Synthesis, spectroscopic, thermal, antimicrobial and electrochemical characterization of some novel Ru(iii), Pt(iv) and Ir(iii) complexes of pipemidic acid

Article abstract of DOI:10.1039/c8ra03879a

Three new solid complexes of pipemidic acid (Pip-H) with Ru³⁺, Pt⁴⁺ and Ir³⁺ were synthesized and characterized. Pipemidic acid acts as a uni-dentate chelator through the nitrogen atom of the -NH piperazyl ring. The spectroscopic data revealed that the general formulas of Pip-H complexes are [M(L)_n(Cl)_x]·yH₂O ((1) M = Ru³⁺, L: Pip-H, n = 3, x = 3, y = 6; (2) M = Pt⁴⁺, L: Pip-NH₄, n = 2, x = 4, y = 0 and (3) M = Ir³⁺, L: Pip-H, n = 3, x = 3, y = 6). The number of water molecules with their locations inside or outside the coordination sphere were assigned via thermal analyses (TG, DTG). The DTG curves refer to 2-3 thermal decomposition steps where the first decomposition step at a lower temperature corresponds to the loss of uncoordinated water molecules followed by the decomposition of Pip-H molecules at higher temperatures. Thermodynamic parameters (E?, ΔS?, ΔH? and ΔG?) were calculated from the TG curves using Coats-Redfern and Horowitz-Metzeger non-isothermal models. X-ray powder diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) techniques were carefully used to assign properly the particle sizes of the prepared Pip-H complexes. The biological enhancement of Pip-H complexes rather than free chelate were assessed in vitro against four kinds of bacteria G(+) (Staphylococcus epidermidis and Staphylococcus aureus) and G(-) (Klebsiella and Escherichia coli) as well as against the human breast cancer (MCF-7) tumor cell line.

Full text of DOI:10.1039/c8ra03879a

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PAPER
Synthesis, spectroscopic, thermal, antimicrobial
and electrochemical characterization of some
novel Ru(III), Pt(IV) and Ir(III) complexes of pipemidic
acid
Cite this: RSC Adv., 2018, 8, 22515
bc
Khuloud A. Alibrahim,a Foziah A. Al-Saif,a M. T. Alghamdi,b M. S. El-Shahawi,
ef
Y. M. Moustafad and Moamen S. Refat
*
Three new solid complexes of pipemidic acid (Pip–H) with Ru3+, Pt4+ and Ir3+ were synthesized and
characterized. Pipemidic acid acts as a uni-dentate chelator through the nitrogen atom of the –NH
piperazyl ring. The spectroscopic data revealed that the general formulas of Pip–H complexes are
[M(L)n(Cl)x]$yH2O ((1) M ¼ Ru3+, L: Pip–H, n ¼ 3, x ¼ 3, y ¼ 6; (2) M ¼ Pt4+, L: Pip–NH4, n ¼ 2, x ¼ 4, y ¼
0 and (3) M ¼ Ir3+, L: Pip–H, n ¼ 3, x ¼ 3, y ¼ 6). The number of water molecules with their locations
inside or outside the coordination sphere were assigned via thermal analyses (TG, DTG). The DTG curves
refer to 2–3 thermal decomposition steps where the first decomposition step at a lower temperature
corresponds to the loss of uncoordinated water molecules followed by the decomposition of Pip–H
molecules at higher temperatures. Thermodynamic parameters (E*, DS*, DH* and DG*) were calculated
from the TG curves using Coats–Redfern and Horowitz–Metzeger non-isothermal models. X-ray
powder diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy
(TEM) techniques were carefully used to assign properly the particle sizes of the prepared Pip–H
complexes. The biological enhancement of Pip–H complexes rather than free chelate were assessed in
vitro against four kinds of bacteria G(+) (Staphylococcus epidermidis and Staphylococcus aureus) and
G(ꢀ) (Klebsiella and Escherichia coli) as well as against the human breast cancer (MCF-7) tumor cell line.
Received 7th May 2018
Accepted 9th June 2018
DOI: 10.1039/c8ra03879a
rsc.li/rsc-advances
isoelectric point (pH ¼ 6.8) and alkaline for pH values higher
1 Introduction
than pKa ¼ 8.2.3 The Pip–H antibiotic drug is important as an
2
antibacterial agent against Pseudomonas aeruginosa.4 It
Pipemidic acid (Pip–H; Fig. 1) has the IUPAC formula 8-ethyl-
5,8-dihydro-5-oxo-2-(1-piperazinyl)-pyrido[2,3-d]pyrimidine-6-
carboxylic acid.1 Pip–H has medical efficacy in the treatment
of urinary tract infections because of its antibacterial agency
against Gram-negative and some Gram-positive bacteria.2
Concerning the Pip–H moiety, the –COOH group existing at
the C6-position gives this drug an acidic nature, while the
piperazine ring in the C2-position includes an –NH group that
is basic in character. In aqueous media solution, 2-piperazinyl
quinolone exists in three different species: acidic for pH
robustly damages DNA in the absence of an exogenous
metabolizing system and it can act as a multi-dentate chelator,
binding with metal ions.5
Quinolone-metal chelates have the potential ability to
interact with various metal ions and record biological activity
towards different microorganisms.6,7 Quinolones can be act as
uni-dentate, bi-dentate and bridging chelates. In general, qui-
nolones are coordinated in bi-dentate fashion, and this takes
place through one oxygen atom upon deprotonation of the
–COOH group and carbonyl oxygen atom (Fig. 2a). Rarely,
values below pKa ¼ 5.4, neutral for pH values close to the
1
aCollege of Science, Princess Nourah bint Abdulrahman University, Department of
Chemistry, Kingdom of Saudi Arabia
bDepartment of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, P. O.
Box 80203, Saudi Arabia
cDepartment of Chemistry, Faculty of Science, Damiatta University, Damiatta, Egypt
dFaculty of Applied Science, Umm Al-Qura University, P. O. Box 16722, Makkah 21955,
Saudi Arabia
eDepartment of Chemistry, Faculty of Science, Taif University, Al-Hawiah, P. O. Box
888 Zip Code 21974, Taif, Saudi Arabia. E-mail: msrefat@yahoo.com
fDepartment of Chemistry, Faculty of Science, Port Said University, Port Said, Egypt
Fig. 1 Structure and numbering of the pipemidic acid (Pip–H) anti-
biotic drug.
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Fig. 2 (a–d) Chelation modes of quinolone drugs towards metal ions.
quinolones can act as bi-dentate chelators via two carboxyl synthesis and spectroscopic characterizations of
a new
oxygen atoms (Fig. 2b) or through both piperazinic nitrogen complexation mode between ruthenium(III), platinum(IV) and
atoms (Fig. 2c). Quinolones can also form complexes via uni- iridium(III) metal ions with the Pip–H drug as a 1st generation of
dentate ligand binding to the metal ion through the terminal quinolone antibacterial drugs. The new complexes were synthe-
piperazinyl nitrogen (Fig. 2d).8
sized in CH3OH solvent with ratios of 1 : 3 and 1 : 2. These
The medicinal usage of platinum(II,IV) compounds was limited complexes have been interpreted using micro-analytical, FT-IR,
1
by the development of tumor resistance to the drugs9 and by their conductance, magnetic, UV-vis, H-NMR and TG-DTG analyses.
side effects.10 These limitations caused further research to be The morphological surface and particle size of these three new
oriented toward nding new, more active, less toxic, anti-tumor complexes were investigated using XRD, SEM and TEM.
agents based on other chelates. Ruthenium(III) complexes had
shown ligand exchange kinetics similar to those of the platinum
2 Experimental
2.1 Chemical materials
anti-tumor agents currently used in the clinic and exhibited
a reduced toxicity.11 The interactions of different metal ions with
pipemidic acid as an antimicrobial agent have been discussed12
Pipemidic acid (Pip–H) was purchased from the Aldrich-Sigma
and can be referenced by chemical formulas with different molar
ratios between Pip–H and some metal ions as follows (Table 1):
Metal ions are considered essential to the human body, being
an integral part of organic moieties in performing actions of
physiological interest and having vital properties in the body.13
The synthesis and assignment of new metal complexes with
quinolones are of wide importance for a better understanding of
drug-metal interactions.14 Complexes of quinolone drugs and
metal ions are synthesized with different chemical structures and
different types of chelation,15,16 so, this article refers to the
Chemical Company. RuCl3, H2PtCl6$6H2O and IrCl3$xH2O
and solvents like CH3OH and dimethylsulfoxide (DMSO) were
purchased from the Fluka Chemical Company and used without
further purication. Tetrabutylammonium perchlorate (TBAP)
(Sigma-Aldrich) was used as supporting electrolyte at various
scan rates (50–2000 mV sꢀ1).
2.2 Synthesis of pipemidic acid complexes
A hot methanolic solution (3 mmol, 20 mL) of pipemidic acid
(91 mg) was added to an aqueous solution (20 mL) of RuCl3
Table 1 Different Pip–H complexes with different metal ions, chemical formulas and molar ratios
Molar ratio
Formula
Reference
Pip–H complexes
1 : 1
1 : 2
[Fe(PPA)(HO)2(H2O)]
17–19
[VO(PPA)2(H2O)], [Mn(PPA)2(H2O)2], [Co(PPA)2(H2O)2],
[Ni(PPA)2(H2O)2], [Zn(PPA)2(H2O)2], [MoO2(PPA)2],
[Cd(PPA)2(H2O)2], [UO2(PPA)2], [Cu(PPA)2(H2O)]
[Fe(PPA)3]
1 : 3
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(1 mmol, 20.8 mg) and IrCl3$xH2O (1 mmol, 29.9 mg). The Jeol Jem-1200 EX II scanning electron microscope (SEM) at an
reaction mixtures were reuxed for 1–2 h at ꢁ70–80 ꢂC. The acceleration voltage of 25 kV was used for recording the SEM
solutions were ltered off and le to slowly evaporate. Aer images of the complexes. An X Pert Philips X-ray diffractometer
a day a black-dark green microcrystalline product was depos- was used for recording X-ray diffraction (XRD) patterns of the
ited, collected by ltration, washed with methanol and dried samples using CuKa1 radiation, with
a graphite mono-
under vacuum. The same procedure was repeated for the plat- chromator at 0.02ꢂ minꢀ1 scanning rate. Transmission electron
inum(IV) complex with a molar ratio 1 : 2 of H2PtCl6$6H2O microscopy (TEM) images were performed on a JEOL 100 s
(1 mmol, 51.8 mg) and Pip–H (2 mmol, 60.7 mg). However, then microscope. The mass susceptibility (Xg) of the complexes was
an aliquot of aqueous ammonia was added to Pip–H/H2PtCl6- measured at room temperature using a Gouy magnetic balance.
$6H2O and an ammonia-based complex was consequently The effective magnetic moment (meff) value was measured as
formed.
[Ru(Pip–H)3(Cl)3]$6H2O complex (1). Yield: 96.15 mg, 86%.
Anal calc. for complex (1) (C42H63Cl3N15O15Ru) (MW
reported earlier.17
¼
1225.47 g molꢀ1): calcd: C, 41.16; H, 5.18; N, 17.14; Ru, 8.25.
Found: C, 41.04; H, 5.09; N, 17.12; Ru, 8.19%. The complex is
black in color, soluble in (DMSO and DMF) and is a non-
electrolyte (0.022 mS).
2.4 Molecular modeling studies
The calculations of quantum chemical and molecular modeling
studies for the Pip–H drug chelate are useful to support the
suggested structures.18 The geometrical optimization and
conformational analysis were performed using semi-empirical
PM3 level19 as implemented in the soware of the HyperChem
7.5 program20 (Fig. 3 and Table 2). A number of quantum
chemical parameters have been estimated:18,19 the highest
occupied molecular orbital energy (EHOMO), the lowest unoc-
cupied molecular orbital energy (ELUMO), the difference between
the HOMO and LUMO energy levels (DE), Mulliken electroneg-
ativity (c), chemical potential (Pi), global hardness (h), global
soness (S), global electrophilicity (u), absolute soness (s) and
electronic charge (DNmax). The high value of the energy gap (DE)
led to hard molecules as well as low reactivity, but, the low
energy gap data led to so molecules, with more reactivity and
[Pt(Pip–NH4)2(Cl)4] complex (2). Yield: 90 mg, 80%. Anal
calc. for complex (2) (C28H40Cl4N12O6Pt) (MW ¼ 977.58 g
molꢀ1): calcd: C, 34.40; H, 4.12; N, 17.19; Pt, 19.96. Found: C,
34.22; H, 4.06; N, 17.06; Pt, 19.90%. The complex is dark green,
soluble in (DMSO and DMF) and is a non-electrolyte (0.042 mS).
[Ir(Pip–H)3(Cl)3]$6H2O complex (3). Yield: 100.35 mg, 83%.
Anal calc. for complex (3) (C42H63Cl3IrN15O15) (MW ¼ 1316.62 g
molꢀ1): calcd: C, 38.31; H, 4.82; N, 15.96; Ir, 14.60. Found: C,
38.29; H, 4.57; N, 15.92; Ir, 14.55%. The complex is dark green in
color, soluble in (DMSO and DMF) and is a non-electrolyte
(0.011 mS).
2.3 Instrumentation and analytical measurements
The micro-analytical analyses of % C, % H and % N were made
using a PerkinElmer CHN 2400 instrument (USA). Metal
contents (%) were determined by conventional gravimetric
analysis methods as the stable metal oxides MO2 formed. A
Jenway 4010 conductivity meter was used for recording the
molar conductivities of the complexes (1.0 ꢃ 10ꢀ3 mol cmꢀ3) in
DMSO. A UV2-Unicam UV/vis spectrophotometer tted with
a quartz cell of 1.0 cm path length was used for recording the
electronic spectra of the prepared metal complexes. Infrared
spectra with KBr discs were recorded on a Bruker FT-IR Spec-
trophotometer (4000–400 cmꢀ1). Cyclic voltammetric
measurements were carried out using an Autolab potentiostat
PGSTAT 302 (Eco Chemie, Utrecht, The Netherlands) driven by
General Purpose Electrochemical Systems data processing
soware (GPES, soware version 4.9, Eco Chemie). A three-
compartment electrochemical cell was used with Pt wires as
the working and counter electrodes and Ag/AgCl as the refer-
ence electrode. The electrochemical experiments were per-
formed in DMS–TBAP (tetrabutylammonium perchlorate). A
ꢂ
Shimadzu thermogravimetric analyzer under N2 at 800 C was
used for recording thermal measurements (TG/DTG-50H)
using a single loose top-loading platinum sample pan under
nitrogen aꢀtm1 osphere at 30 mL minꢀ1 ow rate and
a 10 ꢂC min heating rate in the temperature range 25–800 ꢂC.
1H-NMR spectra were recorded in DMSO solution on a Bruker
600 MHz spectrometer using TMS as the internal standard. A Fig. 3 HOMO and LUMO structure of Pip–H free drug.
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Table 2 The quantum chemical parameters of Pip–H drug chelate
of 0.5% (w/v) crystal violet and 50% methanol made up to
volume with ddH2O and ltered through a Whatman no. 1 lter
paper.
Parameters
Pip–H
The cells were propagated in Dulbecco's Modied Eagle's
Medium (DMEM) supplemented with 10% heat-inactivated
fetal bovine serum, 1% L-glutamine, HEPES buffer and 50 mg
mlꢀ1 gentamycin. All cells were maintained at 37 ꢂC in
a humidied atmosphere with 5% CO2 and were subcultured
twice a week. Cytotoxicity evaluation was undertaken using
viability assay: for the cytotoxicity assay, the cells were seeded in
a 96-well plate at a cell concentration of 1 ꢃ 104 cells per well in
100 mL of growth medium. Fresh medium containing different
concentrations of the test sample was added aer 24 h of
seeding. Serial two-fold dilutions of the tested chemical
compound were added to conuent cell monolayers, dispensed
into 96-well, at-bottomed microtiter plates (Falcon, NJ, USA)
using a multichannel pipette. The microtiter plates were incu-
bated at 37 ꢂC in a humidied incubator with 5% CO2 for
Total energy (a.u)
Binding energy (a.u)
Heat formation (a.u)
Electronic energy (a.u)
Dipole moment (debye)
EHOMO (eV)
ELUMO (eV)
DE (eV)
c (eV)
h (eV)
s (eV)
164.3
282.4
287.4
ꢀ948.1
568.30
ꢀ3.279
1.0078
4.2876
1.1359
2.1438
0.4665
ꢀ1.136
0.2332
0.3009
0.5299
Pi (eV)
S (eV)
u (eV)
DNmax (eV)
highly exible transfer of electrons from the donor (ligand) to a period of 48 h. Three wells were used for each concentration of
the acceptors (metal ions). Lower values of ELUMO gave high the test sample. Control cells were incubated without test
acceptability for electrons,19 and high values of EHOMO allowed sample and with or without DMSO. The small percentage of
electrons to be easily liberated. High values of EHOMO conrmed DMSO present in the wells (maximum 0.1%) was found not to
that the Pip–H ligand has powerful donation behavior. The affect the experiment. Aer incubation of the cells at 37 ꢂC,
difference between the energy gaps for the ligands reects the various concentrations of sample were added, the incubation
presence of a complexation status. The global electrophilicity was continued for 24 h, and the yield of viable cells was deter-
(u) of Pip–H increases to that attributed to the highest capacity mined by a colorimetric method. In brief, aer the end of the
of accepted electrons. The calculation of both global hardness incubation period, media were aspirated and the crystal violet
(h) and absolute soness (s) parameters is useful for recog- solution (1%) was added to each well for at least 30 minutes.
nizing their molecular stability and reactivity. The negative data The stain was removed and the plates were rinsed using tap
for both ELUMO and EHOMO were assigned to the stability of the water until all the excess stain had been removed. Glacial acetic
synthetic complexes.
acid (30%) was then added to all the wells and mixed thor-
oughly, and then the absorbance of the plates was measured
aer gentle shaking on a microplate reader (TECAN, Inc.), using
a test wavelength of 490 nm. All the results were corrected for
2.5 Biological experiments
In accordance with Gupta et al.,21 the hole well method was background absorbance detected in wells without added stain.
applied. The investigated isolates of the bacteria were seeded in Treated samples were compared with the cell control in the
tubes with a nutrient broth (NB). The seeded NB (1 cm3) was absence of the tested compounds. All experiments were carried
homogenized in the tubes with 9 cm3 of melted (45 ꢂC) nutrient out in triplicate. The cell cytotoxic effect of each tested
agar (NA). The homogeneous suspensions were poured into compound was calculated. The optical density was measured
Petri dishes. Holes (diameter 4 mm) were made in the cooled with a microplate reader (SunRise, TECAN, Inc, USA) to deter-
medium. Aer cooling in these holes, 2 ꢃ 10ꢀ3 dm3 of the mine the number of viable cells and the percentage viability was
investigated compounds were applied using a micropipette. calculated as [(ODt/ODc)] ꢃ 100% where ODt is the mean
Aer incubation for 24 h in a thermostat at 25–27 ꢂC, the optical density of wells treated with the tested sample and ODc
inhibition (sterile) zone diameters (including the disc) were is the mean optical density of untreated cells. The relation
measured and expressed in mm. An inhibition zone diameter between surviving cells and drug concentration is plotted to get
over 7 mm indicates that the tested compound is active against the survival curve of each tumor cell line aer treatment with
the bacteria under investigation. The antibacterial activities of the specied compound. The 50% inhibitory concentration
the investigated complexes were tested against bacteria G(+) (IC50), the concentration required to cause toxic effects in 50%
(Staphylococcus epidermidis and Staphylococcus aureus) and G(ꢀ) of intact cells, was estimated from graphic plots of the dose
(Klebsiella and Escherichia coli).
response curve for each concentration using Graphpad Prism
Mammalian cell lines: MCF-7 cells (human breast cancer cell soware (San Diego, CA. USA).22,23
line) were obtained from VACSERA Tissue Culture Unit.
Chemicals used: dimethyl sulfoxide (DMSO), crystal violet and
trypan blue dye were purchased from Sigma (St. Louis, Mo.,
USA). Fetal bovine serum, DMEM, RPMI-1640, HEPES buffer
3 Results and discussion
3.1 Micro-analytical and conductance measurements
solution, L-glutamine, gentamycin and 0.25% trypsin–EDTA This work aimed to synthesise, and make chemical and elec-
were purchased from Lonza. Crystal violet stain (1%): composed trochemical characterizations of Ru(III), Pt(IV) and Ir(III)
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Fig. 4 Proposed chemical structures of the prepared Ru(III), Pt(IV) and Ir(III) Pip–H complexes 1–3.
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complexes with pipemidic acid as a rst generation of quino- wavenumber (ꢁ2930 cmꢀ1), the characteristic band at 1613–
lone drugs. The main target of this study was to identify the 1624 cmꢀ1 due to n(C]O)COOH has still not shied and the
chelation mode under the inuence of mixed solvent CH3OH/ stretching vibration band of n(C]O)pyridone has shied to
H2O (50/10 v/v). The percentages of essential elements (C, H, a higher wavenumber 1723–1731 cmꢀ1 compared with free Pip–H
and N) are in agreement with the general formulas of three new (1640 cmꢀ1). These assignments mean that the Pip–H drug acts
Pip–H complexes as [M(L)n(Cl)x]$yH2O ((1) M ¼ Ru3+, L: Pip–H, n as a uni-dentate chelator through the nitrogen atom of the
¼ 3, x ¼ 3, y ¼ 6; (2) M ¼ Pt4+, L: Pip–NH4, n ¼ 2, x ¼ 4, y ¼ 0 and piperazyl ring. The new absorption bands present within the
(3) M ¼ Ir3+, L: Pip–H, n ¼ 3, x ¼ 3, y ¼ 6) (Fig. 4). The Pip–H range of 2720–2472 cmꢀ1 are assigned to the stretching vibra-
complexes are stable in air and have high melting points above tions of crystallization water molecules under the effects of
ꢂ
250 C. The conductance data of complexes 1–3 is within the hydrogen bonds. Since the n(O–H)COOH vibration changes little, it
range for non-electrolytic nature (0.022–0.110 mS) with a low can be inferred that there is no coordination between the metal
limit comparable with electrolyte materials as a ref. 24. From ions and the oxygen atoms. The O–H stretch of a carboxylic acid
the conductance values it is deduced that the chlorine atoms are is also broadened by hydrogen bonding and it is associated with
exhibited inside the chelation sphere.
two characteristic infrared stretching absorptions which change
markedly with hydrogen bonding. The assignments of the other
stretching vibration motions n(M–N) in Ru(III), Pt(IV) and Ir(III)
Pip–H complexes 1–3 are observed at 500–400 cmꢀ1
.
26
3.2 Infrared spectra
The FT-IR spectra of Ru(III), Pt(IV) and Ir(III) Pip–H complexes 1–3
were compared with free Pip–H in order to discuss the coordi-
nation modes in three different Ru3+, Pt4+ and Ir3+ metal ions
3.3 Magnetic measurements and electronic spectra
(Table 3). The FT-IR spectrum of free Pip–H drug does not have The electronic UV-vis. spectra of Pip–H free drugs and their
a characteristic stretching vibration band n(C]O)COOH at wave- Ru3+, Pt4+ and Ir3+ complexes 1–3 at a concentration of 10ꢀ3
M
number ꢁ1700 cmꢀ1, because the carboxylic group is deproto- in DMF solvent in the 800–200 nm range were scanned. These
nated and present in the zwitterionic state.25,26 The other spectra of three new Pip–H complexes have some distinguish-
distinguishable bands, which exist at 2971 and 1640 cmꢀ1, can be able bands within two regions at 280–350 nm and 350–390 nm.
assigned to the stretching vibrations of n(N–H)piperazyl, and n(C] The rst range may be assigned to the p / p* electronic
O)pyridine,
25 respectively. An N–H bond is less polar than an O–H transition for the aromatic hydrocarbon rings and the second
bond because nitrogen is less electronegative than oxygen. From range includes some electronic absorption bands which may be
this, the N–H stretch is less intense, and the peak narrower attributed to the n / p* transition for the ketonic, –NH imine
because the hydrogen bonding is not as strong. Aer chelation and carboxylic groups, respectively.27 In a solid sample, the
towards Ru3+, Pt4+ and Ir3+ metal ions (complexes 1–3), the n(N– electronic spectral values of the ruthenium(III) Pip–H complex
2
H)piperazyl band has disappeared or shied to
a
lower are listed in Table 4. The ground state of Ru(III) is T2g and the
Table 3 FT-IR assignments of Ru3+, Pt4+ and Ir3+–Pip–H complexes 1–3
Assignments (cmꢀ1
)
Compounds
n(O–H)COOH
n(C]O)COOH
n(C]O)pyridone
d(C–H)aromatic
n(N–H)piperazyl
Pip–H
3459
3430
3424
3426
1617
1617
1613
1624
1640
1728
1731
1723
890
912
906
918
2971
2931
2939
—
Complex 1
Complex 2
Complex 3
Table 4 Electronic spectral bands (cmꢀ1) and ligand field parameters of the Pip–H complexes
Complex
lmax (cmꢀ1
)
Assignments
n2/n1
10Dq (cmꢀ1
25 661
)
B (cmꢀ1
)
C (cmꢀ1
)
b
1
13 568
19 048
22 124
30 675
28 249
26 738
25 707
30 675
34 246
2T2g / 4T1g (n1)
2T2g / 4T2g (n2)
2T2g / 2A2g, 2T1g (n3)
1A1g / 3T1g
1.40
685
2167
1.08
2
3
—
—
—
—
—
1A1g / 3T2g
1A1g / 1T1g
1A1g / 1T2g
1A1g / 1T1g (n1)
1A1g / 1T2g (n2)
1.12
31 567
223
892
0.34
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rst excited doublet levels in order of increasing energy are 2A2g
The values of the ligand eld parameters are comparable to
and 2T1g, which are known to arise from the t2g e1g congura- those of different ruthenium(III) complexes reported in the
tion.28 The Ru(III) complex shows three electronic transitions at literature.30 The Racah interelectronic repulsion parameter (B)
13 568 cmꢀ1, 19 048 cmꢀ1 and 22 124 cmꢀ1, which may be observed for this complex is less than that for a Ru(III) ion (B0 ¼
assigned to 2T2g / 4T1g (n1), 2T2g / 4T2g (n2), and 2T2g / 2A2g 630 cmꢀ1).30 The 10Dq value is high and the nephelauxetic
4
ꢀ
ꢁ
(n3) in increasing order of energy. The interelectronic repulsion
parameters (B, and C) and ligand eld parameters (10Dq)
parameters were calculated using the following equations:29
B
B0
parameter b ¼
is #1.0. The decrease in b value is also
associated with a reduction in the effective positive charge of
the metal ion and with an increasing tendency to reduction to
the lower oxidation state.31 These results suggest the presence of
strong covalent bonding between the Pip–H donor and Ru3+
ions.30 The magnetic susceptibility of [Ru(Pip–H)3(Cl)3]$6H2O
complex (1) was measured using a Gouy magnetic balance at
room temperature. The ruthenium(III) complex being d5 (low
spin), S ¼ 1/2 has a paramagnetic character. The magnetic
4
2T2g / T1g (n1) ¼ 10Dq ꢀ 5B ꢀ 4C,
4
2T2g / T2g (n2) ¼ 10Dq + 3B ꢀ 4C,
2T2g / 2A2g,
2T1g (n3) ¼10Dq ꢀ 2B ꢀ C
Fig. 5 1H-NMR spectrum of Pt(IV) complex 2.
Table 5 1H-NMR data of Pip–H and its Pt(IV) complex 2
Compounds
Pip–H
H-NMR (d, ppm)
0
0
1.36(3H8b: ꢀCH 3CH2), 3.14–3.25(4H2a,2a : piperazinyl group), 3.86(4H2b,2b : piperazinyl group),
4.39(2H8a: ꢀCH3CH 2), 8.90(2H4,7: pyrimidine and quinolone groups); 9.19(1H11: –NH piperazinyl group)
0
0
Complex 2
1.363–1.380(3H8b: ꢀCH 3CH2), 3.341(4H2a,2a : piperazinyl group), 4.060, 4.095(4H2b,2b : piperazinyl group),
4.347(2H8a: ꢀCH3CH 2), 8.992(2H4,7: pyrimidine and quinolone groups); 9.253(1H11: –NH piperazinyl group);
7.345(8H: 2NH4 group)
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1
1
moment of the ruthenium(III) Pip–H complex is 1.90 B.M., and A1g / T2g transitions. The shi to lower frequency aer
which conrms the exhibition of a single unpaired electron in complexation is due to the binding between the Pt(IV) ion and
a low-spin 4 d5 conguration for a Ru3+ ion in an octahedral the nitrogen atom of the piperazyl ring.
environment.32 This value is lower than the predicted value of
The iridium(III) complex 3 is diamagnetic in character. The
2.10 B.M. This lowering may be due to the presence of ligand UV-vis spectrum of [Ir(Pip–H)3(Cl)3]$6H2O shows bands in the
elds of lower symmetry, or extensive electron delocalization in range of 26 525–30 675 cmꢀ1 and 34 246–34 602 cmꢀ1. These
the species.33 Therefore, the magnetic moment value gives an two regions can be deduced from the ground state 1A1g and exist
impression that the ruthenium(III) complex has been found in in the expected ranges35 for two spin-allowed transitions 1A1g
/
1
the (+3) oxidation state.
1T1g (n1) and A1g
/
1T2g (n2). The ratio n2/n1 in the Ir(III)
The electronic spectrum of [pt(Pip–NH4)2(Cl)4] complex (2) complex 3 is 1.12, which is agreement with the octahedral
1
shows that charge transfer transitions may interfere and geometry for iridium(III) complexes in the literature.36 The A1g
prevent the observation of all the expected bands.34 The distinct / 1T1g (n1) and 1A1g / 1T2g (n2) transitions have been used to
bands at 326 and 354 nm are assignable to a combination of calculate the ligand eld parameters 10Dq and nephelauxetic
metal ligand charge transfer (M / LCT) and d–d transition (B) based on the following equations:31
band. The other weak band at 389 nm is attributed to a combi-
2
86ðBÞ
nation of N / Pt(IV) metal charge transfer (Lp / MCT) and d–
n1 ¼ 10Dq ꢀ 4B þ
10Dq
d transition bands. The Pt(IV) complex 2 is found to be
diamagnetic in character, so the platinum(IV) complex must
have octahedral geometry. The Pt(IV) is a d6 system and four
2
2ðBÞ
bands are expected due to 1A1g / 3T1g, 1A1g / 3T2g, 1A1g / 1T1g
n2 ¼ 10Dq þ 12B þ
10Dq
Fig. 6 TGA and DTG of [Ru(Pip–H)3(Cl)3]$6H2O complex 1.
Table 6 Thermodynamic parameters of the thermal decomposition of Ru(III), Pt(IV) and Ir(III) Pip–H complexes 1–3
Parameter
Complex
Stage
2nd
2nd
2nd
Method
E (J molꢀ1
)
A (sꢀ1
)
DS (J molꢀ1 Kꢀ1
)
DH (J molꢀ1
)
DG (J molꢀ1
)
r
1
2
3
CR
HM
CR
HM
CR
HM
7.35 ꢃ 104
8.32 ꢃ 104
1.56 ꢃ 105
1.56 ꢃ 105
3.18 ꢃ 104
4.46 ꢃ 104
3.24 ꢃ 103
4.95 ꢃ 104
3.74 ꢃ 1010
6.81 ꢃ 1010
3.62 ꢃ 10ꢀ1
4.71 ꢃ 100
ꢀ1.84 ꢃ 102
ꢀ1.61 ꢃ 102
ꢀ4.88 ꢃ 101
ꢀ4.39 ꢃ 101
ꢀ2.61 ꢃ 102
ꢀ2.39 ꢃ 102
6.83 ꢃ 104
7.79 ꢃ 104
1.51 ꢃ 105
1.51 ꢃ 105
2.59 ꢃ 104
3.86 ꢃ 104
1.84 ꢃ 105
1.80 ꢃ 105
1.82 ꢃ 105
1.79 ꢃ 105
2.12 ꢃ 105
2.10 ꢃ 105
0.9804
0.9677
0.9394
0.9314
0.9781
0.9829
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The outcome data of n2/n1, 10Dq, B, C and b parameters are in
agreement with other iridium(III) complexes in previous
studies.35,36 The B value is about 34% of the free iridium ion
(660 cmꢀ1) in the Ir(III) complexes, which refers to the overlap
with signicant covalency in the metal ligand s-bond.
3.5 Thermal analyses and thermodynamic parameters
Thermogravimetric (TG) and differential thermogravimetric
(DTG) analyses were carried out to identify the formulas of
Ru(III), Pt(IV) and Ir(III) Pip–H complexes 1–3 reported in this
study. TGA and DTG thermograms are performed under N2
ow, as shown in Fig. 6a–c. Table 6 includes the maximum
ꢂ
temperature values, DTGmax Cꢀ1, and the mass losses of the
3.4 1H-NMR spectra
1H-NMR spectra of Pip–H and [pt(Pip–NH4)2(Cl)4] complex (2)
have been recorded in d6-DMSO. The assignment of each signal
has been achieved by comparing the H-NMR spectrum of the
thermal decomposition steps for each synthetic complex. The
thermal data led us to nd the number of crystallized water
molecules outside the coordination sphere for Pip–H complexes
1–3.
1
The thermal decomposition of [Ru(Pip–H)3(Cl)3]$6H2O
complex (1) proceeds with approximately three main degrada-
tion steps (Fig. 6).ꢂ The rst stage occurs at a maximum
temperature of 103 C with weight loss of 9.863% (theoretical
8.810%) due to dehydrated 6H2O crystallization water mole-
cules. Therefore, it could be associated with changes in the
lattice structures. While the second and third stages occur at
Pt(IV) complex (Fig. 5) to that of the Pip–H free drug ligand and
these spectra have been reported in the literature.37 The
assignable results are shown in Table 5. The proton-NMR
spectrum of the platinum(IV) complex showed a set of signals
which were almost identical to those of Pip–H, while shis
0
occurred particularly at the piperazinyl protons ((3.341(4H2a,2a
:
0
piperazinyl group) and 4.060, 4.095(4H2b,2b : piperazinyl group))
and the singlet proton of the –NH piperazinyl group
(9.253(1H11: –NH piperazinyl group)). The singlet peak at d ¼
7.345 ppm was assigned to eight protons of two –NH4 groups
which existed instead of the deprotonated carboxylic group. The
spectrum showed a singlet peak at d ¼ 4.347 ppm for –CH2
protons and a singlet at d ¼ 8.992 ppm for the two protons of
the pyrimidine and quinolone moieties at positions H4 and H7
(Table 5). No broad weak band for the acidic proton at d ¼ 11.00
ppm can be seen in the spectrum of complex 2, indicating that
this moiety is deprotonated by the –NH4 basic ion, so Pip–H acts
as a uni-dentate deprotonated ligand bound to the target metal
ion through the piperazinyl nitrogen and completed coordina-
tion sphere by chlorine atoms.38
ꢂ
two different maximum temperatures of 345 and 554 C. The
weight loss associated with these stages is 80.584%, which is
very close to the theoretical value of 81.637% corresponding to
the loss of three Pip–H molecules. The nal thermal product
ꢂ
obtained at 800 C is RuO (found 9.553%; theoretical 9.553%).
Table 7 The XRD collected data of crystallite sizes (D), dislocation
density (d), 2q, intensities, and d-spacing
Complex
D (nm) d (1012 lin mꢀ2
)
2 theta Intensity d-Spacing
Complex 1 28
Complex 2 22
Complex 3 14
0.001
0.002
0.005
21
24
24
100
100
100
4.2088
3.6395
3.6395
Fig. 7 X-ray powder diffraction patterns of [M(L)n(Cl)x]$yH2O ((1) M ¼ Ru3+, L: Pip–H, n ¼ 3, x ¼ 3, y ¼ 6; (2) M ¼ Pt4+, L: Pip–NH4, n ¼ 2, x ¼ 4, y ¼
0 and (3) M ¼ Ir3+, L: Pip–H, n ¼ 3, x ¼ 3, y ¼ 6) complexes 1–3.
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The thermal degradation of [pt(Pip–NH4)2(Cl)4] complex (2) respectively. The weight loss at these steps is 73.224% associ-
takes place with three degradation stages. This complex is ated with the loss of three Pip–H molecules. The theoretical
anhydrous, so the rst stage of decomposition occurs at a high weight loss value is 74.767%. The weight found for the residue
maximum temperature of 258 ꢂC. Therefore, the complex starts aer decomposition is 18.481%, giving an actual total weight
to decompose at the rst DTGmax and continuously decomposes loss in agreement with our calculated total weight loss value of
through the second and third stages, with a total weight loss of 17.030%. The nal thermal decomposition product is IrO2.
80.475%, corresponding to the loss of two Pip–NH4 molecules.
Three different methods are used for the evaluation of the
Theoretically, the loss of these molecules corresponds to kinetic parameters: the Freeman and Carroll (FC) differential
a weight loss of 80.045%. The weight found for the residue (Pt method,39 the Horowitz and Metzger (HM) approximation
metal) aer nal decomposition is 19.525% (theoretical, method40 and the Coats and Redfern (CR) integral method41.
19.955%) giving an actual total weight loss in agreement with The kinetic parameters were evaluated by using two of these
our calculated total weight loss value of 80.475%.
methods: the Horowitz and Metzger (HM) approximation
The thermal decomposition of [Ru(Pip–H)3(Cl)3]$6H2O method40 and the Coats and Redfern (CR) integral method,41
complex (3) proceeds with three main degradation steps. The and the data are listed in Table 6. The satisfactory values of
rst stage of the decomposition occurs at a maximum temper- correlation coefficients (ꢁ1) in all cases indicate good agree-
ꢂ
ature of 67 C and is accompanied by a weight loss of 8.295% ment with the experimental data and the values of the kinetic
corresponding to the loss of the six uncoordinated water parameters are reasonable and in good agreement.
molecules. Theoretically, the loss of these molecules corre-
sponds to a weight loss of 8.203%, which agrees with the
Table 6 can be used to make some points:
(i) The higher values of activation energies Pt(IV)
experimental result. The second and third decomposition (156 kJ molꢀ1) > Ru(III) (78.35 kJ molꢀ1) > Ir(III) (38.20 kJ molꢀ1
)
stages occur at maximum temperatures of 317 and 587 ꢂC, lead to the thermal stability of the Pip–H complexes.
Fig. 8 SEM images of [M(L)n(Cl)x]$yH2O ((A) M ¼ Ru3+, L: Pip–H, n ¼ 3, x ¼ 3, y ¼ 6; (B) M ¼ Pt4+, L: Pip–NH4, n ¼ 2, x ¼ 4, y ¼ 0 and (C) M ¼ Ir3+, L:
Pip–H, n ¼ 3, x ¼ 3, y ¼ 6) complexes 1–3.
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˚
(ii) The thermodynamic data resulting from the two methods where l is the wavelength of the X-ray (1.5418 A) for Cu Ka
are in harmony with each other.
radiation, K is a constant taken to be 0.94, b is the full width at
(iii) The correlation coefficients (r) of the Arrhenius plots of half maximum (FWHM) of the prominent intensity peak (100%
the thermal decomposition steps were found to lie in the range relative intensity peak), and q is a peak position. The grain sizes
0.98–0.93, showing a good t with the linear function.
using the Debye–Scherrer formula were found to be 28, 22 and
(iv) It is clear that the process of thermal decomposition of 14 nm for Ru(III), Pt(IV) and Ir(III) complexes, respectively. The
the complexes is non-spontaneous (DS* ¼ negative value); i.e., lower grain size can be discussed according to the increase in
the complexes are thermally stable.
Pip–H chelates around the metal ions (ratio 1 : 3 or 1 : 2).43 The
collected data of XRD such as 2q, intensities and d-spacing are
listed in Table 7. The dislocation density (d) was evaluated from
eqn (2)44 and is listed in Table 7; it indicates the formation of
high-quality complexes.
3.6 X-ray powder diffractions
The X-ray solid powder diffractions of [M(L)n(Cl)x]$yH2O ((1) M
¼ Ru3+, L: Pip–H, n ¼ 3, x ¼ 3, y ¼ 6; (2) M ¼ Pt4+, L: Pip–NH4, n
¼ 2, x ¼ 4, y ¼ 0 and (3) M ¼ Ir3+, L: Pip–H, n ¼ 3, x ¼ 3, y ¼ 6)
complexes 1–3 are shown in Fig. 7. These diffraction patterns
are semi-crystalline in nature. The particle size (D) of Pip–H
complexes 1–3 was estimated from the major diffraction
patterns of the respective complex using the Debye–Scherrer
formula (eqn (1)):42
1
D2
d ¼
(2)
The XRD of the Ru(III) complex has three signicant peaks at
36.47, 45.35, and 48.41ꢂ due to the presence of the (002), (100),
and (101) planes of ruthenium metal.45 The XRD patterns due to
metallic platinum (JCPDS PDF card no. 04-0802)46 are present at
41.07, 51.16, and 66.00ꢂ for the (111), (200), and (220) planes,
Kl
D ¼
(1)
b cos q
Fig. 9 TEM images of [M(L)n(Cl)x]$yH2O ((A) M ¼ Ru3+, L: Pip–H, n ¼ 3, x ¼ 3, y ¼ 6; (B) M ¼ Pt4+, L: Pip–NH4, n ¼ 2, x ¼ 4, y ¼ 0 and (C) M ¼ Ir3+, L:
Pip–H, n ¼ 3, x ¼ 3, y ¼ 6) complexes 1–3.
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respectively. XRD patterns of the synthesized iridium metal in compound. In general, the SEM photograph shows single phase
situ of the Ir(III) complex agreed well with standard card JCPDS formation with well-dened grain-like shape and particle size in
no. 06-0598 for bulk iridium at 2q ¼ 41.75, 49.09, and 68.57ꢂ. the range of 1 mm to 20 mm. The SEM images of the Pip–H
The considerably broadened contours of the peaks resulted complexes 1–3 are depicted in Fig. 8a–c.
from the ultrasmall grain sizes of iridium metal.47
TEM photos of Pip–H complexes 1–3 (Fig. 9a–c) conrm the
presence of spherical or semispherical NPs, which appear as
dark spots.
3.7 SEM and TEM morphology
The scanning electron microscope images are used here to
investigate the surface morphology and particle size of the Pip–
3.8 Redox behavior of [Ir(Pip–H)3(Cl)3]$6H2O
H complexes 1–3, revealing a crystalline, regular, and glassy Cyclic voltammograms (CVs) of the complex [Ir(Pip–H)3(Cl)3]$
structure. Layers in the micrograph reveal that the system 6H2O in (Bu)4N+$BF4ꢀ–DMSO solution at 100 mV sꢀ1 vs. Ag/
contains atoms in a well-dened pattern; thus the reactants AgCl electrode are shown in Fig. 10. One well-dened anodic
have reacted completely to form
a
clear homogenous peak at 1.25 V is assigned to the Ir3+/Ir4+ electrode couple. In the
Fig. 10 CV of (Ir(Pip-H)3(Cl)3]$6H2O in (Bu)4N+$BF4ꢀ–DMSO solution at 100 mV sꢀ1 vs. Ag/AgCl, voltage.
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reverse scan, three well-dened cathodic peaks at ꢀ0.6, ꢀ1.1 favors the EE-type mechanism.50 The product of this reduction
and ꢀ1.5 V were noticed and were safely assigned to the couples step undergoes a very rapid follow-up chemical reaction and the
Ir4+/Ir3+, Ir3+/Ir2+ and the ligand centre.48 The potential–poten- redox processes are of the EE type.49,50 The observed behavior
tial difference (DEp ¼ Ep,a ꢀ Ep,c) was < 90 mV, revealing the may possibly be explained by considering that the protonation
quasi-reversible nature of the reduction process. The irrevers- reaction is very fast or virtually complete. The irreversibility and
ible nature of the couple Ir4+/Ir3+ was also conrmed from the most oen quasi-reversibility is attributed to the adsorption
observed increase in DEp on increasing the scan rate. Thus, the onto the electrode surface.
couple Rh4+/Rh3+ is most likely to be irreversible metal-based
reduction.48,49
The plot of ip,c vs. n1/2 was linear (R2 ¼ 0.986) (Fig. 11)
3.9 Biological studies
reecting the diffusion-controlled feature of the electro-
chemical process.48,49
3.9.1 Antibacterial assessments. The antibacterial effi-
ciency of pipemidic acid complexes (Pip–H) with Ru3+, Pt4+ and
Ir3+ was assessed in vitro against four kinds of bacteria G(+)
(Staphylococcus epidermidis and Staphylococcus aureus) and G(ꢀ)
(Klebsiella and Escherichia coli). Inhibition zone diameters of the
test samples are summarized in Table 8. The ruthenium(III)
The variation in the current function (ip,c/n1/2) with the scan
rate (50–2000 mV sꢀ1) was also studied. The plot of the current
function (ip,c/n1/2) vs. the scan rate (n) increased linearly at a low
sweep rate (Fig. 12). Thus, the reduction process of the complex
Fig. 11 Plot of ip,c vs. the square root of the scan rate for the (Ir(Pip-H)3(Cl)3]$6H2O complex in (Bu)4N+$BF4ꢀ–DMSO solution at the Pt electrode
vs. Ag/AgCl reference electrode.
Fig. 12 Plot of current function (ip,c/n1/2) vs. the scan rate of the [Ir(PipH)3(Cl)3]$6H2O complex in (Bu)4N+$BF4ꢀ–DMSO at the Pt electrode vs. Ag/
AgCl electrode.
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Table 8 Inhibition zone diameter (mm mgꢀ1 sample) of (IrIII, PtIV and RuIII) pipemidic acid complexes against some kinds of bacteriaa
Inhibition zone diameter (mm mgꢀ1 sample)
Escherichia
Staphylococcus
Staphylococcus
Sample
Klebsiella (Gꢀ)
coli (Gꢀ)
epidermidis (G+)
aureus (G+)
Control: DMSO
Standard
0.0
0.5
0.2
0.5
0.3
0.7
0.0
0.3
0.1
0.2
0.0
0.3
0.0
1.0
1.0
0.0
0.0
0.2
0.0
0.4
0.2
0.0
0.0
0.0
Augmentin
Unasyn
Ir(III) complex
Pt(IV) complex
Ru(III) complex
a
(ꢀ)G: gram reaction. Solvent: DMSO.
Table 9 Inhibitory activities against MCF-7 cell lines for the pipemidic
acid, complexes of (IrIII, PtIV and RuIII) and (doxorubicin and cisplatin)
standard drugs
3.9.2 Anticancer assessments
In vitro cytotoxicity assessments of the pipemidic acid
complexes of Ru3+, Pt4+ and Ir3+ metal ions comparable with two
commonly anticancer drugs (doxorubicin and cisplatin) were
carried out against the human breast cancer (MCF-7) tumor cell
line. The inhibitory activity data assessed based on the calcu-
lation of the inhibitory concentration IC50 are listed in Table 9.
The IC50 of the platinum(IV) complex shows that it is more
effective than ruthenium(III) and iridium(III) complexes against
the MCF-7 cell line.
Viability (%)
Sample conc.
Ir(III)
Pt(IV)
Ru(III)
(mg mLꢀ1
)
Doxorubicin Cisplatin complex complex complex
500
250
125
62.5
31.25
15.6
7.8
3.9
2
1.51
2.36
3.21
5.07
6.93
15.46
19.89
24.98
31.69
100
3.72
4.98
7.83
14.68
23.79
34.62
46.71
52.85
61.74
100
8.63
12.94
23.18
30.97
43.52
67.45
82.13
96.58
99.71
100
20.45
32.78
46.29
71.56
86.31
94.20
98.76
100
16.79
24.82
39.46
56.89
74.04
90.64
98.15
100
Conflicts of interest
100
100
5.9
There are no conicts to declare.
0
100
1.8
100
1.2
IC50 (mg mLꢀ1
)
0.03
0.5
Acknowledgements
This work was funded by the Deanship of Scientic Research at
“Princess Nourah bint Abdulrahman University”, through the
Research Groups Program No. RGP-1438-0001.
complex has a higher antibacterial efficiency than augmentin or
unasyn, standard drugs against Klebsiella. Also, both iridium
and platinum(IV) complexes have more antibacterial inhibition
than the unasyn standard drug against Klebsiella. The Ru3+ and
Ir3+ complexes have more antibacterial efficiency than the
unasyn standard drug against Escherichia coli bacteria. The
ruthenium(III), platinum(IV) and iridium(III) complexes have no
inhibition against Staphylococcus epidermidis or Staphylococcus
aureus, comparable with the unasyn and augmentin standard
drugs. The +ve charge on the metal ions is partially shared with
the donation sites in the chelates and there is p-electron delo-
calization over the whole chelate ring. This leads to increases in
the lipophilic character of the metal chelate and favors its
permeation through the lipoid layers of the bacterial
membranes.51 The increased activity of the metal complexes can
be explained on the basis of chelation theory.52 It is known that
chelation tends to make the ligand act as a more powerful and
potent bactericidal agent, killing more of the bacteria than the
ligand. There are other factors which also increase the activity,
such as solubility, conductivity, and the bond length between
the metal and the ligand, which may explain the values shown
in the present case.53
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