Design of ciprofloxacin derivatives that inhibit growth of methicillin resistant staphylococcus aureus (MRSA) and methicillin susceptible staphylococcus aureus (MSSA)

Article abstract of DOI:10.2174/157340610791321442

Three derivatives of ciprofloxacin (compound B, C, and D) were constructed utilizing microwave synthesis methodology (compound D) or diazoalkane reaction in nonaqueous solvent (compounds B and C). The final structures of the derivatives featured an ester group in place of the original carboxyl group of the ciprofloxacin. These ester groups contained aliphatic single carbon (compound B), two carbon length (compound C), or three carbon length propyl ester group (compound D). The ester groups strongly affected the molecular properties of the parent ciprofloxacin. As the size of the ester group increased the formula weight, molar volume, and number of rotatable bonds increased. The Log P for these compounds were -0.701, -0.441, -0.065, 0.437 for ciprofloxacin, B, C, and compound D, respectively. Numerical values of dermal permeability coefficient (Kp) increased rapidly as length of the ester carbon chain increased. The immediate consequence of Kp increase is an increased skin penetration rate based on dose and time span of administration. Polar surface area for ciprofloxacin is 74.569 Angstroms², but decreases to 63.575 Angstroms² for all three derivatives. All three derivatives of ciprofloxacin showed zero violations of the Rule of 5, indicating these drugs would have favorable bioavailability. Compounds A, B, C, and D were placed into tissue culture with methicillin resistant and susceptible Staphylococcus aureus (MRSA and MSSA, respectively) to determine levels of bacterial growth inhibition. All compounds induced greater than 60 % inhibition of MSSA at concentrations as low as 15.63 micrograms/milliliter. All four compounds induced greater than 80 % inhibition of MRSA at concentratins as low as 15.63 micrograms/milliliter. Development of novel drug designs will benefit the clinical treatment of dangerous infections of MSSA and MRSA.

Full text of DOI:10.2174/157340610791321442

Medicinal Chemistry, 2010, 6, 51-56
51
Design of Ciprofloxacin Derivatives that Inhibit Growth of Methicillin
Resistant Staphylococcus aureus (MRSA) and Methicillin Susceptible
Staphylococcus aureus (MSSA)
Ronald Bartzatt1,*, Suat L.G. Cirillo2 and Jeffrey D. Cirillo2
1University of Nebraska, College of Arts & Sciences, Durham Science Center, Chemistry Department, 6001 Dodge
2
Street, Omaha, Nebraska 68182 USA; Texas A & M Health Science Center, Dept. of Microbial and Molecular Patho-
genesis, 467 Reynolds Medical Building, College Station, Texas 77843 USA
Abstract: Three derivatives of ciprofloxacin (compound B, C, and D) were constructed utilizing microwave synthesis
methodology (compound D) or diazoalkane reaction in nonaqueous solvent (compounds B and C). The final structures of
the derivatives featured an ester group in place of the original carboxyl group of the ciprofloxacin. These ester groups con-
tained aliphatic single carbon (compound B), two carbon length (compound C), or three carbon length propyl ester group
(compound D). The ester groups strongly affected the molecular properties of the parent ciprofloxacin. As the size of the
ester group increased the formula weight, molar volume, and number of rotatable bonds increased. The Log P for these
compounds were -0.701, -0.441, -0.065, 0.437 for ciprofloxacin, B, C, and compound D, respectively. Numerical values
of dermal permeability coefficient (Kp) increased rapidly as length of the ester carbon chain increased. The immediate
consequence of Kp increase is an increased skin penetration rate based on dose and time span of administration. Polar sur-
face area for ciprofloxacin is 74.569 Angstroms2, but decreases to 63.575 Angstroms2 for all three derivatives. All three
derivatives of ciprofloxacin showed zero violations of the Rule of 5, indicating these drugs would have favorable
bioavailability. Compounds A, B, C, and D were placed into tissue culture with methicillin resistant and susceptible
Staphylococcus aureus (MRSA and MSSA, respectively) to determine levels of bacterial growth inhibition. All com-
pounds induced greater than 60 % inhibition of MSSA at concentrations as low as 15.63 micrograms/milliliter. All four
compounds induced greater than 80 % inhibition of MRSA at concentratins as low as 15.63 micrograms/milliliter. Devel-
opment of novel drug designs will benefit the clinical treatment of dangerous infections of MSSA and MRSA.
Keywords: Ciprofloxacin, Staphylococcus aureus, MRSA, MSSA.
INTRODUCTION
[4]. New designs for antimicrobials are urgently needed to
treat infections of the growing number of multi-drug resis-
tant Staphylococcus aureus [4,5]. Resistance to ciprofloxacin
has been shown not to differ significantly between detected
isolates of HA-MRSA and CA-MRSA [5]. The accessibility
of antimicrobials for treatment of Neisseria gonorrhoeae is
being threatened because of the rise of drug resistance, in-
cluding the fluoroquinolone class [6].
Ciprofloxacin is a broad spectrum fluoroquinolone drug
that is a synthetic chemotherapeutic agent used in the clinical
treatment of severe and life threatening infections. Cipro-
floxacin is active against both gram-positive and gram-
negative bacteria by interfering with DNA replication by
inhibiting DNA gyrase [1]. Ciprofoxacin inhibits DNA gy-
rase, a type II topoisomerase, and topoisomerase IV [1].
Other bacteria inhibited by ciprofloxacin include: Proteus
mirabilis, Proteus vulgaris, Escherichia coli, Pseudomonas
aeruginosa, and Neisseria gonorrhoeae.
Long term care facilities have been recently recognized
as repositories for multi-drug resistant gram negative bacte-
ria and that more than 80 % of detected isolates of these bac-
teria are resistant to ciprofloxacin and ampicillin/sulbactam
[7]. The bacteria resistance to commonly used antimicrobials
at long term care facilities is reducing the therapeutic options
for treatment [7]. Localization of HA-MRSA at catheter sites
raises concern for their implementation due to high resis-
tance of isolates to ciprofloxacin (33%), oxacillin (34%),
erythromycin (41%), and gentomicin (4.4%) [8]. Fully 50%
of derived nasal swabs have been shown to contain Staphy-
lococcus aureus resistant to ciprofloxacin and macrolides
[9]. Staphylococcus aureus has been found in lower urinary
tract infection isolates associated with diabetic patients [10].
Methicilllin resistant Staphylococcus aureus (MRSA) is
recognized as a world wide nosocomial pathogen and is a
cause of community acquired (CA-MRSA) infections that
are found world wide [2]. The liberal use of vancomycin to
treat the new threat increases the potential for developing
resistance by gram-positive bacteria [2]. Staphylococcus
aureus (and E. coli) have been found to be among the most
common hospital acquired (ie. HA-MRSA) bacteria showing
high resistance rates to ciprofloxacin (82.0 %) and ofloxacin
(83.4 %) [3], which are spreading rapidly across the world
Staphylococcus aureus is the most important bacteria for
human diseases associated with skin and mucous membrane
infections. Children have been recognized as particularly
important in the appearance and spread of MRSA with the
*Address correspondence to this author at the University of Nebraska,
College of Arts
& Sciences, Durham Science Center, Chemistry
Department, 6001 Dodge Street, Omaha, Nebraska 68182 USA; Tel: 402-
554-3612; Fax: 402-554-3888; E-mail: rbartzatt@mail.unomaha.edu
1573-4064/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

52 Medicinal Chemistry, 2010, Vol. 6, No. 2
Bartzatt et al.
additional hazards of relatively high rates of resistance to
antibiotics [11].
ethyl ester of the ciprofloxacin. In the case of drug D, mi-
crowave methodology (synthesis by microwave excitation of
functional groups in solid state conditions) was applied. Ini-
tially the carbonyl carbon of ciprofloxacin (see Fig. 2, lower)
is activated by thionyl chloride (SOCl2) during microwave
irradiation, then the introduction of n-propanol with addi-
tional irradiation forms the final propyl ester compound.
FIGURE 1
Circulating strains of CA-MRSA have characteristic
pathogenesis that are distinct from HA-MRSA [12]. Circu-
lating strains of CA-MRSA behave more like strains of CA-
MSSA, both of which have emerged on a global scale [12].
CA-MRSA causation of skin and soft tissue infections can
be site and population specific, a scenario that amplifies
problems for clinical diagnoses and treatment [13]. CA-
MRSA induction of even mild skin infections does not abro-
gate the need for adequate hygiene because severe necrotiz-
ing fascitis and pneumonia can follow [14-16]. CA-MRSA
can follow an aggressive clinical course that involves the
skin and leads to the lungs [15]. Skin and soft tissue infec-
tions are the most common manifestations of Staphylococcus
aureus among children [16,17]. Close contact among in-
fected individuals aggravates spread of infection particularly
with CA-MRSA [18-20] among children and site contamina-
tion in surgical environments [21]. High frequency of drug
resistance of Staphylococcus aureus (including MRSA) as-
sociated with cutaneous abscesses of HIV patients has re-
quired clinical focus on chemotherapy method [22]. The
observations cited clearly entails the need for new designs of
therapeutic antimicrobials.
Drug A Ciprofloxacin
O
O
F
OH
N
N
HN
1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydroquinoline-3-carboxylic acid
Drug B Methyl derivative of ciprofloxacin
O
O
F
CH3
O
N
N
HN
methyl 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydroquinoline-3-carboxylate
Drug C Ethyl derivative of ciprofloxacin
RESULTS AND DISCUSSION
Although ciprofloxacin is presently a broad spectrum
antimicrobial, the appearance of multidrug resistant patho-
genic bacteria clearly exacerbates clinical application. The
need for new drug designs to respond to these challenges is
striking. This work presents three derivatives of ciproflox-
acin which feature molecular properties that are advanta-
geous for bioavailability in addition to effective antibacterial
action against methicillin resistant and susceptible Staphylo-
coccus aureus.
O
O
F
O
CH3
N
N
HN
ethyl 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydroquinoline-3-carboxylate
Drug D Propyl derivative of ciprofloxacin
Ciprofloxacin as a synthetic fluoroquinolone (or qui-
nolone) drug features a fluorine atom, 1,4-dihydroquinoline
moiety, carboxyl group, and piperazine ring (see structure,
Fig. 1). The derivatives of ciprofloxacin (drugs B, C, and D)
will have ester functional groups to replace the former car-
boxyl group of ciprofloxacin. The ester groups will alter mo-
lecular properties of the parent structure and improve skin
permeation and penetration of lipid by-layers while retaining
substantial levels of antibacterial activity that is at least as
great as the parent ciprofloxacin or better. The structures and
chemical nomenclature of derivatives B, C, and D are pre-
sented in Fig. (1). Note the change of the carboxyl group
(inset circle) to aliphatic ester groups having one carbon
(drug B) to as many as three nonbranched carbons (drug D).
All other structural features of ciprofloxacin are retained in
these derivatives. The methyl (B), ethyl (C), and propyl (D)
ester of ciprofloxacin comprise a homologous series of an-
timicrobial chemotherapeutics.
O
O
F
CH3
O
N
N
HN
propyl 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydroquinoline-3-carboxylate
Fig. (1). The molecular structures of ciprofloxacin (compound A)
and derivatives B, C, and D are presented here for comparison. The
parent ciprofloxacin structure contains a prominent carboxyl group
(-COOH) (see inset circle0, aromatic ring, two tertiary amines, one
secondary amine, and fluorine atom. Drug B is a methyl ester de-
rivative of A, in which the carboxyl group is replaced by an ester
group (see inset rectangle). Drug C is an ethyl ester derivative of A,
in which the carboxyl group is replaced by an ester group (see inset
rectangle). Drug D is a proply ester derivative of A, in which the
carboxyl group is replaced by an ester group (see inset rectangle).
The synthesis of drugs B and C was accomplished by
application of diazoalkane reaction in a nonaqueous solvent
system. The general process is represented in Fig. (2). The
reactant ciprofloxacin is placed in acetonitrile (or ethyl ether)
and generated diazomethane is bubbled extensively through
the mixture. In the case of drug C the gas is diazoethane.
After several passes the product is specifically the methyl or
A comparison of molecular properties of ciprofloxacin to
these derivatives reveals several important features gained by
the formation of ester groups in place of the carboxyl group.
Expectedly the modification of carboxyl to ester functional
group (see Table 1) increases molecular weight and molar

Inhibition of Staphylococcus aureus
Medicinal Chemistry, 2010, Vol. 6, No. 2 53
GENERAL SYNTHESIS MECHANISM OF CIPROFLOXACIN DERIVATIVES
ALKYLATION OF CIPROFLOXACIN
O
N
O
O
N
O
F
CH3
F
O
N+
N
O~
N2
H3C
+
N
N
HN
HN
PROPYLATION OF CIPROFLOXACIN
O
N
O
O
N
O
F
OH
F
SO2
Cl
SOCl2
HCl
+
+
+
N
N
HN
HN
O
O
O
N
O
F
Cl
F
CH3
O
CH3CH2CH2OH
+
N
N
N
HN
HN
HCl
+
Fig. (2). Top: The alkylation of the carboxyl group initially present on the parent ciprofloxacin structure is reverted to an ester group by using
diazoalkane reaction synthesis in a nonaqueous solvent. The reaction is highly selective to acidic protons of a carboxyl group and results in
high yields after multiple passes. Drugs B (methyl ester) and C (ethyl ester) were synthesized by diazoalkane. Lower: The proplylation of
drug D, also done by microwave methodology, was carried out by activation of the carboxyl group utilizing thionyl chloride and then fol-
lowed by reaction with n-propanol.
Table 1. Molecular Properties of Ciprofloxacin and Derivatives
Drug
Log P
Polar Sur-
face Area
(Angstroms2)
Molecular
Weight
Number of
Oxygens
and
Number of Violations of
Number
Kp
Molar
Volume
(cm3 )
Hydroxyls
and
Rule of 5
of Rotatable (cm/hour)
Bonds
Nitrogens
Amines
A, Ciprofloxacin
B, Methyl-Cipro
C, Ethyl-Cipro
D, Propyl-Cipro
-0.701
-0.441
-0.065
0.437
74.569
63.575
63.575
63.575
331.35
345.37
359.40
373.43
6
6
6
6
2
1
1
1
0
0
0
0
3
4
5
6
2.87E-05
3.83E-04
7.01E-04
1.29E-03
226.7
252.1
268.6
285.1
volume.Additionally the presence of lengthening aliphatic
ester branch increases the lipophilic nature of the drug as
indicated by the steadily increasing numerical values of the
partition coefficient Log P (ie. From -0.441 of B to 0.437 of
D). The increase of Log P values indicates a steadily increas-
ing solubility of the drug into the lipid by-layers of the cellu-
lar membrane of the bacteria and presumably increased
penetration into the microbe. Increased penetration by the
ciprofloxacin derivative into the target bacteria would en-
hance efficacy of the drug. The number of oxygens and ni-
trogens (hydrogen bond acceptors) as well as hydroxyls
(-OH) and amine (-NHn) (hydrogen bond donors) remain the
same for the derivatives as for ciprofloxacin. A reduction in
the polar surface area of the derivatives compared to cipro-
floxacin parent would enhance bioavailability of the drug
[23] whereas the increase in formula weigh and number of
rotatable bonds would not be beneficial. Drug movement
across the transcellular direction and by passive interaction
should not have a polar surface area greater than 120 Ang-
stroms2 [23]. Altogether the properties of the derivatives still
support favorable bioavailability for clinical application, as
assertion auspicated by the determination that drugs B, C,

54 Medicinal Chemistry, 2010, Vol. 6, No. 2
Bartzatt et al.
and D show zero violations of the Rule of 5 [24]. The Rule
of 5 states that poor permeation is more likely when a drug
possesses more than 5 hydrogen bond donors, formula
weight greater than 500, Log P greater than 5, and more than
10 hydrogen bond acceptors [24]. None of these criteria de-
scribe drugs A, B, C, and D. Values of polar surface areas
for B, C, and D suggests that greater than 60% of orally ad-
ministered dose would be absorbed by the intestinal system
[25]. Other investigators have reported that drugs having 10
or fewer rotatable bonds and polar surface area less than 140
Angstroms2 will have good bioavailability [26]. These two
criteria are fulfilled with all three ester derivatives of cipro-
floxacin presented in this work. Therefore drugs B, C, and D
are expected to show favorable bioavailability.
MSSA. This would significantly improve the prognosis of
limiting extent and damage of Staphylococcus aureus infec-
tions. Advantages of an effective topical agent for skin based
incidents of MRSA or MSSA include: 1) Drug application is
directly to site of bacteria; 2) Decreased chance of allergic
reaction to drug; 3).
The comparison of B, C, and D to ciprofloxacin in terms
of bacterial inhibition and specifically inhibition of MRSA
and MSSA, all drugs were placed into tissue culture simi-
larly. Results presented as percent inhibition of colony form-
ing units (CFU) are presented in Fig. (3). Derivatives B, C,
and D showed striking and comparable inhibition of both
MRSA and MSSA as did ciprofloxacin. The inhibition of
MSSA by ciprofloxacin (drug A), B, C, and D was near total
(100%) at concentration as little as 15.63 micro-
grams/milliliter. This was followed at essentially 100 % in-
hibition by CFU at all concentrations above 15.63 μg/mL.
These results suggest that ester forms of ciprofloxacin form a
potent advent group of fluoroquinolone type chemotherapeu-
tics to augment the clinical treatment of serious diseases pre-
viously managed by ciprofloxacin. This extends the number
of fluoroquinolone compounds available to clinical workers.
In addition, the results of similar testing with MRSA (see
Fig. 3) demonstrated that derivatives B, C, and D are compa-
rable to ciprofloxacin inhibiting bacterial growth. Over 80 %
inhibition by CFU was observed for all drugs at concentra-
tion of 15.63 microgram/milliliter. At all concentrations
above 15.63 μg/mL the derivatives induced greater than 80
% inhibition. Again, these results extends the number of
fluoroquinolone compounds available to clinical workers.
The profound inhibition of MRSA and MSSA coupled with
enhancement of choice molecular properties via ester group
modification provide clinical antimicrobials having a di-
verse, but highly effective, antimicrobial activity.
Fig. (3). Comparison of MSSA and MRSA growth inhibition in-
duced by ciprofloxacin (A) and ester derivatives B, C, and D. Top:
A very strong growth inhibition of MSSA is demonstrated by all
compounds of this study. The growth inhibition measured by col-
ony forming units (CFU) for all compounds is greater than 80 % at
concentrations starting at 15.63 micrograms/milliliter and higher.
Essentially drugs A, B, C, and D are identical in their performance
and strong inhibition of MSSA is achieved. Lower: Again in the
case of MRSA all compounds induce greater than 80 % inhibition
of MRSA as measured by colony forming units. All concentrations
of A, B, C, and D induce strong inhibition, starting at 15.63 micro-
grams/milliliter.
Infections of Staphylococcus aureus often make their
presentation in the form of skin or soft tissue contagion [16-
20]. Although beginning as skin infections, MRSA or MSSA
can travel to the lung tissue and result in formation of pneu-
monia [14-16]. More effective drugs are necessary to pro-
hibit the advancement of these infections to other organs. A
notable action of the replacement of the carboxyl group by
ester functional groups is the profound increase in the rate of
skin penetration, which is affirmed by the dermal permeabil-
ity coefficient Kp. Measuring the rate (as cm/hour) of a dose
administered as a topical agent, the Kp for B, C, and D are
exceedingly greater than the Kp for the ciprofloxacin parent
(see Fig. 4). Beginning with ciprofloxacin (see Table 1) the
Kp numerical value jumps more than one-order of magnitude
to 0.000383 cm/hour for drug B. Values of Kp for C and D
are greater yet than ciprofloxacin and drug A. Clearly the
modification of ciprofloxacin to an ester compound substan-
tially improves the potential of topical usage which is an
advantage for treating skin based infections of MRSA and
Decreased chance of drug-drug interaction; 4) Ease of
use; and 5) Rapid response following clinical presentation.
These results present stark assertions that ester forms of
ciprofloxacin have considerable potential as chemo-
therapeutics for the clinical treatment of dermal and non-
dermal infections of MSSA and/or MRSA.
Hydrophobic drugs with high partition coefficients are
preferentially distributed to hydrophobic compartments such
as lipid by-layers of cells while hydrophilic drugs (low parti-
tion coefficients) preferentially are found in hydrophilic
compartments such as blood serum [27]. The lengthening of
the aliphatic carbon chain of the ester substituent induces a
numerical increase of Log P values. The derivatives of cipro-
floxacin B, C, and D have increased solubility in hydropho-
bic compartments, such as the bacterial cell membrane. The
relationship of ester substituent size and Log P is presented

Inhibition of Staphylococcus aureus
Medicinal Chemistry, 2010, Vol. 6, No. 2 55
in Fig. (5). As the length of the ester substituent increases, so
does the Log P and Kp numerical values of the derivatives B,
C, and D. This work shows that alteration of the molecular
structure of ciprofloxacin preserves the antibacterial activity
as well as modifies molecular properties so that the clinical
potential and types of administration of these novel drug
designs is diversified.
MSSA isolates across the globe. Many infections of Staphy-
lococcus aureus are manifested through skin and soft tissue
infections of children and patients in long term care facili-
ties. This work presents three ester derivatives of ciproflox-
acin that show very strong inhibition of MRSA and MSSA.
The three ciprofloxacin derivatives B, C, and D induced
greater than 80 % growth inhibition of both MRSA and
MSSA beginning at concentrations of as little as 15.63 mi-
crograms/milliliter. The replacement of the carboxyl group
of in the parent ciprofloxacin by ester groups increased mo-
lar volume, formula weight, and number of rotatable bonds,
but decreased the polar surface area from 74.569 Angstroms2
of ciprofloxacin to 63.575 Angstroms2 for the derivatives.
All three derivatives of ciprofloxacin showed a substantial
increase in the rate of skin penetration as indicated by Kp
numerical values. The ester derivatives would then be ex-
pected to have greater penetration and higher efficacy in the
treatment of Staphylococcus aureus infections of skin and
soft tissues. These promising features of ciprofloxacin ester
compounds clearly indicate a substantial potential for the
clinical treatment of MRSA and MSSA.
EXPERIMENTAL
Reagents and Instrumentation
Chemicals and reagents were obtained from Aldrich
Company (P.O. Box 2060, Milwaukee, WI 53201). Infrared
spectroscopy use a Mattson Galaxy FTIR in dimethylsulfox-
ide dried over molecular sieves.
Fig. (4). As the number of carbon atoms within the aliphatic ester
group increases so does the Kp numerical value for compounds B,
C, and D. The rapid increase in Kp value clearly indicates a sub-
stantial increase in the rate of skin penetration by compounds B, C,
and D compared to the parent ciprofloxacin. Measured as centime-
ters per hour these results indicate an improved capability to treat
skin and soft tissues infections by MRSA and MSSA.
Molecular Modeling
Molecular modeling and molecular properties were de-
termined by utilizingChemSketch v. 5 (90 Adelaide Street
West, Toronto, Ontario M5H 3V9,Canada), Molinspiration
(Liscie Udolie 2, SK-841 04 Bratislava, SlovakRepublic).
Values of Kp were determined by DERMWIN U.S. Envi-
ronmental Protection (copyright (c) 2000 U.S. Environ-
mental Protection Agency).
Bacterial Strains and Growth Conditions
Methicillin resistant Staphylococcus aureus strain
MRSA252 and methicillin sensitive strain MSSA476 were
kindly provided by Dr. Greg A. Somerville, University of
Nebraska, Lincoln, NE. Staphylococcus cultures were grown
by suspending a single colony with normal morphology on
tryptic soy (BD Biosciences) agar in 30 ml of tryptic soy
broth (TSB). Serial dilutions were made 1:2 in 25 cm2 cul-
ture flasks (Sarstedt) and cultures were grown in a final vol-
ume of 15 ml. Cultures were incubated at 37ºC overnight
with shaking. Cultures at early stationary phase (OD630 2-4)
were used to inoculate flat bottom 96-well plates (Sarstedt)
with 106 bacteria in a final volume of 100 ꢀl of TSB with
variousconcentrations of the test compounds added previ-
ously. After 5 h of incubation at 37ºC the optical density
(OD) and colony forming units (CFU) were determined for
all cultures. OD were determined at 630nm using a Dynatech
Revelation 2.0. CFU were determined through microdilution
by plating 20 ꢀl of each dilution on Luria Broth (Difco) agar
plates.
Fig. (5). As the length of the aliphatic ester substituent increases the
Log P value for the drug increases. As Log P increases the solubil-
ity of drug in the lipophilic by-layer of cell membranes also in-
creases. Increase of Log P correlates with increase of Kp and the
number of carbon atoms in the ester substituent increases. Drug A
(ciprofloxacin) has no carbon ester atoms, drug B has one carbon,
drug C has two carbon atoms, and drug D has three carbon atoms.
CONCLUSION
Ciprofloxacin is a broad spectrum antimicrobial and has
seen the substantial increase in the number of MRSA and

56 Medicinal Chemistry, 2010, Vol. 6, No. 2
Bartzatt et al.
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Synthesis of Ciprofloxacin Derivatives
All reagents be kept dried and free of water. All glass-
ware used in synthesis must be clean and dry. For methyla-
tion of ciprofloxacin (compound B): Place 20 milligrams of
ciprofloxacin into 15 mL of dried acetonitrile, then bubble
diazomethane through the mixture three to five passes (dia-
zomethane generated by placing 5 molar NaOH onto 1-
methyl-3-nitro-1-nitrosoguanidine). For ethylation of cipro-
floxacin (compound C): Place 15 milligrams of ciprofloxacin
into 10 mL dried acetonitrile, then bubble diazoethane
through the mixture four to six passes (diazoethane gener-
ated by placing 5 molar NaOH onto 1-ethyl-3-nitro-1- nitro-
soguanidine). For propylation of ciprofloxacin (compound
D): Place 15 milligrams of ciprofloxacin into a clean dry
glass reaction tube. Place 15 microliters of SOCl2 into the
vessel and microwave briefly for 30 seconds. Then add 100
microliters of n-propanol and microwave up to 60 seconds.
Allow to cool and remove excess alcohol by vacuum. Keep
products dry and store at -10oC. For ciprofloxacin the car-
boxyl group gives a noticeable bands in I.R. spectra at about
3000 cm-1, 1700 cm-1, 1400 cm-1, 1300 cm-1. For the methyl
ester (drug B) peaks at about 1725 cm-1 and 1150 cm-1 are
indicative. For the ethyl ester (drug C) peaks about 1750 cm-
1 and about 1250 cm-1. For drug D the propyl ester derivative
peaks at 1750 cm-1 and 1200 cm-1.
[12]
[13]
[14]
[15]
[16]
[17]
[18]
ACKNOWLEDGEMENTS
This work was supported by the College of Arts & Sci-
ences of the University of Nebraska, Omaha, Nebraska
68182 U.S.
[19]
[20]
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Received: February 10, 2010
Revised: April 06, 2010
Accepted: April 08, 2010