Synthesis, characterization, and antimicrobial activity investigations of ruthenium (II)–bipyridine complexes of ciprofloxacin derivatives

Article abstract of DOI:10.1002/aoc.6407

A series of ruthenium (II) complexes derived from the reaction between cis-bis (2,2′-bipyridine) dichloro ruthenium (II) dihydrate and enaminone derivatives of ciprofloxacin were synthesized and fully characterized using elemental analysis, cyclic voltammetry and different spectroscopic techniques (Uv–vis, FTIR, NMR, mass spectroscopy, and X-ray photoelectron spectrometry (XPS)). The isolated compounds were tested for their antibacterial and antifungal activities against gram-negative and gram-positive bacteria. The FTIR data revealed that ciprofloxacin derivatives act as bidentate ligands through the pyridone carbonyl and the carboxylate oxygen atom. The UV–visible data showed that the charge transfer CT band is blue shifted upon the coordination of the ciprofloxacin derivatives compared to the CT band of the parent complex. The XPS results revealed the characteristic peaks of Ru_3p3/2 and Ru_3p1/2 as well as Ru_3d5/2 and Ru_3d3/2, which confirmed the assembly of the ruthenium (II) ciprofloxacin derivative complexes. Cyclic voltammetry data showed that the ciprofloxacin enaminone derivatives have a similar reduction potential for the Ru (II)/Ru (III) redox couple, and it revealed that the coordination of the ruthenium (II) ion altered the redox property of the ligands and enhanced their electron transfer rate. The electrochemical and the UV–visible results suggest that the ciprofloxacin derivative ligands are (Formula presented.) -acceptor ligands. Further, the complexes showed higher antibacterial activities than the parent ciprofloxacin antibiotic and did not show antifungal activities among the tested fungi strains.

Full text of DOI:10.1002/aoc.6407

Received: 22 March 2021
DOI: 10.1002/aoc.6407
Revised: 12 July 2021
Accepted: 25 July 2021
F U L L P A P E R
Synthesis, characterization, and antimicrobial activity
investigations of ruthenium (II)–bipyridine complexes of
ciprofloxacin derivatives
1
2
1
2
Dhuha Al-Wahaib
| Ali El-Dissouky
| Nada M. Abrar
| Tarek E. Khalil
1
Faculty of Science, Chemistry
Department, Kuwait University, Safat,
Kuwait
Abstract
A series of ruthenium (II) complexes derived from the reaction between cis-bis
2
0
Chemistry Department, Faculty of
(2,2 -bipyridine) dichloro ruthenium (II) dihydrate and enaminone derivatives
Science, Alexandria University,
Alexandria, Egypt
of ciprofloxacin were synthesized and fully characterized using elemental anal-
ysis, cyclic voltammetry and different spectroscopic techniques (Uv–vis, FTIR,
NMR, mass spectroscopy, and X-ray photoelectron spectrometry (XPS)). The
isolated compounds were tested for their antibacterial and antifungal activities
against gram-negative and gram-positive bacteria. The FTIR data revealed that
ciprofloxacin derivatives act as bidentate ligands through the pyridone car-
bonyl and the carboxylate oxygen atom. The UV–visible data showed that the
charge transfer CT band is blue shifted upon the coordination of the ciproflox-
acin derivatives compared to the CT band of the parent complex. The XPS
results revealed the characteristic peaks of Ru3p3/2 and Ru3p1/2 as well as
Ru3d5/2 and Ru3d3/2, which confirmed the assembly of the ruthenium
Correspondence
Tarek E. Khalil, Chemistry Department,
Faculty of Science, Alexandria University,
P.O. Box 426-Ibrahimia, 21321,
Alexandria, Egypt.
Email: tarekakel@alexu.edu.eg
(II) ciprofloxacin derivative complexes. Cyclic voltammetry data showed that
the ciprofloxacin enaminone derivatives have a similar reduction potential for
the Ru (II)/Ru (III) redox couple, and it revealed that the coordination of the
ruthenium (II) ion altered the redox property of the ligands and enhanced
their electron transfer rate. The electrochemical and the UV–visible results
suggest that the ciprofloxacin derivative ligands are π-acceptor ligands. Fur-
ther, the complexes showed higher antibacterial activities than the parent cip-
rofloxacin antibiotic and did not show antifungal activities among the tested
fungi strains.
K E Y W O R D S
antimicrobial, ciprofloxacin, cyclic voltammetry, Ru (II) complexes, XPS
[
1–5]
1
| INTRODUCTION
activities.
The quinolone in these complexes coordi-
nates with the metal ion as a bidentate ligand via the
ring's carbonyl group and the oxygen atoms of the car-
boxylate group. It was noticed that in these complexes,
the divalent cations are preferred over the trivalent cat-
The study of the interactions between drugs and metal
ions is considered an active research area. Therefore, the
complexes of various metal ions with fluoroquinolones
have been prepared and explored for their biological
[
6]
ions, such as iron (III) and ruthenium (III).
Appl Organomet Chem. 2021;e6407.
wileyonlinelibrary.com/journal/aoc
© 2021 John Wiley & Sons, Ltd.
1 of 11
https://doi.org/10.1002/aoc.6407

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AL-WAHAIB ET AL.
Among the quinolones, ciprofloxacin, which coordi-
1.1 | Significance of the study
nates to the metal ion via the carbonyl and the carboxyl-
ate oxygen atoms, exhibits both identical or greater
bioavailability, greater plasma concentration, and an
increase in tissue penetration. Molecular modifications of
ciprofloxacin are made to further improve its biological
The synthesis of novel antimicrobial and antitumor com-
pounds is considered to be an active research area. Sev-
eral infectious diseases caused by the presence or the
overgrowth of pathogens currently do not have a cure,
and more research is required. Ciprofloxacin is a highly
effective and wide spectrum antibiotic. Its antimicrobial
activity might be enhanced by the coordination of metal
ions or by the incorporation of an active functional
group. Therefore, the synthesis of new derivatives of cip-
rofloxacin and studding their metal complexes are con-
sidered to be important toward our understanding of the
rules that govern their biological reactivities and chemi-
cal properties.
[2]
activities. The coordination of metal ions to ciprofloxa-
cin and its derivatives enhanced their antibacterial
[4,7,8]
activity.
Ruthenium (II) might also bind to ciprofloxacin
0
0
ligands via the N,N -coordination site, or via the O,O -
0
coordination site. The chelation via O, O site is reported
[9–11]
for ruthenium (II)–arene frameworks,
and recently,
[12]
Ziga Ude,
synthesized and characterized a half-
sandwich organo-ruthenium (II) complex, [Ru(η6-p-
cymene)(CipA-H) Cl], which has the 7-(4-[decanoyl]
piperazin-1-yl)-ligand (CipA), as a derivative of ciproflox-
acin. The x-ray crystallography data showed that the
2 | MATERIALS AND METHODS
2.1 | Materials
0
metal ion binds to the ciprofloxacin ligand via the O, O -
site. The complex is highly cytotoxic and revealed poten-
tial antitumor activity against different human cancer cell
lines, similar to cisplatin, the well-known anticancer
drug. However, the complex is also cytotoxic against the
cell lines that are resistant to cisplatin and oxaliplatin,
which suggests a different mode of action by this com-
plex. Moreover, the complex has a moderate and a dose-
dependent antibacterial activity against two Escherichia
coli strains that are resistant to antibiotics. Accordingly,
this complex has dual-biological reactivities, an anti-
cancer and anti-bacterial property.
The following chemicals were purchased from Sigma-
Aldrich: dimethyl formamide dimethyl acetate (94%),
acetophenone
4-nitroacetophenone
(99%),
(98%),
2-acetylfuran
(99%),
4-methylacetophenone
(95%), 2-acetylpyrrole (99%), 4-chloroacetophenone
(97%), p-xylene (99%), ethanol absolute (99.8%), metha-
nol (99.9%), sodium metal (99.9%), and ammonium
hexafluorophosphate (95%). The following chemicals
were purchased from Merck Group: diethylether (99.7%),
dimethylformamide (99%), dioxane (99.8%), acetonitrile
(99.9%), acetic acid, and meluller hinton agar. The fol-
lowing chemicals were purchased from Fluka:
dimethylsulphoxide, sodium hydroxide (98%), and cipro-
floxacin (98.0%). N,N dimethyl formamide (99.5%) was
A unique half-sandwich ruthenium (II) complex of
aminomethyl (diphenyl)-phosphine ligands, as well as
a ciprofloxacin derivative, were also synthesized and
their chemotherapeutics properties were investigated.
The complexes showed cytotoxicity in vitro and have
[13]
0
IC50 values lower than cisplatin.
The platinum-
purchased from Scharlau. Cis-bis (2,2 -bipyridine)
based drug is one of the best known drugs in the
treatment of various kinds of human cancers, but it
has severe side effects and cell resistance. Thus, explor-
ing alternative metal complexes of chemotherapeutic
properties with less or no side effects is required.
Ruthenium compounds have been reported as anti-
dichlororuthenium (II) dihydrate was prepared from
RuC1 .3H O and bipyridine, both purchased from Sigma-
3
2
Aldrich, using the method described by Sullivan et al
(1978). Enaminone (E) and ciprofloxacin derivatives
ligands (CFE) were synthesized as described previ-
[
18]
ously.
Whatman
Filter paper discs (No.1) was pursued from
[14,15]
®
tumor metallotherapeutic agents,
and they display
Inc. The following antibiotic susceptibility
biological selectivity while overcoming cell resistance
encountered by cisplatin drugs. Therefore, they are
considered promising compounds that can be used in
the design and in the development of oncotherapeutic
drugs due to their low cytotoxicity and genotoxicity,
testing discs were purchased from Himedia: ceftazidime,
gentamycin, erythromycin and penicillin G. Potato dex-
trose agar purchased from Oxoid.
[16,17]
and to their high biological activity.
The pres-
2.2 | Instrumentation
ented study is aimed to synthesize and characterize
ruthenium (II) complexes of ciprofloxacin-enaminone
derivatives and to examine their biological activity
along with their electrochemical properties.
Elemental analysis was performed using Elementar Vario
Micro Cube CHNS analyzer. The HNMR spectra were
recorded on a Burker DPX 400- and 600-MHz instrument
1

AL-WAHAIB ET AL.
3 of 11
using tetramethyl silane (TMS) as internal reference.
Infrared spectra were recorded on a Jasco FTIR-6300
spectrophotometer. Samples were prepared as KBr discs
and measurements were taken at the range 4000 to
added to it. The reaction mixture was refluxed for three
hours, then the product was filtered out, washed with
ethanol (3 ꢁ 25 mL) and distilled water (3 ꢁ 25 mL),
and crystallized using DMF.
ꢀ
1
4
00 cm . The UV–vis spectra were recorded using Var-
ian Cary-5 double beam spectrometer. Mass spectroscopy
was performed on high resolution gas chromatography
mass spectrometer-double focusing sector (GC–MS–
DFS). Ionization was accelerated with Cs ions with ener-
gies of ꢀ70.1 eV. 3-nitrobenzyl alcohol was used as the
matrix in the fast atomic bombardment (FAB) mass spec-
troscopy. X-ray photoelectron spectrometry (XPS) mea-
2.4 | Synthesis of ruthenium
(II) enaminone ciprofloxacin derivatives
complexes
Ruthenium (II) complexes of the ciprofloxacin derivatives
were synthesized according to the following general pro-
surements were conducted on
a
VG ESCALAB
cedure:
ciprofloxacin
derivative
(CFE1–CFE6)
2
00 spectrometer using MgKα radiation 1253.6 eV and
(0.08 mmol) was dissolved in DMF-ethanol (4:14, v/v)
operating at 300 W (15 kV, 20 mA). All binding energy
values were determined with respect to C 1 s line
with continuous stirring, then NaOMe (0.08 mmol) was
added. Cis-bis (2,2 -bipyridine) dichlororuthenium
0
(
284.6 eV) obtained from adventitious carbon. Depth pro-
filing was done with an Ar ion gun with 5 kV energy and
-mA current. Cyclic voltammetry (CV) experiments
(II) dihydrate (0.08 mmol) was dissolved in ethanol
(14 mL) and stirred for one hour at 50 C, then slowly
ꢂ
1
added to the ciprofloxacin derivative solution. The reac-
tion mixture was refluxed for five to six hours and a satu-
rated aqueous solution of NH PF (2 g NH PF in 60-mL
were carried out using BASi Epsilon 100w potentiostat. A
single compartment cell was used, and the electrode sys-
tem consisted of glassy carbon working electrode, plati-
num wire auxiliary electrode, and Ag/AgCl reference
electrode. The supporting electrolyte solution was
TBAPF6 in DMSO or 0.1 M TBAPF6 in acetonitrile
depending on the solubility of the compound. All of the
CV measurements were conducted after purging the solu-
tion with nitrogen gas. The concentration of the com-
4
6
4
6
water) was added slowly to precipitate the complex. The
reaction mixture was left overnight, and the precipitated
complex was filtered off and washed with water (3 ꢁ 25
mL) and diethyl ether (3 ꢁ 25 mL). The complex was fur-
ther purified by dissolving it in acetonitrile and filtering
off the impurities. Anal. Calcd. for [Ru (bipy) (CFE1)]
2
PF .(H O) : C, 51.49; H, 4.23; N, 9.14%. Found: C
6
2
3
ꢀ
4
1
plexes was 10 M and prior to any measurements, the
potential was calibrated against ferrocene couple (0.44 V
Fc /Fc vs. Ag/AgCl reference electrode) and the parent
51.44; H, 4.432; N, 9.16%. H NMR (400 MHz, CDCl ) δ
3
1.1 (m, 2H), δ 1.45 (d, 2H), δ 2.9 (m, 2H), δ 3.2 (m, 3H),
δ 3.4 (m, 2H), δ 3.7 (m, 4H), δ 7.1 (m, 1H). δ 7.2 (m, 1H),
δ 7.5 (m, 5H), δ 7.7 (m, 3H), δ 7.9 (m, 5H), δ 8.1 (m, 2H),
δ 8.3 (m, 1H), δ 8.5 (m, 3H), δ 8.8 (m, 1H), δ 9.0 (m, 1H)+,
+
Ru (bpy) .Cl .2H O complex.
2
2
2
Melting points were measured using Electrothermal
100. pH measurements were made using Orion
20APlus. The synthesized compounds were dried using
9
4
δ 9.1 (m, 1H). ESI (+)MS (m/z) [M + (bipy) (CFE1)]
2
ꢂ
calcd. 873.9, found 874.4, M. P 222–231 C. (yield: 53%).
an Isotemp 281A vacuum oven.
Anal. Calcd. for [Ru (bipy) (CFE2)]PF .(H O) : C,
2
6
2
5
5
8
0.27; H, 4.58; N, 8.73%. Found: C, 50.05; H, 4.409; N,
1
.87%. H NMR (400 MHz, CDCl ) δ 1.1 (d, 2H), δ 1.35
3
2
.3 | Synthesis of enaminone
(m, 2H), δ 3.2 (s, 1H), δ 3.3 (m, 1H), δ 3.4 (m, 2H), δ 3.7
(m, 3H), δ 7.1 (m, 1H),7.2 δ (m, 1H). δ 7.5 (m, 4H), δ 7.65
(E) ciprofloxacin derivative ligands
(
m, 1H), δ 7.8 (m, 1H), δ 7.89 (m, 2H), δ 7.95 (m, 1H), δ
The enaminone-derivatives (E1–E6) were synthesized as
8.1 (m, 2H), δ 8.3 (m, 1H), δ 8.5 (m, 2H), δ 8.75 (m, 1H)+,
[18]
described previously,
in which N, N-dimethyl form-
δ 9.1 (m, 1H). ESI(+)MS (m/z) [M + (bipy) (CFE2)]
2
ꢂ
amide dimethylacetal (DMF–DMA) (0.1 mole, 13 mL)
was dissolved in ethanol (10 mL), then an equivalent
amount of the corresponding phenone derivatives (0.1
mol) was added. The reaction mixture was refluxed for
calcd. 978.02, found 978.0, M. P 215–226 C (yield: 51%).
Anal. Calcd. for [Ru (bipy) (CFE3)]PF .(H2O) : C,
2
6
5
47.3; H, 4.23; N, 8.58%. Found: C, 47.92; H, 4.234; N,
+
8.83%. ESI(+)MS (m/z) [M + (bipy) (CFE3)] calcd.
2
ꢂ
4
8 h, cooled to room temperature and its volume was
908.4, found 908.4. M. P 226–235 C (yield: 52%). Anal.
Calcd. for [Ru (bipy) (CFE4)]PF .(H O) : C, 50.23; H,
3.85; N, 10.19%. Found: C, 50.2; H, 4.103; N, 10.2%. H
reduced. The enaminone-ciprofloxacin derivatives
2
6
2
2
1
(
CFE1–CFE6) were also synthesized as previously
[18]
explained,
in which ciprofloxacin (CF) (5–10 mmol)
NMR (400 MHz, CDCl ) δ 1.15 (d, 2H), δ 1.35 (m, 2H), δ
3
was dissolved in distilled water/dioxane mixture (5:10,
3.3 (m, 3H), δ 3.55 (m, 2H), δ 3.7 (m, 2H), δ 7.1 δ (m,
1H), δ 7.6 (m, 3H), δ 7.8 (m, 3H), δ 8.0 (m, 1H), δ 8.1
v/v) then the enaminone (E1–E6) (5–10 mmol) was

4
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AL-WAHAIB ET AL.
(
8
m, 2H), δ 8.2 (m, 1H), δ 8.35 (m, 3H), δ 8.5 (m, 1H), δ
confirm that the solvent ACN has no effect tested strains.
The prepared disks were allowed to air dry for 24–48 h
and carefully placed on an agar inoculated with the spe-
cific bacteria and incubated in an L-C incubator
+
.7 (m, 1H). ESI (+)MS (m/z) [M + (bipy) (CFE4)]
2
ꢂ
0
calcd. 918.91, found 919.0. M. P C 251–257 C (yield:
5%). Anal. Calcd. for [Ru (bipy) (CFE5)]PF .
5
(
4
2
6
ꢂ
H O) : C, 49.72; H, 4.10; N, 9.22%. Found: C, 49.45; H,
(Barnstead Labline) at 37 C for 24 to 36 h. The inhibition
2
3
1
.538; N, 9.23%. H NMR (400 MHz, CDCl ) δ 1.1 (s, 2H),
zone surrounding each disk was measured in millimeters
and used to calculate the mean of the inhibition zones.
The assignment of the activity levels was made based on
the following code (included in the booklet provided by
Himedia where the controls antibiotics were purchased):
gram negative strain (<14 mm resistant, 15–22 mm inter-
mediate, >22 mm sensitive), gram positive strain
(<12 mm resistant, 13–14 mm intermediate, >14 mm
sensitive).
3
δ 1.35 (m, 2H), δ 3.25 (s, 1H), δ 3.35 (m, 4H), δ 3.6 (m,
3
7
2
H), δ 7.12 δ (m, 1H). δ 7.2 (m, 1H), δ 7.55 (m, 3H), δ
.65 (m, 1H), δ 7.75 (m, 2H), δ 7.85 (m, 2H), δ 8.15 (m,
H), δ 8.35 (m, 2H), δ 8.8 (d, 1H), δ 9.07 (m, 2H). ESI (+)
+
MS (m/z) [M + (bipy) (CFE5)] calcd. 863.9, found
8
[
1
2
ꢂ
64.1, M. P 252–260 C (yield: 48%).. Anal. Calcd. for
Ru (bipy) (CFE6)]PF .(H O) : C, 48.94; H, 4.29; N,
2 6 2 4
1
0.38%. Found: C, 49.3; H, 4.338; N, 10.34%. H NMR
(
400 MHz, CDCl ) δ 1.1 (d, 2H), δ 1.35 (m, 2H), δ 3.15 (s,
3
2
H), δ 3.3 (m, 3H) δ 3.65 (m, 2H), δ 7.05 (m, 1H). δ 7.2
(m, 1H), δ 7.5 (m, 4H), δ 7.8 (m, 2H), δ 8.05 (m, 2H), δ
2.6 | Antifungal testing
8
2
9
.25 (m, 2H), δ 8.45 (m, 2H), δ 8.75 (d, 1H), δ 9.03 (m,
+
H). ESI (+)MS (m/z) [M + (bipy) (CFE6)] calcd.
The antifungal activity of the ciprofloxacin enaminone
derivatives ligands and their ruthenium (II) complexes
were tested against the following fungi strains: Aspergil-
lus flavus, Aspergillus niger, Alternaria alternata,
Fusarium solani, and Ttichophyton rubrum. The fungal
strains were isolated from salt-marsh soil in Kuwait
and were identified macroscopically and microscopically
for characteristic morphology. In a typical experiment,
the ligands and their complexes (15 mg) were dissolved
in DMF or acetonitrile (1.5 mL) and sonicated to ensure
complete dissolution. A 100 μL of this solution was
then dispensed into a conical flask containing potato
2
ꢂ
34.95, found 935.0, M. P > 300 C m.p (yield: 51%).
2
.5 | Biological study
2
.5.1 | Antibacterial testing
[19,20]
A Kirby–Bauer disc diffusion method,
was followed
to determine the antibacterial activity of the synthesized
ciprofloxacin enaminone derivative ligands and their
ruthenium (II) complex compounds against three gram-
negative (E. coli ATCC 25922, Klebsiella pneunomiae and
ESBL positive K. pneunomiae) bacteria and one gram-
positive bacterium (Staphylococcus aureus, ATCC 25923).
K. pneunomiae ESBL strain that used in this study was
identified and confirmed to be K. penumoniae by using
the Vitek 2 GNI (BioMerieux, Marcy L'Etoile, France).
ESBL production was screened by using the integrated
ESBL screen on the Vitek AST-N020 cards (BioMerieux,
Marcy L'Etoile, France). The test was performed under
sterile conditions. Ceftazidime and cephotaxime antibi-
otics were used as positive controls in the case of the
gram-negative bacteria, while gentamicin and erythromy-
cin antibiotics were used as positive controls in the case
of the gram-positive bacterium. The tested compounds
were dissolved in acetonitrile (ACN). The concentrations
of the tested ruthenium (II) ciprofloxacin derivative com-
plexes ranged from 10–20 mg mLꢀ and at least 2–3 ster-
ilized filter paper disks were made for each compound.
The preparation was made by dissolving the correspon-
dent mass (mg) of the complex, for example 2.5 and
ꢂ
dextrose agar media at 42–60 C and mixed well, then
poured into Petri dishes (triplicate), and allowed to
solidify. A control plate was also prepared by adding a
100 μL of the solvent into a conical flask of the media.
A 100 μl of the fungus inoculum was then inoculated
into the compound's plate. The plates were kept at
ambient temperature for 2 weeks and were observed
regularly.
3 | RESULTS AND DISCUSSION
3.1 | Synthesis of ruthenium
(II) ciprofloxacin enaminone derivatives
The synthesis and the characterization of ciprofloxacin
enaminone derivative ligands (CFE1–CFE6) used in the
preparation of the ruthenium (II) complexes were
1
[
18]
reported previously;
however, their electrochemical
and XPS properties are examined in this study. The gen-
eral reaction pathway of the synthesis is carried out by
the addition of cis-Ru (bpy) Cl to the deprotonated cip-
5
.0 mg, in 250-μL ACN. The solution was sonicated for
about 2 minutes to ensure complete dissolution. Disks
saturated with only ACN solvent were also made to
2
2
rofloxacin derivative ligands using 1:1 molar ratio in the

AL-WAHAIB ET AL.
5 of 11
SCHEME 1 Synthesis of ruthenium (II) ciprofloxacin
enaminone complexes
3.3 | FTIR spectra
The FTIR spectra of the synthesized ruthenium
II) ciprofloxacin enaminone complexes are shown in
(
Figures S7 and S8, and Table 1 summarizes the results.
The vibrational band that is due to the (C=O)carb
stretching frequency of the carboxylate group, which is
present in the spectra of the ligands around 1703–
ꢀ
1 [18]
1729 cm
,
is absent from the spectra of the com-
plexes, indicating the coordination of the Ru (II) ion at
this site of the ligand. The pyridone carbonyl stretch
FIGURE 1 Common fragments in the synthesized Ru
(
II) ciprofloxacin complexes
ν(C=O) of the complexes are present in the range of
p
ꢀ
ꢀ1
presence of PF6 ion according to the following reaction
and as shown in Scheme 1.
1624–1629 cm . Two characteristic bands are present in
ꢀ
1
the range 1550–1581 and 1343–1371 cm that could be
ꢀ
assigned to the asymmetric ν (COO )
and symmetric
asym
ꢀ
cisꢀRuðbpyÞ Cl
ν (COO )sym carboxylate ion stretching vibrations,
2
 2
Ã
ꢀ
þðCFEÞPF RuðbpyÞ ðCFEÞ PF ðH OÞ
respectively. The difference in the stretching modes of
6
2
6
2
x
!
ꢀ
ꢀ
the carboxylate ion (Δν
= ν (COO )
ꢀ ν
COO
asym
ꢀ
The elemental analysis data of the complexes con-
firmed their expected stoichiometry and the percentage
yield varied from 43%–63%. The complexes were dark red
(COO )sym) can be used to determine the coordination
mode of the caboxylato ligands. The Δ value falls in the
ꢀ
1
range 195–211 cm (Table 1), which indicates a mono-
ꢂ
and their melting points ranged from 215–300 C. They
dentate coordination mode of the carboxylato group of
[
21,22]
were insoluble in aqueous and some organic solvents, but
the ciprofloxacin derivative ligands.
These changes
soluble in acetonitrile and DMF.
in the FTIR spectra suggest that the ciprofloxacin deriva-
tive ligands were coordinated to the Ru (II) via the
pyridone oxygen and one carboxylato oxygen. The FTIR
spectra of the complexes display a medium broad absorp-
3.2 | Mass spectra
ꢀ
1
tion band at 3430–3433 cm , which can be attributed to
the ν(O-H) stretching frequency of a coordinated water
The mass spectra of the synthesized ruthenium
II) complexes are shown in Figures S1–S6. All of the
complexes mass spectra have the parent ion peak [M-
[
22,23]
(
molecule.
+
+
PF6] and the fragments [Ru (bpy) (CFE)]
and
2
2
+
1
[
Ru (bpy)2] , as shown in Figure 1. The spectra con-
3.4 | H NMR spectra
firmed the presence of the expected masses of the
complexes.
1
The HNMR spectrum of the ruthenium (II) complexes
Most of the mass spectra of the ruthenium
II) ciprofloxacin derivative complexes have the
enaminone fragment, which is bonded to ciprofloxacin
during the synthesis of the derivative ligands.
of ciprofloxacin derivatives reveal the disappearance of
the carboxylate hydrogen atom, which supports the coor-
dination of the ruthenium ion via the carbonyl and the
carboxylate atoms of the ciprofloxacin derivatives. On the
(

6
of 11
AL-WAHAIB ET AL.
ꢀ
1
TABLE 1 FTIR spectra diagnostic bands (in cm ) of the ruthenium (II) ciprofloxacin derivative complexes
Carboxylate ion
a
ν (C=O)
carboxylic
ν (C=O)
pyridone
Asymmetric ν
(COO )asym
Symmetric ν
(COO )sym
Δν
ꢀ
ꢀ
ꢀ
Compound
COO
CFE1
1703
1709
1703
1632
1627
[
Ru (bipy)
O)
CFE2
Ru (bipy)
O)
CFE3
Ru (bipy)
O)
CFE4
Ru (bipy)
O)
CFE5
Ru (bipy)
O)
CFE6
Ru (bipy)
O)
2
2
2
2
2
2
(CFE1)]PF
(CFE2)]PF
(CFE3)]PF
(CFE4)]PF
(CFE5)]PF
(CFE6)]PF
6
6
6
6
6
6
.
.
.
.
.
.
1581
1576
1575
1550
1575
1566
1370
1369
1368
1343
1366
1371
211
207
207
208
209
195
(
H
2
3
1628
1628
[
(
H
2
5
1632
1626
[
(
H
2
5
1726
1625
1629
[
1726 weak
(
H
2
2
1715
1724
1632
1624
[
(
H
2
3
1627
1627
[
(
H
2
4
a
Δν = ν(COO )asym – ν (COOꢀ)sym
ꢀ
.
TABLE 2 UV–visible absorption bands of the ciprofloxacin
other hand, the propyl group and the piperazinyl groups
retained the same chemical shifts throughout the com-
plexes. The aromatic protons of pyridone and the aryl
a
enaminone ligands CFE1–CFE6 , ruthenium (II) ciprofloxacin
b
derivatives complexes of RuCFE1–RuCFE6 , and the parent cis-bis
0
(
2,2 -bipyridine) dichloro ruthenium (II) dihydrate (in nm)
1
rings overlapped with the bipyridine protons. The H
Compound
λ
max
NMR spectra are shown in Figures S9–S13.
Both the FTIR and 1HNMR spectra of the ruthenium
cis-Ru (bpy)
2
Cl
2
242
283
246
281
247
281
250
284
249
280
247
282
246
296
341
295
344
294
346
284
368
294
346
294
340
295
377
339
343
344
376
345
339
550
519
517
514
515
519
517
(II) complexes of ciprofloxacin derivatives suggest that
CFE1
the ciprofloxacin derivative ligands were coordinated to
the Ru (II) via the pyridone oxygen and one carboxylato
oxygen indicating that the ligand behaves as mono-
negative bidentate ligand as a result of the deprotonation
of carboxylic acid group.
[
Ru (bipy)
CFE2
Ru (bipy)
CFE3
Ru (bipy)
CFE4
Ru (bipy)
CFE5
Ru (bipy)
CFE6
Ru (bipy)
2
2
2
2
2
2
(CFE1)]PF
(CFE2)]PF
(CFE3)]PF
(CFE4)]PF
(CFE5)]PF
(CFE6)]PF
6
6
6
6
6
6
.(H
.(H
.(H
.(H
.(H
.(H
2
2
2
2
2
2
O)
3
O)
5
O)
5
O)
2
O)
3
O)
4
[
[
3.5 | UV–visible spectra
[
The UV–visible spectra of the ruthenium (II) complexes
of ciprofloxacin derivatives are shown in Figures S14–S19
and Table 2 summarizes the results. The spectra show a
broad band at 514–519 nm, which is assigned as metal to
[
[
[24]
a
ligand charge transfer (MLCT) transition,
in which an
Measured in DMF.
b
electron located in a metal-centered d-orbital is promoted
Measured in acetonitrile.
into a ligand–centered π*-orbital. The UV–visible spectra
0
of the parent complex, cis-bis (2,2 -bipyridine)
increase in the energy of the electronic transition in the
ruthenium (II) ciprofloxacin derivative complexes indi-
cate a stabilization in the molecular orbitals of the
dichlororuthenium (II), has its MLCT bands at 550 nm,
which is “blue” shifted in the synthesized complexes. The

AL-WAHAIB ET AL.
7 of 11
complex, and it is a characteristic of a π-acceptor ligand.
Thus, ciprofloxacin enaminone derivative ligands are
classified as π-acceptor ligands based on the UV–visible
and the electrochemistry data (see below). The bands at
derivative ligands CFE1–CFE6, Figures S21–S24, and
their ruthenium (II) complexes RuCFE1–RuCFE6,
Figures S21–S24. The cyclic voltammograms were
recorded in the potential range +2800 mV to ꢀ2800 mV.
Table S2 summarizes the obtained electrochemical data
of the ciprofloxacin derivative ligands and their ruthe-
nium (II) complexes.
2
46–250, 284–295, and 339–376 nm can be attributed to
ligands π- π* electronic transitions. The RuCFE4 complex
shows the highest value of this transition, which is an
indication of the influence of the enaminone's substitu-
ent, the p-nitro group, compared to the other
substituents.
The CV data of the complexes showed one redox
wave in the 0- to +2000-mV region (positive region
Figures S23 and S24), which is assigned to the Ru (II)/
+
Ru (III) redox couple (ꢃ600 mV, vs. Ag/Ag ). Since
the peak-to-peak separation (ΔE ) of this wave is shifted
p
3
.6 | X-ray photoelectron spectroscopy
with the scan rate, and the peak current (I ) varies line-
p
arly with the square root of the scan rate (Figure S25),
this wave is described as a quasi-reversible electron trans-
The investigated ciprofloxacin enaminone derivative
ligands (CFE1–CFE6) consist of C, O, N, and F atoms,
while their ruthenium (II) complexes consist of the same
atoms in addition to a second source of the P and F
[
26,27]
fer process.
Among the synthesized complexes, this
wave did not show significant changes, which indicates
that there is no effect of the enaminone substituents on
the redox potential value of the ruthenium metal in these
complexes. However, the rate of the electron transfer of
this redox wave is different between the complexes. The
ꢀ
atoms, which is the counter ion PF . The XPS spectra of
6
the free ciprofloxacin enaminone derivatives and their
ruthenium (II) complexes have been measured. The XPS
of the isolated complexes are shown in Figure S20 and
the binding energy (BE) values with the peak assign-
ments are given in Table S1. Relative to the spectra of the
free ligands, ruthenium (II) complexes have the same
binding energies for C1s, O1s, F1s, and N1s. In addition,
the XPS spectrum of RuCFE3 complex, exhibits one peak
at 200.4 eV owing to the binding energy of the Cl2p. On
the other hand, the XPS spectra of all the complexes
exhibit a characteristic peak at 135.83–136.89 eV, which
belongs to P2p. In addition, the spectra of the complexes
display two series of peaks at 461.92–462.12 and 483.60–
values of the ΔE vary between 63 and 88 mV (Table S2),
p
and the ratio of I /I varies between 1.2 and 3.2
pa pc
(Table 3) are also characteristics of a quasi-reversible
electron transfer process. This also showed variations in
the electron transfer rate between the complexes. The
peak separation ΔE is the greatest for RuCFE2 (88 mV)
p
and RuCFE4 (87 mV) complexes, emphasizing the
greatest decrease in the reversibility of the electron trans-
fer process in these complexes, which is attributed to the
different enaminone substituents. RuCFE2 complex has
the methyl substituent and RuCFE4 has the nitro substit-
4
84.10 eV, which are assigned to Ru3p3/2 and Ru3p1/2,
uent. Moreover, the current response, I /I , is the
pa pc
respectively, with a binding energy difference (ΔE = BE
Ru3p1/2 ꢀ BE Ru3p3/2) of 21.64–22.15 eV. Also, the XPS
spectra show another two series of bands at 280.41–
highest for the RuCFE6 complex, which indicates a faster
electron transfer for this complex. RuCFE6 complex has
the pyrrole substituent, which increased the inductive
property of the complex. The differences in the values of
ΔE and I among the ruthenium (II) ciprofloxacin com-
2
80.57 and 284.60–284.78 eV, that are assigned to
Ru3d5/2and Ru3d3/2, respectively, with a binding energy
p
p
difference (ΔE = BE Ru3d3/2 ꢀ BE Ru3d5/2) of 4.12–
plexes demonstrate the influence of the enaminone
4
.32 eV. The information derived from the XPS results is
[
25]
in accordance with those reported for Ru (II) ions.
The
peaks assigned to Ru3p3/2 and Ru3p1/2 as well as
Ru3d5/2and Ru3d3/2 with their binding energy differences,
TABLE 3 Anodic current I
a
, cathodic current I
c
and currents
ꢀ1
ratio at scan rate 200 mV s for the ruthenium (II) ciprofloxacin
confirmed
the
formation
of
the
ruthenium
enaminone derivatives complexes, RuCFE1–RuCFE6
(II) ciprofloxacin derivative complexes. In addition, it has
Complex
RuCFE1
RuCFE2
RuCFE3
RuCFE4
RuCFE5
RuCFE6
I
pc
I
pa
Ipa/Ipc
been observed that the peak assigned to Ru3d3/2 overlaps
with the peak of C1s at 284.7 eV.
1.3
2.1
1.8
2.4
2.8
1.0
3.2
3.2
3.9
2.9
3.3
3.2
2.5
1.5
2.1
1.2
1.2
3.3
3.7 | Cyclic voltammetry
Cyclic voltammetry (CV) was carried out to investigate
the redox properties of the synthesized ciprofloxacin

8
of 11
AL-WAHAIB ET AL.
substituents on the reversibility of the electron transfer
process and its rate in these compounds.
3.8 | Biological activity of the ruthenium
(II) complexes
Compared to the parent complex, Ru (bpy) Cl , which
2
2
+
has a redox potential at ꢃ315 mV (vs Ag/Ag ) for the Ru
The
antibacterial
activity
of
the
ruthenium
(II)/Ru (III) couple, this wave is shifted to higher positive
(II) complexes of ciprofloxacin derivatives was investi-
gated against gram positive, S. aureus, and gram nega-
tive, E. coli, K. pneunomiae, and ESBL positive
K. pneunomiae, bacteria. The solvent ACN has no effect
on the antibacterial activity of the tested bacteria.
Table 4 summarizes the inhibition zone obtained by
each tested organism. Inspection of the data revealed
that all of the ruthenium (II) complexes are active
against S. aureus, and only the complexes RuCFE1,
RuCFE5 and RuCFE6 are active against E. coli. Inter-
mediate activity against E. coli was observed for
RuCFE2, RuCFE3, and RuCFE4.The complex RuCFE6
has the highest activity against S. aureus and E. coli,
and as explained above, it has the highest electron
transfer rate and the highest negative redox potential
among the examined complexes, which is attributed to
the presence of the pyrrole substituent. Moreover, pyr-
values, which indicates that the ruthenium (II) ciprofloxa-
cin complexes are more difficult to be oxidized compared
to the parent complex, implying that the ciprofloxacin
ligands withdrew the electron density from the metal cen-
ter, and hence are classified as good π-acceptor ligands,
which is also suggested from the UV–visible data that
showed a blue shift in the charge transfer (CT) band of the
complexes compared to the parent complex.
The CV of the ligands in the 0- to +2000-mV regions
showed irreversible oxidation wave (ꢃ1200 mV,
+
vs. Ag/Ag ), in which ligand CFE1, which has the phenyl
substituent, and the lowest oxidation potential value, is
thus considered the easiest one to be oxidized among the
investigated ciprofloxacin derivative ligands.
The negative region of the CV (0 to ꢀ 2800 mV) of the
complexes showed multiple quasi-reversible electrochem-
ical waves (Figures S23 and S24), which is most likely
due to the reduction and/or the oxidation of the coordi-
nated ligands, since their CVs have similar waves, but are
irreversible. Ruthenium (II) ion coordination to the cip-
rofloxacin derivative promoted the reversibility of the
electron transfer process (Figure S21) and hence
improved the electrical conductivity of the ligands. These
results demonstrate the influence of the metal ion on the
redox properties of the ligands and vice versa. Moreover,
the values of the redox potentials of these electrochemical
waves are different for each complex (Table S2), which
illustrate the effect of the enaminone substituents on the
redox properties of the complexes. For example, RuCFE6
complex has the highest E1/2 value, ꢀ 2080 mV, with the
smallest peak-to-peak separation ΔE p of 103 mV. Thus,
this complex has the highest reducing power and the
highest electron transfer rate compared to the other
investigated complexes. As explained above, RuCFE6 com-
plex has the pyrrole substituent that influences its electro-
chemical property, consequently influencing its biological
activity (see below). Both RuCFE5 and RuCFE2 also have
high E1/2 values (ꢀ 2063 and ꢀ 2070 mV, respectively),
but the ΔE p value of the former (137 mV) is less than
that of the later (170 mV), and therefore the rate of the
electron transfer is higher in the RuCFE5 complex than
in RuCEF2 complex. The substituent in RuCFE5 is furan
and in RuCEF2 is p-methylphenyl. Thus, pyrrole, furan,
and methylphenyl substituents have greater effect on the
electrochemistry of the complexes than the phenyl and
the p-chlorophenyl substituents.
[
28]
role is known for its antibacterial activity.
All of the
complexes are inactive against K. pneunomiae and ESBL
positive K. pneunomiae. This is possibly due to different
resistance mechanisms among these gram-negative
strains.
The coordination of ruthenium (II) ion improves
the antibacterial activity of some of the investigated
ciprofloxacin derivative ligands against S. aureus. For
example, ligands CFE1 and CFE3 are inactive against
S. aureus, whereas their ruthenium (II) complexes are
active. Even though there are slight differences in the
ꢀ
1
1 [18]
concentrations between the ligands (8.0 mg mL
)
ꢀ
and their ruthenium (II) complexes (10 mg mL ), the
zone of inhibition remained almost the same with
higher concentrations. Thus, the binding of the metal
ion to the ciprofloxacin derivatives influenced their
antibacterial activity. Furthermore, upon comparing the
values of the inhibition zone, the antibacterial activity
of copper (II) complexes of ciprofloxacin derivative
[
18]
ligands
is more than that of the ruthenium
(II) complexes of the same ligands. This demonstrates
the effect of the metal ion “type” on the antibacterial
activity of the ligands. Moreover, copper (II) complexes
are active against all tested gram-negative bacteria, in
contrast to the ruthenium (II) complexes, who are
active only against E. coli. In addition, none of the
tested compounds showed activity against the fungi
strains within the concentrations of the examined com-
pounds. The inhibition zones of the tested bacteria are
shown in Figures S26–S29.

AL-WAHAIB ET AL.
9 of 11
a
b
TABLE 4 Zone of inhibition (in mm) for ruthenium (II) ciprofloxacin derivatives complexes against the tested bacteria
Staphylococcus
Concentration aureus (G )
Escherichia
coli (G )
Klebsiella
pneunomiae (G )
ESBL Klebsiella
pneunomiae (G )
+
ꢀ
ꢀ
ꢀ
Sample
c
Gentamycin
10 mcg
15 mcg
30 mcg
5 mcg
8 mg mL
8 mg mL
8 mg mL
8 mg mL
8 mg mL
8 mg mL
30
19
—
21
NZH
21
NZH
16
20
26
—
—
27
21
20
22
13
21
25
24
—
—
16
21
—
—
—
—
—
—
—
—
14
21
—
—
—
—
—
—
c
Erythromycin
c
Cefotaxime
Ciprofloxacin
d
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
e
CFE1
CFE2
CFE3
CFE4
CFE5
CFE6
d
d
d
d
d
ꢀ
1
Ru (II)complex
of CFE1
10 mg mL
22
22
19
18
19
18
20
16
21
22
23
25
24
24
21
20
16
15
18
15
21
23
25
25
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
NZC
ꢀ1
20 mg mL
ꢀ
1
Ru (II) complex
of CFE2
10 mg mL
ꢀ1
20 mg mL
ꢀ
1
Ru (II) complex
of CFE3
10 mg mL
ꢀ1
20 mg mL
ꢀ
1
Ru (II) complex
of CFE4
10 mg mL
ꢀ1
20 mg mL
ꢀ
1
Ru (II) complex
of CFE5
10 mg mL
ꢀ1
20 mg mL
ꢀ
1
Ru (II) complex
of CFE6
10 mg mL
ꢀ1
20 mg mL
a
Average of triplicate measurements. Activity levels: gram negative strain (<14 mm resistant/inactive, 15–22 mm intermediate sensitivity/activity, >22 mm
sensitive/active), gram positive strain (<12 mm resistant/inactive, 13–14 mm intermediate sensitivity/activity, >14 mm sensitive/active).
b
Complexes were dissolved in ACN and triplicate disks were made for each complex. All disks were dried completely prior to incubation with the bacteria
ꢂ
strains at 37 C for 24 h.
c
For gram positive strain gentamycin and erythromycin antibiotics were used as positive control, and for gram negative strain cefotaxime antibiotic was used as
positive control, blank sterilized disk and disk with solvent only were used as negative controls.
d
From reference 18.
e
NZC = No zone of clearance.
4
| CONCLUSIONS
complex, this band is blue shifted in the newly prepared
ruthenium (II) ciprofloxacin complexes, suggesting an
increase in the stability of the molecular orbitals, which
is a characteristic of a π-acceptor ligand. Cyclic
voltammetry results showed one quasi-reversible wave in
the positive region at ꢃ600 mV, which is assigned to the
Ru (III)/Ru (II) couple and was similar among the com-
plexes. In comparison to the parent complex, this reduc-
tion is shifted to a higher positive potential value, which
indicates a decrease in the electron density on the metal
center. The values of ΔE and I /I of the complexes are
different, which is contributed to the different rate of the
electron transfer process and are related to
the enaminone substituent of the ligands. The UV–visible
and the cyclic voltammetry results suggest that the cipro-
floxacin derivative ligands are π-acceptor ligands. The
Six new ruthenium (II) complexes of ciprofloxacin
enaminone derivative ligands have been synthesized and
characterized. Elemental analysis, mass spectroscopy,
1
FTIR, cyclic voltammetry, UV–Visible spectroscopy, H
NMR, and XPS were used to determine their structures
and to explore their properties. FTIR spectra revealed
that the ciprofloxacin derivatives coordinate to the Ru
(II) ion as bidentate ligands via its pyridone carbonyl and
its carbroxylato oxygen atom. The complexes were shiny
dark-red compounds of high melting points and were
insoluble in aqueous solution. The UV–visible spectra of
the complexes showed a band in the visible region at
p
pa pc
5
14–519 nm, which is assigned as metal to ligand charge
transfer (MLCT) transition. In comparison to the parent

10 of 11
AL-WAHAIB ET AL.
XPS results showed the characteristic peaks of Ru3p3/2
and Ru3p1/2 as well as Ru3d5/2and Ru3d3/2 along with their
binding energy values, which confirmed the formation of
the ruthenium (II) ciprofloxacin complexes. The newly
synthesized compounds have promising activity against
gram-positive and gram-negative bacteria. All of the
ruthenium (II) complexes were active against S. aureus
and only RuCFE1, RuCFE5 and RuCFE6 complexes were
active against E. coli. The complexes were inactive on
K. pneunomiae and ESBL positive K. pneunomiae bacteria,
which may be due to the different resistance mechanisms
performed by the tested gram-negative bacteria strains.
Some of the complexes enhanced the antibacterial activ-
ity of the ligands. CFE1 and CEF3 ligands were inactive
against S. aureus, however the coordination of the Ru
Nada M. Abrar https://orcid.org/0000-0002-5789-010X
Tarek E. Khalil https://orcid.org/0000-0002-4441-733X
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Dhuha Al-Wahaib: Conceptualization; methodology;
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Tarek Khalil Akel: Conceptualization; investigation;
methodology; visualization.
[
[
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CONFLICT OF INTEREST
[21] E. K. Efthimiadou, Y. Sanakis, C. P. Raptopoulou, A.
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DATA AVAILABILITY STATEMENT
The data that support the findings of this study are avail-
able in the supporting information of this article.
ORCID
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