Synthesis and evaluation of 1-cyclopropyl-2-thioalkyl-8-methoxy fluoroquinolones

Article abstract of DOI:10.1016/j.bmcl.2011.05.112

Novel fluoroquinolone derivatives substituted with a 2-thioalkyl moiety, with and without a concomitant 3-carboxylate group, were synthesized to evaluate the effect of C-2 thioalkyl substituents on gyrase binding and inhibition. The presence of a 2-thioalkyl group universally decreased activity as compared to parent fluoroquinolones. However, with derivatives of moxifloxacin the presence of either a 2-thioalkyl group or a 3-carboxylate moiety increased activity over the 2,3-unsubstituted derivative. Energy minimization of structures provides an explanation for relative activities of fluoroquinolones having a C-2 thio moiety.

Full text of DOI:10.1016/j.bmcl.2011.05.112

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4585–4588
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of 1-cyclopropyl-2-thioalkyl-8-methoxy
fluoroquinolones
Kevin R. Marks a, Muhammad Malik b, Arkady Mustaev b, Hiroshi Hiasa c, Karl Drlica b, Robert J. Kerns a,
⇑
a Division of Medicinal and Natural Products Chemistry, University of Iowa College of Pharmacy, Iowa City, IA 52242, USA
b Public Health Research Institute, New Jersey Medical School, UMDNJ, 225 Warren St., Newark, NJ 07103, USA
c Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel fluoroquinolone derivatives substituted with a 2-thioalkyl moiety, with and without a concomitant
3-carboxylate group, were synthesized to evaluate the effect of C-2 thioalkyl substituents on gyrase bind-
ing and inhibition. The presence of a 2-thioalkyl group universally decreased activity as compared to par-
ent fluoroquinolones. However, with derivatives of moxifloxacin the presence of either a 2-thioalkyl
group or a 3-carboxylate moiety increased activity over the 2,3-unsubstituted derivative. Energy minimi-
zation of structures provides an explanation for relative activities of fluoroquinolones having a C-2 thio
moiety.
Received 9 November 2010
Revised 27 May 2011
Accepted 27 May 2011
Available online 6 June 2011
Keywords:
Fluoroquinolone
Antibacterial
Ulifloxacin
Ó 2011 Elsevier Ltd. All rights reserved.
Moxifloxacin
DNA gyrase
Fluoroquinolones are broad-spectrum antimicrobials1,2 that in-
hibit DNA gyrase or topoisomerase IV (TopoIV) in bacteria.3–6 Of
primary concern in the clinical use of fluoroquinolone drugs is
the emergence of fluoroquinolone-resistant strains of bacteria.7–9
The quinolone class of antibacterial agents has undergone many
structural changes in efforts to gain potency against resistant
strains.10 These antibiotics are generally based on the structure
of the naphthyridone nalidixic acid (Fig. 1), the first active agent
in the class. Subsequent generation quinolones consist of fluoro-
quinolones such as norfloxacin and ciprofloxacin, which contain
a C-6 fluorine. These were followed by the 8-methoxy fluoroquin-
olones (e.g., gatifloxacin and moxifloxacin). The addition of an 8-
methoxy substituent generally affords more equipotent inhibition
of DNA gyrase and TopoIV, and it has been shown to facilitate more
rapid killing and chromosome fragmentation.1 Continued explora-
tion of structural diversity in substituents at the N-1, C-2, C-7 and
C-8 positions has led more recently to a variety of unique tricyclic
structures that include the C-2-thio derivative ulifloxacin and the
thiazoloquinolones (Fig. 1).3,11-13
Figure 1. Representative structures of quinolone-class antibiotics and fluoroquin-
olones used or referred to in this work.
Recently, several crystal structures with fluoroquinolone bound
to DNA–TopoIV or DNA–DNA gyrase have been reported.14–17 Even
though none of these structures were obtained using a C-2 thioqu-
inolone, analysis of the structures revealed possible binding con-
tacts for a C-2 sulfur atom, and it suggested that a C-2 thioalkyl
group may form additional binding interactions with the enzyme.
This evidence is supported by studies in which we modeled uliflox-
acin into the putative binding site of TopoIV (unpublished).
Literature examples of 2-thioquinolone derivatives where the
C-2 sulfur atom is not incorporated into a fused ring are limited18
;
⇑
Corresponding author. Tel.: +1 319 335 8800; fax: +1 319 335 8766.
E-mail address: robert-kerns@uiowa.edu (R.J. Kerns).
only ring-fused structures such as the thiazoloquinolones and
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.112

4586
K. R. Marks et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4585–4588
thiazetidinylquinolones (Fig. 1) and are reported to have potent
antibacterial activity.19–21 Despite extensive modification of the
fluoroquinolone core, little precedent exists for removing the
3-carboxylate due to its assumed requirement for activity.13 How-
ever, quinazoline-2,4-diones and 1,3-diones have recently been
shown to possess potent, broad-spectrum antibacterial properties
despite the lack of a 3-carboxylate substituent,22–30 thus suggest-
ing the possibility that further modification to the C-2 and C-3
positions of quinolones will provide novel structures that maintain
antibacterial activity.
intermediate with ethyl iodide or isopropyl iodide in situ afforded
ethyl esters 4a and b, respectively, in high yield. Potassium tert-
butoxide catalyzed intramolecular nucleophilic aromatic substitu-
tion yielded the target fluoroquinolone core structures 5a and b.
Nucleophilic aromatic substitution of the C-7 fluorine with the
piperazine and octahydropyrrolopyridine rings was carried out in
DMF at 60 °C to yield moxifloxacin-like and ciprofloxacin-like fluo-
roquinolone ethyl esters 6a–d (Scheme 1).33 The choice of pipera-
zine and octahydropyrrolopyridine as the C-7 substituents is
derived from their inclusion at the same position of ulifloxacin
and ciprofloxacin, and moxifloxacin, respectively (Fig. 1).
Described here are studies initiated to evaluate the effect of a C-
2 thioalkyl group on fluoroquinolone inhibition of DNA gyrase and
antibacterial activity. Because the presence of a 3-carboxylate was
anticipated to effect gyrase binding of C-2 S-alkyl derivatives, C-2
S-alkyl fluoroquinolone derivatives were synthesized with and
without an adjacent C-3 carboxylate group. Synthesis of the
2-thioalkyl fluoroquinolone derivatives was achieved by modifica-
tion of reported procedures for creating tricyclic C-2 sulfur-
containing quinolones (Scheme 1).31 Decarboxylation of parent
fluoroquinolones and the 2-thioalkyl derivatives was anticipated
to proceed using an established method for cyanide-mediated
decarboxylation of fluoroquinolones.32 All compounds were evalu-
ated for bacteriostatic activity (MIC) with wild-type Escherichia
coli, E. coli tolC knockout (an efflux pump knock out), and Mycobac-
terium smegmatis.
Commercially available 2,4,5-trifluoro-3-methoxy benzoic acid
(1) was stirred at reflux in ethyl acetate with thionyl chloride to
form the acid chloride (2) in near quantitative yield. Malonate ester
3 was then generated in a two-step process by reacting acid chlo-
ride 2 with potassium ethyl malonate in the presence of anhydrous
magnesium chloride followed by decarboxylation with 6 N hydro-
chloric acid and crystallization of product to give the aryl propio-
nate ethyl ester 3.
To our surprise, hydrolysis of ethyl esters 6a–d34–36 to give the
C-2 thioalkyl substituted fluoroquinolones was highly problematic.
Previously described conditions for the hydrolysis of many other
fluoroquinolone esters and modifications to these procedures were
generally unsuccessful with the C-2 thioalkyl compounds here.37–42
We found that no reaction occurred with 6a–d under aqueous
hydrolytic conditions without elevated temperature. However, at
the elevated temperatures under both acidic and basic pH decarbox-
ylation products rather than hydrolysis products were observed
(Scheme 2).
Formation of the 2-hydroxyl compound (8) during hydrolysis of
6b and d likely follows an addition/elimination mechanism previ-
ously described for cyanide-mediated decarboxylation of fluoro-
quinolones.32 In this reported mechanism for fluoroquinolone
decarboxylation, the 1,4-addition of cyanide to the C-2 position
delocalizes electrons to the alpha carbon at C-3, which promotes
decarboxylation. Upon decarboxylation the double bond is re-
formed by ejecting cyanide as the leaving group. We propose a
similar mechanism for the loss of C-2 thioalkyl groups upon
base-mediated hydrolysis. Hydroxide anion first attacks the C-2
position of a C-2 thioalkyl substituted quinolone, and upon decar-
boxylation the thioalkyl group serves as a better leaving group
than hydroxide. The thioalkyl group is ejected, and decarboxylated
2-hydroxy fluoroquinolone is obtained.
Deprotonation of 3 with potassium hydroxide followed by cou-
pling with cyclopropyl isothiocyanate and trapping the thiolate
Hydrolysis of esters 6a–d under acid conditions also afforded
unexpected results. Following established literature proce-
dures,38,43 the heating of esters 6a–d in 1–10% sulfuric acid
Scheme 1. Synthesis of C-2 S-alkyl fluoroquinolone ethyl esters.
Scheme 2. Ester hydrolysis and decarboxylation reactions.

K. R. Marks et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4585–4588
4587
Figure 2. Comparison between 7a (A) and ulifloxacin (B) showing loss of planarity
when C-2 thioether is not constrained in the thiazetidine ring system. Minimiza-
tions performed by MM2 (shown) and HF 6-31G⁄⁄ were similar.
Scheme 3. Decarboxylation of control fluoroquinolones.
ated derivates (Table 1). As expected the decarboxylated analogs
of ciprofloxacin, moxifloxacin and ulifloxacin were 60-fold to over
25,000-fold less active than the parent agents against each strain
tested (Table 1). Interestingly, both the parent and the decarboxyl-
ated compound showed lower MIC with the tolC knockout of E. coli
as compared to wild type, demonstrating the 3-carboxylate group
is not important for recognition and efflux by the TolC transport
system.
MIC values for all C-2-thioalkyl derivatives are high in compar-
ison to parent fluoroquinolones. In contrast, comparison of MICs
for descarboxy moxifloxacin with the decarboxylated C-2-thioeth-
yl and C-2-thioisopropyl derivatives shows that, in the absence of a
C-3 carboxylate group, a C-2-thioalkyl group can impart lower MIC
when in place of the C-2H. For example, incorporating a C2-S-iso-
propyl group into descarboxy moxifloxacin (compound 9d) gives a
lower MIC than for descarboxy moxifloxacin with each strain
tested. These data demonstrate that either a 2-thioalkyl group or
a 3-carboxylate moiety can afford increased activity over corre-
sponding 2,3-unsubstituted derivatives, with the 3-carboxylate
imparting a much lower MIC than the 2-thioalkyl group.
solution provided the decarboxylated C-2 thioalkyl products in
good yield (Scheme 2). Ultimately, hydrolysis of the ethyl esters
using fuming sulfuric acid at room temperature42,44 gave isolatable
C-2 thioethyl products 7a and b in poor yield. Having these com-
pounds characterized and in hand, analytical HPLC studies of 7a
and b in water at various pH revealed the compounds to be stable
at neutral pH but unstable under both acidic and basic conditions.
We were then able to use HPLC to observe hydrolysis of the C-2-S-
isopropyl derivatives 6c and d to give desired 3-carboxylate-2-
thioisopropyl analogs, but these compounds proved to be unstable,
readily undergoing decarboxylation. Thus their isolation was
abandoned.
Decarboxylated control compounds were prepared from parent
fluoroquinolones. Moxifloxacin (10) and ciprofloxacin (12) were
decarboxylated with cyanide to give 11 and 13 (Scheme 3).32 This
procedure was ineffective when applied to ulifloxacin (14), further
enforcing the detrimental effect of a C-2 thio moiety on reactions
of the 3-carboxylate that are routinely performed with other fluo-
roquinolones. However, guided by experimental observations,
treatment of ulifloxacin (14) with 10% sulfuric acid for 6 days at
100 °C gave descarboxyulifloxacin 15 in good isolated yield after
preparative HPLC (Scheme 3).
Unlike ulifloxacin, where the 3-carboxyl group and the thiazeti-
dine ring combined to afford a significant increase in potency (low-
er MIC), compounds 7a and b, which have both the 3-carboxylate
and a 2-thioethyl group, have high MICs. In fact, the elevated MICs
of the C-2-S-alkyl compounds overall is in contrast to typically low
Bacteriostatic activity of the parent 3-carboxy fluoroquinolones
was compared with activity of the C-2-thioalkyl and decarboxyl-
Table 1
MIC of C-2 and C-3 modified quinolones in E. coli and M. smegmatis
Compound
C-2
C-3
C-7
Bacterial Strain (MIC lg/mL)
E. colia
E. coli tolCb
M. smegmatisc
Ciprofloxacin
13
Ulifloxacin
15
H
H
CO2H
H
CO2H
H
CO2H
H
CO2H
CO2H
H
Piperazinyl
Piperazinyl
Piperazinyl
Piperazinyl
Octahydropyrrolopyridinyl
Octahydropyrrolopyridinyl
Piperazinyl
Octahydropyrrolopyridinyl
Piperazinyl
Octahydropyrrolopyridinyl
Piperazinyl
Octahydropyrrolopyridinyl
0.04
50
0.008
1.56
0.016
200
0.004
100
12.5
>50
25
0.156
6.25
3.13
200
0.08
>200
>200
50
Thiazetidine
Thiazetidine
H
0.062
>200
0.156
>200
200
>50
>50
>200
>50
>50
Moxifloxacin
11
7a
7b
9a
9b
9c
9d
H
S-ethyl
S-ethyl
S-ethyl
S-ethyl
S-isopropyl
S-isopropyl
>50
>200
>50
H
H
H
100
>50
50
50
a
b
c
KD65.
KD1397.
KD1163.

4588
K. R. Marks et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4585–4588
18. Naik, P. N.; Chimatadar, S. A.; Nandibewoor, S. T. Ind. Eng. Chem. Res. 2009, 48,
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Cabrera, L. Antimicrob. Agents Chemother. 2010, 54, 2188.
21. Vera-Cabrera, L.; Campos-Rivera, M. P.; Escalante-Fuentes, W. G.; Pucci, M. J.;
Ocampo-Candiani, J.; Welsh, O. Antimicrob. Agents Chemother. 2010, 54, 2191.
22. Beylin, V.; Boyles, D. C.; Curran, T. T.; Macikenas, D.; Parlett, R. V.; Vrieze, D.
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D. Q.; Singh, R. J. Med. Chem. 2006, 49, 6435.
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Chemother. 2008, 52, 3915.
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Decarboxylated ciprofloxacin was prepared as follows: 65.1 mg (0.20 mmol)
ciprofloxacinÁHCl and 40.6 mg (0.82 mmol) NaCN were stirred in 2 mL DMSO at
100 °C for 17 h. Product 13 was purified by semi-preparative HPLC.
Descarboxymoxifloxacin (15) was prepared similarly. 13 1H NMR (DMSO-d6)
d 1.04 (br s, 2H), 1.21 (br d, J = 6.6 Hz, 2H), 3.34 (br s, 4H), 3.42 (m, 4H), 3.57 (m,
1H), 6.00 (d, J = 7.4 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.77 (d, JH-F = 13.9 Hz, 1H),
7.98 (d, J = 8.2 Hz, 1H). 19F NMR À126.30. MS, ESI, calcd (M+H+) 288.14, found
288.24.
33. Compound 5a was prepared by stirring 182.7 mg (0.45 mmol) 4a and 53.0 mg
(0.47 mmol) KOtBu in toluene while heating to reflux for 19 h. Product 5a was
purified by flash column eluted with 3:1 hexanes. 1H NMR (CDCl3) d 0.69 (br s,
2H), 1.17 (br s, 2H), 1.34 (m, 6H), 3.06 (q, J = 7.4 Hz, 2H), 3.70 (m, 1H), 4.06 (d,
J = 2.3 Hz, 3H), 4.38 (q, J = 7.1 Hz, 2H), 7.75 (dd, 1H). 19F NMR (CDCl3) d À146.03
(m, 1F), À137.12 (m, 1F). MS, ESI, calcd (M+H+) 384.10, found 384.02.
Compound 5b was prepared similarly.
34. Compound 6a was prepared by stirring 37.8 mg (0.10 mmol) 5a with 44.3 mg
(0.5 mmol) piperazine in 2 mL DMF at 130 °C for 26 h. Product was purified by
semi-preparative HPLC. Compounds 6b–d were prepared similarly. Compound
6b 1H NMR (CD3CN) d 0.62 (br s, 2H), 0.99 (br s, 2H), 1.31 (m, 6H), 1.83 (m, 4H),
2.73 (m, 1H), 3.06 (m, 4H), 3.35 (m, 1H), 3.55 (s, 3H), 3.74 (m, 1H), 3.89 (br s,
1H), 4.04 (t, J = 1.1 Hz, 1H), 4.29 (dq, J = 7.1, 1.6 Hz, 2H), 7.32 (d, JH-F = 12.8 Hz,
1H), 9.70 (br s, 1H). MS, ESI, calcd (M+H+) 490.21, found 490.18.
35. Compound 7a was prepared by stirring 71 mg 6a in 1 mL fuming sulfuric acid
for 2 h. Product was purified by semi-preparative HPLC and confirmed by ESI
MS, calcd (M+H+) 422.15, found 422.03. Compound 7b was prepared similarly.
MS, ESI, calcd (M+H+) 462.18, found 462.11.
MICs reported in the literature for ulifloxacin and for other C-2-S
substituted quinolones in which the C-2 sulfur is incorporated into
a fused ring system such as isothiazolidinone (isothiazoquinolones)
and thiazetidine (ulifloxacin) rings (Fig. 1).19–21 Similar results were
found when direct inhibition and poisoning of purified gyrase was
characterized: the C-2-thioalkyl compounds were orders of magni-
tude less active than the fused-ring congeners (data not shown).
A likely reason for the improved activity of isothiazole- and
thiazetidine-containing fluoroquinolones is binding interactions
with gyrase involving the C-2 sulfur atom. However, addition of
thioalkyl groups to position 2 of quinolones, as described in this
work, while modestly enhancing activity over 2-unsubstituted
3-descarboxy fluoroquinolone, does not enhance antibacterial
activity. Molecular modeling studies provide a likely explanation
for this dramatic difference in activity for C-2-thioalkyl versus
C-2-S-fused ring compounds. As shown ( Fig. 2, panel A), steric
conflict between a C-2-thioalkyl group and the 3-carboxylate
moiety significantly distorts orientation of the 2-thioalky group
and carboxylate out of planarity with the quinolone core. In
contrast, when the C-2 sulfur atom is incorporated into a fused ring
system, the 3-carboxylate and fused ring system remains co-planar
with the quinolone ring system (exemplified by ulifloxacin in
Fig. 2, panel B).
In conclusion, we have identified structural features of 2-thio
derivatives of fluoroquinolones that contribute to both increased
and decreased antibacterial activity. Synthetic methods employed
in this work have revealed additional types of 1,4-addition reac-
tions that can be exploited to functionalize position 2 on the fluo-
roquinolone core. Thus guided by these results and the recently
reported quinolone–topoisomerase–DNA crystal structures, we
are now working to characterize the potential binding interactions
of a C-2-sulfur in the drug–topoisomerase complex and to synthe-
size new type II topoisomerase inhibitors that will be active against
mutants resistant to current agents.
Acknowledgment
This work was supported by NIH Grants R01-AI73491 and
R01-AI087671.
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