 | Docking analysis
The prepared thiazole drug was optimized by using
known standard computational methods. The computa-
tional method is an intensive tool used to reinforce the
designing field. Autodock Tools were used to explain
the biological properties for the novel drug to support
the gained experimental results. Our study aims to design
a modern drug for biological applications such as antifun-
gal, anticancer and antibacterial applications. The
docking implementation was carried out employing pro-
tein receptors of the microorganisms examined in the lab-
oratory work: 3gcw, 1zjc and 1zap as hosts for liver
carcinoma cell line, Staphylococcus aureus and Candida
albicans, respectively. The computed energies for all
investigated complexes are given in Table 5. The binding
free energy, electrostatic energy, total intercooled energy
as well as constant of inhibition and receptor‐inhibitor
complex interaction surface were calculated for keto and
enol forms. Increasing interaction capability towards host
receptors is assigned to minimization in binding energy
(due to mutation).[24] The obtained data display inhibi-
tion activity in the case of 3gcw and 1zap receptors. This
reflects the instability of the complex which appeared
clearly through the high energy values calculated. As well
as, the ignored value of inhibition constant verify the
instability proposed. The computed results indicate the
superiority of enol form over keto form in bioactivity. Fig-
ures 7 and 15S–17S show the docked complexes. The hp
plots (Figures 8 and 18S) indicate the various interaction
behaviors, in accordance with computation. The red spots
concerning hydrogen‐bonding interaction are basically
concentrated with 3gcw and 1zap. Hence, the outstanding
interaction with 3gcw and 1zap protein receptors is
3.9.2 | Quantitative structure–activity
relationship (QSAR) calculations
The value of log P (partition coefficient) is considered as
the genuine result acquired through QSAR study of the
optimized structure, applying HyperChem software. The
molecular framework was optimized enforcing MM+
(molecular mechanics force field), followed by full
modulation using semi‐empirical AM1. Without asserting
any indexes, the molecular framework was optimized,
leading to equilibrium state data. An investigation of
the interconnection between log P of the sulfa drug and
its anticancer efficacy was carried out, applying the
reversed relationship.[43] Log P is an essential indicator
of lipophilicity for non‐ionized molecules, in which large
log P refers to a small absorption or penetration of the
sulfa drug. Each keto and enol form displays a plausible
probability of full absorption and these values should
not be strictly considered. The obtained values of log P
are low especially for keto form (−0.92), which denotes
a biological behavior for it. Good merit has been expected
for enol form in coordinating with metal atoms, which
increases the priority of the complexes in bioactivity.
Furthermore, applying energy minimization protocol
TABLE 5 Docking energies for H2L–protein receptor complexes
Est. free
Total
energy of
binding
(kcal mol−1
Est.
intercooled
inhibition
constant, Ki
(μM)
vdW + bond + Electrostatic energy
desolve energy energy
(kcal mol−1
(kcal mol−1 (kcal mol−1
)
) Frequency Interaction
Compound Receptor
)
)
(%)
surface
Enol (keto) 3gcw
Enol (keto) 1zap
Enol (keto) 1zjc
−1.63 (−1.75) 64.34 (52.28)
−3.52 (−3.40)
+0.01 (+0.17) −3.51 (−3.23) 20
−0.15 (+0.60) −7.19 (−6.07) 10
−0.36 (+0.80) −3.47 (−2.11) 10 (20)
596.453 (572.595)
755.164 (760.39)
447.158 (412.165)
−5.44 (−4.32) 102.89 (676.05) −7.03 (−6.67)
−1.89 (−0.84) 41.07 (242.98) −3.11 (−2.91)

SAAD
11 of 13
the compound concentrations which lead to 50%
reduction in cell proliferation during sample
incubation.[45] The mean IC50 is the concentration of
sample that reduces cell growth by 50% under the
experimental conditions. Each data point was determined
as the median of three separate experimental trials and
expressed as mean
standard deviation. From the
obtained data, the growth inhibition of the cells was
strongly affected by the type of metal ion and increases
in the order: H2L (IC50 > 50) < Cr(III) complex (IC50
>
50) < ZrO(II) complex (IC50 > 50) < Fe(III) complex
(IC50 = 47.5) < Ce(II) complex (IC50 = 42.3) < Sn(II)
complex (IC50 = 36.0) < Pb(II) complex (IC50 = 34.8) <
Cu(II) complex (IC50 = 22.8). This reveals that the type
of metal ion plays a significant role in anticancer
activity.[26]
FIGURE 7 Docked complex for H2L drug (enol form) with 3gcw
receptor
3.11 | In Vitro Antimicrobial Activity
In vitro antimicrobial activities of H2L and metal com-
plexes 1–7 were screened (agar well diffusion method)[27]
against C. albicans, S. aureus, Aspergillus fumigatus and
Escherichia coli. Comparing the results for the free ligand
and complexes 1–7 showed that most complexes
displayed higher antimicrobial efficacy than the ligand
(Table 5S). Such increased activity upon complex forma-
tion can be accounted for based on Tweedy's chelation
theory and Overton's concept.[46] The mode of action of
the compounds may involve formation of a hydrogen
bond using azomethine group of the complexes and
ligand with the constituents of the cell, leading to
interference with the general operation of the cell.
Furthermore, these compounds may disorganize the
respiration operation in the cell and so hinder proteins
synthesis, limiting organism growth. Generally, the
higher antimicrobial performance of complexes
compared with free ligands is assignable to the presence
of metal ions. They are more hypersensitive towards
bacterial cells than ligands.[47] The Cr(III) complex
displayed high activity against E. coli, and Fe(III), Cu(II),
Pb(II) and Ce(III) complexes showed moderate activity,
whereas H2L and ZrO(II) and Sn(II) complexes showed
no activity towards that bacterial type. Cu(II) and Fe(III)
complexes exhibited high activity towards S. aureus, and
H2L and Cr(III), ZrO(II), Sn(II), Pb(II) and Ce(III)
complexes showed moderate efficiency against it. Fe(III)
complex exhibited activity equivalent to that of the
standard amphotericin B against C. albicans, whereas
H2L and Cr(III), Cu(II), ZrO(II), Sn(II), Pb(II) and Ce(III)
complexes showed moderate activity towards this fungus.
Sn(II) complex showed moderate activity towards A.
fumigatus while all other investigated compounds were
inactive against that organism. The examined organisms
FIGURE 8 hp plot of H2L drug (enol form) with 1zap receptor
suggested. Two‐dimensional plot curves (Figures 19S and
20S) evidence the manner of interaction inside the
docking complexes. Furthermore, the obtained data prove
the good interaction of the novel thiazole drug with liver
carcinoma cells and C. albicans.
3.10 | Antitumor Evaluation
Novel synthetic antitumor agents are in great demand to
improve the outcome for the large number of patients
who suffer setbacks after treatment with the presently
available cancer therapies.[44] Our aim was to determine
the antitumor efficacy of H2L and metal complexes 1–7
towards HEPG2. Doxorubicin was employed as a refer-
ence drug and untreated cells were utilized as a reference
standard. Growth inhibition of 50% (IC50) is specified as

12 of 13
SAAD
[5] Y. Hiranoi, M. Hatanaka, K. Na, J. Polym, Polym. Chem. 2017,
55, 2150.
were selected as follows: E. coli was chosen as a
representative Gram‐negative bacterium and S. aureus
as a Gram‐positive bacterium. Also, we chose C. albicans
to represent the unicellular fungi and A. fumigatus as a
higher fungus which represents multicellular fungi.
Hence, these selections represent a vast spectrum of test
organisms. So, the results obtained revealed the potential
of the examined compounds as wide‐spectrum
antimicrobial agents.
[6] F. A. Saad, A. M. Khedr, Bulg. Chem. Commun. 2015, 47, 654.
[7] W.‐K. Dong, J. Zhang, Y. Zhang, N. Li, Inorg. Chim. Acta 2016,
444, 95.
[8] M. Wenzel, A. de Almeida, E. Bigaeva, P. Kavanagh, M.
Picquet, P. Le Gendre, E. Bodio, A. Casini, Inorg. Chem. 2016,
55, 2544.
[9] F. A. Saad, A. M. Khedr, J. Mol. Liq. 2017, 231, 572.
[10] F. A. Saad, J. Therm. Anal. Calorim. 2017, 129, 425.
[11] G. O. Ogunlusi, A. S. Adekunle, N. W. Maxakato, B. B. Mamba,
4 | CONCLUSIONS
Int. J. Electrochem. Sci. 2012, 7, 2904.
[12] T. A. Halgren, J. Comput. Chem. 1996, 17, 490.
Seven nanosized homo‐binuclear Cr(III), Fe(III), Cu(II),
ZrO(II), Sn(II), Pb(II) and Ce(III) complexes with
sulfathiazole ligand (H2L) were synthesized. The
structure and molecular formulae of the newly
synthesized compounds have been investigated
analytically and theoretically. Dibasic tetradentate mode
is proposed for ligand binding towards the metal ions
[13] G. M. Morris, D. S. Goodsell, R. S. Halliday, R. Huey, W. E.
Hart, R. K. Belew, A. J. Olson, J. Comput. Chem. 1998, 19, 1639.
[14] F. J. Solis, R. J. B. Wets, Math. Oper. Res. 1981, 6, 19.
[15] A. P. Wilson, Cytotoxicity and Viability Assays in Animal Cell
Culture: A Practical Approach, 3rd ed., Oxford University Press,
Oxford 2000.
[16] F. A. Saad, M. G. Elghalban, N. El‐Metwaly, H. El‐Ghamry, A.
M. Khedr, Appl. Organometal. Chem. 2017, 31, e3721.
via two coordination sites through
N of CH═N
(azomethine), α‐hydroxyl oxygen, oxygen of sulfonamide
and thiazole nitrogen. TEM and XRD confirmed the
nanometric size of the complex particles. Octahedral
geometry is the main feature proposed for Cr(III), Fe(III)
and Ce(III) complexes, whereas tetrahedral structure is
suggested for Cu(II), ZrO(II), Sn(II) and Pb(II) complexes.
Molecular modeling, docking and QSAR studies gave a
good insight into the biological and structural features
of the thiazole ligand. Predominantly, both antitumor
and antimicrobial influences of sulfathiazole ligand
increased upon metallization. Cu(II) complex displayed
the greatest cytotoxic effect against HEPG2, compared
with the other investigated compounds. Fe(III) complex
showed antimicrobial activity equivalent to that of the
standard bactericide and fungicide towards S. aureus
and C. albicans.
[17] A. M. Khedr, D. F. Draz, J. Coord. Chem. 2010, 63, 1418.
[18] G. G. Mohamed, M. A. Gad‐Elkareem, Spectrochim. Acta A
2007, 68, 1382.
[19] A. A. Fedorova, I. V. Morozov, N. R. Kuznetsova, D. V.
Palamarchuk, I. A. Romanov, S. I. Troyanov, Acta Crystallogr.
2006, A62, s275.
[20] H. P. Meyers, Introductory Solid State Physics, 2nd ed., Taylor &
Francis, London 1997.
[21] A. M. A. Alaghaz, H. A. Bayoumi, Y. A. Ammar, S. A.
Aldhlmani, J. Mol. Struct. 2013, 1035, 383.
[22] A. M. A. Alaghaz, R. A. Ammar, Eur. J. Med. Chem. 2010, 45,
1314.
[23] M. Gaber, N. A. El‐Wakiel, H. El‐Ghamry, S. K. Fathalla,
J. Mol. Struct. 2014, 1076, 251.
[24] K. Tripathi, R. MuttineniR, S. K. Singh, J. Theor. Biol. 2013,
334, 87.
[25] A. M. Khedr, S. Jadon, V. Kumar, J. Coord. Chem. 2011, 64,
ORCID
1351.
Fawaz A. Saad http://orcid.org/0000-0003-4910-361X
[26] X. Riera, V. Moreno, C. J. Ciudad, V. Noe, M. Font‐Bardía, X.
Solans, Bioinorg. Chem. Appl. 2007, 1.
[27] S. M. Abdallah, M. A. Zayed, G. G. Mohamed, Arabian J. Chem.
2010, 3, 103.
REFERENCES
[1] J. Feng, S. Zhang, W. Shi, Y. Zhang, Antibiotics 2017, 6, 1.
[28] A. M. Khedr, N. A. El‐Wakiel, S. Jadon, V. Kumar, J. Coord.
Chem. 2011, 64, 851.
[2] Y. Zhao, W. R. Shadrick, M. J. Wallace, Y. Wu, E. C. Griffith, J.
Qi, M. K. Yun, S. W. White, R. E. Lee, Bioorg. Med. Chem. Lett.
2016, 26, 3950.
[29] R. K. Shah, K. S. Abou‐Melha, F. A. Saad, T. Yousef, G. A. A.
Al‐Hazmi, M. G. Elghalban, A. M. Khedr, N. El‐Metwaly,
J. Therm. Anal. Calorim. 2016, 131, 731.
[3] M. Gaber, A. M. Khedr, M. Elsharkawy, Appl. Organometal.
Chem. 2017, 31, e3885.
[30] F. A. Saad, J. H. Al‐Fahemi, H. El‐Ghamry, A. M. Khedr, M.
G. Elghalban, N. El‐Metwaly, J. Therm. Anal. Calorim. 2018,
131, 1249.
[4] O. G. Idemudia, A. P. Sadimenko, A. J. Afolayan, E. C. Hosten,
Bioinorg. Chem. Appl. 2015, 1.
[31] R. C. Maurya, S. Rajput, J. Mol. Struct. 2004, 687, 35.

SAAD
13 of 13
[32] A. A. Fahem, Spectrochim Acta A 2012, 88, 10.
[45] S. H. Etaiw, S. A. Amer, M. M. El‐Bendary, J. Inorg.
Organometal. Polym. Mater., 2011, 21, 662.
[33] J. K. Hui, M. J. Mac Lachlan, Coord. Chem. Rev. 2010, 254,
2363.
[46] A. Kulkarni, S. A. Patil, P. S. Badami, Eur. J. Med. Chem. 2009,
44, 2904.
[34] A. Salimi, R. Hallaj, S. Soltanian, Biophys. Chem. 2007, 130, 122.
[47] M. A. Phanib, S. D. Dhumwad, Transition Met. Chem. 2007, 32,
[35] T. M. A. Ismail, A. A. Saleh, M. A. El Ghamry, Spectrochim.
Acta A 2012, 86, 276.
1117.
[36] R. K. Agarwal, H. Agarwal, A. K. Manglik, Synth. React. Inorg.
Met.‐Org. Chem. 1996, 26, 1163.
SUPPORTING INFORMATION
[37] H. A. Bayoumi, A. M. A. Alaghaz, M. S. Aljahdali, Int. J.
Electrochem. Sci. 2013, 8, 9399.
Additional Supporting Information may be found online
in the supporting information tab for this article.
[38] T. M. Ismail, M. A. E. L. Ghamry, S. M. Abu‐El‐Wafa, D. F.
Sallam, Mod. Chem. 2015, 3, 18.
[39] M.J. Frisch. Gaussian 09, Revision D, Gaussian Inc.,
How to cite this article: Saad FA. Nano‐
synthesis and spectral, thermal, modeling,
Wallingford, CT, 2010.
[40] R. Dennington, T. Keith, J. Millam, GaussView, Version 4.1.2,
quantitative structure–activity relationship and
docking studies of novel bioactive homo‐binuclear
metal complexes derived from thiazole drug for
therapeutic applications. Appl Organometal Chem.
2018;e4352. https://doi.org/10.1002/aoc.4352
Semichem Inc., Shawnee Mission, KS, 2007.
[41] R. K. Ray, G. R. Kauffman, Inorg. Chim. Acta 1990, 173, 207.
[42] Z. D. Matovic, B. Ristic, M. Joksovic, S. R. Trifunovic,
Transition Met. Chem. 2000, 25, 720.
[43] R. F. George, Eur. J. Med. Chem. 2012, 47, 377.
[44] A. S. Sultan, H. Brim, Z. A. Sherif, Cancer Sci. 2008, 99, 272.