Synthesis, characterization, antimicrobial activity, 3D-QSAR, DFT, and molecular docking of some ciprofloxacin derivatives and their copper(II) complexes

Article abstract of DOI:10.1002/aoc.5998

Six new derivatives of ciprofloxacin compounds and their copper(II) complexes were synthesized, characterized by spectroscopic methods (ultraviolet–visible [UV–vis], Fourier transform infrared [FTIR], nuclear magnetic resonance [NMR], mass spectrometry [M

Full text of DOI:10.1002/aoc.5998

Received: 17 June 2020
DOI: 10.1002/aoc.5998
Revised: 7 August 2020
Accepted: 15 August 2020
F U L L P A P E R
Synthesis, characterization, antimicrobial activity, 3D-
QSAR, DFT, and molecular docking of some ciprofloxacin
derivatives and their copper(II) complexes
Tarek E. Khalil1
Nada M. Abrar2
| Ali El-Dissouky1
| Doaa S. El-Sayed1
| Dhuha Al-Wahaib2
|
1Chemistry Department, Faculty of
Science, Alexandria University,
Alexandria, 21321, Egypt
2Faculty of Science, Chemistry
Department, Kuwait University, Kuwait
City, 13060, Kuwait
Six new derivatives of ciprofloxacin compounds and their copper(II) complexes
were synthesized, characterized by spectroscopic methods (ultraviolet–visible
[UV–vis], Fourier transform infrared [FTIR], nuclear magnetic resonance
[NMR], mass spectrometry [MS], and electron paramagnetic resonance
[EPR]), and tested for antibacterial activities against gram-negative and gram-
positive bacteria. The data showed that ciprofloxacin derivatives act as bid-
entate ligands and the metal ions coordinate through the pyridone carbonyl
and the carboxylate oxygen atoms. Tetragonally distorted octahedral ligand
fields were assumed for all complexes based on their spectral studies.
Copper(II) complexes of the synthesized ciprofloxacin derivatives revealed
higher antibacterial activities against gram-positive and gram-negative bacte-
rial species than the parent ciprofloxacin antibiotic. Furthermore, three-
dimensional quantitative structure–activity relationship (3D-QSAR) models
were evaluated by studying 30 antibiotic compounds of the quinolone class.
Density function theory (DFT) calculations were applied to evaluate the opti-
mized geometrical structures using the B3LYP method and 6-311G(d,p) basis
set. The 3D-QSAR study revealed that there are eight optimum parameters that
give the best predictive modulation with good reliability (R2 = 0.996,
F = 12.004, sigma = 0.426). In silico molecular docking was also performed on
the derivatives, and the results revealed the presence of two types of interac-
tions between the Escherichia coli and the derivatives, H-bonding and Van der
Waals interactions, and an effective inhibition at the docked site.
Correspondence
Tarek E. Khalil, Chemistry Department,
Faculty of Science, Alexandria University,
P.O. Box 426-Ibrahimia, Alexandria
21321, Egypt.
Email: tarekakel@alexu.edu.eg;
tarekakel@yahoo.com
K E Y W O R D S
antimicrobial, ciprofloxacin, Cu(II) complexes, DFT, molecular docking
1 | INTRODUCTION
the introduction of bulky groups at C-7 were reported to
increase the spectrum of their antibacterial activity.[1]
Quinolones are synthetic antibiotics that are active
against both gram-positive and gram- negative bacteria.
They are efficiently absorbed in vivo and therefore are
bioavailable. Chemical modifications of quinolones by
Recent research on fluoroquinolones publicized that
increasing the lipophilicity at C-7 was found to enhance
its antibacterial activity. Furthermore, the introduction
of
a
triazole moiety into the N-1 position of
Appl Organomet Chem. 2020;e5998.
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© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5998

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KHALIL ET AL.
fluoroquinolones was found to have a great potential
with drug-resistant bacterial infections.[2]
become among the most promising tools used to design
and evaluate new molecules, identifying their effect in
medicinal chemistry.[28]
Ciprofloxacin (CF) belongs to Class II of the second-
generation fluoroquinolone. In addition to its
antibacterial activity, it also exhibits good antitumor
activity against P388 leukemia. Most of the research done
on ciprofloxacin has been focused on the functionality at
the C-7 position, but there is not enough research on cip-
rofloxacin derivatives or metal complexes of ciprofloxa-
cin.[3] The fluorine atom at C-6 and the piperazine ring at
C-7 play a significant role on the antibacterial activities
of ciprofloxacin.[4] Introducing a new substituent to the
terminal nitrogen atom of the ciprofloxacin piperazinyl
ring enhances its antibacterial activity.[5] For example,
Sriram et al.[6] used an indole moiety as a substituent at
C-7, which revealed better antimicrobial activities than
the parent ciprofloxacin. Also, a series of 1,2,4-triazole-
ciprofloxacin were found to possess higher antibacterial
activity than the parent ciprofloxacin. Identifying the
mode of the interaction between ciprofloxacin and RNA
proteins was used as a guide for drug design.[7-11]
The action of many drugs and their microbial inhibition
activity is influenced by their coordination with metal
ions.[12] In contrast, the presence of antacids or metal-
containing drugs decreases the bioavailability of ciprofloxa-
cin[13]; therefore, the interaction of metal ions with ciproflox-
acin has been investigated.[14–17] Generally, ciprofloxacin acts
as a bidentate ligand through the carbonyl and the carboxyl-
ate oxygen atoms. In strong acidic media, ciprofloxacin is
protonated and appears as a cation in the metal complexes.
In basic media, ciprofloxacin is deprotonated and acts as a
binding site for metal complexes.[17]
Ciprofloxacin complexes of Co(II), Ni(II), and
Cu(II) show antibacterial activities against different bacte-
rial strains.[18] Furthermore, Ni(II), Co(II), Ca(II), Zn(II),
Ag(II), Au(II), Mn(II), Mg(II), and Fe(II) complexes of
modified quinolones enhance the antibacterial activity of
the quinolone.[19,20] Recently, six novel transition metal
complexes of ciprofloxacin-p-nitro benzoyl have been syn-
thesized and tested for their medicinal applications.
Among the investigated complexes, copper(II) complexes
show the highest activity against human pathogens.[21]
Enaminones (E) are one of the most attractive inter-
mediates that can be used for the synthesis of therapeuti-
cally active heterocyclic compounds, such as quinolones.
They have been used as a preliminary material for the
synthesis of antibacterial, anti-inflammatory, anticonvul-
sant, and antitumor agents. Enaminones are versatile
synthones because of their rapidity in both electrophilic
and nucleophilic attacks.[22–24]
Because there are not many studies about ciprofloxa-
cin derivatives with enaminones, the objectives of the
present research are to synthesize and to characterize
new ciprofloxacin derivative ligands by reacting cipro-
floxacin with six different enaminones (E1–E6), to syn-
thesize and to characterize copper(II) complexes of the
new ciprofloxacin derivatives (CFE1–CEF6), and to study
their antimicrobial activities. Also, the research aims to
investigate the electronic and the geometric structures of
the derivatives using the DFT, the three-dimensional
quantitative structure–activity relationship (3D-QSAR),
and in silico molecular docking to understand the mode
of the interactions between the derivatives and the
Escherichia coli's receptors, which are believed to be
important in drug design.
2 | MATERIALS AND METHODS
2.1 | Materials
Dimethylformamide dimethylacetate (94%), acetophe-
none (99%), 2-acetylfuran (99%), 4-nitroaceto-phenone
(98%), 4-methylacetophenone (95%), 2-acetylpyrrole
(99%), 4-chloroacetophenone (97%), p-xylene (99%), etha-
nol absolute (99.8%), methanol (99.9%), and sodium
metal (99.9%) were purchased from Sigma-Aldrich.
Diethylether (99.7%), dioxane (99.5%), acetonitrile
(99.9%), acetic acid, and meluller hinton agar were pur-
chased from Merck Group, whereas dimethylsulphoxide
and sodium hydroxide (98%) were purchased from Fluka.
The following chemicals were purchased from different
sources as indicated: copper(II) chloride dihydrate (FSA,
98%) and N,N-dimethylformamide (Scharlau, 99.5%). The
following antibiotic susceptibility testing disks were pur-
chased from Himedia: ceftazidime, cefotaxime, gentami-
cin, and erythromycin. All materials and solvents were
used as received.
2.2 | Instrumentation
Elemental analyses were performed using an Elementar
1
Vario Micro Cube CHNS analyzer. The H NMR spectra
were recorded on a Burker DPX 400 and 600 MHz using
tetramethyl silane (TMS) as an internal reference. Infra-
red spectra measurements (KBr disks, 4,000–400 cm−1
)
Moreover, computational studies, such as density
function theory (DFT), quantitative structure–activity
relationship (QSAR), and molecular docking,[25–27] have
were recorded using Jasco FT-IR-6300 spectrophotome-
ter. The ultraviolet (UV)–visible spectra were recorded
using a Varian Cary-5 double beam spectrometer. Mass

KHALIL ET AL.
3 of 16
spectroscopy and fast atomic bombardment (FAB) were
performed on high-resolution gas chromatography–mass
spectrometer–double-focusing sector (GC-MS-DFS). Ioni-
zation was accelerated with Cs ions with energies of
−70.1 eV. 3-Nitrobenzyl alcohol was used as the matrix.
Electron spin resonance (ESR) spectra were recorded on
a Burker ECS 106 ESR spectrometer, operating at
9–10 GHz. The melting point was recorded on an
Electro-thermal 9100 melting point instrument with a
temperature range of 45–350ꢀC. The pH value was mea-
sured using Orion 420APlus basic bench-top pH meter.
The synthesized compounds were dried in an Isotemp
281A vacuum oven with a temperature up to 280ꢀC.
2.6 | Biological activity study
A Kirby–Bauer disk diffusion method[29] was followed to
study the activity of the synthesized compounds against
three gram-negative bacteria (E. coli, Klebsiella
pneumoniae, and extended-spectrum β-lactamases
[ESBL] positive K. pneumonia) and one gram-positive
bacterium (Staphylococcus aureus). The test was per-
formed under sterile conditions. Ceftazidime and
cefotaxime antibiotics were used as controls in the case of
the gram-negative bacteria, whereas gentamicin and
erythromycin antibiotics were used as controls for the
gram-positive bacterium. The tested compounds were dis-
solved in DMSO (2–20 mg ml−1) and at least 2–3 filter
paper disks were made from each compound. The disks
were allowed to air dry for 24–48 h prior to its inocula-
tion with the specific bacteria. The plates were then incu-
bated in an L-C incubator (Barnstead Labline) at 37ꢀC for
24–36 h. The inhibition zone surrounding each disk was
measured in millimeter.
2.3 | Synthesis of enaminones (E)
Enaminone compounds (E1–E6) were synthesized as fol-
lows: N,N-dimethylformamide-dimethylacetal (DMF-
DMA) (100 mmol, 13 ml) was added to an equivalent
amount of the corresponding phenone derivative
(100 mmol) in the presence of ethanol (10 ml) as a sol-
vent. The reaction mixture was refluxed for 48 h and then
slowly evaporated to half its volume. On cooling, the
product was separated out by filtration and then dried
under vacuum.
2.7 | Computational methodology
2.7.1 | Method of calculations
The calculations performed on 30 previously synthesized
quinolone derivatives[30,31] were carried out using Gauss-
ian 09[32] computational package in the gas phase. The
optimized geometries were verified by performing the
DFT/B3LYP method combined with 6-311G(d,p) basis set
and by frequency calculation.[33,34] Gauss view 06 was
used to visualize the molecular electrostatic potential sur-
face and the highest occupied molecular orbital
(HOMO)–lowest unoccupied molecular orbital (LUMO)
structures.[35] The 3D structures of the compounds were
visualized using Avogadro[36] and Chemcraft software.[37]
Chem3D software was used for the generation of Protein
Data Bank (PDB) files of the designed models for molecu-
lar docking. The bond dissociation energy (BDE) of the
hydroxyl group in each flouroquinolonic compound was
calculated using the following equation:
2.4 | Synthesis of ciprofloxacin derivative
ligands (CFE)
The ciprofloxacin derivative ligands (CFE1–CFE6) were
synthesized by dissolving ciprofloxacin (CF) (5–10 mmol)
in distilled water (5 ml); then, dioxane (10 ml) and the
enaminones (E1–E6) (5–10 mmol) were added to the cip-
rofloxacin solution. The reaction mixture was refluxed
for 3 h, and the product was filtered and washed with
ethanol (3 × 25 ml) and distilled water (3 × 25 ml) and
then crystallized using DMF.
2.5 | Synthesis of copper(II) complexes
BDE = Eradical + EH −Eneutral molecule
,
ð1Þ
Ciprofloxacin derivatives (CFE1–CFE6) (0.3 mmol) were
dissolved in DMF-ethanol (5:20, v/v) with continuous
stirring. Next, NaOMe (0.3 mmol) was added to
deprotonate the derivatives. CuCl2.2H2O (0.15 mmol) in
ethanol (10 ml) was then added slowly to the derivatives
reaction mixture and the reaction was refluxed for 6 h.
The precipitated complex was filtered off and washed
with DMF (3 × 25 ml), followed by ethanol (3 × 25 ml)
and dried under vacuum for 24 h.
where EH is the energy of a single H atom at the
B3LYP/6-311G(d,p) level and Eradical is the energy obtained
by geometry optimization of the radicals formed after
abstracting a hydrogen atom from the OH group of the
studied ciprofloxacin derivatives. The polarizable contin-
uum model (PCM)[38,39] was performed to examine the sol-
vent effects on the properties of the designed compounds.

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KHALIL ET AL.
2.7.2 | QSAR model prediction
visualization. The binding sites with the PDB file were
prepared using iGemdock 2.1 software, and the best
docked pose of the ligand is analyzed with the receptor
for interactions.
QSAR modeling is one of the most suitable approaches for
the prediction and validation of applicable quantitative
properties.[40] Previous studies identified some quinolone
derivatives as potent antibiotics. As determined from the
technique of model construction, the compounds were
divided into a training class (80%) and a test class (about
20%) of quinolones. The result evaluated from molecular
docking can become more efficient when it is compared
with biological system analysis.[41,42] Prior to the statistical
modulation, 3D-PaDEL molecular descriptors[43] of
30 optimized structures were calculated using the online
ChemDes, which is an integrated web-based platform for
molecular descriptor and fingerprint computation.
3 | RESULTS AND DISCUSSION
3.1 | Synthesis and characterization of
ciprofloxacin derivative ligands
The general reaction pathways for the synthesized
enaminones and ciprofloxacin derivative ligands (CFE1–
CFE6) are shown in Scheme 1. The enaminones were
first produced from the reaction between DMF-DMA and
acetophenone, and then they were reacted with ciproflox-
acin to produce the ciprofloxacin derivative ligands. The
elemental analysis and the physical properties of the syn-
thesized ciprofloxacin derivative ligands (CFE1–CFE6)
are listed in Table 1. The elemental analysis data of the
prepared ciprofloxacin derivative ligands confirmed their
expected stoichiometry. All ciprofloxacin derivative
ligands were soluble in DMSO, DMF, as well as pyridine.
They were sparingly soluble in most organic solvents and
were insoluble in water.
2.7.3 | Molecular docking performance
Novel sets of flouroquinolones were selected for
the model prediction in the molecular docking studies.
The 3D molecular target of the protein was retrieved
from the PDB. Molecular docking was applied on E. coli
as the receptor (PDB ID: 3T88), in which ions, small
ligands, and water molecules were removed and polar
hydrogens were added. The optimized molecules were
docked into the active site of the E. coli to study their
interactions and to make a theoretical correlation with
their anticancer activities. A molecular docking study
was performed using the iGemdock 2.1 software[44] and
Chimera 1.13.1[45] along with the pymol software[46] for
1
3.1.1 | H NMR
The d6-1H NMR spectra are shown in Figures S1–S3 and
the characteristic chemical shifts of the protons (δ, ppm)
SCHEME 1 Synthesis of enaminones and ciprofloxacin derivative ligands

KHALIL ET AL.
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TABLE 1 Elemental analysis, color and melting point of the synthesized ciprofloxacin derivatives and their copper(II) complexes
Experimentally obtained
(theoretically expected)
Compound (Formula of compound)
CFE1 (C26H24FN3O4)
MW
461.48
Color
Yellow
Yield % m. p. ꢀC % C
% H
67.24 (67.67) 5.02 (5.24)
68.03 (68.2) 5.57 (5.51)
60.46 (60.76) 4.62 (4.90)
% N
9.13 (9.11)
72
70
71
73
61
292
273
251
281
275
CFE2 (C27H26FN3O4)
475.51
513.95
515.48
469.46
Yellow
Yellow
Orange
8.91 (8.84)
8.13 (8.18)
CFE3.H2O (C26H25FClN3O5)
CFE4.1/2H2O (C26H24FN4O6.5
CFE5.H2O (C24H24FN3O6)
)
60.51 (60.52) 4.49 (4.65) 10.88 (10.86)
61.57 (61.4) 5.2 (5.15) 9.05 (8.95)
Light
yellow
CFE6 (C24H23FN4O4)
450.46
1,038.6
Light
yellow
65
70
268
63.45 (63.99) 5.43 (5.15) 12.14 (12.44)
[Cu(CFE1)2(H2O)].2H2O
(C52H52CuF2N6O11)
Green
>300
60.63 (60.14) 5.15 (5.05)
61.9 (61.85) 5.3 (5.19)
8.05 (8.09)
[Cu(CFE2)2(H2O)2] (C54H54CuF2N6O10)
1,048.6
1,089.4
Green
Green
63
67
>300
>300
8.3 (8.01)
[Cu(CFE3)2(H2O)2]
(C52H48CuCl2F2N6O10)
57.63 (57.33) 5.05 (4.44)
54.95 (54.47) 4.84 (4.57)
56.38 (56.61) 4.92 (4.75)
8.02 (7.71)
[Cu(CFE4)2(H2O)2].2H2O
(C52H52CuF2N8O16)
1,146.6
1,018.5
998.5
Orange
Green
Green
64
57
52
>300
>300
>300
10.2 (9.77)
8.06 (8.25)
[Cu(CFE5)2(H2O)2].H2O
(C48H48CuF2N6O13)
[Cu(CFE6)2(H2O)].H2O
(C48H48CuF2N8O10)
57.74 (57.74) 4.87 (4.85) 10.75 (11.22)
with their assignments are given in Table 2. Ciprofloxa-
cin piperazine ring protons, which appear at 2.9 δ ppm
and 3.2 δ ppm in ciprofloxacin, have been shifted further
downfield in ciprofloxacin derivatives.[47] This shift can
be attributed to the deshielding effect of the enaminone
derivatives through the piperazine ring of the ciprofloxa-
cin. The propyl group, flouro phenyl ring, pyridone ring,
and carboxylic hydrogen atoms retained their chemical
TABLE 2 1H NMR data for ciprofloxacin derivative ligands (in δ ppm)
Piperazine
ring
Flouro
Pyridone
ring
Ligand Propyl ring
COHC CH
phenyl ring
Aryl ring
7.45 (m, 2H), 7.5
COOH
CFE1
CFE2
CFE3
CFE4
CFE5
CFE6
1.20 (d, 2H), 1.32
3.44 (t,4H),
3.72 (s, 4H)
6.16(d, 1H),
7.79 (d, 1H)
7.61 (d, 1H),
7.94 (d, 1H)
8.67
15.16
(d, 2H), 3.84 (m, 1H)
(s, 1H)
(m, 1H), 7.93 (d, 2H),
(s, 1H)
1.20 (d,2H,), 1.32
3.44 (t, 4H)
3.71 (s, 4H)
6.15(d, 1H),
7.76 (d, 1H)
7.61 (d, 1H),
7.95 (d, 1H)
8.68
7.26 (d, 2H), 7.84
15.19
(d, 2H), 3.84 (m, 1H)
(s, 1H)
(d, 2H), 2.36 (s, 3H, CH3)
(s, 1H)
1.20 (m, 2H), 1.32
3.44 (t, 4H)
3.73 (s. 4H)
6.16(d, 1H),
7.82 (d, 1H)
7.61 (d, 1H),
7.95 (d, 1H)
8.68
7.51 (d, 2H),
7.96 (d, 2H)
15.18
(m, 2H), 3.84 (m, 1H)
(s, 1H)
(s, 1H)
1.20 (s, 2H), 1.32
3.46 (s, 4H)
3.78 (s. 4H)
6.22(d, 1H),
7.90 (d, 1H)
7.62 (d, 1H),
7.95 (d, 1H)
8.68
8.16 (d, 2H),
8.29 (d, 2H)
15.14
(t, 2H) 3.84 (m, 1H)
(s, 1H)
(s, 1H)
1.20 (s, 2H), 1.32
3.43 (s, 4H)
3.68 (s. 4H)
5.95(d, 1H),
7.75 (d, 1H)
7.61 (d, 1H),
7.95 (d, 1H)
8.67
6.63 (t, 1H), 7.18
15.19
(d, 2H) 3.84 (m, 1H)
(s, 1H)
(d, 1H), 7.83 (s, 1H)
(s, 1H)
1.21 (t, 2H), 1.31
3.42 (t, 4H)
3.63 (s. 4H)
5.94(d, 1H),
7.62 (d, 1H)
7.60 (d, 1H),
7.92 (d, 1H)
8.66
6.12 (m, 1H), 6.88
(d, 2H), 6.91 (d, 2H),
11.48 (s, 1H, NH)
15.16
(t, 2H) 3.83 (m, 1H)
(s, 1H)
(s, 1H)

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KHALIL ET AL.
shifts in the synthesized derivatives, whereas the chemi-
cal shifts of the piperazinyl ring and the alkene seg-
ment showed a slight difference among the derivatives,
which can be explained by the different substituents
attached to the α,β-unsaturated ketone moiety present
in all ciprofloxacin derivatives. The hydrogen atoms of
the p-nitro phenyl substituent in the CFE4 derivative
revealed the greatest downfield shift in the aryl ring
hydrogen atoms compared with the other substituents.
This shift may be due to the higher electronegativity of
the nitro group (electron withdrawing). The d6-1H
NMR spectra of CFE5 and CFE6 ligands display a
remarkable up-field shift in the alkene and aryl ring
hydrogen atoms compared with the other substituents.
The up-field shift of the enaminone-containing furan
(CFE5) and pyrrole (CFE6) could be a result of their
shielding effect.
broad absorption band at 3,421–3,502 cm−1 assigned to
the hydroxyl ν(O H) stretching frequency of the carbox-
ylic group. The band at 1,703–1,726 cm−1 is assigned to
the carboxylate ν(C O)carb stretching frequency. The
band at 1,625–1,632 cm−1 is assigned to the pyridone car-
bonyl band ν(C O)py.[12,48] The UV–visible spectra of the
ciprofloxacin derivatives are shown in Figure S9. The
spectra display two absorption bands at 280–284 and
340–368 nm, which are assigned to π ! π* and n ! π*
transitions, respectively.
3.2 | Synthesis and characterization of
copper(II) complexes
Copper(II) complexes were synthesized by the addition of
copper(II) solution to a deprotonated ciprofloxacin deriv-
ative solution in basic media at a molar ratio of 1:2 as
shown in Scheme 2 and according to the following chem-
ical equation.
3.1.2 | Mass spectra
Â
Ã
Cu2 + + 2ðCFEÞ− ! CuðCFEÞ ðH2OÞ :mH2O,
n = 1-2and m = 0-2:
The mass spectra of the ciprofloxacin derivatives are
shown in Figures S4–S6, and the general fragmentation
pattern is shown in Figure 1. All spectra display the par-
ent ion [M + H]+. The fragments with m/z = 202,
257, 287, and 331 are commonly observed in all spectra.
In addition, the aryl ketone segment in each ligand is also
detected at mass range m/z = 94–150.
2
n
The elemental analysis and some of the physical
properties of the synthesized copper(II) complexes are
given in Table 1. The elemental analysis data confirmed
the expected stoichiometry of the complexes. All
copper(II) complexes were insoluble in most organic sol-
vents and water but soluble in DMSO and other coordi-
nating solvents, such as pyridine derivatives. The melting
point values indicate that copper(II) complexes are ther-
mally more stable compared with the free ciprofloxacin
derivative ligands. This may be attributed to the forma-
tion of a strong coordinate bond.
3.1.3 | FTIR and UV–visible
The Fourier transform infrared (FTIR) and UV–visible
spectra of the ciprofloxacin derivatives are shown in
Figures S7–S9. Their FTIR characteristic absorption
bands along with their UV–visible data are summarized
in Table 3. The ciprofloxacin displays a broad absorption
band at 3,528, 1,707, and 1,624 cm−1, assigned to
hydroxyl ν(O H), carboxylate ν(C O)carb and pyridone
carbonyl ν(C O)py stretching bands, respectively.[48] The
spectra of all derivatives (CFE1–CFE6) display a medium
3.2.1 | Mass spectra
The mass spectra of all copper(II) complexes are shown
in Figures S10–S12. The spectra display the parent ion
FIGURE 1 (a) Common fragments and
(b) general fragmentation pattern in the
synthesized ciprofloxacin derivatives

KHALIL ET AL.
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KHALIL ET AL.
SCHEME 2 Synthesis and proposed structures of copper(II) complexes derived from ciprofloxacin derivative ligands
[M + 1]+, except the spectrum of the [Cu(CFE2)2(H2O)2]
complex, where the molecular ion peak does not have
the aryl vinyl ketone segment. Also, all complexes spectra
show the loss of one ligand molecule except
[Cu(CFE2)2(H2O)2] complex.
coordinated water molecule.[49–51] The elemental analysis
and FTIR spectral data confirm the assumed structures of
the complexes shown in Scheme 2. Furthermore, all
ligands act as monobasic bidentate ligands and are coor-
dinated to the copper(II) ions via the carboxylato and
quinolone oxygen atoms.
3.2.2 | Fourier transform infrared
The FTIR spectra of the copper(II) complexes are shown
in Figures S13–S14, and the characteristic absorption
bands are listed in Table 3. Upon copper(II) complexa-
tion, the characteristic carboxylate ν(C O)carb band dis-
appeared, whereas the pyridone carbonyl ν(C O)py band
appeared at 1,628–1,632 cm−1. In addition, the spectra
show two characteristic bands in the range of 1,552–1,608
and 1,341–1,400 cm−1 that could be assigned to the asym-
metric carboxylate ν(COO−)asym and the symmetric car-
boxylate ν(COO−)sym stretching frequencies, respectively.
The difference between these stretching frequencies [Δ
3.2.3 | UV–visible spectra and magnetic
moment measurements
The electronic spectra of copper(II) complexes are
shown in Figures S15 and S16, and the data are summa-
rized in Table 3. The UV–visible spectra of all the com-
plexes exhibit two bands at 280–284 and 331–368 mm
because of π ! π* and charge transfer (CT) transitions,
respectively. Furthermore, the electronic absorption
spectra of [Cu(CFE2)2(H2O)2], [Cu(CFE3)2(H2O)2],
[Cu(CFE4)2(H2O)2].2H2O, and [Cu(CFE5)2(H2O)2].H2O
complexes exhibit one asymmetric broad absorption
band in the visible region with a maximum at 748, 723,
νCOO = ν(COO−)asym − ν(COO−)sym] is in the range of
−
193–212 cm−1, which indicates a monodentate coordina-
tion mode of the carboxylato group of the ligands. More-
over, the FTIR spectra of the complexes display a
medium broad band at 3,403–3,443 cm−1, which is
assigned to the hydroxyl ν(O H) stretching band of a
721, and 738 nm, respectively. This band is assigned to
2
the d–d transition B1g
!
2A2g that corresponds to a
distorted octahedral geometry (Scheme 2).[52] The
electronic spectra of [Cu(CFE1)2(H2O)].2H2O and
TABLE 4 ESR parameters for copper(II) complexes
Complex
g
g┴
gav
G
A
k
Ƒ
α2
Α
k
[Cu(CFE1)2(H2O)].2H2O
[Cu(CFE2)2(H2O)2]
[Cu(CFE3)2(H2O)2]
[Cu(CFE4)2(H2O)2].2H2O
[Cu(CFE5)2(H2O)2].H2O
[Cu(CFE6)2(H2O)].H2O
2.237
2.282
2.266
2.271
2.276
2.276
2.035
2.058
2.056
2.058
2.052
2.054
2.102
2.133
2.126
2.129
2.127
2.128
6.771
4.682
4.750
4.672
5.308
5.111
141.746
142.998
139.425
135.847
148.147
146.573
157.8
159.6
162.5
167.2
153.6
155.3
0.682
0.741
0.714
0.709
0.746
0.742
0.826
0.861
0.845
0.842
0.864
0.862
Abbreviation: ESR, electron spin resonance.

KHALIL ET AL.
9 of 16
[Cu(CFE6)2(H2O)].H2O complexes display a broad band
at 668 and 618 nm, respectively, which is consistent
with that reported for a five-coordinate copper(II) com-
plex or a cis-distorted octahedral copper(II) complex.[53]
Assuming a C4v symmetry for copper(II) complexes of
CFE1 and CFE6 ligands, the bands at 668 and 618 nm
of such parallel hyperfine structure indicates a covalent
copper-ligand bond. However, such splitting in the g┴
region is not observed due to the unresolved ligand
hyperfine interaction at room temperature. The values of
the
hyperfine
line
splitting
factor
A
of
k
135.847–148.147 G that are obtained from the spectra are
consistent with a strong and/or moderate distortion from
the planarity. In general, the empirical factor ƒ = g /A is
for those complexes could be assigned to 2B1
!
2E1
transitions.[52] The square pyramidal structure could be
attained via the coordination of four oxygen atoms from
two ciprofloxacin derivatives in addition to an oxygen
atom from one water molecule as shown in Scheme 2.
The effective magnetic moment (μeff) at room tempera-
ture for the isolated copper(II) complexes were found to
be in the range of 1.79 B. M.–1.90 B. M., which is con-
sistent with the spin-only value, suggesting the octahe-
dral or square pyramidal structure for these complexes.
k
k
an index of the tetragonal distortion and is calculated to
be 153.6–167.2 cm−1. The value is higher than or equal to
150 cm−1, indicating a weak and/or moderate distortion
that could be due to the flexible structure. In general, the
distortion from the planarity toward the tetragonally dis-
torted octahedral or tetrahedral structure results in a
decrease in the A and an increase in the g as shown in
k
k
several synthetic and biologically active examples involv-
ing copper(II). The value of the in-planar π bonding
parameter α2 can be estimated from the expression:
3.2.4 | ESR spectra
ꢀ
ꢁ
À
Á
α2 = A =0:036 + g −2:0023 + 3=7 g −2:0023 + 0:04:
The room temperature X-band ESR spectra of the poly-
crystalline copper(II) complexes are shown in
Figures S17–S18, and the spectral parameters are pres-
ented in Table 4. The spectra are of axial shape with the
k
k
┴
parameters g = 2.237–2.276 and g┴ = 2.035–2.058,
which are characteristics of dx −y and are popular in the
The values of 0.682–0.746 are consistent with covalent
copper-in-plane-ligand bonding, which agrees with the
results obtained for several ciprofloxacin copper(II)
complexes.[52,54]
k
2
2
ground state for all complexes. Moreover, the average
2
g value of 2.102–2.133 supports a dx −y2 ground state. The
values of G parameter of 4.682–6.771 indicate a negligible
direct or strong copper–copper interaction in the solid
state and an intermediate ligand field. The spectra show
a hyperfine structure in the parallel region because of the
coupling of the unpaired electron with the nuclear spin
(I = 3/2) of both 63Cu and 65Cu isotopes. The appearance
3.3 | Biological activity
The antibacterial activity of the newly synthesized cipro-
floxacin derivative ligands (CFE1–CFE6) is investigated
TABLE 5 Zone of inhibition for ciprofloxacin derivative ligands against the tested bacteria
Sample
Concentration
5 mcg
Staphylococcus aureus (G+) (mm)
Escherichia coli (G−) (mm)
Ciprofloxacin
CFE1
21
NZC
NZC
20
21
10
20
19
22
12
13
15
21
21
25
21
24
4 mg ml−1
8 mg ml−1
4 mg ml−1
8 mg ml−1
4 mg ml−1
8 mg ml−1
4 mg ml−1
8 mg ml−1
4 mg ml−1
8 mg ml−1
4 mg ml−1
8 mg ml−1
CFE2
CFE3
CFE4
CFE5
CFE6
21
NZC
NZC
12
16
19
20
25
26
Abbreviation: NZC, no zone of clearance.

10 of 16
KHALIL ET AL.
TABLE 6 Zone of inhibition for copper(II) complexes against the tested bacteria
Staphylococcus
Escherichia
coli (G−)
(mm)
Klebsiella
pneumonia (G−)
(mm)
aureus (G+)
ESBL positive Klebsiella
pneumonia (G−) (mm)
Sample
Concentration (mm)
Ciprofloxacin
5 mcg
21
21
21
21
8
[Cu(CFE1)2(H2O)].2H2O
2 mg ml−1
4 mg ml−1
10 mg ml−1
2 mg ml−1
4 mg ml−1
10 mg ml−1
2 mg ml−1
4 mg ml−1
10 mg ml−1
2 mg ml−1
4 mg ml−1
10 mg ml−1
2 mg ml−1
4 mg ml−1
10 mg ml−1
2 mg ml−1
4 mg ml−1
10 mg ml−1
31
32
9
32.5
35.5
34.5
36
28
11
11.5
13
10
13.5
16
8
26.5
38
13
[Cu(CFE2)2(H2O)2]
11
31
15
39.5
32
30
16
[Cu(CFE3)2(H2O)2]
36
9.5
11.5
14.5
7.5
7
32.5
35.5
21
29
13.5
14
–
29.5
31.5
26
[Cu(CFE4)2(H2O)2].2H2O
[Cu(CFE5)2(H2O)2].H2O
[Cu(CFE6)2(H2O)].H2O
27
9
32.5
36
25
11
11
11
15
17
10
16
17
43
14
38.5
40
29.5
30
15
16.5
11
37
40
36.5
39
30.5
30.5
16.5
16
FIGURE 2 Correlations between
(a) MIC and EHOMO, (b) MIC and
ELUMO, (c) BDE and EHOMO, and
(d) BDE and ELUMO. BDE, bond
dissociation energy; HOMO, highest
occupied molecular orbital; LUMO,
lowest unoccupied molecular orbital;
MIC, minimum inhibitor concentration

KHALIL ET AL.
11 of 16
more sensitive against S. aureus than the parent cipro-
floxacin. Figures S19 and S20 show the zone of inhibi-
tion of the derivatives.
The antibacterial activity of copper(II) complexes of
ciprofloxacin was investigated against the bacteria
S. aureus, E. coli, K. pneumoniae, and ESBL positive
K. pneumonia (Table 6). All complexes are sensitive to
E. coli and S. aureus, and their sensitivity is higher than
the parent ciprofloxacin. Moreover, the complexes show
moderate sensitivity to K. pneumoniae and ESBL positive
K. pneumoniae. The results revealed that the presence of
the copper(II) metal ion enhanced the antibacterial reac-
tivity of the derivatives. For example, the derivative CFE3
was not active at all toward E. coli and S. aureus, but the
presence of copper(II) ion enhanced the derivative's reac-
tivity against the bacteria, and it became even more effec-
tive than the parent compound. This result illustrates the
profound effects of the metal ion on the properties of the
ligands. Figures S21–S24 show the zone of inhibition of
the synthesized copper(II) complexes.
FIGURE 3 Correlation between experimental and predicted
minimum inhibitor concentration (MIC) values
against the bacteria S. aureus, and E. coli (Table 5). All
derivatives, except CFE3, are active against E. coli; some
derivatives were found to be more sensitive to E. coli
than the parent ciprofloxacin (CFE2, CFE5, and CFE6).
Derivatives CFE2, CFE5, and CFE6 are sensitive to
S. aureus as well, where CFE6 derivative is found to be
FIGURE 4 The optimized theoretically efficient tested compounds using density function theory (DFT)/B3LYP method

12 of 16
KHALIL ET AL.
FIGURE 4 (Continued)
FIGURE 5 Docking poses between the protein of Escherichia coli and (a) ciprofloxacin, (b) CFE1, (c) CFE5, (d) CFE4, (e) CFE2, (f)
CFE6, and (g) CFE3

KHALIL ET AL.
13 of 16
3.4 | Computational calculations
but also depends on other important variables that may
cancel out the effect of the MO energies. On the other
hand, the studied trained antioxidant compounds have
closer MO energy values, which means that the antioxi-
dant activity appears in a specific range of HOMO and
LUMO energy values and this explains why these com-
pounds are biologically active.
The 3D optimized structures for the 30 selected
quinolones antioxidants using the B3LYP/6-311G(d,p)
method is shown in Figure S25. The HOMO, the LUMO,
the BDEs and the minimum inhibitor concentration
(MIC), as well as the energy gap values of the optimized
structures of the trained quinolones are shown in
Table S1. The plotting of either BDE or MIC with EHOMO
and ELUMO values gives an indirect or random correlation
(Figure 2). This indicates that the free radical formed via
bond dissociation mechanism does not only depend on
the energy values of HOMO and LUMO orbitals alone
3.4.1 | Model development and validation
Among the 3D-PaDEL molecular descriptors for the
30 quinolones that were classified as a training class, seven
FIGURE 6 Hydrogen bonding
between the designed compounds:
(a) CF, (b) CFE1, (c) CFE2, (d) CFE3,
(e) CFE4, (f) CFE5, (g) CFE6, and
Escherichia coli

14 of 16
KHALIL ET AL.
of them were classified as a test class, to ensure the validity
of the model. Different data sets have been performed
using SPSS 16 software.[55] Every quinolone derivative was
characterized by 435 variables. The key variables related to
the activity were screened using principal component
analysis (PCA) and multiple linear regression (MLR) sta-
tistical tools[56] applying the “leave-one-out” cross-
validation technique. The resulting model consist of eight
3D molecular descriptors with R2 = 0.996, F statis-
tic = 12.004, and sigma (standard deviation) = 0.426
(Figure 3). The training set and the test set comprised 80%
and 20% of the whole data set, respectively. Table S3 shows
the physical meaning of the molecular descriptors[57,58]
that are predicted to be effective in inhibiting the deriva-
tive effect in cells. Table S2 shows the values of the 3D
molecular descriptors of the trained compounds with the
experimental and the calculated MIC.
The possible H-bond formation is shown in Figure 6,
in which there are four possible H-bonds with two amino
acids, ARG 45 and GLN 112 of chain A, with bond
lengths 2.401 and 2.526 and 1.894 and 2.712 Å for ARG
45A and GLN 112, respectively. The modeling shows that
all ciprofloxacin derivatives have a larger docking (bind-
ing) energy than the parent ciprofloxacin and all deriva-
tives exhibit VDW binding mode with the receptor's
amino acids. This could explain the enhancement in the
sensitivity of the derivatives against E. coli compared with
the parent ciprofloxacin, which is also concluded from
the biological study results above. Therefore, the modifi-
cations of the parent compound produced more potent
antibacterial derivatives.
4 | CONCLUSIONS
The MIC falls in the normal range of the trained
quinolone compounds, which are biologically active. The
linear regression equation (Equation 1) gives a general
formula for the seven tested compounds in evaluating the
predicted MIC. Table S4 shows the effective 3D molecu-
lar descriptors with the calculated MIC for the eight
tested quinolone compounds. By applying the LR-
produced modeling equation on the tested compounds,
knowing the selected 3D molecular descriptors for each
one, the predicted values of MIC are determined, and
their values were found to be 0.01, 0.17, 0.13, 0.09, 0.22,
0.30, and 0.39 mol L−1 for CF, CFE1, CFE5, CFE4, CFE2,
CFE6, and CFE3, respectively. Figure 4 shows the opti-
mized structures of the tested quinolone compounds.
Novel ciprofloxacin derivative ligands have been synthe-
sized and characterized by H NMR spectroscopy, ele-
1
mental analysis, mass spectroscopy, FTIR, and UV–
visible. The ciprofloxacin derivatives were yellowish
powder-like compounds of high melting points and were
insoluble in water. The FTIR spectra of the ligands dis-
played carboxylate stretching bands ν(C O)carb at
1,703–1,726 cm−1 and pyridone carbonyl stretching bands
ν(C O)py at 1,625–1,632 cm−1. Copper(II) complexes of
the synthesized ciprofloxacin derivatives were also pre-
pared and characterized. The FTIR spectra of the com-
plexes showed that ciprofloxacin derivatives coordinated
to copper(II) ions as bidentate ligands via a pyridone car-
bonyl oxygen atom and carbroxylato oxygen atom.
The UV–visible spectra suggested a distorted octahe-
dral geometry for the complexes of CFE2, CFE3, CFE4,
and CFE5 ligands via the coordination of four oxygen
atoms from two ciprofloxacin molecules and two oxygen
atoms from two water molecules and a square pyramidal
geometry for the complexes of CFE1 and CFE6 ligands
via the coordination of four oxygen atoms from two cip-
rofloxacin molecules and an oxygen atom from a water
molecule. The ESR spectra confirmed the proposed
geometries of the complexes.
Most of the derivatives were sensitive toward E. coli,
and some were even more effective than the parent cipro-
floxacin. Derivatives CFE2, CFE5, and CFE6 were sensi-
tive to S. aureus as well. Therefore, the synthesized
derivatives are proven to be promising antibacterial
agents. Copper(II) complexes of the synthesized ciproflox-
acin derivatives also showed sensitivity against S. aureus,
E. coli, K. pneumoniae, and ESBL positive K. pneumoniae.
The presence of copper(II) ions enhanced the
antibacterial reactivity of the derivatives, illustrating the
effect of the metal ion on the properties of the ligands.
3.4.2 | Molecular docking of the designed
models
Computer drug design mainly deals with the tools of
molecular docking, which is used to explore the structural
and the interactions between drugs and the biological mol-
ecules; it is considered as a molecular recognition simula-
tion process. Molecular docking can be used to determine
the binding sites in the biological molecules and receptors.
In this study, molecular docking is used to determine the
possible binding sites between the synthesized ciprofloxa-
cin derivatives and E. coli crystal structures (BDP: 3T88).
Figure 5 shows the favorable interaction sites between the
ciprofloxacin derivatives and the E. coli receptor. The cal-
culated total binding energy, H-bond, and Van der Waals
(VDW) energies are listed in Table S5. The CFE4 deriva-
tive has the highest binding energy (−129.1 kcal mol−1).
This may be due to the presence of the nitro group that
possesses a suitable environment for H-bonds with the
amino acid of the receptor.

KHALIL ET AL.
15 of 16
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CONFLICT OF INTEREST
The authors declare that no conflict of interest.
AUTHOR CONTRIBUTIONS
Ali El-Dissouky: Supervision; visualization. Dhuha Al-
Wahaib: Investigation; methodology; visualization. Nada
Abrar: Methodology; resources; visualization. Doaa El-
Sayed: Formal analysis; methodology; software; validation.
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ORCID
Tarek E. Khalil https://orcid.org/0000-0002-4441-733X
Ali El-Dissouky https://orcid.org/0000-0001-6329-3259
Dhuha Al-Wahaib https://orcid.org/0000-0002-3081-
6911
Nada M. Abrar https://orcid.org/0000-0002-5789-010X
Doaa S. El-Sayed https://orcid.org/0000-0002-2366-
418X
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Khalil TE, El-
Dissouky A, Al-Wahaib D, Abrar NM, El-
Sayed DS. Synthesis, characterization,
antimicrobial activity, 3D-QSAR, DFT, and
molecular docking of some ciprofloxacin
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