Spectroscopic, DFT analysis, antimicrobial and cytotoxicity studies of three gold(III) complexes

Article abstract of DOI:10.1080/24701556.2021.1891102

Three gold(III) complexes were synthesized using 2-pyrazinecarboxamide, pyridine or bipyridine ligand. Complexes were characterized by spectroscopic and analytical techniques (IR, Raman, 1H NMR, mass spectrometry and elemental analysis). Thermogravimetry

Full text of DOI:10.1080/24701556.2021.1891102

Inorganic and Nano-Metal Chemistry
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Spectroscopic, DFT analysis, antimicrobial and
cytotoxicity studies of three gold(III) complexes
Ramadan M. Ramadan, Amani F. H. Noureldeen, Mohamed M. Abo-Aly &
Samir M. El-Medani
To cite this article: Ramadan M. Ramadan, Amani F. H. Noureldeen, Mohamed M.
Abo-Aly & Samir M. El-Medani (2021): Spectroscopic, DFT analysis, antimicrobial and
cytotoxicity studies of three gold(III) complexes, Inorganic and Nano-Metal Chemistry, DOI:
10.1080/24701556.2021.1891102
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INORGANIC AND NANO-METAL CHEMISTRY
https://doi.org/10.1080/24701556.2021.1891102
Spectroscopic, DFT analysis, antimicrobial and cytotoxicity studies of three
gold(III) complexes
Ramadan M. Ramadana, Amani F. H. Noureldeenb, Mohamed M. Abo-Alya, and Samir M. El-Medanic
b
aChemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt; Department of Biochemistry, Faculty of Science, Ain Shams
c
University, Cairo, Egypt; Chemistry Department, Faculty of Science, Fayoum University, Fayoum, Egypt
ABSTRACT
ARTICLE HISTORY
Received 1 September 2020
Accepted 1 December 2020
Three gold(III) complexes were synthesized using 2-pyrazinecarboxamide, pyridine or bipyridine
ligand. Complexes were characterized by spectroscopic and analytical techniques (IR, Raman, 1H
NMR, mass spectrometry and elemental analysis). Thermogravimetry and conductivity of com-
plexes were investigated. IR, Raman and theoretical calculations of spectral modes of vibrations
using DFT and MP2 methods were performed. Biological activities of the complexes against two
bacteria Escherichia coli and Staphylococcus aureus and two fungi Aspergillus flavus and Candida
albicans were screened. They exhibited activities toward both bacteria and fungi. Potency assays
of the complexes against two breast cancer and liver carcinoma cell lines were evaluated. They
exhibited in vitro activities toward the tumors relative to cis-platin. In addition, fluorescence
quenching studies viscosity measurements of the complexes are performed. Theoretical calcula-
tions based on accurate DFT were established to verify the optimized structures of complexes.
Global chemical reactivity descriptors were estimated from energy of HOMO and LUMO orbitals.
KEYWORDS
Pyrazine derivatives; gold
complexes; IR and Raman
studies; DFT studies;
anticancer drugs
1. Introduction
and the typical d8 electronic configuration.[5,11] However, for
gold complexes, especially those adapted different structures
than square planer, we cannot rule out the interaction of with
DNA as one of the possible mechanisms. Recently, there are
many reports appeared to explore the use of gold(III) com-
plexes as anticancer drugs.[11–16] Various classes of gold(III)
compounds, such as gold(III) dithiocarbamates,[17] gold(III)
porphyrinates,[18] dinuclear gold(III) complexes[19] and a variety
of organogold(III) compounds,[20] were prepared and character-
ized showing an appreciable stability under physiological-like
conditions and manifesting at the same time important in vitro
antiproliferative effects. Moreover, for a few gold(III) com-
pounds, preliminary but truly encouraging in vivo data were
obtained.[13,21]
Our interest in the synthesis of various transition metal
complexes with heterocyclic ligands, which they have appro-
priate biological activities and showed promising applica-
tions as antitumor drugs[3,4,8] has prompted us to continue
the investigation of some gold complexes of these ligands.
In this article, we report the synthesis, characterization and
the biological activity (including antimicrobial, cytotoxicity,
fluorescence quenching and viscosity measurements) of
three Au(III) complexes. Although the characterization of
most previously reported complexes involved infrared stud-
ies, there are less extensive Raman analyses were observed.
In addition, the infrared analysis was generally limited to
certain narrow regions. Therefore, we studied the reported
Transition-metal-based complexes represent important class of
chemotherapeutics, widely used in the clinical centers as antitu-
mor and antiviral agents. They offer potential advantages over
the more common organic-based drugs. Vast efforts are com-
mitted to develop novel transition metal-based derivatives, such
as platinum, gold and ruthenium complexes. These complexes
may have higher antitumor activity and overcome the disad-
vantages of cis-platin (The more established antitumor metallo-
drug).[1–6] Considerable amount of interest has focused on the
use of platinum complexes with pyridine bases as mimics of
cis-platin.[7,8] These studies have shown that the use of planar
ligands, such as the substituted pyridines in platinum (II) com-
plexes, can reduce the rate of deactivation by sulfhydryl groups
without interfering with DNA binding, considered to be the
mode of action of cis-platin.[7–10] On the other hand, Au(III)
complexes have shown to be particularly promising class of
anticancer agents. The development of various types of ligands
capable of stabilizing the Au(III) cation in physiological condi-
tions (nitrogen-donor based, dithiocarbamate and cyclometalled
ligands) opened the way for exploration of their mechanisms of
action. At the same time, the bio-conjugation of Au(III) com-
plexes has emerged as a potential way for improving the select-
ivity of this class of compounds for cancer cells over healthy
tissues.[5] Gold(III) complexes showed chemical features that
are very close to those of clinically employed platinum(II) com-
plexes, such as the preference for square planar coordination gold complexes using infrared, Raman as well as the
CONTACT Ramadan M. Ramadan
r_m_ramadan@yahoo.com
Chemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt.
Supplementary data for this material can be accessed at https://doi.org/10.1080/24701556.2021.1891102.
ß 2021 Taylor & Francis Group, LLC

2
R. M. RAMADAN ET AL.
ꢁ
1
was heated for = h at 60 C, at which the complex was pre-
2
cipitated. The resultant residue was filtered off and washed
with hot petroleum ether. The obtained residue was recrys-
tallized from hot ethanol. The isolated fine crystals were left
to dry under vacuum for 5–6 h.
AuPCA: C5H5N3OCl3Au: Orange red. M.Wt.¼426.44.
Yield: 58%. Elemental analysis, Found (Calc.): % C ¼ 14.05
(14.08); % H ¼ 1.15 (1.18); % N ¼ 9.80 (9.85); % Cl ¼ 24.98
(24.94). Mass spectrometry (m/z)¼391 [P–Cl]þ.
2.2.2. Synthesis of AuPy and AuBpy complexes
An equimolar mixture of AuCl3 and either pyridine or
bipyridine in aqueous ethanol was heated for 1 h at 60 ꢁC.
The reaction mixture was cooled to room temperature, and
the solvent was removed by evaporation on a vacuum line.
The residue was washed with hot ether, and then recrystal-
lized from ethanol giving powder product. The isolated
complex was left to dry under vacuum for 5–6 h.
Figure 1. Structure of ligands with the charge density indicated on the donor
nitrogen atoms.
AuPy: C5H5NCl3Au: Light orange. M.Wt.¼382.43. Yield:
67%. Elemental analysis, Found (Calc.): % C ¼ 15.67 (15.70);
% H ¼ 1.36 (1.32); % N ¼ 3.62 (3.66); % Cl ¼ 27.79 (27.81).
Mass spectrometry (m/z)¼383 [P]þ.
theoretical calculations of the spectral modes of vibrations
using DFT and MP2 methods. The optimized structures of
the complexes were also explored using DFT calculations.
Figure 1 gives the structure of the ligands used in the study.
AuBpy: C10H8N2Cl3Au: Light orange. M.Wt.¼459.52.
Yield: 72%. Elemental analysis, Found (Calc.): % C ¼ 25.91
(26.14); % H ¼ 1.82 (1.76); % N ¼ 5.96 (6.10); % Cl ¼ 23.00
(23.15). Mass spectrometry (m/z)¼425 [P–Cl]þ.
2. Experimental methods
2.1. Materials and instruments
Gold(III) chloride and the heterocyclic nitrogen donor
ligands were purchased from Aldrich. All the solvents were
of analytical reagent grade and were purified using standard
methods. IR measurements were carried out on a Unicam-
Mattson 1000 FT-IR (4000–400 cmꢀ1) as KBr pellets. Raman
spectra were measured on a dispersive Raman spectrometer
of Santerra-Bruker, with a wavelength of 785 nm, laser
power of 10 mW and a resolution of 9.18 cmꢀ1. The samples
in the solid form were deposited on a slide and the spec-
trum was recorded using a small value laser power to pre-
vent any photodegradation of the complexes during Raman
2.3. Biological assay
2.3.1. Biological activity
In vitro antibacterial and antifungal activity of the synthe-
sized complexes were tested against the two bacteria:
Escherchia coli as gram-negative bacteria and Staphylococcus
aureus as gram-positive bacteria, and the two fungi:
Aspergillus flavus and Candida albicans. The tests were car-
ried out using paper disk diffusion method (The Central
Lab, Ain Shams University). The detailed procedure was
previously reported.[3,4] The obtained data were compared
with those of the two standards: tetracycline antibacterial
agent and Amphotericin B antifungal agent.
1
measurements. H and 13C NMR measurements were per-
formed on a Spectrospin-Bruker 300 MHz spectrometer
using DMSO, d6 solvent. Thermogravimetric analysis meas-
urements were carried out (N2 atmosphere) at a heating rate
of 10 ꢁC/min using a Shimadzu DT-50 thermal instrument.
Elemental analyses were measured using Perkin-Elmer 2400
CHN elemental analyzer. Mass spectrometry measurements
of the solid complexes (70 eV, EI) were carried out on a
Finnigan MAT SSQ 7000 spectrometer. Conductivity meas-
urements were made on a YSE conductivity meter model
32. Samples of concentration ca. 1 ꢂ 10-3-1 ꢂ 10-6 M in
DMSO were used for the measurements.
2.3.2. In vitro cytotoxicity studies
Three human cancer cell lines were used for the in vitro
screening experiments: two breast cancer cell lines (MCF7
and T47D) and human liver carcinoma cell line (HepG2).
Screening tests were carried out in the National Cancer
Institute, Cairo University, Egypt. Complete and detailed
procedure is previously reported.[3,4]
2.3.3. Fluorescence quenching measurements
DNA competitive binding studies with ethidium bromide
solution (EB) were carried out at different concentrations
ranged from 1.0 M to 8.0 ꢂ 10ꢀ5 M. The concentrations of
2.2. Synthesis of complexes
2.2.1. Synthesis of AuPCA complex
A solution of PCA ligand (0.5 mmol) in a minimum amount EB and Calf thymus-DNA (CT-DNA) were kept constant at
of ethanol is added dropwise with constant stirring to a 1.0 ꢂ 10ꢀ5 M. Before measurements, the resulting solutions
0.5 mmol aqueous ethanol solution of AuCl3. The mixture were shaken up and incubated for 30 min. All the samples

INORGANIC AND NANO-METAL CHEMISTRY
3
were excited at 510 nm and the emission spectra were
recorded in the wavelength range of 540–680 nm. The
quenching constant (Ksv) was calculated using the
Stern–Volmer equation[22]
:
Io
¼ I þ Ksv complex
½
ꢃ
I
where Io and I are the fluorescence intensities in absence
and presence of the quencher (complex). The Ksv value was
obtained from the slope of the plot of Io/I versus complex
concentrations.
Figure 2. The proposed structures of the complexes.
molecular formulas. The electrical molar conductance in
DMSO at room temperature for the two complexes AuPCA
and AuBpy exhibited high molar conductance (125.5–136.4
mS) due to their electrolytic characteristics, while the molar
conductance of AuPy was in the 21–25 mS range, which
indicated that it is nonelectrolyte.
2.3.4. Viscosity measurements
Viscosity experiments were performed using Ostwald visc-
ometer immersed in a water bath at a constant temperature
(30.0 0.1 ꢁC). CT-DNA samples of approximately 0.5 mM
were prepared by sonication in order to minimize complex-
The IR and Raman spectra of AuPCA complex are
ities arising from CT-DNA flexibility. Flow time was meas- shown in Figures 1S and 2S, and the data are tabulated in
ured with an automated timer three times for each sample
and an average flow time was calculated. Data were pre-
sented as (g/go)1/3 versus the ratio [complex]/[DNA]; g and
go are the viscosities of the CT-DNA solution in presence
and absence of the complex. Viscosity values were calculated
after correcting the flow time of buffer alone (to),
g¼(t–to)/to.
Table 1. The IR spectrum of PCA which is similar to
Favipiravir drug without OH and F atom showed character-
istic bands due to ꢀasNH2 and ꢀsNH2 at 3413 and
3160 cmꢀ1, respectively, Table 1.[8,24] The vibration modes
dNH2, ꢀC¼O, ꢀC–N, rNH2 and sNH2 were found at 1713,
1610, 1438, 1087, 618 cmꢀ1, respectively. It is interesting to
note that chelation reverses the ꢀC¼O and dNH2 vibrations.
The in-phase out of plane cCH was observed at 787 cmꢀ1
,
with medium intensity in comparison with pyrazine mol-
ecule.[25] The other infrared bands corresponded to skeletal
vibrations of the pyrazine ring involving coupled C¼C and
C¼N stretches and CH bends were observed in the wave-
number range 1600–1400 and 1400–1100 cmꢀ1. As expected,
the CO stretch and NH2 scissor of PCA were changed to
lower wavenumbers due to complex formation since these
coordinates are coupled.[26,27] The lowering from 1713 to
1660 cmꢀ1 in the IR spectrum indicated that metal–oxygen
stretch link is relatively strong. The other bands of pyrazine
ring of PCA were also altered since gold ion is linked to the
nitrogen of pyrazine ring as well as the CO group via the
oxygen atom. The metal–ligand stretches were observed as
new bands in the Raman spectra with medium intensity.
The density functional theory (DFT) and the Møller–Plesset
perturbation theory (MP2) calculations for the 45 vibrations
expected for the AuPCA complex using Gaussian 09 soft-
ware were used to assign the experimental wavenumbers
based on the IR intensity, activity and depolarization ratio
in the Raman spectra. In LAuCl3-type compounds for C1
symmetry, the three AuCl stretching modes or the bending
modes are all active. The Au–Cl and Au–N coupled motions
were calculated and observed at lower frequencies as given
in Table 1. Bending vibrations of AuCl3 were observed at
lower wavenumbers by comparing with the stretching
modes.[28,29] The assignments of in-plane (ip) and out of
plane (oop) modes were also based on the calculated inten-
sity and polarization of each vibration. Calculation indicated
that oop modes are depolarized whereas the in-plane vibra-
tions were polarized. It is interesting to note that vibrations
2.4. Computational details
All the calculations were performed using the hybrid density
functional theory (DFT) method B3LYP as implemented in
the Gaussian 09 software package.[23] The geometries were
optimized using the standard double zeta plus polarization
basis set 6–31G (d,p) for ligands atoms and effective core
potential basis set LANL2DZ for metal complexes. The pur-
pose of the quantum mechanics calculations validates the
proposed 3D structure of the obtained complexes as well as
to find out key factors for their reactivity. The theoretical
calculations of the spectral modes of vibrations were carried
out using DFT and MP2 methods.
3. Results and discussion
3.1. Spectroscopic studies
Three gold(III) complexes were isolated from the reactions
of 2-pyrazinecarboxamide (PCA), pyridine (Py) or bipyri-
dine (Bpy) with molecular formulas [Au(PCA)Cl2]Cl,
AuPCA, [Au(Py)Cl3], AuPy and [Au(Bpy)Cl2]Cl, AuBpy,
Figure 2. The structures of the complexes were characterized
using elemental analysis, mass, IR, Raman, 1HNMR spec-
trometry as well as thermogravimetry (TG) technique. The
ionized and total chloride contents of the complexes were
determined potentiometrically using silver ion electrode.
The color, yield, elemental analysis and mass spectrometry
data of the complexes are given in the Experimental section.
The fragmentation patterns in the mass spectra of the com-
plexes along with the thermal analysis as well as the elemen-
tal analysis data revealed the correctness of the suggested at lower frequencies in the Raman spectra were enhanced

4
R. M. RAMADAN ET AL.

INORGANIC AND NANO-METAL CHEMISTRY
5
Table 2. Infrared spectral bands of AuPy complex and their assignments based on DFT calculations.
Vibration number
Measured IR for AuPy (cm–1
)
DFT Calc. for AuPy
Assignment of AuPy vibrations
1
2
3
4
3104
3080
3050
3031
–
–
–
–
–
ꢀCH
ꢀCH
ꢀCH
ꢀCH
5
–
ꢀCH
6
7
8
9
1614vs
1577m
1483w
1455vs
1372m
1285w
1211w
1186mw
1074s
1067m
1049w
1049w
1019m
980v
946w
–
759 s
682s
660sh
–
474m
423vw
–
1650
1612
1516
1490
1407
1322
1264
1207
1107
1091
1066
1056
1031
1023
992
903
795
716
670
662
465
407
335
335
ꢀring, dCH
ꢀring, dCH
ꢀring, dCH
ꢀring, dCH
dCH in phase
ꢀring
ꢀring
dCH
dCH
dCH
dring
dCH
dring
cCH
cCH
cCH
cCH in phase
cCH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
dring
dring
cring
cring
ꢀas AuCl2trans, dAuNC
ꢀas AuClN, dClAuN,
–
ꢀ, stretch; d, in-plane bend, c, out of plane bend; r, rocking; s, torsion; s, symmetric; as, asymmetric.
1
due to complex formation, which may give these bands structure. Figure 3 illustrates the H NMR spectra the two
some analytical significance.
complexes AuPCA and AuBpy, while Table 4 gives all the
spectral data. All the spectra performed signals due to pro-
tons of the coordinated ligands.[8,26] From the IR and NMR
studies, it can be concluded that the present gold(III) com-
plexes formed only square planer binary derivatives. The 1H
NMR spectrum of AuPCA complex displayed signals due
the PCA ligand only, while the other two complexes, AuPy
and AuBpy showed that the gold ion coordinated solely to
either pyridine or bipyridine ligand (Figure 3; Table 4).
Interestingly, platinum(II) and platinum(IV) gave ternary
complexes with pyrazinecarboxamide and either pyridine or
bipyridine.[8,33] This could be due to the higher charge dens-
ity and lower ionic size of the gold ions relative to the
platinum(II) ones. Also, the prevalence of the formation of
the pyridine or bipyridine gold complexes over the expected
ternary complexes could be revealed from the different
charge values on the nitrogen atoms of the three ligands
(Hu€ckel molecular orbital calculation), Figure 1. In case of
Pt(IV) derivatives, the formation of the ternary complexes
was also facile due to octahedral configuration.[8,33]
Therefore, according to the spectroscopic, analytical and phys-
ical results, we suggest that the ligands coordinated to the gold
species to give square planar structures as illustrated in
Figure 2. The elucidated structure of AuBpy complex is analo-
gous to that found for 1,2-dichloro(o-phenanthroline)gold(III)
chloride.[34] Also, the AuPy complex is consistent to that
found by X-ray study for the complex.[35]
The measured IR wavenumbers of AuPy, Bpy and
AuBpy and the assignment of the frequencies using DFT
method are tabulated in Tables 2 and 3. Figure 3S gives the
measured and calculated IR spectra of AuBpy. As can be
noticed, the experimental and calculated stretching in-plane
(ip) and out of plane bending vibrations (oop) were existed
at higher wavenumbers up to around 400 cmꢀ1. The vibra-
tions around 1600 cmꢀ1 represented coupled ring stretch
vibrations. Below 400 cmꢀ1, the vibrations of the chelating
ring and AuCl2 stretching and bending modes were assigned
based on DFT calculation and by comparison with previous
experimental and calculation work.[30] The 5 cCH vibrations
expected for pyridine were found below 1000 cmꢀ1 till up to
700 cmꢀ1 with two intense characteristic bands at 759 and
682 cmꢀ1. For AuBpy complex with a Cs symmetry, its
vibrations were located at the same wavenumber zones as
for AuPy, which has a tetrahedral structure (Tables 2 and
3). In-plane vibrations were of A’ type whereas out of plane
vibrations were of A’’ symmetry. The vibrations of the com-
plexed part are different since their symmetries are different.
The characteristic modes of higher intensity occurred at 768,
1449 and 1600 cmꢀ1 for the AuBpy complex, whereas the
calculated were at 825, 1520 and 1758 cmꢀ1. These values
corresponded to in phase out of plane (oop) CH bend,
coupled ring stretch, CH bend, and ring stretch, respectively.
The modes of AuCl3, AuCl2 and for chelating rings were
found below 400 cmꢀ1. Below 400 cmꢀ1, stretching and
bending modes of AuCl2 were observed as expected by com-
parison with numerous previous experimental data.[31,32]
3.2. Thermal analysis
The 1H and 13C (H-decoupled) NMR spectra of the Thermogravimetric (TG) studies were carried out to exam-
reported gold complexes gave more insight on their ine the thermal stability of the gold complexes.[36] The TG

6
R. M. RAMADAN ET AL.
Table 3. Infrared spectral bands of AuBpy complex and their assignments based on DFT calculations.
DFT calc. for AuBpy
(Cs point group)
Vibration number
Measured IR of Bpy (cm–1
)
Measured IR of AuBpy (cm–1
)
Assignment of AuBpy vibrations
1
2
3
4
5
6
7
8
3200w
3138vw
3110w
3081 m
3056w
sh, w
sh, w
sh, w
1600s
1566w
–
1566s
1500s
1467m
1449s
–
3269
3269
3058
3054
3050
3048
3040
3037
1758
1632
1627
1603
1600
1530
1491
1476
1459
1364
1352
1341
1311
1304
1223
1216
1154
1131
1088
1075
1058
1055
1048
1046
1016
1013
1009
922
907
825
804
774
740
710
683
657
651
562
473
463
432
369
356
292
ꢀCH
ꢀCH
ꢀCH
ꢀCH
ꢀCH
ꢀCH
ꢀCH
ꢀCH
ꢀring A’’
ꢀring, dCH A’
ꢀring A’’
ꢀring A’’
ꢀring A’
ꢀring, dCH A’
ꢀring, dCH A’’
ꢀring A’
ꢀring A’
ꢀring A’
ꢀring A’’
ꢀring A’
dCH A’’
dCH A’
dCH A’
dCH A’’
dCH A’’
dCH A’
dCH A’’
dCH A’
dring A’
cCH A’’
cCH A’’
cring A’
cCH A’
cring A’’
3086 w
3053 w
9
1578s
1555 m
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
1490w
1454 vs
1415 m
1419m
–
1311s
1300sh
1249s
1198w
1179
1159w
1123w
1108m
1069m
1045w
1027m
–
1000w
–
–
–
–
892vw
–
795vw
768vs
–
706m
675w
659m
vw band
vw band
539vw
486w
439m
409w
–
1249 m
1210 w
1167 wbr
1137 w
1086 w
1062 m
1038 m
–
991 m
cCH A’’
cCH A’
cCH A’’
cring A’
891 w
758 vs
cCH in phase A’’
dring A’
cCH, cring A’
cring A’’
dring A’
dring A’’
dring, ꢀasAuN2 A’’
ctwist inter-ring A’’
d inter-ring A’’
cwag inter-ring A’’
cring A’
651 m
617m
428w
d inter-ring A’
s inter-ring A’’
ꢀsAuCl2, A’
d chelated ring, ꢀsAuCl2 A’
–
–
–
255
ꢀ, stretch; d, in-plane bend, c, out of plane bend; r, rocking; s, torsion; s, symmetric; as, asymmetric.
data of the complexes are tabulated in Table 5. The for- range 158–724 ꢁC. The first step corresponded to the loss
mulas of liberated fragments in the decomposition steps of Cl2 species with a weight loss of 18.53%. The other
were suggested depending on the percentage mass loss. In decomposition step was assigned to the elimination of a
addition, the formula of final residue was dependent on C5H5NCl moiety to leave a metallic gold residue. The TG
elemental analysis. The TG curve of AuPCA complex curve of AuBpy complex also illustrated two decꢁompos-
exhibited three (two overlapped and one resolved) decom- ition steps within the temperature range 111–648 C. The
position steps. The first two steps at 186–377 ꢁC, with a
first decomposition step corresponded to the loss of loss
weight loss of 26.25%, could be attributed to the liberation
of C2H4þ NCl2 moieties. The final step exhibited a weight
loss of 19.12% and assigned to elimination of HOCl and
N2 moieties to leave AuC3 species as a residue, % C found
of Cl2 species. The second step involved the loss of a
bipyridine and a Cl species to give metallic gold as
a residue.
According the thermogravimetric patterns of the investi-
(calc.)¼15.2 1). The TG plot of the AuPy complex showed gated complexes, the thermal stability increases in the order
two resolved decomposition steps within the temperature AuBpy <AuPy ˂ AuPCA.

INORGANIC AND NANO-METAL CHEMISTRY
7
3.3. Biological evaluation
have the capacity of inhibiting the metabolic growth of the
investigated bacteria and the fungi to different extents,
which may indicate broad-spectrum properties; especially for
the Bpy ligand. The activity of these compounds may arise
from the presence of NH, C¼N and C¼O groups. The mode
of action may involve formation of hydrogen bonding
between those functional groups and the active centers of the
cell constituents, leading to interference with the normal cell
process.[37,38] The gold complexes showed some activities
against both Escherichia coli and Staphylococcus aureus bac-
teria, but they were less than Tetracycline standard. On the
other hand, the complexes showed better antifungal activities
against the fungus Candida albicans with comparison to the
fungus Aspergillus flavus. Activity of the metal complexes
could be related to the lipophilic nature of the complexes,
which arose from the chelation pattern. It was also noted that
the toxicity of the metal complexes increases with increasing
the concentration. This elevation is probably due to faster dif-
fusion of the chelates through the cell membrane. The che-
lated derivatives may block the enzymatic activity of the cell
or it may catalyze the toxic reactions among cellular constitu-
ents.[37,38] It is worth to mention that the biological activity of
the ligands was better than those of complexes, i.e., complex-
ation did not improve the activity. However, in vivo studies
are required in this case to differentiate between the toxicity
and activity of the compounds.
3.3.1. Antibacterial and antifungal activities
The free ligands (PCA and Bpy) and the gold complexes
were screened against Escherchia coli as Gram-negative bac-
teria and Staphylococcus aureus as Gram-positive bacteria as
well as the two fungi Aspergillus flavus and Candida albicans
to assess their potential activity relative to the two standards:
Tetracycline antibacterial agent and Amphotericin B antifun-
gal agent, Table 6. The data showed that the free ligands
3.3.2. Cytotoxicity studies
To evaluate the potential usefulness of the PCA ligand and
the reported gold complexes as antitumor agents, three
human cell lines (two breast cancer cell lines, MCF7 and
T47D, and a liver carcinoma cell line, HepG2) were treated
by the compounds and compared with cis-platin activity as
a standard. The complexes showed reasonable activities
against the studied cell lines, which were better than the
PCA ligand. The IC50 values (concentration that produce
50% inhibition of cell growth) of PCA ligand and the com-
plexes as well as those of the cis-platin were determined and
given in Table 7. The IC50 values of the compounds
Figure 3. The 1H NMR spectrum of A, AuPCA complex; B, AuBpy complex.
Table 4. The H and 13C NMR data for the PCA ligand and the gold complexes.
1
Compound
PCA
1H NMR data (ppm)
13C NMR data (ppm)
9.28 (d, 1 Hz, Pz–CH), 8.95 (d, 8 Hz, Pz–CH), 8.81
(dd, 8, 1 Hz, Pz–CH), 8.42 (bs, NH), 8.02 (bs, NH).
9.33 (d, 1 Hz, Pz–CH), 9.13 (d, 8 Hz, Pz–CH), 8.65
(dd, 8, 1 Hz, Pz–CH), 8.23 (bs, NH), 7.83 (bs, NH).
9.29 (m, Py–CH), 8.95 (m, Py–CH), 8.65 (m, Py–CH),
8.13 (m, Py–CH).
161.79 (s, C¼O), 146.01 (s, Pz–C), 145.03 (s, Pz–C),
144.65 (s, Pz–C), 144.69 (s, Pz–C)
AuPCA
AuPy
162.15 (s, C¼O), 153.70 (s, Pz–C), 144.76 (s, Pz–C),
144.52 (s, Pz–C), 141.19 (s, Pz–C)
149.8 (s, Py–C), 137.8 (s, Py–C), 121.9 (s, Py–C)
AuBpy
8.88 (m, Py–CH), 8.65 (m, Py–CH), 8.40 (m, Py–CH),
7.87 (m, Py–CH).
157.4 (s, Bpy2 and 20-C), 150.0 (s, Bpy–C), 137.2 (s,
Bpy–C), 124.2 (s, Bpy–C), 120.8 (s, Bpy–C)
Table 5. Thermal analysis data for the gold complexes.
Molecular
formula
Molecular
weight
Decomposition
% Weight
loss
Eliminated
species
% Solid decomposition
temperature (oC)
residue
AuPCA
426.61
382.60
459.52
186–377
378–705
158–261
262–724
111–393
394–648
26.25
19.12
18.53
29.95
15.45
41.70
NCl2 þ C2H4
HOCl þ N2
Cl2
54.45
(AuC3)
51.49
(Au)
42.86
(Au)
AuPy
1
C H N þ = Cl
2
5
5
2
AuBpy
Cl2
1
C10H N þ = Cl
2
8
2
2

8
R. M. RAMADAN ET AL.
Table 6. In vitro antibacterial and antifungal activities of the gold complexes.
Inhibition zone (mg/mm)
Reagent
Escherichia coli
Staphylococcus aureus
Aspergillus flavus
Candida albicans
PCA
Bpy
AuPCA
AuPy
AuBpy
Tetracycline
Amphotericin B
0
14
8
7
8
4
13
6
8
8
14
35
4
6
7
–
14
20
28
14
13
13
–
30
–
27
–
20
of the DNA binding of the second molecule. The emission
spectra of DNA-bound EB in the absence and the presence
of different concentrations of the gold complexes are shown
in Figures 4–6. It is clearly seen that the addition of the
reported complexes to CT-DNA pretreated with EB caused
an appreciable reduction in the emission intensity. These
results indicated that the gold complexes bind to DNA at
the sites occupied by EB itself. Fluorescence quenching can
occur by different mechanisms, which are usually classified
as dynamic and static quenching. The former may result
from collision between the quencher and the fluorophore,
while the latter could be due to the formation of a complex
between the fluorophore and quencher.[46] The quenching
plots in Figures 4–6, illustrate that the quenching of EB
bound to CT-DNA by the gold complexes are in good
agreement with the linear Stern–Volmer equation. The Ksv
values are: AuBpy¼0.93 ꢂ 104, AuPy¼0.75 ꢂ 10ꢀ4 and
AuPCA¼2.25 ꢂ 104.
Table 7. The IC50 values, mg/ml (mmol/L), of the gold complexes and cis-
platin as a standard.
Complex
MCF7
T47D
HepG2
PCA
AuPCA
AuPy
AuBpy
cis-platin
13.45 (10.92)
12.20 (28.60)
16.60 (43.40)
15.50 (20.32)
5.71 (19.03)
–
15.07 (12.24)
22.00 (51.59)
23.50 (61.45)
17.90 (23.46)
3.67 (12.23)
16.30 (38.22)
16.30 (42.62)
9.23 (12.10)
–
qualitatively determine the strength of anticancer drug.
Accordingly, the obtained IC50 values (ranged from 9 to
23 mg/ml) are considered due to intermediate anticancer
reagents.[39,40] The increase of anticancer potency of the
gold complexes over the ligand may be due to the metal
atom, which is implicated by the chelation as suggested by
Tweedy’s chelation theory.[41] On chelation, the polarity of
the metal ion is reduced to some extent due to the overlap
of the ligand orbital and partial sharing of the positive
charge of the metal ion with donor parts. In addition, it
increases the delocalization of p electrons of the chelating
ring and enhances the lipophilicity of the complexes, which
enhances, in turn, the penetration of the complexes into
lipid membranes and blocks the metal binding sites in the
tumor. However, further in vivo studies on the activity of
3.3.4. Viscosity measurements
In order to further investigate the interaction mode between
the gold complexes and CT-DNA, viscosity measurements
were carried out to clarify the effect of interaction on the
the complexes are required to evaluate the potency of these length of CT-DNA (Figure 7). Although optical photophysi-
cal probes usually offer essential information about the
binding modes of complexes to DNA, they are lacking cer-
tain evidences to support an intercalative binding model.[47]
In the absence of crystallographic structure data, hydro-
dynamic methods, which are sensitive to the change of
DNA length, are regarded as the least ambiguous and most
critical tests of binding in solutions. Intercalating agents are
expected to be increased in the relative specific viscosity
(g/go)1/3 of CT-DNA. This is due to elongation of the dou-
ble helix to accommodate the compounds in-between the
base pairs. The plots of the relative viscosity (g/go)1/3 versus
R, R¼ [Complex]/[DNA], showed a significant increase in
the relative specific viscosity of DNA solution with increas-
ing the concentration of complexes. This indicates that com-
plexes bind to CT-DNA through an intercalation-binding
mode.[48] The classical intercalators like ethidium bromide
are known to increase the base pair separation resulting in
an increase in the relative viscosity of the CT-DNA. The
effect of the gold complexes is far less than that observed
for the EB intercalator, which indicates that the existence of
a weak intercalative interaction between the complexes and
CT-DNA. Therefore, it can be concluded that the gold com-
plexes exhibited high binding extent with CT-DNA. The
derivatives as antitumor reagents.
3.3.3. Fluorescence quenching studies
Fluorometric competitive binding experiments are widely
used to investigate the interaction between small molecules
and macromolecules such as protein and DNA.[42]
Information about the binding properties of these small
molecules to protein/DNA can be obtained, such as the
binding mechanism, binding mode, binding constant, bind-
ing sites, and intermolecular distances.[43] Fluorescence
quenching refers to any process that decreases the fluores-
cence intensity from a fluorophore induced by a variety of
molecular interactions including excited-state reactions,
molecular rearrangements, energy transfer, ground-state
complex formation and collisional quenching.[44]
Ethidium bromide (EB) is used to investigate the poten-
tial DNA binding mode of many compounds. EB emits
intense fluorescence at 608 nm in the presence of CT-DNA
due to its strong intercalation between the adjacent DNA
base pairs. The addition of a second molecule, which binds
to DNA more strongly than EB would quench the DNA-
induced EB emission.[45] The extent of quenching of the
fluorescence of EB bound to DNA would reflect the extent increased degree of viscosity, which may depend on its

INORGANIC AND NANO-METAL CHEMISTRY
9
Figure 4. (A) Fluorescence emission spectra of EB–DNA system in absence (dashed line) and presence (solid line) of AuPCA complex; arrow indicates the intensity
changes upon increasing concentration of complex. (B) Fluorescence variation profile of AuPCA complex versus molar concentration.
Figure 5. (A) Fluorescence emission spectra of EB–DNA system in absence (dashed line) and presence (solid line) of AuPy complex; arrow indicates the intensity
changes upon increasing concentration of complex. (B) Fluorescence variation profile of AuPy complex versus molar concentration.
affinity
to
DNA,
follows
the
order
of respectively. The structure of AuPCA is almost planar with
AuBpy >AuPy >AuPCA. Obviously, this is consistent with a dihedral angle C1–N7–Au16–Cl14 equal to 179.9ꢁ. Also, the
the foregoing conclusion suggested from the fluorescence two bond angles N7–Au16–O9 and Cl14–Au16–Cl15 were
found to be 78.0ꢁ and 89.1ꢁ indicating a distorted square
quenching data. The results of DNA binding studies indi-
cated that the suggested mechanism for interaction between
the gold complexes and DNA was via an intercalative mode.
planar coordination around the metal. In addition, the bond
angle O9–Au16–Cl14 approaches the linearity (175.2ꢁ). On
the other hand, the bond lengths Cl14–Au16, N7–Au16 and
O9–Au16 were found to be in the normal range (2.37, 2.13
and 2.12 Å).[35,49] In case of the AuPy complex, the opti-
mized structure illustrated that gold existed in a regular
square planar as indicated from the bond angles around Au
(Cl8–Au10–Cl12, 89.8ꢁ; Cl9–Au10–Cl12, 89.9ꢁ; N7–Au10–Cl12,
180.0ꢁ and Cl8–Au10–Cl9, 179.7ꢁ). The bond lengths around
the gold ion were found to be comparable to those observed
for AuPCA complex. For example, Au10–Cl12 and N7–Au10
3.4. The stereochemistry and chemical
reactivity prediction
The stereochemistry of the reported gold complexes was
investigated by the hybrid density functional theory (DFT)
method. According to the analytical and spectroscopic inves-
tigations, the gold complexes have the molecular formulas
[Au(PCA)Cl2]þ,
[Au(Py)Cl3]
and
[Au(Bpy)Cl2]þ.
Optimized structures of these complexes (Figure 8) showed were found to be 2.38 and 2.10 Å, respectively and also with
that they have square planar arrangements with total mini- previously DFT and X-ray studies especially for Au–N bond,
mized energy
¼
21.74, 10.11, and 22.98 kcal/mol, bond angles Cl–Au–Cl and N–Au–Cl, where the four angles

10
R. M. RAMADAN ET AL.
Figure 6. (A) Fluorescence emission spectra of EB–DNA system in absence (dashed line) and presence (solid line) of AuBpy complex; arrow indicates the intensity
changes upon increasing concentration of complex. (B) Fluorescence variation profile of AuBpy complex versus molar concentration.
given in Table 8.[41,42] The frontier molecular orbital ener-
gies were estimated using DFT method (B3LYP) and illus-
trated in Figure 9 The HOMO orbital energy represents the
electron donating ability, while the LUMO orbital energy
characterizes the electron withdrawing ability. The energy
gap between HOMO and LUMO shows the molecular
chemical stability; it is a critical parameter for determining
molecular electrical transport properties. Smaller energy gap
reflects the easiness of the charge transfer (CT), and the
polarization, which occurs within the molecule.[43,50,51]
Therefore, the order of increasing reactivity of the reported
complexes is: AuBpy > AuPCA > AuPy. Interestingly, the
calculations revealed that the gold complexes have higher
reactivity relative to the corresponding platinum deriva-
tives.[33] In addition, the electronegativity parameter is a
reflection for the electrostatic potential, where the electron
partially transferred from one of lower electronegativity
Figure 7. Effect of increasing concentrations of complexes on the relative vis-
cosity of CT-DNA.
to another of higher electronegativity.[52] The results
showed that the order of decreasing
X
is:
Cl–Au–Cl are 90ꢁ giving
a symmetric square planar
AuPCA > AuBpy > AuPy. On the other hand, the results
of small chemical hardness values for the reported deriva-
tives reflect the ability of charge transfer within the mol-
ecule. The order of increasing the charge transfer within
the molecule is: AuPy < AuPCA < AuBpy. Thus, the elec-
tronegativity and chemical hardness descriptors indicated
that the gold complexes have better charge transfer ability
than those of the platinum ones.[33] On the other hand,
the binding energy was calculated using the following
structure.[35]
The energetically minimized structure of AuBpy complex
displayed large deviation from the square planar arrange-
ments expected for gold complexes, Figure 8. The bond
angles around the gold ion showed different values than
those detected for the other two gold complexes. For
example, the bond angles N22–Au3–N23, Cl1–Au3–Cl2,
Cl1–Au3–N22 and Cl2–Au3–N23 have the values 78.1ꢁ, 93.7ꢁ,
123.28ꢁ and 120.9ꢁ, respectively. Interestingly, the bond
lengths also showed different values than the other two
complexes. The Au–Cl bond was elongated while the Au–N
bond was shortened (Cl1–Au3, 2.50 Å; Cl2–Au3, 2.52 Å;
Au3–N22, 2.09 Å and Au3–N23, 2.10 Å).[35,49]
equation[53]
aEAu þ bEC þ cEH þ dEN þ eEo þ fEC1 ꢀ Ecomplex
ꢃ
:
½
ꢃ
½
BE ¼
a þ b þ c þ d þ e þ f
where a, b, c, d, e and f are the number of Au, C, H, N,
O and Cl atoms and EAu, EC, EH, EN, EO and ECl are the
ground state total energies of Au, C, H, N, O and Cl
atoms, respectively. Ecomplex is the energy of optimized
The global chemical reactivity parameters including
HOMO, LUMO, energy gap (DE), electronegativity (X),
chemical potential (V), electron affinity (A), ionization
potential (I), chemical hardness (g), chemical softness (S) complex. As can be seen from Table 8 the order of
and electrophilicity (x) of the reported compounds are increasing the binding energy of the complexes follows

INORGANIC AND NANO-METAL CHEMISTRY
11
Figure 8. The optimized structures of gold complexes.
Figure 9. The frontier molecular orbitals of the gold complexes.
the order: AuBpy < AuPy < AuPCA. The calculated value complex (AuPCA). This might indicate that the stability
of binding energy of PCA was found to be 11.99 eV, of the formed complex is comparable with that of
which is slightly higher than the corresponding the free ligand.

12
R. M. RAMADAN ET AL.
Table 8. The global chemical reactivity descriptors for the gold complexes.
Methylpyridine)] Platinum(II) (AMD473). Anticancer Drug Des.
1998, 13, 1–18.
Parameter
AuPCA
AuPy
AuBpy
8. Ramadan, R. M.; Al-Raddady, N. S. Spectroscopic Studies,
Biological Activity, and Cytotoxicity of Some Binary and Ternary
Palladium and Platinum Complexes of Certain Heterocyclic
Ligands. Synth. React. Inorg. Met-Org. Nano-Met. Chem. 2015,
45, 1183–1190. DOI: 10.1080/15533174.2013.862663.
DM (Debye)
HOMO (eV)
LUMO (eV)
DE (eV)
X (eV)
V (eV)
A (eV)
I (eV)
g (eV)
S (eV)
x (eV)
13.06
–11.70
–9.07
2.62
10.38
–10.38
9.07
11.70
1.31
0.66
11.10
–7.55
–4.80
2.75
6.17
–6.17
4.80
7.55
1.37
0.69
13.85
14.61
–10.48
–9.55
0.93
10.02
–10.02
9.55
10.48
0.47
0.23
9. Hay, M. ZD-0473 Johnson Matthey Plc. Curr. Opin. Oncol.
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ica.2009.02.046.
41.09
11.89
107.81
11.40
BE (eV)
11.63
11. Rubbiani, R.; Zehnder, T. N.; Mari, C.; Blacque, O.; Venkatesan,
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4. Conclusion
Three gold(III) complexes with heterocyclic nitrogen donor
ligands were found to have interesting spectroscopic and
structural features. The vibrational analysis of the ligands
and their complexes in the ground state (using DFT and
MP2) gave more insight on the appropriate assignments of
the important functional groups of these types of complexes
such as C¼O, C¼N, NH and Au–Cl. The reactivity and
binding energies of the complexes, calculated from the fron-
tier orbitals, were stemmed from the quantum global param-
12. Wang, S.; Shao, W.; Li, H.; Liu, Wang, C. K.; Zhang, J. Synthesis,
Characterization and Cytotoxicity of the Gold(III) Complexes of
4,5-Dihydropyrazole-1-Carbothioamide Derivatives. Eur. J. Med.
Chem. 2011, 46, 1914–1918. DOI: 10.1016/j.ejmech.2011.02.031.
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extent with DNA. The results indicated that the suggested
mechanism for interaction between the gold complexes and
15. Al-Jaroudi, S. S.; Fettouhi, M.; Wazeer, I. M.; Isab, A. A.;
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Altuwaijri, S. Synthesis, Characterization and Cytotoxicity of
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Supplementary Materials
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K. D.; Al-Deyab, S. S.; Dinda, J. Silver(I), Gold(I) and Gold(III)-
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