Characterization of new Pt(IV)–thiazole complexes: Analytical, spectral, molecular modeling and molecular docking studies and applications in two opposing pathways

Article abstract of DOI:10.1002/aoc.5099

New thiazole derivatives were synthesized and fully characterized, then coordinated with PtCl₄ salt. Also, the newly synthesized Pt(IV) complexes were investigated analytically (elemental and thermogravimetric analyses), spectrally (infrared, UV–visible, mass, ¹H NMR, ¹³C NMR, X-ray diffraction) as well as theoretically (kinetics, modeling and docking). The data extracted led to the establishment of the best chemical and structural forms. Octahedral geometry was the only formula proposed for all complexes, which is favorable for d⁶ systems. The molecular ion peaks from mass spectral analysis coincide with all analytical data, confirming the molecular formula proposed. X-ray diffraction (XRD) and scanning electron microscopy (SEM) allowed discrimination of features between crystalline particles and other amorphous morphology. By applying Gaussian09 as well as HyperChem 8.2 programs, the best structural forms were obtained, as well as computed significant parameters. Computed parameters such as softness, hardness, surface area and reactivity led us towards application in two opposing pathways: tumor inhibition and oxidation activation. The catalytic oxidation for CO was conducted over PtO₂, which was yielded from calcination of the most reactive complex. The success of catalytic role for synthesized PtO₂ was due to its particulate size and surface morphology, which were estimated from XRD patterns and SEM images, respectively. The antitumor activity was tested versus HCT-116 and HepG-2 cell lines. Mild toxicity was recorded for two of the derivatives and their corresponding complexes. This degree of toxicity is more favorable in most cases, due to exclusion of serious side effects, which is coherently attached with known antitumor drugs.

Full text of DOI:10.1002/aoc.5099

Received: 7 January 2019
DOI: 10.1002/aoc.5099
Revised: 12 June 2019
Accepted: 14 June 2019
F U L L P A P E R
Characterization of new Pt(IV)–thiazole complexes:
Analytical, spectral, molecular modeling and molecular
docking studies and applications in two opposing pathways
Ismail Althagafi1 | Nashwa M. El‐Metwaly1,2
| Thoraya Farghaly1,3
1 Department of Chemistry, Faculty of
New thiazole derivatives were synthesized and fully characterized, then coordi-
nated with PtCl4 salt. Also, the newly synthesized Pt(IV) complexes were inves-
tigated analytically (elemental and thermogravimetric analyses), spectrally
(infrared, UV–visible, mass, H NMR, 13C NMR, X‐ray diffraction) as well as
Applied Science, Umm Al‐Qura
University, Makkah, Saudi Arabia
2 Department of Chemistry, Faculty of
Science, Mansoura University, Mansoura,
Egypt
1
3 Department of Chemistry, Faculty of
Science, Cairo University, Cairo, Egypt
theoretically (kinetics, modeling and docking). The data extracted led to the
establishment of the best chemical and structural forms. Octahedral geometry
was the only formula proposed for all complexes, which is favorable for d6
systems. The molecular ion peaks from mass spectral analysis coincide with
all analytical data, confirming the molecular formula proposed. X‐ray diffrac-
tion (XRD) and scanning electron microscopy (SEM) allowed discrimination
of features between crystalline particles and other amorphous morphology.
By applying Gaussian09 as well as HyperChem 8.2 programs, the best struc-
tural forms were obtained, as well as computed significant parameters. Com-
puted parameters such as softness, hardness, surface area and reactivity led
us towards application in two opposing pathways: tumor inhibition and oxida-
tion activation. The catalytic oxidation for CO was conducted over PtO2, which
was yielded from calcination of the most reactive complex. The success of
catalytic role for synthesized PtO2 was due to its particulate size and surface
morphology, which were estimated from XRD patterns and SEM images,
respectively. The antitumor activity was tested versus HCT‐116 and HepG‐2
cell lines. Mild toxicity was recorded for two of the derivatives and their corre-
sponding complexes. This degree of toxicity is more favorable in most cases,
due to exclusion of serious side effects, which is coherently attached with
known antitumor drugs.
Correspondence
Ismail Althagafi and Nashwa M. El‐
Metwaly, Department of Chemistry,
Faculty of Applied Science, Umm Al‐Qura
University, Makkah, Saudi Arabia.
Email: iithagafi@uqu.edu.sa;
n_elmetwaly00@yahoo.com
Funding information
Deanship of Scientific Research at Umm
Al‐Qura University, Grant/Award Num-
ber: (project ID: 17‐SCI‐1‐01‐0004) project
ID: 17‐SCI‐1‐01‐0004
KEYWORDS
antitumor activity, catalytic oxidation, docking, modeling, Pt(IV)–thiazole complexes
1 | INTRODUCTION
diamminedichloroplatinum(II) (known as cisplatin) is a
commercially available drug for human malignancies.
Over the last decade, platinum complexes have become
well known for their high potential anticancer activity
and as industrial catalysts.[1–3] For example, cis‐
This may be attributed to crosslinking of DNA strands by
metal complexes via coordination of nucleic acid bases,
which then encourages apoptosis of cancer cells.[4] Also,
Appl Organometal Chem. 2019;e5099.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5099

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ALTHAGAFI ET AL.
platinum‐based complexes are significant catalysts for
cycloisomerization, hydrosilylation and selective hydroly-
sis of peptides containing either histidine or methionine
residues.[5–7] Platinum‐based antitumor drugs are associ-
ated with serious side effects (loss of balance, swelling of
feet or lower legs, ringing in ears, trouble in hearing) and
drug impedance in the therapeutic process.[8] This has
prompted chemistry and pharmaceutical researchers to
design and synthesize more effective, less toxic metal‐
based anticancer drugs.[9–11] Heterocyclic compounds with
multiple donors (N, S and O) are considered as sensors
for several bioactive coordination compounds.[12,13] Thia-
zole and its derivatives, as multi‐donor ligands with
nitrogen and sulfur atoms, are considered interesting in
coordination chemistry, not only for their multifunctional
coordination modes, but also for their significant pharma-
ceutical activity.[14–16] Using 4′‐bis(pyridine‐2‐ylmethyl)
amino‐2‐phenylbenzothiazole), a Pt(II) complex was
prepared as [PtLCl]Cl which interacted with human
serum albumin, the data indicating a moderate binding
affinity between complex and protein.[17] [PtL(EtOH)Cl]
was prepared using N‐(2‐thiazolyl)‐1H‐benzotriazole‐1‐
carbothioamide ligand. Square planar was the proposed
structural form for the complex. Molecular modeling was
executed with the density functional theory (DFT) method.
The complex was tested for its antimicrobial activity and
cytotoxicity, the result showing inhibition towards the
MCF7 cell line.[1] Ceria (CeO2) has a broad diversity of
application in, for instance, catalysis for fuel cell technolo-
gies, ceramic biomaterials, optical glass‐polishing, electro-
chemical applications and gas sensors. It is characterized
by its facile redox couple (Ce4+/Ce3+) and high oxygen
ion migration capacity. As such, it has been applied for a
long time as one of the components of automobile catalytic
exhaust transformers. However, this oxide catalyst has
many disadvantages, including its specific surface area,
which is significantly reduced when exposed to high
temperatures. This leads to minimization of oxygen
release/storage ability, and its critical redox properties.
Thus, modification of ceria is the aim of researchers,
through using appropriate transition metals or metal
oxides, which improves the oxidation activity of the
resulting catalysts.[18]
tumor cells; secondly, we tested them as activators for
monitoring oxidation reaction, to prepare an economic
product (CO2). Such application may basically be affected
by the inductive effect of p‐substituents on the thiazole
derivatives, which is discussed.
2 | METHODOLOGY
The chemicals or reagents used in the synthesis
stage such as thiourea, phenacyl bromide derivatives,
ethylacetoacetate, sodium acetate and PtCl4 were
purchased from Sigma‐Aldrich. Also, the solvents used in
all experiments (ethanol, methanol and dimethylsulfoxide
(DMSO)) were from PDH and used as received without
previous treatments.
2.1 | Synthesis of thiazole derivatives
(5a–e)
The synthesis of thiazole derivatives 5a–e started with the
reaction of substituted phenacyl bromide (0.05 mol) with
thiourea (7.6 g, 0.1 mol) in ethanol solvent under reflux
for 5 h. The reaction afforded 2‐amino‐4‐substituted
thiazole derivatives (3a–e) and the purity was tested
by TLC.[19,20] Each aminothiazole derivative (0.01 mol in
ethanol) was condensed at 180°C with acetoacetate
(2.6 g, 0.02 mol in ethanol) in the presence of
dimethylformamide (DMF; 2 ml) for 30 min. After cooling,
the reaction mixture was filtered, and recrystallized from
ethanol–dioxane mixture to afford the target ligands 5a–e
(Scheme 1). The scientific names of them are as follows: 3‐
oxo‐N‐ (4‐ p‐ tolythiazil‐2‐yl)butanamide (5a, H‐OTTB),
N‐(4‐ (4‐ methoxyphenyl)thiazol‐2‐yl)‐3‐oxobutanamide
(5b, H‐ MTOB), 3‐oxo‐N‐(4‐phenylthiazol‐2yl)butanamide
(5c,
H‐OPTB),
N‐(4‐(4‐chlorophenyl)thiazol‐2yl)‐3‐
oxobutanamide (5d, H‐CTOB) and N‐(4‐(4‐bromophenyl)
thiazol‐2‐yl)‐3‐oxobutanamide (5e, H‐BTOB).
2.2 | Synthesis of platinum(IV) ion
complexes
In continuation of our research[12,13] concerning the
synthesis of new metal ion complexes, the work reported
here involved the synthesis of new Pt(IV)–thiazole
complexes. All newly synthesized compounds were fully
characterized using analytical, spectral and theoretical
techniques. As reported previously, Pt(IV) complexes
have a superior activity in various applications. Proceed-
ing from this, two opposing applications for the new com-
plexes were be considered in this study. Firstly, we were
interested in testing the complexes as inhibitors against
An amount of 0.532 g (2 mmol) of platinum(IV) chloride
was dissolved in ethanol solvent, and then an equimolar
ethanolic solution of each thiazole derivative was added.
The amounts were 0.549, 0.581, 0.521, 0.590 and 0.678 g
of thiazole derivatives 5a–e, respectively. The reaction
mixture was left under reflux with vigorous stirring for
15 h. After that, approximately 0.5 g of sodium acetate
was added, to raise the reaction pH, to be suitable for pre-
cipitation,[21] then the solid products were precipitated.
The colored solid complexes were filtered off, washed

ALTHAGAFI ET AL.
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SCHEME 1 Synthesis process for
thiazole derivatives 5a–e
with ethanol followed by diethyl ether, and then dried
over CaCl2 desiccators.
reader (Tecan, Inc.). Each absorbance measurement
obtained was corrected based on background absorbance
in wells, in the absence of stain. The treated samples were
compared to cell control in the absence of test compounds.
Each experiment was repeated three times and the mean
values were recorded. The degree of toxicity for all test
compounds was extracted. In order to calculate the num-
ber of viable cells, the density was measured using a micro-
plate reader (SunRise, Tecan Inc., USA). The viable cell
percentage was computed using: [1 − (ODt/ODc)] × 100%,
where ODc is the mean optical density of untreated cells
and ODt is the mean optical density for cells treated with
tested samples.[22,23]
2.3 | Antitumor study
The reagents used (trypan blue dye and crystal violet stain
1%) were from Sigma‐Aldrich. Two carcinoma cell lines,
human colorectal cells (HCA‐7) and human hepatoma
cells (HepG‐2), were obtained from VACSERA Tissue
Culture Unit. Crystal violet stain (1%) was prepared from
0.5% crystal violet and 50% methanol, then completed with
double‐distilled water and filtered off. The cells were repli-
cated in Dulbecco's modified Eagle's medium completed
with 1% L‐glutamine, 10% heat‐inactivated fetal bovine
serum, 50 μg ml−1 gentamycin and HEPES buffer. All cells
were preserved in a humidified atmosphere (37°C) in the
presence of 5% CO2, and sub‐cultured twice a week. To
evaluate the toxicity, the cells were cultivated in a 96‐well
plate (1 × 104 cells per well) in 100 μl of evolution medium.
New medium involved different concentrations of test
compound, which was added after seeding for 24 h.
Sequenced two‐fold dilutions for the tested substance were
added to confluent cell monolayers distributed into 96‐
well, flat‐bottomed microtiter plates (Falcon, NJ, USA)
using a multichannel pipette. In a humidified incubator
using 5% CO2, at 37°C, incubated microtiter plates were
settled for a 48 h period. Three wells were used for each
concentration of test compound. The control cells were
incubated with or without DMSO in absence of test com-
pound. A small percentage (maximal 0.1%) of DMSO in
the wells did not exhibit an obvious effect on the experi-
ment pathway. Various concentrations of sample were
used, then incubated for 24 h (at 37°C), and the yield of via-
ble cells was estimated by applying a colorimetric method.
The media were aspirated, and crystal violet solution (1%)
was added to each well (until 30 min at least) after the incu-
bation period. The stain was separated and the plates were
rinsed with water until the remaining stain was removed.
Acetic acid (30%) was then added to the wells and was
mixed thoroughly. Absorbance was measured at 490 nm
(λmax) after a gentle shaking of the plate with a microplate
2.4 | Catalytic application
2.4.1 | Synthesis of catalyst
One Pt(IV) ion complex, [PtCl3(BTOB)(C2H5OH)], was
selected for catalytic application. This selection was based
on the advancement in some structural–property relation-
ships, among them surface area and reactivity. But the
complex itself was not used in catalytic application, due
to its instability at applied temperature (300°C). The com-
plex was preliminarily treated to calcination, by which a
full ignition was carried out in an oven (at 650°C) until
constant weight. The produced oxide was PtO2, based on
platinum analysis, X‐ray diffraction (XRD) and scanning
electron microscopy (SEM) (Figure 1). The platinum con-
tent of the oxide was estimated after complete digestion
by conc. HNO3, followed by quantitative analysis via a
literature method.[24] The XRD pattern exhibits nano‐
crystalline feature, with particulate size of 6.93 nm. Also,
the SEM image displays granulate topographic surface,
rich in cavities, which support the catalytic role.
2.4.2 | Catalytic oxidation of CO
To carry out the catalytic process, a sample was placed in a
Thermolyne 2100 programmable tube furnace reactor. A
thermocouple close to the sample was used to measure

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ALTHAGAFI ET AL.
FIGURE 1 XRD pattern and SEM image for calcination product PtO2
the sample temperature. A gaseous mixture of CO (4 wt%)
and O2 (20 wt%) in helium was passed over the sample dur-
ing temperature rise. The rate of flow for the gaseous mix-
ture was 100 ml min−1, controlled by an MKS digital flow
meter. Through an infrared gas analyzer (ACS, Automated
Custom Systems Inc.), the conversion process for CO to
CO2 was monitored. The catalytic feature was estimated
for 0.08 g of sample. This investigation was carried out after
pre‐treatment of the sample by heating at 300°C with He
flow for 15 min. Such treatment aimed to eliminate mois-
ture and adsorbed impurities. We used dry‐ice to cool the
reactor to 75°C (lower temperature), then started to mea-
sure CO oxidation until reaching room temperature. After
that, we ran the furnace tube to oxidize CO at high
temperatures.[18]
conductance bridge. Infrared (IR) spectral analysis was
achieved using a JASCO FT‐IR‐4100 spectrophotometer
1
within the range 400–4000 cm−1. H NMR and 13C NMR
spectra were obtained with a Bruker Avance DRX
500 MHz NMR spectrometer. Mass spectral analysis was
conducted at 70 eV with an AEIMS 30 mass spectrometer
at a heating rate of 40°C min−1 for the mass range 50–
1000. Electronic transition analysis (in DMSO) was con-
ducted with a UV2 Unicam UV–visible spectrophotometer
in the wavelength range 200–900 nm. Thermogravimetric
analysis (TGA) was carried out under nitrogen with a
Shimadzu thermogravimetric analyzer (20–900°C) at a
heating rat of 10°C min−1. XRD analysis was carried out
using an X‐ray diffractometer (GNR, APD2000PRO, Italy)
with a graphite monochromator, using Cu Kα1 radiation.
The used scanning range was 10° < 2θ <80° at 0.03° min
−1. SEM analysis was achieved with a Jeol JSM‐6390 instru-
ment. Theoretical implementation was achieved using
Gaussian09 and AutoDock Tools 4.2, as a known advanced
program. The antitumor investigation was carried out in
professional laboratories. The catalytic activity was deter-
mined using a Thermolyne 2100 programmable tube fur-
nace reactor.
2.5 | Kinetics
ΔH, ΔS and ΔG were the significant parameters calculated
as well as n (the order) and E (the activation energy). This
theoretical implementation was achieved over distinct
degradation stages in DTG/DTA curves. The kinetics may
be calculated through many known relations.[25–32] Many
researchers have succeeded in establishing various equa-
tions for such purpose. Among them, the Coats–Redfern
and Horowitz–Metzger equations[27,32] were utilized in
this calculation, through a comparative view. Chosen
stages were selected based on their moderate sharpness,
and applied for the relation between weight loss and
temperature.
2.7 | Computational study
2.7.1 | Modeling study
The best fitting distribution for the atomic structure was
achieved using Gaussian 09 software.[33] All investigated
thiazole derivatives and their Pt(IV) complexes were
treated. The most suitable methods were DFT/B3LYP(3‐
21G) and RTD‐HF‐FC for the derivatives and complexes,
respectively. Log and chk were the files extracted, which
included all computed physical characteristics. All files
were displayed on the program screen to extract such
data, including numbering scheme and other essential
parameters.[34–36]
2.6 | Equipment
Elemental analysis was carried out with a PerkinElmer
2400 CHN elemental analyzer. The content of platinum
or chloride was quantitatively determined using standard
known methods.[24] The molar conductivity (10−3 M in
DMSO) was measured using a JENWAY model 4070

ALTHAGAFI ET AL.
5 of 18
3 | RESULTS AND DISCUSSION
3.1 | General characteristics
2.7.2 | Quantitative structure–activity
relationship (QSAR) study
QSAR parameters such as log P, polarizability, hydration
energy, surface area and reactivity were calculated using
the HyperChem (8.1) program. The treated compounds
were firstly pre‐optimized by choosing MM+ (molecular
mechanics) followed by AM1 (semi‐empirical). The
optimization process was achieved at equilibrium state,
without fixing any parameters. The parameters were com-
puted after minimizing the energy level by Polake–Ribiere
conjugated gradient algorithm.[37]
The elemental content and physical features of the thia-
zole derivatives and their platinum ion complexes are
summarized in Table 1. The elemental analysis indicates
mononuclear complexes with 1:1 molar ratio (L:M).
This finding was confirmed spectrally and analytically
(as discussed below). The complexes are stable,
non‐hygroscopic and have high m.p. (˃300°C). All the
complexes were insoluble in traditional organic solvents
(ethanol and methanol), but completely soluble in
DMSO and DMF. The molar conductivity (Λm) for
10−3 M solutions was measured for all complexes and the
results were dissimilar. A conducting feature was recorded
for three complexes, while a non‐conducting feature
was recorded for complexes [PtCl3(OPTB)(H2O)] and
[PtCl3(BTOB)(C2H5OH)]. The values of conductivity fall
in the range 4.62–54.1 Ω−1 cm2 mol−1, confirming the
assumed conductivity.[42] This dissimilar feature may refer
to chloride mode of bonding, which is considered the best
dual nature player in ionic or covalent bonding with the
same efficiency.
2.7.3 | Protein docking study
The docking process was concerned with two selected
proteins, 4k9g and 4dk7, attributed to colon and liver
carcinoma, respectively. 4k9g is the macrophage migra-
tion inhibitory factor, a pleiotropic pro‐inflammatory
cytokine, which has a contributing role in cancer pro-
gression and metastasis and thus is now considered a
promising anticancer drug target. 4dk7 is a structural
modification of a series of dual LXRα/β agonists, which
led to the identification of a new class of LXRβ partial
agonists. AutoDock Tools 4.2 software was implemented
for docking achievement. Such computational process is
considered an advanced revolutionary approach in the
drug designing industry, which produces a best simula-
tion for the interaction mode between a pathogen pro-
tein and a test inhibitor (drug). All files were in PDB
format, to be suitable for the docking process. In the
pretreatment step, the treated inhibitors must eliminate
rotatable bonds and nonpolar hydrogen atoms must be
fixed. The treated compound will bind to the selected
receptor after the following additions: significant hydro-
gen atoms, Kollman atomic charges and solvation
parameters.[38] Autogrid program was responsible for
drawing affinity maps (of × × Å grid points) by
0.375 Å spacing.[39] Van der Waals forces and electro-
static terms were computed through AutoDock parame-
ter set and dielectric functions (distance‐dependent),
respectively. Also, for the docking process to be accom-
plished, a local search method (Solis and Wets) and
Lamarckian genetic algorithm must be used.[40] Initial
position, orientation and torsions for the tested com-
pounds must be adjusted. During the docking process,
the tested compounds must eliminate rotatable torsions.
The parameters calculated were the mean values for 10
close runs at ca 250 000 kcal mol−1 energy level. The
sizes were commonly 150 and 0.2 Å is the applied trans-
lational, quaternion and torsion for five steps.[41]
3.2 | Bases for organic synthesis
elucidation
The synthesis stages for derivatives 5a–e are depicted in
Scheme 1. Regarding, 2‐aminothiazoles 3a–e, the synthe-
sis was carried out according to the Hantzsch procedure.
Such was accomplished through the reaction of thiourea
with phenacyl bromide derivatives under reflux in ethanol
solvent.[18,19] Reaction of the formed derivatives 3a–e with
ethylacetoacetate (4), in the presence of drops of
AcOH/DMF, was carried out at 180°C to produce target
ligands 5a–e. The structural and molecular chemical
forms (Figures 2 and 1S) were proposed based on spectral
(IR, 1H NMR, 13C NMR and mass) and analytical results.
IR spectral data (Table 2) displayed bands assigned to
υ(OH), υ(NH), δ(OH) and δ(NH) vibrations. So, the func-
tional presence of hydroxyl group besides secondary
amine strongly suggests the presence of thiazole tauto-
meric forms (keto–enol). Also, the marked reduction of
υ(C&dbond;O) vibration band wavenumber may point to
intra‐ligand hydrogen bonding, as already expected.
1H NMR spectra for three chosen derivatives (Figure 2S)
displayed functional signals (Table 3), which support the
assumption for the presence of tautomeric forms.
Furthermore, the relative integration percentage offers
the superiority of enol form in derivative 5c (80%), which
orients to its precedence in coordination. While the other

6 of 18
ALTHAGAFI ET AL.
FIGURE 2 Structural formulae of keto tautomeric forms of
thiazole derivatives 5a–e
derivative (5e) displays opposing feature (keto form by
60%). This feature, due to the overlapping of OH signal
with that of DMSO, led to untrue integration relative
percentage. 13C NMR spectra (Figure 2S) were obtained
for two derivatives, and the peaks appearing (Table 3)
coincide comfortably with carbon hybridization degree,
which is obvious in the structural forms. Also, the num-
bers of peaks were completely in agreement with the car-
bon skeleton form. The shifted position for carbonyl
group (reduced ppm value) may confirm its contribution
in intra‐ligand hydrogen bonding. Mass spectral analysis
(Figure 3S) was carried out for most derivatives and
strongly supports the molecular formulae proposed. The
most intense peaks were aggregated and are presented in
Table 1S. The values of molecular ion peaks (m/z) which
are mainly attributes to M+ + 1 basically agree with the
isotopic nature of sulfur atom. A scheme for the most suit-
able fragmentation process was constructed for a chosen
example (5b, H‐MTOB) and is displayed in Scheme 2.
3.3 | Mode of bonding in Pt(IV) complexes
The type of bonding attributed to the thiazole derivatives
with Pt(IV) ion was examined through comparative IR
study. Regarding the presence of sodium acetate in the
reaction medium, mono‐negative tridentate mode of bond-
ing was the main mode of bonding except for 5e, H‐BTOB
derivative, which displayed mono‐negative bidentate coor-
dination mode. The mono‐negative tridentate mode was
realized through the bonding of C&dbond;N, C&dbond;O
and C&bond;O groups to the central atom. While the other
mode was as a result of bonding with C&dbond;O and
C&bond;O groups. This is supported by an observable

ALTHAGAFI ET AL.
7 of 18
TABLE 2 Fundamental IR bands (cm−1) of thiazole derivatives (5a–e) and their Pt(IV) complexes
υ(OH); υ(NH) υ(C&dbond;O C&bond;O
δ(NH) δ(OH) M&bond;O M&bond;N
Compound
C&dbond;N)s
C&bond;S
1 C14H14N2SO2, 5a, H‐OTTB
3385.4; 3126.0 1628.6; 1037.5 1571.7; 1511.9 630.6
BC at 3422.1 1586.2; 1025.0 1504.2 680.5
3381.6; 3125.1 1623.8; 1092.5 1561.1; 1509.0 618.1
BC at 3431.7 1619.9; 1078.1 1573.9; 1448.3 715.6
3391.2; 3123.2 1684.5; 1075.1 1569.8; 1497.5 648.0
BC at 3429.8 1616.1; 1068.9 1566.8; 1438.6 690.4
1296.9
1414.5
—
—
2 [PtCl2(OTTB)(H2O)]Cl⋅2H2O
3 C14H14N2SO3, 5b, H‐MTOB
4 [PtCl2(MTOB)(H2O)]Cl⋅2H2O
5 C13H12N2SO2, 5c, H‐OPTB
6 [PtCl3(OPTB)(H2O)]
—
1457.9
1341.5
1382.7
1290.1
1383.7
1399.1
1385.6
1395.3
1391.4
604.6
—
538.0
—
1298.8
—
570.8
—
482.5
—
—
—
612.3
—&bond;
614.2
—
453.2
—
7 C13H11Cl N2SO2, 5d, H‐CTOB) 3425.0, 3118.3 1627.6; 1089.6 1566.9; 1494.6 627.72
1307.5
—
8 [PtCl2(CTOB)(H2O)2]Cl
BC at 3427.8; 1668.8; 1087.7 1588.8; 1465.7 741.5
426.2
—
9 C13H11BrN2SO2, 5e, H‐BTOB
10 [PtCl3(BTOB)(C2H5OH)]
3434.6
1684.5; 1102.1 1566.9; 1484.0 612.29
1689.3; 1069.3 1569.8; 1478.2 768.5
1307.5
—
BC at 3428.8
616.2
529.4
BC, broad centered (OH in complexes for solvent only).
TABLE 3 1H NMR data for two thiazole derivatives and their Pt(IV) complexes
Compound
1H NMR
13C NMR
5 5c (tautomeric
(DMSO‐d6) δ = 2.51 (s, 3H, CH3), 2.88 (s, 20%H, OH), 3.60 13C NMR (DMSO‐d6) δ: 34.75 (CH3), 39.09 (CH2),
forms)
(s, 2H, CH2), 7.27 (s, 1H, thiazole‐H), 7.42–7.75 (m, 5H,
Ar&bond;H), 8.53 (s, 80%H, NH)
103.38(C&bond;S), 126.19, 128.43, 128.76, 129.24,
129.53, 129.89 (6C, benzene), 139.80 (C&dbond;N),
167.77 (OH&bond;C&dbond;N), 170.65 (C&dbond;O)
6 [PtCl3(OPTB)
(H2O)]
(DMSO‐d6) δ =1.92 (s, 3H, CH3), 3.36 (s, 4H, CH2, H2O), —
7.01–7.96 (m, thiazole‐H and 5H, Ar&bond;H)
9 5e (tautomeric
(DMSO‐d6) δ = 2.28 (s, 3H, CH3), 2.51 (s, 60%H, OH), 3.46 13C NMR (DMSO‐d6) δ: 23.50 (CH3), 39.15 (CH2), 104.94
forms)
(s, 2H, CH2), 6.06 (s, 1H, thiazole‐H), 7.37 (d, J = 7 Hz,
2H, Ar&bond;H), 7.57 (d, J = 7 Hz, 2H, Ar&bond;H),
7.80 (s, 40%H, NH)
(C&bond;S), 111.98, 122.34, 128.14, 130.46, 131.60,
131.75 (6C, benzene), 136.53 (C&bond;N), 159.42
(C&dbond;N),163.12 (OH&bond;C&dbond;N), 163.92
(C&dbond;O)
10 [PtCl3(BTOB)
(C2H5OH)]
(DMSO‐d6)δ = 1.92 (s, 3H, CH3), 3.36 (s, 2H, CH2), 6.07(s, 13C NMR (DMSO‐d6) δ: 21.48 (CH3‐ethanol), 23.50
1H, OH, ethanol), 3.36 (m, 2H, CH2,ethanol), 7.37 s,
1H, thiazole‐H), 7.57 (d, J = 7 Hz, 2H, Ar&bond;H),
7.80 (d, J = 7 Hz, 2H, Ar&bond;H)
(CH3), 39.05 (CH2, CH2‐ethanol), 104.91 (C&bond;S),
111.98, 122.34, 130.46, 130.67, 131.71, 136.51 (6C,
benzene), 159.42 (C&dbond;N), 167.19 (O&bond;
C&dbond;N), 172.76 (C&dbond;O)
lower shifted appearance for their vibrational bands.[43]
Significant vibrational bands υ(OH), υ(NH), υ(C&dbond;
O), (C&bond;O), (C&dbond;N), (C&bond;S), δ(NH) and
δ(OH) are summarized in Table 2 and compared to known
mode of bonding. The ionized enolic tautomer was the
responsible chelating agent with Pt(IV), in all complexes,
based on the following. (i) The complete disappearance of
the δ(NH) band points to the de‐protonation after hydro-
gen migration, although there is uncertainty around the
υ(NH) band, due to the broadness. (ii) The presence
of highly shifted bands assigned to υ(OH) and δ(OH) sug-
gests their belonging to new functional hydroxyl group,
which may refer to solvent molecules. Such a proposal
was supported by the appearance of bands at ca 731–752
and 652–669 cm−1, assigned to δr(H2O) and δw(H2O)
vibrations, in all complexes, except for [PtCl3(BTOB)
(C2H5OH)]. Though the assumption for presence of coordi-
nating ethanol was basically based on confirmed elemental
analysis, it was but supported strongly by spectral data
1
(IR, H NMR and 13C NMR). The vibrational bands of
coordinating ethanol were observed at 3428.8, 1391.4,
1153.1 and 950.3 cm−1 [44]
and further confirmation is
,
discussed in Section 3.4. The noticeable increase of
υ(C&bond;S) band may point to its being ruled out

8 of 18
ALTHAGAFI ET AL.
SCHEME 2 Fragmentation pattern for
N‐(4‐(4‐methoxyphenyl)thiazol‐2‐yl)‐3‐
oxobutanamide (5b, H‐MTOB)
TABLE 4 Significant electronic transition bands of thiazole
derivatives (5a–e) and their Pt(IV)complexes
3.4 | NMR and mass spectra of complexes
Fundamental 1H NMR and 13CNMR peaks were measured
and are presented in Table 3. Two selected derivatives (5c
and 5e) and their corresponding complexes were analyzed
and compared, as examples (Figure 2S). The [PtCl3(OPTB)
(H2O)] complex, that of derivative 5c, showed a perfect dis-
appearance of OH and NH signals, which clearly appeared
in the spectrum of free derivative at 2.88 and 8.53 ppm,
respectively. While the [PtCl3(BTOB)(C2H5OH)] complex,
that of derivative 5e, displayed new signals at 6.07 ppm
(s, 1H, OH) and 3.36 ppm (m, 2H, CH2), which may be
attributed to coordinating ethanol molecule, that was
proposed formerly. Furthermore, the 13C NMR spectrum
of the [PtCl3(BTOB)(C2H5OH)] complex (Figure 2S) was
obtained to shed light on its strange coordination type,
compared to the other complexes. This strange feature
was proposed due to exclusion of the role of C&dbond;N
in coordination of such complex, while contributing to
the others. All the displayed signals corresponding to
carbon skeleton appeared quantitatively (Table 3). The
functional peaks that appeared were (DMSO‐d6; ppm):
21.48 (CH3 of ethanol), 39.05 (CH2CH2 of ethanol),
159.42 (C&dbond;N), 167.19 (O&bond;C&dbond;N) and
172.76 (C&dbond;O). The shifted position of the signals
of O&bond;C&dbond;N and C&dbond;O groups, com-
pared to that of the free derivative, points to their contribu-
tion in bidentate mode of bonding that is proposed. The
non‐shifted position of the signal of the C&dbond;N group
indicates its exclusion from coordination, as already
proposed.
d–d transition bands Intra‐ligand
(cm−1
)
and charge
transfer
Compound
υ1 υ2
bands (cm−1
)
1 C14H14N2SO2, 5a,
H‐OTTB
35 327; 31 679;
28 431
2 [PtCl2(OTTB)(H2O)] 16 156; 20 261
Cl.2H2O
35 211; 33 557;
27 624
3 C14H14N2SO3, 5b,
H‐MTOB
38 628; 33 721;
29 431
4 [PtCl2(MTOB)(H2O)] 16 691; 19 682
Cl.2H2O
33 784; 26 882
5 C13H12N2SO2, 5c,
H‐OPTB
35 623; 32 931;
28 644
6 [PtCl3(OPTB)(H2O)] 20 471;23 719
33 784; 31 847;
27 624
7 C13H11Cl N2SO2, 5d, 19 983; 22 632
H‐CTOB)
35 171; 33 790;
28 547
8 [Pt Cl2(CTOB)
(H2O)2]Cl
33 784; 32 051;
27 624
9 C13H11BrN2SO2, 5e,
H‐BTOB
35 911; 33 012;
28 608
10 [PtCl3(BTOB)
(C2H5OH)]
21 110; 22 312
33 784; 32 179;
27 841
from coordination.[45,46] New Pt&bond;L bands were
observed at low wavenumber (˂620 cm−1), and assigned to
υ(Pt&bond;O) and υ(Pt&bond;N). But the band attributes
to υ(Pt&bond;Cl), which must appear at ˂400 cm−1, cannot
observed for the applied scanning range (400–4000 cm−1).
Mass spectral analysis was executed for two chosen
complexes as examples (Figure 3S), namely [PtCl2(OTTB)

ALTHAGAFI ET AL.
9 of 18
(H2O)]Cl⋅2H2O and [PtCl2(MTOB)(H2O)]Cl⋅2H2O. All sig-
nificant intense peaks were measured and are presented in
Table 4. The two molecular ion peaks appeared at m/z
629.21 and 646.43 for the two complexes, respectively.
The m/z value of 629.21 (9%, calcd 628.82, M+) was fully
matched with that presumed from elemental analysis.
While the m/z value of 646.43 (11%, calcd 644.82) was
matched with M+ + 2, which coincides with the presence
of various atoms (chloride and sulfur) having isotopic
nature. Such molecular ion peaks, displaying low intensity,
reflect the stability of molecules after evaporation process.
Other essential fragmentation peaks, manifested at m/
z = 195 (13%), 193 (9%), 192 (51%), 191 (54%) and 197
(18%), 195 (9%), 194 (%), 193 (1%), correspond to platinum
isotopes in the two spectra, respectively. The proposed
most suitable fragmentation pattern for [PtCl2(MTOB)
(H2O)]Cl⋅2H2O is exhibited in Scheme 3.
conducted with UV–visible spectrophotometers, in DMSO
solvent. Fundamental electronic transition bands of thia-
zoles and their Pt(IV) complexes are summarized in
Table 4. Intra‐ligand transition bands appeared at 31 679–
38 628 and 28 547–29 431 cm−1, which are assigned to
π → π* and n → π* transitions, respectively. These bands
suffer shifts to reduced wavenumber in the spectra of all
Pt(IV) complexes. This points to significant changes in
electronic cloud over coordinating functional groups,
which refers to their binding with the central atom. Also,
effective d–d transition bands were observed for such
low‐spin octahedral complexes (Figure 3). Though a lim-
ited spin‐allowed transition in low‐spin d6 systems, it is
considered a significant basis for verifying the structural
0
forms. The electronic configuration for Pt(IV) is t2g6eg ,
1
which translated to A1g term. So, the excitation of one
1
electron leads to t2g5eg configuration, which is split into
1
3
3T1g + T2g + T2g terms. Two spin‐allowed transition
bands were observed at 22 312–19 682 and 21 110–
16 156 cm−1 in the spectra of all complexes. These bands
are attributed to 1A1g → 3T1g(υ1) and 1A1g → 1T1g(υ2) tran-
sitions, respectively, in octahedral configuration around
the central atom.[21] Also, weak bands appeared in the
3.5 | Electronic spectral analysis
Qualitative electronic transition analysis of free thiazole
derivatives and their corresponding Pt(IV) complexes was
SCHEME 3 Fragmentation pattern
assumed for [PtCl2(MTOB)(H2O)]Cl⋅2H2O
complex

10 of 18
ALTHAGAFI ET AL.
FIGURE 3 Best structures for Pt(IV)–thiazole complexes 5a–e
range ca 13 468–14 241 cm−1, which may be assigned to
spin‐forbidden transition of 1A1g → 3T2g type.[47]
of reactants. Furthermore, the unit cell dimensions can
be determined. The purity of synthesized compounds,
as well as their homogeneity, have been determined
by known methods.[48] Only two thiazole derivatives
(5a and 5c) displayed a good uniformity for obvious
pattern peaks, which reflected nanocrystalline feature
among the other derivatives. Moreover, their correspond-
ing Pt(IV) complexes, as well as [PtCl3(OPTB)(H2O)]
complex, were the only ones appearing clearly with nano-
crystalline feature. While all the other compounds
displayed irregular patterns, due to conjoined peaks,
which reflect their amorphous forms. The crystallinity
3.6 | XRD and SEM analysis
XRD analysis was carried for all investigated compounds,
up to 2θ ˂ 80° (Figures 4 and 4S). Such analytical tech-
nique was used in identifying the material phases and
the degree of regularity inside the particles. Also, a judg-
ment as to the purity of synthesized compounds can be
made through comparing the product patterns with those
FIGURE 4 XRD patterns for H‐MOBT
(5a) derivative and its Pt(IV) complex

ALTHAGAFI ET AL.
11 of 18
(10°C min−1), up to 900°C. This study led to essential
information about the thermal stability of the tested
compounds as well as confirming the molecular formu-
lae. The degradation process of thiazole derivatives
exhibited two to three stages; however, their Pt(IV)
complexes mostly extended to four stages. The most
fitted assumptions for the decomposition technique,
attributed to all tested compounds, are presented in
Table 2S. As the data indicated, and regarding thiazole
derivatives, we concluded the following. All treated
derivatives were decomposed completely and vaporized
up to 530°C, with or/without carbon residue. Further-
more, and regarding Pt(IV) complexes, we also garnered
the following information. (i) Lower thermal stability
was the general feature noticed for most of them except
[PtCl3(OPTB)(H2O)] and [PtCl3(BTOB)(C2H5OH)] com-
plexes. (ii) The presence of crystal water molecules is
behind such reduced stability, through the easier
decomposition at lower temperature (˂100°C). (iii) The
successive sequence of decomposition stages up to ca
900°C led to much mass loss, yielding free PtO2 residue,
or contaminated (with carbon atoms). The residual
carbon atoms may be due to the TGA process being
conducted in nitrogenous atmosphere instead of oxygen.
(iv) The satisfactory conformity between the found mass
loss and that calculated confirms well the best identifi-
cation for sequential stage borders, as well as the exact
molecular formulae. The successful treatment of TGA
will lead to more accuracy in kinetic parameter compu-
tation. E, ΔH, ΔS and ΔG were the kinetic parameters
which were calculated over distinct decomposition
stages. The stages selected for this study were various
(second and third) for the tested compounds. This selec-
tion is based on the moderate fraction decomposed (α)
against temperature. Coats–Redfern[26] and Horowitz–
Metzger methods[31] were applied in calculating these
parameters from the point view of comparison. From
the extracted relations (Figure 6S), these parameters
were calculated from the following equations:
ΔH = E − RT, ΔG = ΔH − TΔS and ΔS* = Rln(Ah/
kBTs), where kB is the Boltzmann constant, h is the
Planck constant and Ts is the mid‐temperature point
of the chosen stage. From the data exhibited (Table
3S) we concluded essential features as follows. (i) Posi-
tive sign of ΔH values reflects the endothermic feature
for all decomposition stages. (ii) Also, its value suffers
significant rise in complexes compared to thaizoles,
which indicates the positive influence of central atom
on thermal stability. Moreover, the activation energy
values were increased for complexes, which points to
high energy barrier for decomposition, also asserting
the positive effect of metal atom. (iii) Negative sign of
ΔS values reflects the great disorder or randomness in
TABLE 5 XRD parameters calculated using FWHM for nano-
crystalline compounds
Size 2θ
(Å) (°)
Intensity d‐
spacing ε (Å)
−2
Compound
δ(Å
FWHM
)
5a, H‐OTTB
1.541 21.60 846 4.111 0.3212 0.4211 0.9565
[PtCl2(OTTB)(H2O)] 31.94 504 2.800 0.0533 0.0250 0.2381
Cl.2H2O 6.325
[PtCl3(OPTB) 2.300 18.86 420 4.701 0.2451 0.1890 0.6383
(H2O)]
5c, H‐OPTB
1.910 16.46 222 5.381 0.3387 0.2741 0.7660
[PtCl3(BTOB) 4.094 26.74 464 3.331 0.0976 0.0597 0.3636
(C2H5OH)]
feature is attributed to the good packing of molecules
around layers and axes inside the crystals. On the other
hand, the amorphous forms may clarify great dislocation
which happened during the packing process around
layers and axes.[49] The crystallite parameters have been
calculated and are displayed (Table 5), using the full
width at half maximum (FWHM) method. Parameters
such as 2θ, d spacing, intensity, size of particles, crystal
strain (ε) and dislocation density (δ) were computed using
standard equations.[49] These parameters will give a great
view about the degree of crystal regularity. All calculated
crystallite sizes (˂64 Å) were found in nanometer scale in
a distinctive manner, which expected a broad application.
The reduced d‐spacing values (˂5.5 Å) agree with their
nanocrystallite sizes. The crystal strain (ε) as well as the
dislocation density (δ) values (˂0.4211) reflect the little
damage in the particulate crystal. The crystal may elimi-
nate strain, and leaving the dislocations inside, or may
be still together. The SEM images of all tested compounds
(Figure 5S) were obtained after screening the surfaces[50]
by a beam of electrons, to detect the degree of purity and
surface topography. The easier discrimination for mor-
phology and the microstructures for each free organic
derivative and its complex clarify the purity of prepared
complexes.[50] Most surface particulates did not have def-
inite shapes, but appeared with rocky or fused shape.
Derivatives 5a and 5c, beside their corresponding com-
plexes, appeared with relatively spherical shape. The reg-
ular morphological feature which appeared in some
compounds is mainly attributed to the presence of the
central atom. Such presence affects directly the degree
of order inside the particles or crystals. This feature is
more favorable in various applications.
3.7 | Thermogravimetric analysis
TGA curves of thizole derivatives and their Pt(IV)
complexes were obtained under constant heating rate

12 of 18
ALTHAGAFI ET AL.
the studied systems. Consequently, the increase of ΔS
values will lead to high ΔG values. These results reflect
generally a non‐spontaneous decomposition process,
which was already expected for all stable systems.
(i) Regarding HOMO levels, in keto tautomer (Figure 5),
widespread electron cloud for such molecular orbital was
observed over donor sites except oxygen atom no. 3. (ii)
The LUMO levels (Figure 8S) generally displayed a broad
elongation for such molecular orbital, covering the whole
molecule, such as exactly exists in the other tautomer (enol
form). This feature asserts easier intra‐ligand transitions
between all functional groups, without exceptions. On
the other hand, and regarding the HOMO levels in enol
tatuomer, we noticed a full covering for such molecular
orbital along all functional groups. This feature points to
the superior donor ability of the enol form in comparison
to the keto tautomer. This conclusion supports the contri-
bution of the enol tautomer, as the only one, in coordina-
tion towards Pt(IV) ion. The frontier orbitals for the
Pt(IV) ion complexes (Figure 9S) appeared concentrated
around the central atom. This introduces a sufficient facil-
ity for d–d transitions of the central atom as well as charge
transfer in or out of the central atom. Also, the frontier
energies were extracted from the same file and used to cal-
culate essential parameters discussed below.
3.8 | Computational study
3.8.1 | Structural optimization
Through the Gaussian09 program, the optimization pro-
cess was executed, using DFT/B3LYP(3‐21G) and
Hartree–Fock methods. The best arrangement for each
molecular skeleton was obtained for thizole derivatives
(keto/enol forms) and their Pt(IV) complexes (Figures 2,
3 and 1S). Some significant parameters were taken from
log file; others were computed based on frontier energies
(HOMO and LUMO) from chk file. All such physical
parameters led to a broad image about their general char-
acteristics, which indicate an adequate way of application.
3.8.2 | Aspects of frontier levels
All relevant images regarding thiazole derivatives in two
tautomeric forms and their Pt(IV) complexes were taken
from chk files (Figures 5 and 7S–9S). Through deliberate
investigation for all thiazole derivatives (two tautomers),
we can summarize the following fundamental findings.
3.8.3 | Computed parameters
Several parameters were calculated for the thiazole tauto-
mers and corresponding Pt(IV) complexes, established
based on frontier energy gaps (ΔE = ELUMO −EHOMO),
FIGURE 5 HOMO level images of thiazole derivatives (keto form, 5a–e)

ALTHAGAFI ET AL.
13 of 18
and presented in Table 4S. Parameters such as electroneg-
ativity (χ), global hardness (η), chemical potential (μ),
global softness (S), absolute softness (б) and global electro-
philicity index (ω) were the computed with reference to
known relations.[36] For the thiazole tautomers, we can
extract the following observations. (i) The electronegativity
values display the progress of enol tautomer.
(ii) Concerning global hardness (η), global softness (S)
and absolute softness (б) values, the progress of softness
feature was recorded for enol tautomer. For the Pt(IV)
ion complexes, we can extract the following observations,
in comparing coordinating thiazole enol tautomers in their
free state. (i) Through the comparison, reduced energy
gaps were generally found for all complexes. This points
to stabilized complexes, as the predictable impact for the
metal atom. (ii) The electronegativity values display the
advancement of all the complexes. This predictable feature
clarifies the high ability of complexes for accepting
electrons from surroundings. This may be based on the
degree of electron deficiency over the whole molecule after
the coordination process. (iii) Concerning global hardness
(η), global softness (S) and absolute softness (б) values,
these go in the same way, for the full progress of complexes,
with the superiority of [PtCl2(OTTB)(H2O)]Cl⋅2H2O.[51]
This advancement for the Pt(IV) complexes offers a broad
expectation for their success in intended application areas
(tumor inhibitor and oxidation reaction activator).
the negative charges on some atoms, instead of reduction.
(ii) General elongation for the recorded bond lengths that
is a logical predicted feature coherent with coordination
for such groups. (iii) An obvious minimization for Pt(IV)
charge, which is logical due to acquisition of electron den-
sity from donor atoms, as well as charge transfer of L → Pt
type. (iv) With regard to the other parameters, the priority
and reactivity of the complexes were mostly recorded from
the data obtained.[52]
3.8.5 | QSAR studies
Surface area, volume, hydration energy, partition coeffi-
cient (log P), reactivity and polarizability were the com-
puted QSAR parameters, which are presented in Table 6.
Such physical parameters were established based on struc-
tural forms that exert some characteristics, matching with
structural building. The preliminary step was the optimiza-
tion process with the HyperChem (8.1) program, by
implementing two sequenced methods (MM+ and AM1).
After establishing the best atomic skeleton for each com-
pound, such parameters were extracted. Essential informa-
tion can be held as follows. (i) Broad surface area was
recorded for [PtCl3(OPTB)(H2O)] and [PtCl3(BTOB)
(C2H5OH)] complexes, one of them undergoing calcina-
tion to prepare a catalyst for application. (ii) Estimated
reactivity values obviously exhibit the advancement of
complexes in comparison with free derivatives, and follow
the order Pt(IV)–5b ˃ Pt(IV)–5e ˃ Pt(IV)–5a ˃ Pt(IV)–5c ˃
Pt(IV)–5d. (iii) Partition coefficient values (log P) offer
the following arrangement: keto form ˂ enol form ˂ corre-
sponding complex. Such sequence is opposite to expected
biological feature, due to the reverse relation between.[53]
This mild toxicity found for the complexes is preferable to
the higher toxicity of free organic derivatives. This is due
to the high reactivity of free organic compounds towards
essential metals that existed in biological systems, such is
completely unwanted behavior.
3.8.4 | Log file parameters study
Fundamental parameters (Table 5S) such as Mulliken
charges, dipole moment, formation energy, oscillator
strength and excitation energies were extracted from out-
put files (log file). Regarding the two tautomeric forms,
we can summarize the following findings. (i) Most
recorded charges over donor atoms were enhanced in the
enol form except for ketonic oxygen (no. 6), which mostly
minimized in electron density, due to its appearance as
OH instead of C&dbond;O. (ii) Chosen bond lengths,
which are attributed to donor atoms, mainly undergo
lengthening in enol form, which led to facilitation of coor-
dination towards the metal atom. (iii) With regard to the
other parameters, they display the priority of each enol
form, as follows: reduced dipole moment and excitation
energies, while enhanced oscillator strength and formation
energy. Such features indicated the high reactivity of enol
tautomer that supports the coordination of that tautomer,
while excluding the other. Furthermore and regarding
the Pt(IV) ion complexes, we can summarize the following
findings. (i) Dissimilar appearance for recorded charges,
referring to the occurrence of charge transfer process, as
opposing feature to coordination result, which promotes
3.8.6 | Interpretation for molecular
docking results
This computational study concerns judgment as to the
degree of inhibition for suggested drugs, before industrial
application. The docking, the interaction between patho-
gen protein and tested compounds (proposed drug), was
dealt with through simulation monitoring technique.
AutoDock Tools 4.2 was the implementing program, using
the five thiazole derivatives versus 4k9g and 4dk7 protein
receptors. Such receptors belong to liver and colon carci-
noma, respectively. The docking process was accom-
plished with the tested derivatives, yielding significant

14 of 18
ALTHAGAFI ET AL.
TABLE 6 QSAR functions for thiazole derivatives (two tautomers; 5a–e) and their Pt(IV) complexes
Function
Surface area
(approx) (Å2)
Surface area
(grid) (Å)
Volume
(Å3)
Hydration energy
Reactivity
(Å3)
Polarizability
(Å3)
Compound
(kcal mol−1
)
Log P
5a (keto form)
5a (enol form)
Pt–5a
444.92
441.09
436.07
470.63
457.06
454.39
410.01
397.14
521.12
447.48
433.82
517.11
456.39
442.52
526.27
494.80
497.87
541.28
511.58
515.49
542.10
471.88
468.22
561.96
491.62
494.61
565.29
504.53
504.16
576.85
801.51
804.56
943.81
828.94
828.57
938.43
751.62
750.90
906.71
794.68
794.52
950.69
815.26
813.88
969.40
−3.56
−6.51
−5.36
−7.14
−9.30
−12.28
−5.55
−7.71
−6.67
−5.18
−7.38
−6.36
−5.17
−7.34
−6.35
0.74
1.78
3.23
−0.41
0.63
1.45
0.59
1.62
3.30
0.36
1.40
3.08
0.64
1.67
3.35
80.49
80.73
95.59
82.58
82.82
96.27
76.21
76.44
95.50
80.93
81.16
93.21
83.74
83.98
96.03
29.60
29.74
35.92
30.24
30.38
35.92
27.77
27.90
32.61
29.70
29.83
34.54
30.40
30.53
35.24
5b (keto form)
5b (enol form)
Pt–5b
5c (keto form)
5c (enol form)
Pt–5c
5d (keto form)
5d (enol form)
Pt–5d
5e (keto form)
5e (enol form)
Pt–5e
computed parameters (Table 7).[54] Among them were
inhibition constant (IC50) values, which indicated the best
inhibition feature recorded for 5a, 5d against 4k9g and 5b,
5c against 4dk7. While an absence for the efficiency in
other docking complexes was obviously concluded from
high IC50 values. All the free energy of binding values were
negative in sign, which indicates that the interaction pro-
cess is commonly exothermic. Also, interaction surface
area points to the degree of interaction inside the docking
complexes by direct relationship between. High inhibition
efficiency appeared attached with interaction surface over
700. Two selected highly interacting docking complexes
are displayed in Figure 6, whilst the other complexes are
displayed in Figure 10S. The two cancer proteins used
introduced the docking in a fixed side that contained active
amino acids, which is considered the aim of inhibitor. Hp
plots for docking complexes were obtained (Figures 7 and
11S), and regarding the best binding among them, 5b–
4dk7 and 5d–4k9g complexes are displayed in Figure 7.
Markedly strong hydrogen bonding appeared with 4k9g,
while a shortage of such hydrogen bonding with 4dk7,
though a significant interaction was recorded with such
receptor (4dk7). This due to the fact that the hydrogen
bonding is not the only type of bonding, but also electro-
static attraction is another binding type. The degree of
interaction between each tested compound and protein
TABLE 7 Molecular docking parameters (kcal mol−1) for thiazole/keto form derivatives (5a–e) against two receptors
Est. free
Total
energy of Est. inhibition
vdW + bond + Electrostatic intercooled Frequency Interact
Ligand
Receptor binding
constant, Ki (μM) desolve energy energy
energy
(%)
surface
5a, H‐OTTB 4k9g
−7.55
−4.43
2.94
569.97
−8.41
−5.59
−0.06
−0.05
−8.47
−5.64
60
40
743.935
564.72
4dk7
5b, H‐MTOB 4k9g
−7.76
−7.09
11.02
1.00
−8.08‐
5.09
+0.06‐
0.03
−8.02‐
5.13
30
30
658.851
711.257
5c, H‐OPTB
4dk7
−7.38‐
4.11
3.88
975.31
−8.55‐
5.07
+0.02‐
0.33
−8.53‐
5.40
50
10
721.636
587.858
5d, H‐CTOB 4k9g
5e, H‐BTOB 4dk7
−7.88‐
4.25
1.69
772.60
−8.92‐
5.10
−0.29
−0.00
−9.21‐
5.10
20
30
752.583
521.104
−7.43‐
4.21
3.56
825.18
−8.38‐
5.15
−0.23
−0.34
−8.61‐
5.49
40
10
713.653
589.561

ALTHAGAFI ET AL.
15 of 18
FIGURE 6 Selected docking of complexes representing the best interaction with 4dk7 and 4k9g proteins
FIGURE 7 Hp plots for two selected
complexes docking against 4dk7 and 4k9g
proteins
receptor (4k9g, 4dk7 and 6gz7) was also supported by two‐
dimensional plots, which are displayed in Figure 12S.
Regarding 5b–4dk7 and 5d–4k9g complexes, N(9) and
O(6) were responsible for binding towards 4dk7 and 4k9g
receptors, respectively, which carried high charges. Whilst
for the other two‐dimensional plots (Figure 12S), attrib-
uted to 4dk7 receptor, the binding sites were varied among
all donor sites.
graphic plots of dose–response curves versus concentra-
tion, by applying the GraphPad Prism software (San Diego,
CA. USA). Each point in the data was expressed as the
mean value for three independent experiments
(value
SD).[56] Regarding the free thiazole derivatives
versus the two cell lines, mild toxicity was obviously
observed for derivatives 5a and 5b, while activity was
completely absent for the others. Furthermore, such mild
toxicity was also recorded for their corresponding com-
plexes, [PtCl2(OTTB)(H2O)]Cl⋅2H2O and [PtCl2(MTOB)
(H2O)]Cl⋅2H2O. While the other complexes were far from
active against the concerned tumor cells. Such mild toxic-
ity is more favorable in most cases for eliminating serious
side effects, which were recorded mainly. Whilst the
absence of any facing contact for the other compounds
against the two cell lines may be a result of some unknown
mechanism that happened inside the cell, which prohibits
such contact or shows counter behavior.
3.9 | In vitro antitumor activity
The inhibition activity of all synthesized compounds (thia-
zoles and corresponding complexes) was investigated
against two tumor cell lines, human colorectal cells
(HCT‐116) and human hepatoma cells (HepG‐2), which
is considered the first application pathway in this study.
As is known, there are many anticancer drugs, but this
field is not sufficiently covered by research, due to the lack
of medication eliminating the disease altogether. To our
knowledge, cisplatin drug is not a fully successful medica-
tion for such disease, due to its significant effect on healthy
cells, inhibiting the production of blood cells in bone mar-
row, which is followed by anemia.[55] Proceeding from this,
we conducted tests against HCT‐116 cells and HepG‐2
cells. The degree of toxicity was extracted according to
50% inhibition of cell growth after 72 h (IC50), and were
tabulated (Table 6S) and also graphed (Figure 8). The
results for IC50 concentrations were estimated from
3.10 | Catalytic oxidation of CO
The catalytic role for calcined PtO2 in CO oxidation is
presented in Figure 9. The chosen complex (Pt(IV)–5e)
which was used to prepare PtO2 through calcination has
distinct characteristics that serve in catalysis. Surface
area, reactivity, crystallite size and surface morphology
were the fundamental features determining this choice,
which certainly have an influence on the resulting oxide.

16 of 18
ALTHAGAFI ET AL.
FIGURE 8 In vitro toxicity for thiazole
derivatives and their Pt(IV) complexes
against HepG‐2 and HCT‐116 cell lines in
order of reactivity, compared with two
standard drugs
feature displayed apparent cavities, which are considered
to strongly influence the catalytic activity. Also, its excel-
lent nanometer particulate size supports such activity.
The successful catalytic role in preparing the economic
product CO2, which has many industrial uses especially
with food, oil and safety manufactures, was the other
application pathway concerned in this study.
4 | CONCLUSIONS
A series of new syntheses were conducted aimed at
Pt(IV)–thiazole complexes. The synthesized compounds
were comprehensively characterized using experimental
and theoretical methods. Hexagonal geometrical shape
was proposed for all Pt(IV) complexes. Utilizing Gaussian
09 and HyperChem 8.2 programs, the softness, hardness,
surface area and reactivity as well as other significant
indexes were estimated. Such computed parameters point
to the application pathways considered in this study. The
first application concerned antitumor activity towards
HCT‐116 and HepG‐2 cell lines; mild toxicity was the
main trend appearing. The second application concerned
catalytic oxidation of CO to produce the economic prod-
uct CO2. This catalytic process was conducted using
synthesized PtO2, which was yielded from calcination
process of a chosen complex, namely [PtCl3(BTOB)
(C2H5OH)].
FIGURE 9 Light‐off curve for CO oxidation using synthesized
PtO2 catalyst
The catalytic success was indicated by CO conversion of
50 and 100%, which were obtained at 140 and 149°C,
respectively. To our knowledge, this satisfactory reduced
temperature indicates the superiority of the potential cat-
alyst as a pure oxide over other known catalysts.[57,58]
Regarding CeO2 and HfO2,[18] although they have small
amounts of oxygen vacancies, they are considered perfect
supporters for the oxidation process. Such favorable activ-
ity is due to the provision of sites for oxygen activation,
which leads to formation of superoxide (O2−) species.
Also, as is known, the noble metals show basically a high
capacity for oxygen dissociation, even at low temperature.
Proceeding from this, and after achieving the nominal
aim, we summarize the main characteristics leading to
such result, which are already expected. (i) The best mor-
phology and nanocrystallinity of the original complex led
to a great impact on the oxide used from its calcination.
(ii) Furthermore, the significant characteristics for PtO2
gathered from XRD pattern and SEM image (Figure 1)
support its distinct catalytic role. Its morphological
ACKNOWLEDGMENTS
The authors thank Deanship of Scientific Research at
Umm Al‐Qura University (project ID: 17‐SCI‐1‐01‐0004)
for the financial support of the research conducted during
the project.

ALTHAGAFI ET AL.
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Wiley, New York 1974.
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How to cite this article: Althagafi I, El‐Metwaly
NM, Farghaly T. Characterization of new Pt(IV)–
thiazole complexes: Analytical, spectral, molecular
modeling and molecular docking studies and
applications in two opposing pathways. Appl
Organometal Chem. 2019;e5099. https://doi.org/
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