New bioactive Pt(II) binary and ternary metal complexes with guaifenesin drug: Synthesis, geometrical structure, and spectroscopic and thermal characterization

Article abstract of DOI:10.1002/aoc.3583

Three new binary and ternary metal complexes of Pt(II) with guaifenesin (GFS) drug have been prepared by chelation to guaifenesin ligand (as primary ligand) and glycine amino acid (HGly) and 1,10-phenanthroline (1,10-Phen) (as secondary ligands). Characterization was conducted based on elemental analysis, molar conductance, infrared (IR) spectroscopy, thermogravimetric analysis and X-ray diffraction. The complexes were found to have the formulae [Pt(GFS)₂]?3H₂O (1), [Pt(GFS)₂(Gly)]Cl?H₂O (2) and [Pt(GFS)₂(Phen)]Cl₂ (3). Magnetic and spectroscopic data revealed complexes 1–3 to have octahedral geometry. IR spectra suggested that GFS ligand coordinated in mononegative tridentate mode (OOO) for 1 but in neutral bidentate mode (OO) for 2 and 3. In addition, HGly behaves as mononegative bidentate coordinated to Pt(II) metal via deprotonated carboxylate O and amino group. IR data also evidenced the bidentate nature of 1,10-Phen ligand. The molecular and electronic structure of Pt(II) complex 1 was optimized theoretically and the quantum chemical parameters were calculated. Complexes 1–3 were screened for their antibacterial activity on Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli and Neisseria gonorrhoeae) and for their in vitro antifungal activity against Candida albicans. The three Pt(II) complexes showed remarkable biological and cytotoxic activity. The chelates were also screened for their in vitro anticancer activity against the MFC7 breast cell line. Complex 3 showed the highest activity with a low IC₅₀ value of 3.38?μg?ml^?1.

Full text of DOI:10.1002/aoc.3583

Received: 1 May 2016
DOI 10.1002/aoc.3583
Revised: 11 July 2016
Accepted: 14 July 2016
F U L L PA P E R
New bioactive Pt(II) binary and ternary metal complexes with
guaifenesin drug: Synthesis, geometrical structure, and
spectroscopic and thermal characterization
*
Walaa H. Mahmoud | Gehad G. Mohamed | Nessma F. Mahmoud
Chemistry Department, Faculty of Science, Cairo
Three new binary and ternary metal complexes of Pt(II) with guaifenesin (GFS)
University, Giza 12613, Egypt
drug have been prepared by chelation to guaifenesin ligand (as primary ligand)
and glycine amino acid (HGly) and 1,10‐phenanthroline (1,10‐Phen) (as secondary
ligands). Characterization was conducted based on elemental analysis, molar con-
ductance, infrared (IR) spectroscopy, thermogravimetric analysis and X‐ray diffrac-
tion. The complexes were found to have the formulae [Pt(GFS)2]⋅3H2O (1), [Pt
(GFS)2(Gly)]Cl⋅H2O (2) and [Pt(GFS)2(Phen)]Cl2 (3). Magnetic and spectroscopic
data revealed complexes 1–3 to have octahedral geometry. IR spectra suggested that
GFS ligand coordinated in mononegative tridentate mode (OOO) for 1 but in neutral
bidentate mode (OO) for 2 and 3. In addition, HGly behaves as mononegative
bidentate coordinated to Pt(II) metal via deprotonated carboxylate O and amino
group. IR data also evidenced the bidentate nature of 1,10‐Phen ligand. The molec-
ular and electronic structure of Pt(II) complex 1 was optimized theoretically and the
quantum chemical parameters were calculated. Complexes 1–3 were screened for
their antibacterial activity on Gram‐positive bacteria (Bacillus subtilis and Staphylo-
coccus aureus) and Gram‐negative bacteria (Escherichia coli and Neisseria
gonorrhoeae) and for their in vitro antifungal activity against Candida albicans.
The three Pt(II) complexes showed remarkable biological and cytotoxic activity.
The chelates were also screened for their in vitro anticancer activity against the
MFC7 breast cell line. Complex 3 showed the highest activity with a low IC50 value
Correspondence
Gehad G. Mohamed, Chemistry Department,
Faculty of Science, Cairo University, Giza, 12613,
Egypt.
Email: ggenidymohamed@sci.cu.edu.eg
of 3.38 μg ml−1
.
KEYWORDS
activity index, biological and anticancer activity, molecular structures, Pt(II) chelates,
quantum chemical parameters, spectroscopy, thermal analyses
1
|
INTRODUCTION
few decades in the use of metal ions and complexes as chemo-
therapeutic agents. Emphasis has been placed mainly on can-
Metal complexes have many characteristics that can be advan-
tageous in drug design. Transition metals have an important
place in medicinal biochemistry. Research has made signifi-
cant progress in utilization of transition metal complexes as
drugs to treat several human diseases like carcinomas, lym-
phomas, infections, diabetes, inflammation and neurological
disorders. The medicinal uses and applications of metals and
metal complexes are of increasing clinical and commercial
importance.[1] There has been an increased interest in the last
cer treatment, as a result of the great success of cisplatin and
new‐generation analogous platinum compounds. The devel-
opment of medicinal inorganic chemistry has been supported
by the advances in bioinorganic chemistry, as can be
evidenced in recent reviews including several applications of
a variety of metal complexes in medicine, as well as the chem-
istry and biochemistry involved.[2] A significantly rising inter-
est in the design of metal compounds as drugs and diagnostic
agents is currently observed in the area of scientific inquiry
Appl. Organometal. Chem. 2016; 1–11
wileyonlinelibrary.com/journal/aoc
Copyright © 2016 John Wiley & Sons, Ltd.
1

2
MAHMOUD ET AL.
that is termed medicinal inorganic chemistry. Investigations in
this area have focused mostly on the speciation of metal spe-
cies in biological media based on possible interactions of
these metal ions with diverse biomolecules, in an effort to
contribute to future development of new therapeutics or diag-
nostic agents. Metallopharmaceuticals used as anticancer
agents, metal‐mediated antibiotics, antibacterials, antivirals,
antiparasitics, antiarthritics, antidiabetics and radio‐sensitiz-
ing agents have appeared in therapeutic medicinal inorganic
chemistry. The medicinal uses and applications of metals
and metal complexes are of increasing clinical and commer-
cial importance.[3]
This medication is used for the temporary relief of coughs
caused by the common cold, bronchitis and other breathing
illnesses. This product is usually not used for ongoing cough
from smoking or long‐term breathing problems (such as
chronic bronchitis and emphysema) unless directed by a
doctor.[9,10]
This paper described the characterization of guaifenesin
drug (GFS) and its Pt(II) complexes [Pt(GFS)2]⋅3H2O (1),
[Pt(GFS)2(Gly)]Cl⋅H2O (2) and [Pt(GFS)2(Phen)]Cl2 (3)
1
using elemental analyses, infrared (IR), H NMR, mass and
UV–visible spectroscopies, X‐ray diffraction (XRD), mag-
netic moment, molar conductance and thermal analysis. The
antimicrobial activities of GFS and its binary and ternary Pt
(II) complexes 1–3 were studied and comparison of their anti-
microbial activities with those of standard antibacterial and
antifungal drugs was carried out. The molecular structure of
Pt(II) complex 1 was studied and quantum chemical parame-
ters were calculated. Moreover, the anticancer activity against
the MCF7 breast cell line was studied.
There has been a rapid expansion in research and devel-
opment of new metal‐based anticancer drugs to improve clin-
ical effectiveness, reduce general toxicity and broaden the
spectrum of activity. Chemical, pharmacological and clinical
research on anticancer coordination complexes has yielded
remarkable anticancer agents such as cisplatin, carboplatin
and oxaliplatin. Cisplatin is regarded as one of the most effec-
tive anticancer drugs, even if severe toxicities and drug resis-
tance phenomena limit its clinical use. Among extensive
research aiming to characterize other anticancer‐active inor-
ganic complexes with improved pharmacological properties
compared to cisplatin is that focusing on the use of biologi-
cally active complexes formed by essential ions such as tran-
sition metals. Complexes with biologically active ligands are
particularly attractive, as they combine qualities of classic
non‐targeted coordination compounds and organic ligands
with selectivity for cellular targets.[4] Studies of such com-
plexes are expected to indicate that new mechanisms of
action are possible through combining the bioactivity of a
ligand with the properties inherent to a metal, leading to the
possibility of overcoming current drug resistance path-
ways.[5,6] Guaifenesin (International Nonproprietary Name;
Figure 1) or guaiphenesin (former British Approved Name)
is an expectorant drug usually taken orally to assist the expec-
toration (‘bringing up’) of phlegm from the airways in acute
respiratory tract infections. It is a common ingredient in
many over‐the‐counter cough/cold medications and its
IUPAC name is 3‐(2‐methoxyphenoxy)propane‐1,2‐diol.[7]
Guaifenesin works by thinning and loosening mucus in the
airways, clearing congestion and making breathing easier.
The principal use of guaifenesin is in the treatment of
coughing. Guaifenesin is sometimes combined with dextro-
methorphan, an antitussive, such as in Mucinex DM or
Robitussin DM,[8] or combined with, for example, propofol,
since guaifenesin does not produce analgesia nor does it pro-
duce unconsciousness. Guaifenesin is a centrally acting mus-
cle relaxant used routinely in large‐animal veterinary surgery.
2
| EXPERIMENTAL
2.1 | Materials and reagents
All chemicals used were of analytical reagent grade, and of
highest purity available. The chemicals used included GFS
drug which was supplied by the National Organization for
Drug Control and Research, PtCl2 and 1,10‐phenanthroline
(Merck) and glycine (BDH, Poole, UK). Organic solvents
were spectroscopically pure from BDH including ethanol,
diethyl ether and dimethylformamide (DMF). Hydrogen per-
oxide, sodium chloride, sodium carbonate and sodium
hydroxide were used. Human tumour cell line (breast cell)
was obtained frozen in liquid nitrogen (−180°C) from the
American Type Culture Collection. The tumour cell line
(MCF7) was maintained in the National Cancer Institute,
Cairo, Egypt, by serial sub‐culturing.
2.2 | Solutions
A fresh stock solution of 1 × 10−3 M of GFS (0.4 g l−1) was
prepared in the appropriate volume of absolute ethanol and
DMF in a ratio of 1:3 (v/v). Dimethylsulfoxide (DMSO;
Sigma Chemical Co., St Louis, MO, USA) was used in cryo-
preservation of cells. RPMI‐1640 medium (Sigma) was used
for culturing and maintenance of the human tumour cell lines.
The medium was supplied in a powder form. It was prepared
as follows: 10.4 g of medium was weighed, mixed with 2 g of
sodium bicarbonate, completed to 1 l with distilled water and
shaken carefully until complete dissolution. The medium was
then sterilized by filtration with a Millipore bacterial filter
(0.22 μm). The prepared medium was kept in a refrigerator
(4°C) and checked at regular intervals for contamination.
Before use the medium was warmed at 37°C in a water bath
FIGURE 1 Structure of guaifenesin

MAHMOUD ET AL.
3
and supplemented with penicillin/streptomycin and foetal
bovine serum (FBS).
The molecular structure of Pt(II) complex 1 was opti-
mized using the HF method with 3‐21G basis set. The mole-
cules were built with PerkinElmer ChemBio Draw and
optimized using PerkinElmer ChemBio3D software.[11,12]
Quantum chemical parameters such as the highest occupied
molecular orbital energy (EHOMO), the lowest unoccupied
molecular orbital energy (ELUMO) and HOMO–LUMO
energy gap (ΔE) were calculated.
Sodium bicarbonate (Sigma) was used for the preparation
of RPMI‐1640 medium. Isotonic trypan blue solution
(0.05%; Sigma) was prepared in normal saline and was used
for viability counting. FBS (10%; heat‐inactivated at 56°C for
30 min), 100 U ml−1 penicillin and 2 mg ml−1 streptomycin
(Sigma) were used for the supplementation of RPMI‐1640
medium prior to use. Trypsin (0.025% (w/v); Sigma) was
used for the harvesting of cells. Acetic acid (1% (v/v); Sigma)
was used for dissolving unbound sulphorhodamine‐B (SRB)
dye (0.4%; Sigma). A stock solution of trichloroacetic acid
(50%; Sigma) was prepared and stored. An amount of 50 μl
of the stock was added to 200 μl of RPMI‐1640 medium
per well to yield a final concentration of 10% used for protein
precipitation. Isopropanol (100%) and ethanol (70%) were
used. Tris base (10 mMl pH = 10.5) was used for SRB dye
solubilization. An amount of 121.1 g of Tris base was
dissolved in 1000 ml of distilled water and the pH was
adjusted using hydrochloric acid (2 M).
2.3 | Preparation of metal complexes
The binary metal complexes were prepared by the addition of
a hot solution (70°C) of the appropriate metal chloride
(1.07 mmol) in an ethanol–DMF mixture (1:3 v/v) to a hot
solution (70°C) of the ligand (0.4 g of GFS, 2.02 mmol) in
the same solvent (20 ml) and ethanolic ammonia solution
was added to adjust the pH of the solution. The ternary metal
complexes were prepared by the addition of a hot solution
(70°C) of the metal chloride (2.02 mmol) in an ethanol–
DMF mixture (1:3 v/v) to a hot solution (70°C) of the ligands
(0.4 g of GFS, 0.149 g of glycine and 0.4 g of 1,10‐
phenanthroline, 2.02 mmol) in the same solvent (25 ml of
each ligand) and ethanolic ammonia solution was added to
adjust the pH of the solution. The resulting mixture was
stirred under reflux for 1.5 h, whereupon the complexes pre-
cipitated. They were removed by filtration, washed with hot
ethanol followed by diethyl ether and dried in a vacuum des-
iccator over anhydrous calcium chloride. The analytical data
for C, H and N were obtained in duplicate. The solid com-
plexes were then dried in a desiccator over anhydrous cal-
cium chloride. The yield ranged from 60 to 80%.
Microanalyses of carbon, hydrogen and nitrogen were
carried out at the Microanalytical Center, Cairo University,
Egypt, using
a CHNS‐932 (LECO) Vario elemental
analyser. IR spectra were recorded with a PerkinElmer
1650 spectrometer (400–4000 cm−1) in KBr pellets. Elec-
tronic spectra were recorded at room temperature with a
Shimadzu 3101pc spectrophotometer as solutions in ethanol.
1H NMR spectra, as solutions in DMSO‐d6, were recorded
with a 300 MHz Varian‐Oxford Mercury at room tempera-
ture using tetramethylsilane as an internal standard. Electron
spin resonance spectra were recorded with a JES‐FE2XG
ESR spectrophotometer at the Microanalytical Center, Tanta
University. Mass spectra were recorded using the EI tech-
nique at 70 eV with a Hewlett‐Packard MS‐5988 GS‐MS
instrument at the Microanalytical Center, National Center
for Research, Egypt. The molar magnetic susceptibility
was measured on powdered samples using the Faraday
method. The diamagnetic corrections were made by Pascal's
constant and Hg[Co(SCN)4] was used as a calibrant. Molar
conductivities of 10−3 M solutions of solid complexes in
DMF were measured using a Jenway 4010 conductivity
meter. Thermogravimetric analyses (TG and DTG) of the
solid complexes were carried out from room temperature
to 800°C using a Shimadzu TG‐50H thermal analyser. Pow-
der XRD analyses were carried out using a Philips Analyti-
cal X‐Ray BV diffractometer type PW 1840. Radiation was
provided by copper target (Cu anode, 2000 W) high‐inten-
sity X‐ray tube operated at 40 kV and 25 mA. Divergence
and the receiving slits were 1 and 0.2, respectively. The anti-
cancer activity experiments were performed at the National
Cancer Institute, Cancer Biology Department, Pharmacol-
ogy Department, Cairo University. The optical density
(OD) of each well was measured spectrophotometrically at
564 nm with an ELIZA microplate reader (Meter Tech,
USA).
Complex 1. Dark brown; yield 66%; m.p. 156°C. Anal.
Calcd (%): C, 38.62; H, 5.36; Pt, 30.22. Found (%): C,
38.54; H, 5.23; Pt, 30.32. μeff (BM): 3.36. Λm (Ω−1 mol
−1
cm2): 19.20. IR (cm−1): ν(OH) stretching (CH2─OHa)
3251br; ν(OH) stretching (CH2─OHb) 3071 s; ν(C─O─Cb)
etheric phenoxy stretching 1252sh; ν(CH3O) methoxy
1224s; ν(CH─C─Ob) etheric 1180 m; ν(M─O) stretching
bands of coordinated water 543 s; ν(M─O) stretching (OH,
1
C─O) 650, 666. λmax (nm): 273 π–π*. H NMR (δ, ppm):
6.81–7.03 (m, 6H, Ar─H), band due to CH─OHb
disappeared, 4.60 (t, 1H, CH2─OHa, J = 2.7 Hz), 3.96 (d,
2H, O─CH2, J = 1.8 Hz), 3.91 (m, 1H, CH─OHb), 3.72 (s,
3H, O─CH3), 3.47 (t, 2H, CH2─OHa, J = 2.4 Hz).
Complex 2. Yellowish white; yield 80%; m.p. 80°C.
Anal. Calcd (%): C, 36.70; H, 4.70; N, 1.90; Pt, 27.37. Found
(%): C, 36.60; H, 4.60; N, 1.70; Pt, 27.96. μeff (BM): 3.32. Λm
(Ω−1 mol−1 cm2): 62.0. IR (cm−1): ν(OH) stretching
(CH2─OHa) 3239br; ν(OH) stretching (CH2─OHb) 3074 s;
ν(NH2)asym 3120 s; ν(COO)asym 1507sh; ν(COO)sym
1461sh; ν(C─O─Cb) etheric phenoxy stretching 1251 m;
ν(CH3O) methoxy 1223sh; ν(CH─C─Ob) etheric 1183 m;
ν(NH2) bending 671 m; ν(M─O) stretching (OH, C─O)
635 m, 511 m; ν(M─N) 445 m. λmax (nm): 272 π–π*.

4
MAHMOUD ET AL.
Complex 3. Orange; yield 60%; m.p. 60°C. Anal. Calcd
The percentage cell survival was calculated as follows:
(%): C, 45.60; H, 4.30; N, 3.30; Pt, 23.20. Found (%): C,
45.43; H, 2.99; N, 2.99; Pt, 25.0. μeff (BM): 3.27. Λm
(Ω−1 mol−1 cm2): 107.0. IR (cm−1): ν(OH) stretching
(CH2─OHa) 3228br; ν(OH) stretching (CH2─OHb) 3101 s;
ν(C═N) stretching 1592sh; ν(C─O─Cb) etheric phenoxy
stretching 1252 m; ν(CH3O) methoxy 1223 m; ν(CH─C─Ob)
etheric 1183 m; ν(pyridine ring) stretching 1125sh; ν(M─O)
stretching (OH, C─O) 535 m, 500 s; ν(M─N) 417 s. λmax
(nm): 271 π–π*.
OD ðtreated cellsÞ
Survival fraction ¼
OD ðcontrol cellsÞ
The IC50 values (the concentrations of the GFS, HGly,
1,10‐Phen or Pt(II) complexes required to produce 50% inhi-
bition of cell growth) were obtained. The experiment was
repeated three times.
3
| RESULTS AND DISCUSSION
2.4 | Spectrophotometric studies
The binary and ternary Pt(II) metal ion complexes with GFS
ligand were synthesized as previously described and charac-
terized by using physical and analytical techniques. IR spec-
tral studies were used to infer the possible coordination sites
of the ligands (GFS, HGly and 1,10‐Phen) involved in bind-
ing to the metal ions. The synthesized complexes are dark
brown, yellowish white and orange in colour and possess
moderate melting points. These complexes are soluble in
DMSO and DMF, slightly soluble in ethanol, but insoluble
in water and other organic solvents. The suggested formula
structures of the complexes are based on the results of molar
The absorption spectra of GFS free ligand and its Pt(II) com-
plexes under study were scanned within the wavelength range
from 200 to 700 nm.
2.5 | Antimicrobial activity
The in vitro antibacterial and antifungal activity tests were
performed through the well diffusion method[13] using
amikacin and ketokonazole as positive controls for bacteria
and fungi, respectively. The bacteria used were Bacillus
subtilis, Staphylococcus aureus (Gram‐positive bacteria),
Escherichia coli and Neisseria gonorrhoeae (Gram‐negative
bacteria). The fungus used was Candida albicans. Stock
solution (0.001 mol) was prepared by dissolving the com-
pounds in DMSO. The diameter of the inhibition zones
was measured in millimetres. Measurements were performed
in triplicate and the average was taken as the final
reading.[14]
1
conductivity measurements, mass, UV–visible and H NMR
spectra and powder XRD. In addition, the thermal analyses
(TG and DTA) were used to confirm the suggested fragmen-
tation patterns, the molecular formula of the chelates to dif-
ferentiate between coordinated and hydrated water
molecules and to determine the decomposition temperatures
of the chelates. In addition, the biological activities of the
ligands (GFS, HGly and 1,10‐Phen) and their metal chelates
were screened against various fungal and bacterial organ-
isms. The complexes were also screened for their in vitro
anticancer activity against the MFC7 cell line and the results
obtained throw more light on the activity of these
complexes.
2.6 | Anticancer activity
Potential cytotoxicity of the compounds was tested using the
method of Skehan and Storeng.[15] Cells were plated in a 96‐
multiwell plate (104 cells per well) for 24 h before treatment
with the compounds to allow attachment of cells to the walls
of the plate. Various concentrations of the compounds under
investigation (0, 5, 12.5, 25, 50 and 100 μg ml−1) were added
to the cell monolayer and triplicate wells were prepared for
each individual dose. The monolayer cells were incubated
with the compounds for 48 h at 37°C and in 5% CO2 atmo-
sphere. After 48 h, cells were fixed, washed and stained with
SRB stain. Excess stain was washed with acetic acid and
attached stain was recovered with Tris–EDTA buffer. The
OD of each well was measured spectrophotometrically at
564 nm with an ELIZA microplate reader and the mean back-
ground absorbance was automatically subtracted and mean
values of each drug concentration were calculated. The rela-
tion between surviving fraction and drug concentration was
plotted to get the survival curve of breast tumour cell line
for each compound.
3.1 | Elemental analysis and molar conductivity of
complexes
The elemental analysis data of the complexes show the for-
mation of the binary Pt(II) complex (complex 1) in the ratio
1:2 (Pt(II):GFS) and correspond to a composition of [Pt
(GFS)2]⋅3H2O. The colour of the binary complex is dark
brown and its molar conductivity value is found to be 19.20
Ω−1 mol−1 cm2, indicating its non‐electrolytic nature.[16]
The ternary Pt(II) complexes with GFS and glycine
amino acid (complex 2) or 1,10‐phenanthroline (complex 3)
are yellowish white and orange in colour, respectively. The
molar conductivity values of the ternary Pt(II) metal com-
plexes are found to be 62.0 and 107.0 Ω−1 mol−1 cm2 for 2
and 3, respectively, which indicate their electrolytic
nature.[17]

MAHMOUD ET AL.
5
3.2 | IR spectra
individually the various bands appearing in this region. The
bands due to the in‐plane and out‐of‐plane bending of the
amino group of HGly at 1524 and 760 cm−1, respectively,
can help in confirming the participation of the amino group
of HGly in chelate formation. The δ(NH2) in‐plane and out‐
of‐plane bending vibrations appear at 1507 and 784 cm−1
in Pt(II) complex 2 confirming the coordination of the amino
group to the Pt(II) ion.[25]
The characteristic IR vibrational frequencies of the free GFS
ligand and its binary and ternary Pt(II) metal complexes were
determined. The IR spectrum of GFS drug exhibits a band at
3246 cm−1 which can be attributed to alcoholic
(─CH2─OHa) group. This band is still broad in the spectra
of all complexes and appears at 3251, 3239 and 3228 cm−1
for complexes 1, 2 and 3, respectively. The band appears at
about the same region for the three metal complexes thus
confirming the non‐involvement of the hydroxyl function
(─CH2─OHa) in coordination with the metal ions. The shift
can also be attributed to either hydrogen bond formation or
the presence of hydrated and coordinated water molecules.
The ν(OH) stretching vibration band due to alcoholic
(─CH2─OHb) group appears in the spectrum of the free
GFS ligand at 3078 cm−1. For metal complex 1, this band
is shifted to lower wavenumber (3071 cm−1) indicating the
involvement of this group in complex formation. The
CH─COb stretching vibration found for the free GFS ligand
at 1183 cm−1 is shifted to lower wave number (1180 cm−1)
which supports coordination of CH2─OHb to metal ion or its
involvement in bond formation. The band shift indicates the
formation of a covalent bond between Pt(II) ion and this
hydroxyl oxygen atom (CH─COb) after deprotonation in the
binary Pt(II) complexes and hence confirms its binding to
The bands arising due to ν(C═N) stretching vibration and
in‐plane bending appear at 1588 and 625 cm−1, respectively,
in the spectrum of the 1,10‐Phen ligand. In the ternary metal
complex 3, these bands are observed at 1592 and 624 cm−1
,
respectively, indicating the involvement of nitrogen of pyri-
dine ring in complex formation.[21,24–30]
The IR spectra of the three complexes each show a new
band which is assignable to ν(M─O) stretching vibration at
543, 511 and 500 cm−1 for complexes 1, 2 and 3, respec-
tively.[31,32] The ν(M─N) stretching vibrations appear at
445 and 417 cm−1 for complexes 2 and 3, respectively.
Therefore, it is concluded from the IR spectra of binary
and ternary metal complexes that:
1. For complex 1, GFS behaves as a uni‐negative tridentate
ligand coordinated to Pt(II) ion via the etheric C─O─C
phenoxy oxygen, methoxy oxygen and deprotonated
hydroxyl oxygen (CH─OHb). But, in the ternary com-
plexes 2 and 3, it behaves as neutral bidentate ligand
coordinated to the metal ions via etheric C─O─C
phenoxy and methoxy oxygen atoms.
1
Pt(II) ion. This is further confirmed by H NMR studies. For
complexes 2 and 3, the CH─C─Ob stretching vibration band
appears in the same position (1183 cm−1) indicating its non‐
participation in complex formation. This is also confirmed by
the elemental and conductance data for complexes 2 and 3
due to the presence of anions in the outer coordination sphere.
Also, two absorption bands due to etheric C─O─C
phenoxy and methoxy groups appear at 1255 and
1227 cm−1, respectively, in the spectrum of free GFS
ligand. The absorption frequencies of etheric C─O─C
phenoxy in metal complexes 1, 2 and 3 are shifted and
appear at 1252, 1251 and 1252 cm−1, respectively, indicat-
ing the involvement of oxygen atom of etheric C─O─C
phenoxy in complexation with the metal ions.[18–21] For
complexes 1–3, the band due to methoxy oxygen atom
(CH3─O) is shifted to lower wavenumber upon chelation
with Pt(II) ion indicating its binding to Pt(II) ion and hence
the CH3─O methoxy is involved in chelation.
2. For complex 2, Gly behaves as a uni‐negative bidentate
ligand with NO donor sites and coordinated to the Pt
(II) ion via the amino group N and deprotonated carbox-
ylic oxygen.
3. For complex 3, 1,10‐Phen behaves as neutral bidentate
ligand coordinated to the metal ion through two pyridine
N atoms.
3.3 | 1H NMR spectra
The 1H NMR spectral data for GFS and its Pt(II) chelate 1 are
discussed. It is found that the uncoordinated GFS has the
respective peak positions and corresponding assignments:
multiplet peak at 6.85–7.0 ppm (m, 6H, Ar─H) which
corresponds to benzene ring; doublet peak occurs at
4.85 ppm (d, 1H, CH─OHb) which is attributed to OHb
hydroxyl group; and triplet peak occurs at 4.61 ppm (t, 1H,
CH2─OHa) which is attributed to OHa hydroxyl group. In
addition, doublet peak occurs at 3.98 ppm (d, 2H, O─CH2)
which is attributed to O─CH2 methylene group, multiplet
peak occurs at 3.94 ppm (m, 1H, CH─OHb) corresponding
to CH─OHb methyne group, singlet peak occurs at
3.74 ppm (s, 3H, O─CH3) which is attributed to methoxy
group and triplet peak occurs at 3.48 ppm (t, 2H, CH2─OHa)
The νasym(COO) and νsym(COO) stretching vibrations are
observed at 1586 and 1412 cm−1, respectively, for HGly free
ligand.[21–24] Coordination with Pt(II) ion via the carboxylate
O atom is indicated by the shift in position of the νasym(COO)
and νsym(COO) stretching vibration bands to 1592 and
1460 cm−1, respectively, for Pt(II) complex 2. In the
3120 cm−1 region of the IR spectrum of complex 2 the
ν(NH2) stretching vibration is observed, which appears at
3400 cm−1 for the free HGly ligand, and the overlap of the
various ν(NH2) vibrations couple in many cases with water
molecules of hydration or coordination which give rise to
strong absorption. This makes it difficult to recognize

6
MAHMOUD ET AL.
which is attributed to CH2─OHa methylene group.[19,20,33]
For Pt(II) complex 1, all the NMR peaks remain almost
unaltered except that the peak corresponding to OHb
hydroxyl group disappears indicating its involvement in com-
plex formation.
Due to the difficulties in solubility of complexes 2 and 3
in DMSO‐d6 solvent, the elemental analysis and IR spectral
tools help in structural interpretation of the complexes.
χ, chemical potentials, Pi, absolute hardness, η, absolute soft-
ness, σ, global electrophilicity, ω, global softness, S, and
additional electronic charge, ΔNmax, have been calculated
according to the following equations:
ΔE ¼ ELUMO−EHOMO
(1)
EHOMO þ ELUMO
χ ¼ −
(2)
2
3.4 | UV–visible spectra
ELUMO−EHOMO
Absorption spectra of the binary and ternary GFS–Pt(II) metal
complexes 1–3 were obtained in DMF and ethanol (3:1 v/v) at
room temperature. UV–visible spectra were recorded for these
complex solutions (1 × 10−4 M) in the range 200–700 nm.
The bands due to n–π* and π–π* transitions of the ligand are
shifted to higher wavelengths in UV–visible spectra of the com-
plexes. It is observed that free GFS has two distinct absorption
bands. The first one at 223 nm may be attributed to π–π* transi-
tion of the benzene ring. The second band observed at 273 nm
can be attributed to n–π* electronic transition.[19,20] In the spectra
of complexes 1, 2 and 3, the band at 223 nm disappears while the
one at 273 nm is observed at 273, 272 and 271 nm, respectively,
indicating that the ligand is coordinated to metal ion.[19,20,29,34]
η ¼
(3)
2
1
σ−
η
(4)
(5)
(6)
Pi ¼ −χ
1
S ¼
2η
Pi2
ω ¼
(7)
(8)
2η
3.5 | Molecular structures
The optimized structure of Pt(II) complex 1 is shown in
Figure 2. Selected geometric parameters, namely bond
lengths and bond angles, of Pt(II) complex 1 are given in
Table 1. The HOMO and LUMO of Pt(II) complex 1 are
shown in Figure 3. The HOMO–LUMO energy gap, ΔE,
which is an important stability index, was applied to develop
theoretical models for explaining the structure and conforma-
tion barriers in many molecular systems.[28,35] The calculated
quantum chemical parameters are given in Table 2. Addi-
tional parameters such as ΔE, absolute electronegativities,
Pi
ΔN max ¼ −
η
3.6 | Mass spectra
MS is a useful technique to interpret the stoichiometric
composition of ligands and complexes. The mass spectrum
of the Pt(II) complex 1 was recorded at ambient tempera-
ture. The electron impact mass spectrum of the [Pt(GFS)
2]⋅3H2O complex shows a molecular ion peak at m/
z = 647.90 amu (calcd = 643 amu). The proposed formula
is confirmed also by the appearance of a peak at
198.26 amu corresponding to the GFS ligand moiety
((C10H14O4, atomic mass 198.216 amu). The observed
peaks are in good agreement with the proposed formula as
indicated by the microanalytical data.[21,36]
3.7 | Powder XRD
The XRD patterns for the Pt(II) chelates 1–3 show the crys-
talline nature of complex 1, and the amorphous nature of
complexes 2 and 3. This can confirm that the presence of
metal ion changes the XRD pattern of the free GFS ligand.
Therefore, the non‐similarity of the XRD patterns suggests
that these chelates have phase structures different from those
of the GFS, glycine and 1,10‐phenanthroline free
ligands.[29,37]
FIGURE 2 Molecular structure of Pt(II) complex 1

MAHMOUD ET AL.
7
TABLE 1 (Continued)
TABLE 1 Selected geometric parameters for Pt(II) complex 1
Bond length (Å)
C(29)–H(55)
C(29)–H(54)
C(29)–H(53)
C(27)–H(52)
C(26)–H(51)
C(25)–H(50)
C(24)–H(49)
O(19)–H(48)
C(18)–H(47)
C(18)–H(46)
C(17)–H(45)
C(16)–H(44)
C(16)–H(43)
C(14)–H(42)
C(14)–H(41)
C(14)–H(40)
C(12)–H(39)
C(11)–H(38)
C(10)–H(37)
C(9)–H(36)
O(4)–H(35)
C(3)–H(34)
C(3)–H(33)
C(2)–H(32)
C(1)–H(31)
C(1)–H(30)
O(28)–Pt(15)
O(6)–Pt(15)
O(13)–Pt(15)
O(5)–Pt(15)
O(21)–Pt(15)
O(20)–Pt(15)
C(18)–O(21)
C(23)–O(28)
O(28)–C(29)
O(21)–C(22)
C(22)–C(27)
C(26)–C(27)
C(25)–C(26)
C(24)–C(25)
C(23)–C(24)
C(22)–C(23)
C(17)–O(20)
C(16)–O(19)
C(17)–C(18)
C(16)–C(17)
C(3)–O(6)
Bond angle (°)
H(48)–O(19)–C(16)
Bond length (Å)
C(11)–C(12)
C(10)–C(11)
C(9)–C(10)
C(8)–C(9)
Bond angle (°)
H(46)–C(18)–C(17)
1.116
1.113
1.116
1.1
109.109
107.845
107.703
112.723
107.017
110.93
1.343
1.345
1.344
1.346
1.538
1.972
1.42
113.542
106.783
125.249
116.036
118.708
109.248
118.981
117.743
107.882
109.546
117.619
114.078
104.479
107.289
111.942
105.253
113.964
113.226
61.95
H(44)–C(16)–H(43)
H(44)–C(16)–O(19)
H(44)–C(16)–C(17)
H(43)–C(16)–O(19)
H(43)–C(16)–C(17)
O(19)–C(16)–C(17)
H(45)–C(17)–O(20)
H(45)–C(17)–C(18)
H(45)–C(17)–C(16)
O(20)–C(17)–C(18)
O(20)–C(17)–C(16)
C(18)–C(17)–C(16)
H(35)–O(4)–C(1)
H(31)–C(1)–H(30)
H(31)–C(1)–O(4)
H(31)–C(1)–C(2)
O(21)–C(18)–C(17)
O(21)–C(22)–C(27)
O(21)–C(22)–C(23)
C(27)–C(22)–C(23)
Pt(15)–O(28)–C(23)
Pt(15)–O(28)–C(29)
C(23)–O(28)–C(29)
Pt(15)–O(21)–C(18)
Pt(15)–O(21)–C(22)
C(18)–O(21)–C(22)
Pt(15)–O(20)–C(17)
H(42)–C(14)–H(41)
H(42)–C(14)–H(40)
H(42)–C(14)–O(13)
H(41)–C(14)–H(40)
H(41)–C(14)–O(13)
H(40)–C(14)–O(13)
Pt(15)–O(5)–C(2)
O(28)–Pt(15)–O(6)
O(28)–Pt(15)–O(13)
O(28)–Pt(15)–O(5)
O(28)–Pt(15)–O(21)
O(28)–Pt(15)–O(20)
O(6)–Pt(15)–O(13)
O(6)–Pt(15)–O(5)
O(6)–Pt(15)–O(21)
O(6)–Pt(15)–O(20)
O(13)–Pt(15)–O(5)
O(13)–Pt(15)–O(21)
O(13)–Pt(15)–O(20)
O(5)–Pt(15)–O(21)
O(5)–Pt(15)–O(20)
O(21)–Pt(15)–O(20)
H(34)–C(3)–H(33)
H(34)–C(3)–O(6)
1.103
1.103
1.101
0.96
C(7)–C(8)
C(2)–O(5)
110.393
108.88
C(1)–O(4)
C(2)–C(3)
1.495
1.699
1.119
1.109
1.119
1.11
109.531
105.909
109.186
108.361
114.807
108.727
100.603
106.415
121.269
102.101
108.31
C(1)–C(2)
1.114
1.116
1.11
1.113
1.101
1.104
1.104
1.1
H(30)–C(1)–O(4)
H(30)–C(1)–C(2)
O(4)–C(1)–C(2)
115.473
132.115
112.904
76.938
78.769
0.959
1.115
1.113
1.192
1.11
H(32)–C(2)–O(5)
H(32)–C(2)–C(3)
152.402
100.558
77.626
H(32)–C(2)–C(1)
O(5)–C(2)–C(3)
106.382
128.607
91.943
109.623
82.541
O(5)–C(2)–C(1)
1.123
1.948
2.085
2.065
1.859
1.945
1.945
1.432
1.239
1.439
1.24
C(3)–C(2)–C(1)
48.466
H(55)–C(29)–H(54)
H(55)–C(29)–H(53)
H(55)–C(29)–O(28)
H(54)–C(29)–H(53)
H(54)–C(29)–O(28)
H(53)–C(29)–O(28)
H(51)–C(26)–C(27)
H(51)–C(26)–C(25)
C(27)–C(26)–C(25)
H(50)–C(25)–C(26)
H(50)–C(25)–C(24)
C(26)–C(25)–C(24)
H(52)–C(27)–C(22)
H(52)–C(27)–C(26)
C(22)–C(27)–C(26)
H(49)–C(24)–C(25)
H(49)–C(24)–C(23)
C(25)–C(24)–C(23)
O(28)–C(23)–C(24)
O(28)–C(23)–C(22)
C(24)–C(23)–C(22)
H(47)–C(18)–H(46)
H(47)–C(18)–O(21)
H(47)–C(18)–C(17)
H(46)–C(18)–O(21)
101.768
109.69
113.66
166.883
51.957
111.65
106.581
113.972
112.542
120.575
120.002
119.423
120.002
120.595
119.402
123.072
115.097
121.824
115.302
122.971
121.724
125.05
128.949
85.916
161.397
118.839
78.57
108.198
110.36
1.35
H(34)–C(3)–C(2)
123.38
1.34
H(33)–C(3)–O(6)
117.04
1.337
1.34
H(33)–C(3)–C(2)
123.936
65.797
O(6)–C(3)–C(2)
1.351
1.352
1.406
1.413
1.533
1.523
1.36
H(38)–C(11)–C(12)
H(38)–C(11)–C(10)
C(12)–C(11)–C(10)
H(37)–C(10)–C(11)
H(37)–C(10)–C(9)
C(11)–C(10)–C(9)
Pt(15)–O(13)–C(8)
Pt(15)–O(13)–C(14)
C(8)–O(13)–C(14)
H(36)–C(9)–C(10)
H(36)–C(9)–C(8)
118.625
119.022
122.345
118.295
118.386
123.271
114.04
116.036
118.901
99.874
C(8)–O(13)
O(13)–C(14)
O(6)–C(7)
1.413
1.441
1.455
1.342
123.58
110.564
109.968
115.968
118.82
118.428
121.56
C(7)–C(12)
(Continues)
(Continues)

8
MAHMOUD ET AL.
TABLE 1 (Continued)
to the loss of 2H2O and C8H16ClO molecules and are accom-
panied by a weight loss of 27.98% (calcd 28.00%). The third
and fourth stages of decomposition involve the removal of
C12H16NO9 molecule in the range 305–995°C, and are
accompanied by a weight loss of 44.06% (calcd 44.63%).
The total weight loss amounts to 72.04% (calcd 72.63%)
leaving platinum as a residue.
The thermogram of the ternary complex 3 shows three
steps of decomposition. The first and second stages of decom-
position occur in the range 30–335°C, corresponding to the
loss of C20H15ClO5 molecule, and are accompanied by a
weight loss of 43.80% (calcd 44.00%). The third stage of
decomposition involves the removal of C12H21ClN2O3 mole-
cule in the range 335–615°C, and is accompanied by a weight
loss of 31.10% (calcd 32.80%). The total weight loss amounts
to 75.00% (calcd 76.80%) leaving platinum as a residue.
Bond length (Å)
Bond angle (°)
C(10)–C(9)–C(8)
119.989
120.314
121.456
118.229
96.571
H(39)–C(12)–C(7)
H(39)–C(12)–C(11)
C(7)–C(12)–C(11)
Pt(15)–O(6)–C(3)
Pt(15)–O(6)–C(7)
C(3)–O(6)–C(7)
O(13)–C(8)–C(9)
O(13)–C(8)–C(7)
C(9)–C(8)–C(7)
O(6)–C(7)–C(12)
O(6)–C(7)–C(8)
C(12)–C(7)–C(8)
112.873
104.155
127.976
115.865
115.85
126.131
113.566
120.242
3.8 | Thermal analysis of metal complexes
3.9 | Structural interpretation
The thermal stabilities of GFS and its metal complexes (1, 2
and 3) were investigated using TG and DTG with a heating
rate of 10°C min−1 from 30 to 1000°C to get information
about the thermal decomposition behaviour of these new
complexes. The TG and DTG data are summarized in
Table 3. The weight losses for each metal complex were cal-
culated within the corresponding temperature ranges.
The structures of the binary and ternary complexes of GFS
with Pt(II) ion were confirmed from elemental analyses, IR,
1H NMR and UV–visible spectra, molar conductance, solid
reflectance, XRD and thermal analyses (TG and
DTG).[20,21,29,30] The proposed structural formulas of the
complexes are summarized as three types of coordination as
shown in Figure 4.
The thermogram of the binary complex 1 shows three
steps of decomposition. The first step of decomposition occurs
in the range 45–130°C, corresponding to the loss of three
hydrated water molecules, and is accompanied by a weight
loss of 7.86% (calcd 8.40%). The second and third stages of
decomposition involve the removal of C20H26O8 molecule in
the range 130–500°C, and are accompanied by a weight loss
of 61.92% (calcd 61.28%). The total weight loss amounts to
69.68% (calcd 69.78%) leaving platinum as a residue.
3.10 | Antimicrobial studies
GFS drug and the newly synthesized Pt(II) complexes 1–3
were screened for their antibacterial activity against two
Gram‐positive bacteria (Bacillus subtilis and Staphylococcus
aureus) and two Gram‐negative bacteria (Neisseria
gonorrhoeae and Escherichia coli) and for their antifungal
activity against Candida albicans using the diffusion agar
technique.[38,39] All the compounds were placed at four equi-
distant places at a distance of 2 cm from the centre in inocu-
lated Petri plates. DMSO served as control, while amikacin
and ketokonazole were used as standard drugs. All determina-
tions were made in triplicate for each of the compounds.
Average of three independent readings for each compound
was recorded. The Petri plates were kept in a refrigerator for
24 h for prediffusion. Finally the Petri plates were incubated
at 30°C for 24 h. The bacterial growth inhibitory capacities
of the ligand and its complexes (Table 4) follow the order:
The thermogram of the ternary complex 2 shows four
steps of decomposition. The first and second stages of
decomposition occur in the range 30–305°C, corresponding
for B. subtilis: GFS = 0 < amikacin <1 = 2 < 3
for E. coli: GFS = 0 < amikacin <2 < 1 < 3
for N. gonorrhoeae: GFS = 0 < amikacin <2 < 1 < 3
for S. aureus: GFS = 0 < amikacin <1 < 2 < 3
FIGURE 3 HOMO and LUMO of Pt(II) complex 1
TABLE 2 Calculated quantum chemical parameters for Pt(II) complex 1
EHOMO (eV)
−4.39
ELUMO (eV)
−1.842
ΔE (eV)
χ (eV)
η (eV)
σ (eV−1
)
Pi (eV)
−3.116
S (eV−1
)
ω (eV)
ΔNmax
2.548
3.116
1.274
0.785
0.393
3.811
2.446

MAHMOUD ET AL.
9
FIGURE 4 Structures of complexes 1–3
The Pt(II) complex 3 shows greater antibacterial activity (
Table 4 and Figure 5) while Pt(II) complex 2 shows lower
antibacterial activity. The variation in the activity of the metal
complexes against different organisms depends on the imper-
meability of the microorganism cells or on differences in
ribosome of microbial cells.[40] The Pt(II) complexes 1–3
show the best growth inhibition with inhibition zone diameter
ranging from 10.0 to 31.0 mm indicating that the coordina-
tion of Pt(II) ion to the GFS ligand enhances the antimicro-
bial activity. Pt(II) complexes 1 and 2 show no antifungal
activity against C. albicans while complex 3 has a marked
antifungal activity. The activities of GFS ligand and its metal
complexes were confirmed by calculating the activity index
according to the following relation:[6,30,41]
Inhibition zone of compound ðmmÞ
Activity index ðAÞ ¼
×100
Inhibition zone of standard drug ðmmÞ
From the data, it is concluded that complex 3 has the
highest activity index followed by complex 1, while complex
2 has the lowest activity index.
3.11 | Anticancer activity
In recent years, there has been a rapid expansion in research
and development of new metal‐based anticancer drugs to
improve clinical effectiveness, reduce general toxicity and
broaden the spectrum of activity. Chemical, pharmacologi-
cal and clinical research on anticancer coordination com-
plexes has yielded remarkable anticancer agents such as
cisplatin, carboplatin and oxaliplatin. The foremost target
of most research groups was to find a convenient anticancer
drug that can be used efficiently for the treatment of human
tumours. The inclusion of biologically active ligands into
organometallic complexes offers much scope for the design
of novel drugs with enhanced, targeted activity. Studies of

10
MAHMOUD ET AL.
TABLE 4 Antimicrobial activity of GFS drug and its Pt(II) complexes 1–3
Inhibition zone diameter (mm per mg sample) (Activity index, %)
Sample
Bacillus subtilis
Escherichia coli
Neisseria gonorrhoeae
Staphylococcus aureus
Candida albicans
Control: DMSO
0
0
0
0
0
Amikacin
6
9
7
6
0
Ketokonazole
—
—
—
—
9
GFS
0
0
0
0
0
HGly
9
9
9
9
0
1,10‐Phen
38
28
36
48
35
1
2
3
12 (200)
10 (166.7)
31 (516.7)
11 (122.2)
10 (111.1)
26 (288.9)
12 (171.4)
11 (157.1)
28 (400)
11 (183.3)
11 (183.3)
22 (366.7)
0
0
16 (177.8)
GFS drug and its binary and ternary Pt(II) metal com-
plexes 1–3 were evaluated for their activity against breast
cancer cell line (MCF7) by using 100 μg ml−1 drug or
metal complex concentration. From the results, it is clear
that complexes 1 and 2 are moderately active against breast
cancer cells with inhibition ratio of 80%, while the ternary
complex 3 utilized in this work is markedly active (86%
inhibition) against breast cancer cells. It is clear that a pat-
tern of activity can be determined using different drug con-
centrations (Table 5 and Figure 6). The IC50 values are
FIGURE 5 Antimicrobial activity of GFS, HGly, Phen and Pt(II) com-
plexes 1–3
TABLE 5 Anticancer activity of GFS and its Pt(II) complexes 1–3
Surviving fraction (MCF7)
IC50
Complex
0.0 μg ml−1
5 μg ml−1
0.843
1
12.5 μg ml−1
0.594
1
25 μg ml−1
0.295
1
50 μg ml−1
0.130
1
(μg ml−1
)
GFS
1
1
1
1
1
1
16.6
0
HGly
1,10‐Phen
0.482
0.914
0.877
0.236
0.318
0.558
0.487
0.210
0.315
0.286
0.327
0.197
0.297
0.219
0.154
0.299
4.73
15.1
12.2
3.38
1
2
3
found to be 15.1, 12.2 and 3.38 μg ml−1 for complexes 1,
2 and 3, respectively. It is found that the ternary complex
3 has an outstanding IC50 value and a very low concentra-
tion of this complex can be used to produce 50% inhibition
of cell growth.[5,24,30]
4
| CONCLUSIONS
Various physicochemical, spectroscopic and thermal methods
of analysis were utilized to characterize the ligand under
investigation and its Pt(II) binary and ternary metal chelates
in addition to studying their biological and anticancer activi-
ties. The cytotoxic activity shown by these metal complexes
against MCF7 cell line indicated that chelation of GFS to Pt
(II) metal ion resulted in metallic complexes with important
biological properties and marked cytotoxic activity,
displaying IC50 values in a better range than those of many
FIGURE 6 Anticancer activity of GFS, HGly, Phen and Pt(II) complexes
1–3 against breast cell line (MCF 7)
such complexes are expected to indicate that new mecha-
nisms of action are possible through combining the bioac-
tivity of a ligand with the properties inherent to a metal,
leading to the possibility of overcoming current drug resis-
tance pathways.[6,42]

MAHMOUD ET AL.
11
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as agents with potential anti‐tumour activity and can therefore
be candidates for further stages of screening in vitro and/or
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