Biology-Oriented Drug Synthesis (BIODS) Approach towards Synthesis of Ciprofloxacin-Dithiocarbamate Hybrids and Their Antibacterial Potential both in Vitro and in Silico

Article abstract of DOI:10.1002/cbdv.201800273

A novel series of ciprofloxacin-dithiocarbamate hybrids 7a?–?7l were designed, synthesized, and evaluated against Gram-positive and Gram-negative bacteria. A significant part of the title compounds showed considerable antibacterial activity against Gram-positive species. The most potent compound against Gram-positive bacteria was 2-chloro derivative 7h and the most potent derivative against Gram-negative bacteria was 3-chloro compound 7i. In?vitro antibacterial evaluation of compound 7h against clinically isolated bacteria methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) showed that this compound acted better than ciprofloxacin against the latter bacteria. Docking study of compound 7h in the active site of S.?aureus DNA gyrase revealed that this ciprofloxacin-dithiocarbamate derivative interacted with the main components of the active site of the enzyme.

Full text of DOI:10.1002/cbdv.201800273

Article Type: Full Paper
Biology-Oriented Drug Synthesis (BIODS) Approach towards Synthesis of
Ciprofloxacin-Dithiocarbamate Hybrids and Their Antibacterial Potential
both in vitro and in silico
Ensieh Nasli Esfahani a, Maryam Mohammadi-Khanaposhtani b, Zahra Rezaei c, Yosef Valizadeh c,
Ramazan Rajabnia d, Meghdad Bagheri e, Fatemeh Bandarian a, Mohammad Ali Faramarzi f, Nasrin
Samadi g, Mohammad Reza Amini h, Mohammad Mahdavi h, *, Bagher Larijani h,
*
a Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran
University of Medical Sciences, Tehran, Iran,
b Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of
Medical Sciences, Babol, Iran
c Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences,
Tehran, Iran
d Infectious Diseases and Tropical Medicine Research Center, Babol University of Medical Sciences,
Babol, Iran
e Infectious Diseases Research Center, Babol University of Medical Sciences, Babol, Iran
f Department of Pharmaceutical biotechnology, Faculty of Pharmacy and Biotechnology Research
Center, Tehran University of Medical Sciences, Tehran, Iran
g Department of Drug and Food Control, Faculty of Pharmacy and Pharmaceutical Quality Assurance
Research Center, Tehran University of Medical Sciences, Tehran, Iran
h Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences
Institute, Tehran University of Medical Sciences, Tehran, Iran, e-mail: momahdavi@tums.ac.ir (M.
Mahdavi), emrc@tums.ac.ir (B. Larijani).
A novel series of ciprofloxacin-dithiocarbamate hybrids 7a-l were designed, synthesized, and
evaluated against Gram-positive and Gram-negative bacteria. A significant part of the title
compounds showed considerable antibacterial activity against Gram-positive species. The most
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potent compound against Gram-positive bacteria was 2-chloro derivative 7h and the most potent
derivative against Gram-negative bacteria was 3-chloro compound 7i. In vitro antibacterial
evaluation of compound 7h against clinically isolated bacteria methicillin-resistant Staphylococcus
aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) showed that this compound
acted better than ciprofloxacin against the latter bacteria. Docking study of the compound 7h in the
active site of S. aureus DNA gyrase revealed that this ciprofloxacin-dithiocarbamate derivative
interacted with the main components of the active site of the enzyme.
Keywords: Ciprofloxacin • Dithiocarbamate • Docking study • Antibacterial activity • BIODS
Introduction
Increasing prevalence of bacterial resistance to the existing antibacterial drugs has become a major
public health concern worldwide [1-3]. Drug-resistant bacteria, especially multidrug-resistant (MDR)
bacteria, cause infections that are often associated with considerable mortality and morbidity [4]. It
has been estimated that MDR bacteria such as MRSA leads to 19000 deaths annually in the United
States [5]. Thus, there is considerable demand for the search, discovery, and development of new
potential antibacterial lead compounds [6].
Fluoroquinolones are an important class of antibacterial agents that are widely used in the
treatment of various bacterial infections [7]. Antibacterial effect of these synthetic drugs is created
by inhibiting bacterial topoisomerase II (DNA gyrase) and IV [8]. The study on structure-activity
relationship (SAR) in fluoroquinolones has revealed that the potency, safety, and physicochemical
properties of these compounds are greatly affected by the nature of available substituent on the C-7
position [9]. Ciprofloxacin (Fig. 1, A), the most commonly used fluoroquinolone derivative, has been
the subject for the synthesis of new antibacterial agents by biology-oriented drug synthesis (BIODS)
[10]. BIODS approach characterized with some structural modifications on existing medications by
one or two step synthesis and is a useful tool for achieve to new safe and effective drugs [11-13].
On the other hand, various derivatives of dithiocarbamate in combination with metals or
antibacterial agents such as monobactam as potent antibacterial agents have been reported [14-17].
Recently, Liu et al. introduced dithiocarbamate derivatives B that exhibited considerable
antibacterial activity (Fig. 1, B) [18].
In this regards, in our effort to identify bioactive compounds, we designed and synthesized a novel
series of C-7 modified ciprofloxacin derivatives 7a-l by incorporating dithiocarbamate moieties based
on BIODS (Fig. 1) [19-23]. The synthesized compounds 7a-l were evaluated for their in vitro
antibacterial activity against both Gram-positive and Gram-negative bacteria. Furthermore, the
docking study of title compounds was performed in the active site of the DNA gyrase, as a bacterial
topoisomerase II.
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Fig. 1. The structures of ciprofloxacin A, dithiocarbamate derivatives B, and designed compounds 7a-
l.
Results and Discussion
Chemistry
The synthetic pathway to obtain ciprofloxacin-dithiocarbamate hybrids 7a-l is presented in Scheme
1. Initially, sodium 4-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)piperazine-1-
carbodithioate 3 was prepared by a reaction of ciprofloxacin 1, carbon disulfide 2, and sodium
hydride in diethyl ether. On the other hand, 2-chloro-N-phenylacetamide derivatives 6 were
obtained from the reaction of aromatic amines 4 and chloroacetyl chloride 5 in the presence of DMF.
Finally, target compounds 7a-l were obtained from the reaction between compound 3 and 2-chloro-
N-phenylacetamide derivatives 6 in DMF.
Scheme 1. Synthesis of ciprofloxacin-dithiocarbamate hybrids 7a-l. Reagents and conditions: (a)
NaH, Diethyl ether, 0 °C, 1 h; (b) DMF, R.T, 7 h; (c) DMF, Reflux, 1 h .
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Pharmacology
In vitro antibacterial activity against standard bacteria. Antibacterial activities of the ciprofloxacin-
dithiocarbamate derivatives 7a-l were evaluated against standard bacteria Staphylococcus aureus
ATCC 6538 and Staphylococcus epidermidis ATCC 12228 as Gram-positive bacteria and Escherichia
coli ATCC 8739 and Pseudomonas aeruginosa ATCC 9027 as Gram-negative bacteria by the
conventional agar dilution procedure (Table 1).
The results demonstrated that most of the synthesized derivatives had satisfactory antibacterial
activity against Gram-positive bacteria. Among the synthesized compounds, compound 7h displayed
high activity against S. aureus and S. epidermidis with MIC value of 0.097 μg/mL, which was better
than that of the parent drug ciprofloxacin (MIC = 0.195 μg/mL). Compounds 7a, 7b, 7d, and 7g were
as potent as ciprofloxacin against both the studied Gram-positive bacteria and compounds 7c and 7f
against S. epidermidis. Regarding the activity against Gram-negative bacteria, compound 7i was the
most potent compound with MIC values 0.024 and 0.195 μg/mL against E. coli and P. aeruginosa,
respectively (Table 1). Moreover, compound 7j showed good antibacterial activity against E. coli with
MIC value of 0.097 μg/mL compared with 0.012 μg/mL for ciprofloxacin.
SAR study. Various substituted 2-chloro-N-phenylacetamides were used in the synthesis of
dithiocarbamate-ciprofloxacin hybrids 7a-l to evaluate the SAR and optimize the antibacterial
activity. These substituents included electron donating groups methyl and methoxy and electron
withdrawing substituent chloro.
The antibacterial screening results revealed that the type of substituents and their positions on the
pendant phenyl ring of the compounds 7a-l play an important role in the observed antibacterial
activities. Compound 7a without a substituent on the pendant phenyl group was as potent as
ciprofloxacin against S. epidermidis and S. aureus; however, it showed weak activity against E. coli
(MIC = 0.39 μg/mL) and P. aeruginosa (MIC = 25 μg/mL). The introduction of a methyl substituent on
the 2-position of the pendant phenyl ring in compound 7a, as in compound 7b, had no effect on the
antibacterial activity against Gram-positive bacteria but led to an increase in the activity against
Gram-negative bacteria (MIC = 0.195 and 3.125 μg/mL against E. coli and P. aeruginosa,
respectively). Changing the position of the methyl substituent on the pendant phenyl group from C-2
to C-4, producing 7c, diminished the activity against S. aureus (MIC = 0.39 μg/mL) and E. coli (MIC =
0.78 μg/mL) while the activity against P. aeruginosa increased (MIC = 1.56 μg/mL). The activity of
compound 7c against S. epidermidis was similar to compounds 7a, 7b, and ciprofloxacin (MIC = 0.195
μg/mL). Adding another methyl group at 5-position of the pendant 2-methyl-phenyl group of the
compound 7b, as in compound 7d, did not change the antibacterial activity against Gram-positive
bacteria but led to the loss of activity against Gram-negative bacteria. Moreover, compound 7e with
3,4-dimethylphenyl group showed a weaker antibacterial effect against all the studied bacteria in
comparison with that of the 4-methyl analog 7c.
Replacing the 2-methyl group with the 2-methoxy group in compound 7b led to decreased activity
against S. aureus (MIC = 0.39 μg/mL) and increased activity against P. aeruginosa (MIC = 1.56
μg/mL), as observed for compound 7f. The mentioned replacement did not affect the activity against
S. epidermidis and E. coli. On the other hand, replacement of the methoxy group instead of the
methyl group in the 4-methyl compound 7c, as in compound 7g, increased the antibacterial effect
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against S. aureus (MIC = 0.195μg/mL) and E. coli (MIC = 0.39 μg/mL) and decreased the activity
against P. aeruginosa (MIC = 50 μg/mL).
The introduction of the 2-chloro substituent on the pendant phenyl ring in compound 7a, as in
compound 7h, improved the antibacterial potency against Gram-positive bacteria whereas there
was no change in the activity against Gram-negative bacteria. Compound 7h was the most potent
compound among the synthesized ciprofloxacin-dithiocarbamate hybrids against S. aureus and S.
epidermidis. The movement of the chloro substituent into the 3-position of the pendant phenyl ring
(compound 7i) caused a significant increase in the activity against Gram-negative bacteria and a
considerable decrease in the activity against Gram-positive bacteria. Furthermore, 4-chloro
compound 7j also exhibited good and moderate activity against E. coli and P. aeruginosa,
respectively. Compounds 7i and 7j showed a moderate antibacterial effect against Gram-positive
bacteria. The introduction of the second chlorine atom on the chloro derivatives 7h-j led to a
significant decrease in antibacterial potency against the studied bacteria as observed for compounds
7k and 7l.
It is worthy to note that the most potent antibacterial derivatives among the synthesized
compounds were the chloro derivatives 7h (against Gram-positive bacteria) and 7i (against Gram-
negative bacteria).
Table 1. In vitro antibacterial data of compounds 7a-l (MIC in μg/mL).
Compound
R
S. aureus
0.195
0.195
0.39
S. epidermidis
0.195
0.195
0.195
0.195
0.78
E. coli
0.39
P. aeruginosa
25
7a
H
7b
2-Me
0.195
0.78
3.125
1.56
>100
>100
1.56
50
7c
4-Me
7d
2,5-dimethyl
3,4-dimethyl
2-OMe
4-OMe
2-Cl
0.195
0.78
>100
>100
0.195
0.39
7e
7f
0.39
0.195
0.195
0.097
0.39
7g
0.195
0.097
0.39
7h
0.39
25
7i
3-Cl
0.024
0.097
6.25
0.195
1.56
50
7j
4-Cl
0.39
0.39
7k
2,4-dichloro
3,4-dichloro
-
50
50
7l
6.25
3.125
0.195
3.125
0.012
50
Ciprofloxacin
0.195
0.195
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In vitro antibacterial activity of compound 7h against MSSA and MRSA. Compound 7h, being the
most potent compound against the standard S. aureus (MIC = 0.097 μg/mL), was evaluated against
the clinically isolated bacteria MSSA and MRSA. The results revealed that compound 7h with MIC
values 0.097 μg/mL against MSSA and 0.39 μg/mL against MRSA acted better than ciprofloxacin
against these clinically isolated bacteria. In this assay, the MIC values of ciprofloxacin against MSSA
and MRSA were 0.195 and 1.56 μg/mL, respectively.
Molecular docking study. To find a possible binding pose of the compound 7h in the active site of S.
aureus DNA gyrase, molecular modeling was carried out. For the docking procedure, the crystal
structure of Staphylococcus aureus DNA gyrase complexed with ciprofloxacin (pdb code: 2XCT) was
obtained from the RCSB protein data bank (http://www.rcsb.org) [24]. The superimposition
structure of ciprofloxacin and compound 7h in the active site of S. aureus DNA gyrase is presented in
Fig. 2.
As seen in Fig. 2, the drug binding pocket includes protein residues, Mn2+ ion, and DNA bases. The
importance of interaction with each of these components to exert the antibacterial effects of
fluoroquinolones is well-documented [25, 26]. Ciprofloxacin forms two hydrogen bonds with
Ser1084 and Arg458, two coordinate bonds with Mn2+, and interactions with thymine (DT8), cytosine
(DC12), guanine (DG9), and adenine (DA13) DNA bases [24]. The detailed 3D interactions of
compound 7h with the DNA gyrase binding pocket are given in Fig. 3. The synthesized compound 7h,
in addition to the hydrogen bonds with Ser1084 and Arg458, can form a hydrogen bond with Glu477
trough in the sulfur atom (Fig. 3). This compound, like ciprofloxacin, interacts with Mn2+ and DNA
bases DT8, DC12, DG9, and DA13 in the enzyme active site.
Fig. 2. Superimposition of the compound 7h (pink) and ciprofloxacin (cyan) in the DNA gyrase active
site.
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Fig. 3. Docking pose of the compound 7h in the active site of DNA gyrase.
Conclusions
In conclusion, a new series of ciprofloxacin-dithiocarbamate hybrids 7a-l were synthesized by a
convenient procedure. These compounds were evaluated against four standard bacteria (S.
Epidermidis, S. aureus, P. aeruginosa, and E. coli). Most of the synthesized hybrids showed good
activity against the Gram-positive bacteria, and among them, the most potent compound was 2-
chloro derivative 7h, with a 2-fold greater activity than ciprofloxacin. On the other hand, the most
potent compound against Gram-negative bacteria was 3-chloro derivative 7i. More evaluation of the
compound 7h showed that this compound had higher antibacterial activity against clinically isolated
bacteria MSSA and MRSA compared with that of ciprofloxacin. Molecular docking of compound 7h
revealed that this compound, compared with ciprofloxacin, forms an additional hydrogen bond in
the S. aureus DNA gyrase active site.
Experimental Section
Chemistry
1
The melting points of derivatives 7a-l were measured on Kofler hot stage apparatus. H- and 13C-
NMR were recorded on Bruker FT-400 and FT-500 (Germany). Infrared (IR) spectra were measured
on a Nicolet Magna FTIR 550 spectrometer (KBr disks). The CHN analysis was carried out using
Elementar Analysensysteme GmbH Vario EL (Germany).
Procedure for the synthesis of sodium 4-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-
7-yl)piperazine-1-carbodithioate 3. First, a solution of ciprofloxacin 1 (15 mmol) in diethyl ether (50
mL) was prepared. Then, sodium hydride (15 mmol) and carbon disulfide 2 (20 mmol) were added to
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the mentioned solution. The obtained mixture was stirred at 0 °C for 1 h. The generated precipitates
were filtered off and washed with Et2O (diethyl ether) and dried at 40 °C.
Synthesis of the 2-chloro-N-phenylacetamide derivatives 6. A mixture of aromatic amines 4 (1.5
mmol) and chloroacetyl chloride 5 (1.5 mmol) in DMF was stirred at room temperature for 7 h. Then,
it was poured into crushed ice, and the precipitated product was filtered off, washed with water,
and purified using recrystallization from ethanol to obtain pure products 6.
Preparation of the ciprofloxacin-dithiocarbamat hybrids 7. A mixture of compound 3 (1 mmol) and
appropriate 2-chloro-N-phenylacetamide derivatives 6 (1.2 mmol) in DMF (5ml) was stirred under
reflux at 100 °C for 1 h. After completion of reaction (monitored by TLC), the obtained mixture was
poured into crushed ice and the precipitated product was filtered off. Then, recrystallization in
ethanol was used to give pure target products 7. (See Supporting Information)
Biological Evaluation
In vitro antibacterial activity. The MIC values of the synthesized compounds 7a-l against four
bacterial strains including S. aureus, S. epidermidis, P. aeruginosa, and E. coli and compound 7h
against MSSA and MRSA were obtained using the conventional agar dilution procedure with
ciprofloxacin as the standard according to the described method by Baron et. al [27].
In silico molecular modeling. Docking study was performed using the Autodock Tools (version 1.5.6),
and the pdb structure of 2XCT was taken from the protein database (http://www.rcsb.org).
Subsequently, water molecules and the other additional molecules were removed from the enzyme
structure. The 3D structure 7h was obtained using MarvineSketch 5.8.3, 2012, ChemAxon
(http://www.chemaxon.com). After the preparation of the autodock format of the protein and
compound 7h, these structures were used as an input file for the AUTOGRID program. Coordinates
of the grid box center were x = 2.58, y = 43.78, and z = 65.25 Å, and the dimensions of the binding
pocket were set at 50 × 50 × 50 Å (centered at the geometrical center of co-crystallized ligand).
Flexible ligand docking was done for the compound 7h. After 50 runs of the AUTODOCK search, the
best position of the ligand (in terms of binding energy) was selected for analyzing the interactions
with enzyme. Discovery Studio 4.0 Client was used to visualize of the results (Figs. 2 and 3).
Supporting Information
Acknowledgements
Authors would like to acknowledge the research council of TUMS (Tehran University of Medical
Sciences) for financial support of this project.
Author Contribution Statement
E.N. Esfahani, F. Bandarian, and M.R. Amini contributed reagents and materials, and analyzed the
data. M. Mohammadi-Khanaposhtani and Z. Rezaei wrote the article and docking study. Y. Valizadeh
performed the synthesis of compounds. R. Rajabnia, M. Bagheri, M.A Faramarzi, and N. Samadi
performed the antibacterial assay. M. Mahdavi and B. Larijani conceived and designed the
experiments.
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