Enhancement of the antimalarial activity of ciprofloxacin using a double prodrug/bioorganometallic approach

Article abstract of DOI:10.1021/jm901357n

The derivatization of the fluoroquinolone ciprofloxacin greatly increases its antimalarial activity by combining bioorganometallic chemistry and the prodrug approach. Two new achiral compounds 2 and 4 were found to be 10- to 100-fold more active than ciprofloxacin against Plasmodium falciparum chloroquinesusceptible and chloroquine-resistant strains. These achiral derivatives killed parasites more rapidly than did ciprofloxacin. Compounds 2 and 4 were revealed to be promising leads, creating a new family of antimalarial agents.

Full text of DOI:10.1021/jm901357n

7
954 J. Med. Chem. 2009, 52, 7954–7957
DOI: 10.1021/jm901357n
Enhancement of the Antimalarial Activity
of Ciprofloxacin Using a Double
Prodrug/Bioorganometallic Approach
†
Faustine Dubar, Guillaume Anquetin,
,
†,^
‡
Bruno Pradines, Daniel Dive, Jamal Khalife, and
§
§,¥
,†, ,¥
Christophe Biot*
†
Universit eꢀ de Lille 1, CNRS UMR 8181, ENSCL, B a^ timent C7,
B.P. 90108, 59652, Villeneuve d’Ascq Cedex, France, Recherche
‡
Biom eꢀ dicale des Arm eꢀ es, Antenne de Marseille, Unit eꢀ de Recherche
en Biologie et Epid eꢀ miologie Parasitaires, UMR 6236, All eꢀ e du
M eꢀ decin Colonel Jamot, Parc le Pharo, B.P. 60109, 13262 Marseille
§
Cedex 07, France, and Universit eꢀ Lille Nord de France, Inserm U547,
Institut Pasteur, 1 Rue du Pr Calmette, B.P. 245, 59019 Lille Cedex,
Figure 1. Chemical structures of grepafloxacin, gatifloxacin, mox-
ifloxacin, and ciprofloxacin.
France. Present address: Universit eꢀ de Lille 1, CNRS UMR 8576,
IFR 147, 59650 Villeneuve d’Ascq C eꢀ dex, France. Present address:
^
are thought to inhibit the plastid gyrase, these classes of
quinolones target the parasite’s cytochrome bc1 complex
11b
and NADH dehydrogenase, respectively.
Laboratoire Itodys, Universit eꢀ Paris Diderot, 15 Rue Jean de Baf,
5013 Paris, France. These authors contributed equally to this work.
¥
7
Received September 14, 2009
In the search for new therapeutic agents, our previous
studies have shown that the incorporation of a ferrocene core
into chloroquine (CQ) can lead to ferrocenyl complexes with a
strong antiplasmodial effect on CQ-resistant strains of
Abstract: The derivatization of the fluoroquinolone ciprofloxacin
greatly increases its antimalarial activity by combining bioorgano-
metallic chemistry and the prodrug approach. Two new achiral
compounds 2 and 4 were found to be 10- to 100-fold more active
than ciprofloxacin against Plasmodium falciparum chloroquine-
susceptible and chloroquine-resistant strains. These achiral deriva-
tives killed parasites more rapidly than did ciprofloxacin. Com-
pounds 2 and 4 were revealed to be promising leads, creating a new
family of antimalarial agents.
1
2
P. falciparum. This approach led to the development of a
ferrocene CQ conjugate (ferroquine, FQ, SR97193), currently
1
3
in phase IIb clinical trials. From the structure-activity
studies of FQ, it appeared that the increase in the hydropho-
bicity of the drug has a predominant role in the enhancement
of its antimalarial activity. In the case of CIPRO, the strategy
of increasing its hydrophobicity, and consequently its activity
toward P. falciparum, has not been tested so far. Hence, we
designed new CIPRO derivatives bearing a ferrocenyl sub-
stituent at position N(1) or at C(7) of the quinolone ring. In
parallel, to enhance the hydrophobic capacity of these pro-
ducts, we adopted a prodrug strategy consisting of the ethyl
The burden of malaria to health and the economy in
1
endemic areas and the emergence of parasite strains resis-
,2
2
,3
tant to several antimalarials underscore the importance of
developing new and/or improved therapeutic strategies
against this infection. An initial study reported that quino-
14
esterification of the carboxylic acids. In this report, we
4
lones and fluoroquinolones were activeagainstP. falciparum.
Their mode of action was first studied in bacteria and
mycobacteria, and they were shown to affect bacterial DNA
compare the antimalarial activity and cytotoxicity of these
derivatives to those of CIPRO and CIPRO ethyl ester to
identify an effective strategy to improve the antimalarial
activity of CIPRO.
5
,6
by targeting topoisomerases II and IV. The subsequent
discovery of an apicoplastic prokaryotic-like organelle in
The ferrocenic fluoroquinolones 1-3 were synthesized
according to a procedure adapted from the method of Cec-
7
Toxoplasma and Plasmodium increased interest in elucidat-
a
ing further the mode of action of ciprofloxacin (CIPRO ) on
15
chetti et al. (Scheme 1). Commercially available 2,4,5-tri-
these parasites. In this context, it has been shown that, as with
T. gondii, CIPRO (Figure 1) affects P. falciparum by causing
the formation of abnormal apicoplasts and a “delayed death”
fluorobenzoic acid 5 reacts with Vilsmeier-Haack reagent
(oxalyl chloride and dimethylformamide (DMF)) in dichlor-
omethane to afford 6 in quantitative yield. The acyl chloride 6
is then condensed with ethyl 3-(diethylamino)acrylate 7
8,9
of treated parasites. The (fluoro)quinolones products tested
against P. falciparum strains (3D7 or NF54-R) all exhibited
IC50 g 10 μM (the most active were grepafloxacin, gatiflox-
(freshly obtained from ethyl propiolate and N,N-diethyl-
amine) in a mixture of toluene/triethylamine to provide the
1
0
acin, and moxifloxacin; Figure 1). Additional studies have
shown that halogenated alkyl-, alkoxy-4(1H)-, and 1-hydroxy-
1
13
cetoester 8 in 73% yield. H and C NMR spectra revealed
that 8 exists in a 1:9 ratio of E to Z stereoisomers. Transami-
nolysis of 8 with cyclopropylamine and successive cyclization
with potassium carbonate in DMF gave the key intermediate
2
oquine-susceptible (D6) and chloroquine-resistant (Dd2)
docecyl-4(1H)-quinolones were active in vitro against chlor-
1
P. falciparum strains. Unlike classical fluoroquinolones that
1
9
obtained by coupling the difluoroquinolone 9 in acetonitrile
in 79% yield. The fluoroquinolones 1, 3, and 4 were then
1
6
*
To whom correspondence should be addressed. Phone:
033320436941. Fax: 0033320434893. E-mail: christophe.biot@univ-
lille1.fr.
Abbreviations: CIPRO, ciprofloxacin; CQ, chloroquine; FQ, ferro-
quine; DMF, dimethylformamide; ASU, artesunate; DOX, doxycycline;
QN, quinine; IC50, inhibitory concentration at 50%; MQ, mefloquine.
with the corresponding amines (1 week, under reflux) in
yields varyingfrom 20% to92%. Target2 was synthesizedina
similar fashion. Transaminolysis of 8 with ferrocenylmethy-
0
a
lamine and cyclization with K CO in DMF gave the difluor-
2
3
oquinolone 10 in 72% yield. The slow nucleophilic aromatic
r
pubs.acs.org/jmc
Published on Web 11/12/2009
2009 American Chemical Society

Letter
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 24 7955
a
Scheme 1. Synthesis of Target Compounds 1-4
a
Reagents and conditions: (i) (COCl)
CO
O (1/2), room temp, 3 h, then DMF, K
2
, DMF, dichloromethane, N
, reflux, 12 h; (iv, vii, viii, and ix) CH
CO3, reflux, 4 h.
2
atm, room temp, 24 h; (ii) toluene, Et
3
N, N
CN, reflux, 48 h to 1 week; (v) CH
2
atm, reflux, 24 h; (iii) EtOH/Et
2
O
(
1/2), room temp, 3 h, then DMF, K
vi) EtOH/Et
2
3
3
3
CN, N atm, room temp, 24 h;
2
(
2
2
Table 1. In Vitro Antimalarial Activity against CQ-Susceptible (3D7) and CQ-Resistant (W2) P. falciparum Strains after Exposures of 48 and 96 h and
in Vitro Cytotoxicity in Mice Spleen Cells
a
IC50 (μM) after 48 h
3D7 W2
IC50 (μM) after 96 h
therapeutic index
compd
3D7
W2
cytotoxicity (μM)
a
b
1
2.7 ( 0.4
1.7 ( 0.2
2.8 ( 0.5
3.1 ( 0.4
3.8 ( 0.7
1.5 ( 0.2
2.2 ( 0.9
3.9 ( 0.6
2.6 ( 0.2
1.0 ( 0.2
3.2 ( 0.3
1.6 ( 0.4
2.9 ( 0.4
0.8 ( 0.2
2.5 ( 0.3
3.1 ( 0.4
>40
>14.8
7.6
4.6
>10.5
8.6
5.9
2
3
4
12.9 ( 2.2
13 ( 2.8
>40
>12.9
>10.2
CIPRO
DOX
45.9 ( 3.8
12.0 ( 1.4
119.3 ( 17.8
10.7 ( 2.1
10.1 ( 3.4
1.7 ( 0.5
14.1 ( 4.3
1.2 ( 0.3
>40
n.d.
>0.8
n.d.
>0.3
n.d.
IC50 (nM) after 48 h
IC50 (nM) after 96 h
therapeutic index
compd
3D7
W2
3D7
W2
cytotoxicity (μM)
a
b
CQ
ASU
QN
19 ( 4
1.7 ( 0.4
186 ( 20
480 ( 50
2.4 ( 0.7
520 ( 42
21 ( 3
2 ( 0.5
162 ( 22
462 ( 57
2.1 ( 0.8
456 ( 61
3.46
nd
182
nd
7.2
nd
nd
nd
nd
a
IC50 values are the mean of five experiments for each strain ( standard deviation. DOX = doxycycline; CQ = chloroquine, ASU = artesunate,
QN = quinine; therapeutic index a = cytotoxicity/3D7 IC50; therapeutic index b = cytotoxicity/W2 IC50 after 48 h; nd = not determined.
substitution of 10 by piperazine in acetonitrile at reflux
produced 2 in 57% yield.
ably constant whatever the strains’ level of resistance to CQ.
This is not surprising, as the molecular targets of CQ and of
the (fluoro)quinolone derivatives are very likely to be diffe-
rent. From the above data, three main conclusions can be
drawn: (1) ethyl esterification of CIPRO (4) resulted in a
dramatic increase in activity after 48 h of contact (15-fold for
3D7 and 30-fold for W2); (2) the exchange of the cyclopropyl
group by a ferrocenylmethyl moiety (comparison of 2 and 4)
resulted in an additional gain of about 2-fold in activity,
Antiplasmodial activities were first determined against the
CQ-susceptible(3D7) andthe CQ-resistant(W2)P. falciparum
strains. The antiplasmodial activities of 1-4 are shown in
Table 1, along with the values for the standard drug CIPRO,
CQ, artesunate (ASU), doxycycline (DOX), and quinine
(
QN). Compounds 1-4 showed micromolar antiplasmodial
activity against both strains. The activities of 1-4 are remark-

7
956 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 24
Dubar et al.
Table 2. In Vitro Antimalarial Activity against Nine P. falciparum Strains after Exposure for 48 h
a
IC50
strains
D7
2 (μM)
CIPRO (μM)
DOX (μM)
CQ (nM)
QN (nM)
ASU (nM)
3
W2
1.7 ( 0.2
1.5 ( 0.2
2.36 ( 1.1
2.0 ( 0.4
0.92 ( 0.1
1.32 ( 0.1
0.72 ( 0.1
0.44 ( 0.2
1.35 ( 0.3
45.9 ( 3.8
119.3 ( 17.8
74.8 ( 9.4
41.3 ( 6.4
51.6 ( 6.8
45.5 ( 2.4
74.3 ( 2.5
45.6 ( 1.5
80.8 ( 5.8
12.0 ( 1.4
10.7 ( 2.1
13.3 ( 3.8
8.4 ( 1.7
9.1 ( 2.1
12.9 ( 4.0
9.7 ( 2.3
19 ( 4
480 ( 50
51 ( 18
250 ( 48
267 ( 26
284 ( 46
501 ( 155
508 ( 63
523 ( 89
186 ( 20
520 ( 42
314 ( 101
543 ( 71
428 ( 69
571 ( 158
650 ( 143
5.8 ( 125
6.7 ( 59
1.7 ( 0.4
2.4 ( 0.7
3.8 ( 0.4
1.7 ( 0.6
3.0 ( 0.7
2.0 ( 0.5
2.1 ( 1.1
1.9 ( 0.5
1.8 ( 0.7
IMT 10500
IMT L1
IMT Vol
PA
FCR3
FCM29
IMT K2
a
11.06 ( 2.5
14.9 ( 3.6
Values are the mean IC50 of five experiments for each strain ( standard deviation.
provoking a decrease in the IC50 of product 2 to the sub-
micromolar range; (3) all of the new compounds are more
active than CIPRO and DOX against both strains (Table 1).
These data also show that there was no significant difference
in the IC50 for products 1 and 4. This suggests that 1 could be
metabolized to 4 by loss of the stable metallocenylcarbenium
ion. Further studies will be required to validate this pathway.
Clearly, modulation of the antimalarial activity of CIPRO
is a consequence of its “double” derivatization as a prodrug
and as a ferrocene conjugate. More importantly, it seems that
the prodrug strategy makes the main contribution to the
improvement in activity. Under their prodrug forms, all these
compounds are more lipophilic than the parent molecule and
are therefore more able to traverse the multiple membranes
Figure 2. Isobolograms of the in vitro interaction between 2 and
CQ, QN, MQ, MDAQ, and DHA against the W2 strain of
P. falciparum. The diagonal line indicates the hypothetical additive
effect. A concave curve indicates synergism, a straight line shows an
additive response, and a convex curve is evidence of antagonism.
present in the intracellular parasite and its plastid to reach
their potential targets. It is noted that potential targets for
(fluoro)quinolones, principally gyrase and topoisomerase IV,
have recently been annotated in the Plasmodium genome.
1
7,18
Thus, we can speculate that the target could be gyrase, which
would lead to a rapid toxic effect of the prodrug molecules on
parasite replication. It is noted, however, that topoisomerase
IV was considered the preferential target of CIPRO, which
study, derivative 2 was tested with known antimalarials
according to the isobologram method, which enables the
exploration of a wide range of drug combinations.
20
1
7
may explain the delay in parasite death that we noted.
Hydrophobicity is increased in 2 by replacement of the
cyclopropyl group by a ferrocenylmethyl moiety and contri-
butes to a higher activity of 2 compared to 4.
Next, the most active derivative, 2, was further tested
against a larger panel of well characterized P. falciparum
laboratory strains or strains obtained from isolates grown in
culture for an extended period of time (Table 2). Compound 2
exhibited a higher level of activity than the parent compound.
The IC50 for 2 ranged from 0.44 to 3.90 μM, with a mean of
Surprisingly, isobologram analysis showed that 2 exerts a
marked antagonistic effect on the two P. falciparum strains
3D7 (resistant in vitro to mefloquine, MQ) (Supporting
Information) and W2 (resistant in vitro to CQ, QN, and
MDAQ) (Figure 2). The same data were observed with the
seven other P. falciparum strains (data not shown). It can be
postulated that 1-4 could be active upon plastid functions
whereas CQ, QN, MQ, MDAQ, and DHA are involved in
inhibition of pigment biocrystallization in the digestive va-
cuole of the parasite. Since the targets are distinct, an additive
effect would be expected. This was not observed under our
experimental conditions. Hence, it could be speculated that
the observed antagonism maybe related to a possible relation-
ship between metabolic pathway(s), yet to be determined,
between the apicoplast and the digestive vacuole which could
in turn influence the mode of action of the drugs tested in
combination. The link between the two organelles is illu-
strated by the synthesis of the iron sulfur clusters in the
1
.79 μM (standard deviation of (1.16 μM). In vitro cross-
resistance was measured by the pairwise correlation of IC50
for all nine strains. The data presented in Table 2 did not
2
reveal any significant correlation between 2 and CIPRO (r =
2
.014), between 2 and DOX (r = 0.052), between 2 and QN
0
2
r = 0.015), or between 2 and ASU (r = 0.074). However,
2
(
CQ and 2 were slightly correlated (r = 0.421).
2
As many compounds have been identified and reported to
1
demonstrate chemosensitization against malaria parasites,
9
21
apicoplast, known to be involved in the active site of
aconitase, and the presence of an aconitase activity in the
the lead fluoroquinolone 2 was tested in association with
quinoline-containing antimalarials such as CQ, QN, MQ,
monodesethylamodiaquine (MDAQ), or dihydroartemisinin
2
1
digestive vacuole.
Next, the in vitro toxicity of 1-4 was tested using mouse
spleencells(Table 1). Compound2 wasfoundtobemoretoxic
than the parent drug CIPRO but less toxic than CQ. More-
over, the selectivity index of 2 remained at about 8 indepen-
dent of the resistance level of the P. falciparum strains used,
while the selectivity index of CQ dropped from 182 to 7
for CQ-susceptible and CQ-resistant P. falciparum strains.
(DHA) against the nine P. falciparum strains.
In an earlier study, Andrade et al. claimed to have found a
synergistic effect between CIPRO and, respectively, artemisi-
nin and MQ in in vitro assays on P. falciparum and in vivo
1
tests on P. berghei. Their conclusions were based on data
9
obtained with single combinations of drugs. In the present

Letter
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 24 7957
Compound 4 also appears very interesting, as it is less toxic
than 2 for an activity only 2-fold lower.
(9) Dahl, E. L.; Rosenthal, P. J. Multiple antibiotics exert delayed
effects against the Plasmodium falciparum apicoplast. Antimicrob.
Agents Chemother. 2007, 51, 3485–3490.
In conclusion, the first series of ferrocenic fluoroquino-
lones related to CIPRO has been successfully prepared and
characterized. Our approach shows that the prodrug strat-
egy resulted in a major increase of CIPRO antimalarial
activity and that the bioorganometallic strategy led to an
additional improvement in activity, allowing the identifica-
tion of two promising hits, 2 and 4. In vitro results have to be
confirmed in vivo to determine the bioavailability of these
two molecules and their potential interest as new antimalar-
ials. Because of the potential cytotoxicity of these comp-
ounds, a program will be initiated to identify new derivatives
at least as active but less toxic. Our ciprofloxacine derivatives
represent a promising family to mine new potential antima-
larials.
(
(
10) Anquetin, G.; Greiner, J.; Vierling, P. Quinolone-based drugs
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(
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13) http://clinicaltrials.gov/ct2/show/NCT00563914.
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Acknowledgment. The authors thank Dr. R. Pierce for
critical reading of the manuscript and R. Amalvict, E. Bare,
S. Charras, and S. Lafitte for technical support.
(
15) (a) Cecchetti, V.; Tabarrini, O.; Sabatini, S.; Miao, H.; Filipponi,
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Supporting Information Available: Details of the synthesis
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experiments; isobolograms of the in vitro interaction between
2 and CQ, QN, MQ, MDAQ, and DHA against the 3D7 strain
of P. falciparum. This material is available free of charge via the
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(
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