Expert Opinion on Investigational Drugs

ISSN: 1354-3784 (Print) 1744-7658 (Online) Journal homepage: http://www.tandfonline.com/loi/ieid20

Monthly Update: Anti-infectives: New

fluoroquinolones issued in 1994

Andr Bryskier

To cite this article: Andr Bryskier (1995) Monthly Update: Anti-infectives: New
fluoroquinolones issued in 1994, Expert Opinion on Investigational Drugs, 4:7, 649-655, DOI:
10.1517/13543784.4.7.649

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 Monthly Update
Anti-infectives

New fluoroquinolones issued in 1994

Andrk Bryskier
Roussel Uclaf, Hoechst-Roussel Anti-infectives,Clinical Pharmacology Department,
102, Route de Noisy, 93230 Romainville,France

1994 was hardly a vintage year for new quinolones. The only new
entities were two from Korea (CFC 222, DW 1 16), one from Mediona-
lum-Italy (MF 5137),two from Argentina (NSFQ-104, 105), one from
Japan Wakunaga (WQ 2128), and a series of 7-azetidinyl derivatives
from Esteves Spain [l].
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Exp.Opin. Invest. Drugs (1995)4(7):649455

CFC 222 CFC 222 displays intermediate antibacterial activity in

~~~

vitro between ciprofloxacin and sparfloxacin against

CFC 222 is a new 6-fluoroquinolone with a bicyclic Gram-positive cocci, but it is more active than the latter
moiety fixed at C-7 (Figure 11, from Cheil food & against S. pneumoniae (one dilution - MIC values 0.2
Chemical, Inc. (Korea). CFC 222 hydrochloride salt is mg/l w s u s 0.4 mg/l). It shows cross-resistance with
highly soluble in water (> 50 mg/ml) and also as a base ciprofloxacin against S. a u m s . It is poorly active
compared to ciprofloxacin (Table 1). -
against P. aeruginosa (MIC value 3.13 m d ) . Against
Entembacteriaceae,it is less active than ofloxacin and
roughly as active as lomefloxacin. It displays identical
activity to ofloxacin and ciprofloxacin against Acine-
tobacter baumannii (MIC 0.20 mgA) (Table 2).
In non-discriminative experimental infections, CFC 222
is more active than sparfloxacin against Gram-positive
Figure 1: CFC 222. cocci such as S. aureus Smith, S.pyogenes C-203 and
S.pneumoniae Type 111. It is less active than ciproflox-
acin against experimental infections due to E. coli
KC-14 and S. maxescem 1-55 and less active than
Table 1: Water solubility of fluoroquinolones. sparfloxacin against P. aeruginosa F2.
Aqueous solubility In a mouse model of respiratory tract mfection due to
(m%W[ b e 1 K.pneumoniaeB-54 (7.1 x lo8 cfdml), CFC 222 seems
CFC 222 0.62 to be more effective than ciprofloxacin and ofloxacin
(1.0 mg/mouse). In experimental urinary tract infec-
Ciprofloxacin 0.09 tions due to E. coli 444 (1.2 x 10 cfdmouse), all the
ofloxacin 2.5 4-quinolones tested exerted the same activity 121.
Sparfloxacin 0.14 The pharmacokinetics of CFC 222 were determined
Tosufloxacin 0.008 both orally and intravenously in mice, rats, dogs and
monkeys. After an oral administration of 20 mg/kg,
Pazufloxacin (T 3761) 0.2 mean serum concentrations were 4.9, 4.4, 5.0, and 6.0
DU 6859a 0.006 mg/l in mice, rats, dogs and monkeys, respectively
(Table 3). Ehination half-lives ranged between 4.5
Balafloxacin (4-35) 0.3 and 6.2 hours.
649
1995 Q Ashley Publications Ltd. ISSN 1354-3784
 650 New fluoroquinolones issued in 1994 - Bryskier

MIC ( m g )
CFC 222 Ciprofloxacin Ofloxacin
S. aureus Smith 0.10 0.20 0.39
MRSA C2208 0.05 0.39 0.39
S.pyogenes ATCC 8668 0.10 0.39 0.78
S. pneumoniae C8027 0.20 0.78 1.56
E. faecalis ATCC 29212 0.20 1.56 3.13
E. coli ATCC 10536 0.012 0.006 0.05
P. aeruginosa C2027 0.05 0.05 0.1

/I
I,

Table 3: Pharmacokinetics of CFC 222 after oral administration (20 mgkg). I

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Cm, Tmax T'/z AUC Protein binding

(mgfl) @) @) (m&w
ICR - mice 4.9 0.25 6.O 12.7
SD - rats 4.4 0.25 4.5 15.2
Beagle dogs 5.0 2.o 5.9 45.7 37.2
C p m o l g u s monkeys 6 .O 2.o 6.2 40.5

Inoculum size MIC EDSO

(celldmouse) (mgfl) (mg/kg)
S. aureus Smith 6.9 x lo6 DW 116 0.39 5.4
Rufloxacin 0.78 16.9
Ofloxacin 0.2 6.7
MRSA y-80-12475 2 lo7 DW 116 0.19 3.1
Rufloxacin 0.39 5.9
Ciprofloxacin 0.007 0.9
Sparfloxacin c 0.002 c 0.8
E. coli D 444 6.5 lo5 DW 116 0.01 0.7
Rufloxacin 0.2 5
Ofloxacin 0.006 1.2
S. marcescens 55
II 7.3x lo5
DW 116
Rufloxacin
I Ofioxacin
II 1.56
1.56
0.2
I 6.7
15.1
2.9
K. pneumoniae DT-S
I 1.3x lo6
DW 116
Rufloxacin
Ciprofloxacin
0.09
0.39
0.007
17.7
> 25
12
SDXflOXXin 0.013 6.2
P. mirabilis 1.0 x 10'O DW 116 0.39 5.3
Rufloxacin 0.39 9.1
Ciprofloxacin 0.007 2.6
SDarflOXacin 0.09 5.5
P. aeruginosa NC-5 8.9 lo5 DW 116 0.78 5.6
Rufloxacin 1.56 40.6
Ofloxacin 0.2 5.8
Acinetobacter 1.0 x 1o'O DW 116 0.19 9.1
Rufloxacin 0.78 29.3
Ciprofloxacin 0.19 15.9
sparfloxacin 0.02 2.7

0 Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs (1995) 4(7)
 Anti-idecdves - Monthlv UDdate 651

Following iv administration, the urinary elimination

was 39.4% and 10.4% in rats (20 mgik@ and monkeys
(10 mg/kg), respectively. Part of the compound is
conjugated in bile. The mean biliary recovery of
unchanged CFC 222 in rats was 9.6Y0, and increased to .HCI
36.5% following hydrolysis of conjugated CFC 222 [31.

DW 116
DW 116 is a new 6-fluoroquinolone prepared by Figure 2: DW116.
Dong-Wha Central Research Laboratories (Korea). It is
a quinoline derivative with an N-1 (5-fluoro-2-pyridyl)
and a 4'-methylpiperazine moiety appended at C-7
(Figure 2). 0

In vim, DW 116 was compared to sparfloxacin,

ciprofloxacin, rufloxacin and ofloxacin against refer-
Y?r?.f
H2N
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ence strains. It is less active than sparfloxacin, oflox-

acin and ciprofloxacin, but more active than rufloxacin i.y CH3A

(Table 4). In vivo, the antibacterial activity of DW 116

was of the same magnitude as that of ofloxacin.
The compounds were orally administered twice, one
and four hours after bacterial challenge. After oral
administration of 20 mg/kg, mean peak serum concen-
trations were 4.9 and 8.6 mg/l in mice and rats,
respectively. The apparent elimination half-lives were
2.04 hours and 6.05 hours, respectively. Compara-
tively, rufloxacin was administered orally to mice and
rats. Mean plasma levels were 2.21 mg/l and 4.35 mg/l,
respectively, with corresponding apparent elimination
half-lives of 1.11 hours and 5.43 hours.
A comparative pharmacokinetic study was carried out
in dogs. After a single oral dose of 10 mgkg, the
apparent elimination half-lives of DW 116 and ruflox-
acin were 9.78 hours and 4.41 hours, respectively.
DW 116 is mainly eliminated in the urine. The tissue
distribution of DW 116 is better than that of ofloxacin
(Table 5) [41.
Figure 3: MF 5 137.
MF 5137
A series of new 6-aminoquinolone derivatives has
been synthesised by Mediolanum. One compound has
been selected for further investigation:MF 5137 (Figure
3).
The originality of MF 5137 lies in the 6-substituent
which is an amino group instead of a fluorine atom.
The molecule has an 8-methyl group, like grepaflox-
acin. The C-7 moiety is a tetrahydroisoquinolyl ring.
This molecule shows good activity against Gram-posi-
tive organisms, including Enterococcusfaecal&. It is
four-to five-fold more active than ciprofloxacin against
E. facalis and S. pneumonia and eight-fold more
active against S. aureus.

1 Table 5: Animal kinetics of DW 116. I

Route Dose CmaX TmaX AUC T'/z U F
(mgflrg) (mgn) (h) (mgW (h) (%I (%I
Mice DW 116 PO 20 4.9 0.5 19.6 2.04
Rufloxacin PO 20 2.2 0.5 5.4 2.1 1
Rats DW 116 PO 20 16.4 0.75 152.7 7.59 32 18.5
iv 20 119.8 6.09
Rufloxacin PO 20 4.3 1.o 30.9 5.43 36.6
Ciprofloxacin PO 20 1.5 0.25 2.6 2.06 5
Dogs DW 116 PO 10 5.8 2.8 63.9 9.78 7.4
Ciprofloxacin po 10 2.7 2 .o 13.2 4.41 27.2

0 Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs (1995) 4(7)
 652 New fluoroqufnolones bmed in 1994 - Bryskier

With the exception of M . catarrhalis(MlC 0.008 mg/l),

F &cow it is moderately active against Gram-negative bacilli
(Table 6). In terms of medicinal chemistry, only 4-qui-
nolones substituted with a Gfluorine are claimed to
R display in vitro activity,but this molecule shows a good
HN
, 0,s
anti-Gram-positive activity with a Gamino group. In
mice infected with S. aureus, h4F 5137 is more active
than ciprofloxacin when administered subcutaneously
NSFQ-104: R = C2H5 (vehicle DMSO/methanol 0.5%) (Table 7) [51.

NSFQ-105: R =
d NSFQ-104, NSFQ-105
Two new fluoroquinolones, NSFQ-1% and NSFQ-105,
Figurr 4: NSFQ-104 and NSFQ-105.
have been described [31. These molecules bear a

rI 0 1
4-(4-aminophenylsulphonyl)4-piperazinyl moiety at
C-7 (Figure 4). They were selected among a series of
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F, compounds synthesised by Allemandi et al. (1992, US

Patent). The program was set up to prepare molecules
.HCI with enhanced activity against Gram-positivemicro-or-
ganisms.
NSFQ-105 is sixteen times more active than ciproflox-
acin against methicillin-susceptible S.aureus isolates,
Figure 5: WQ 2128. but NSFQ-104 is only two times more active. NSFQ-105
is sixteen times more active against methicillin-resistant
isolates, but remains not therapeutically relevant
Table 6: In vitro activity of MF 5137 (adapted from Wise el (MIC5o/9o values 2 and 4 mg/l). However, the types of
a1.[5]). strains and in uitm activity against ciprofloxacin-resis-
tant strains were not specified. These compounds are
of interest because they are among the few with
MF 5137 Ciprdoxacin Rutloxacin
antibacterial activity even with a bulky moiety ap-
pended at the 4-position of the 7-piperazinyl ring [61.
S. uureus (25) 0.008 0.5 1
S. pyogenes (4) 0.06 1 8 WQ 2120
S. ugulactiue ( 5 ) 0.25 2 16 WQ 2128 is a new fluoroquinolone bearing an isoxa-
E.fueculis (5) 0.12 2 8 zole moiety at the N-1 position of the pyridone ring
(Figure 5). WQ 2128 is less active than sparfloxacin
S. pneumoniue (15) 0.12 2 16 against methcillin-susceptible S. aureuS (MIC50 0.39
E. coli (1 5 ) 0.12 0.008 0.5 versus 0.1 mg/l) and S. epidemtidis and shows iden-
tical activity against S.pneumoniue and S.pyogenes. It
Kkbsiella spp. (15) 2 0.015 1
is poorly active against Entwococcus spp. (Table 8).
P. mirubilis (15) 0.5 0.015 2 Against Enterobacteriaceae,it displays in uitm activity
close to that of ciprofloxacin (Table 9).
Sevutiu sp. (15) 16 0.06 1
P. ueruginosu ( 15) 2 0.12 8 In vim, it is as active as levofloxacin against staphylo-
coccal and pneumococcal infections, and less active
H . injluenzue (15) 0.015 0.004 0.5 then levofloxacin against Pseudomonas infections (Ta-
N. gonorrhoeue (23) 0.001 0.001 0.06 ble 10). In rats, mice and dogs, the compound is
eliminated mainly in the urine. Phototoxicity was
evaluated using the ear redness of ICR mice, and
Table 7 : In vivo activity of MF 5137. convulsant activity by giving the 4-quinolone intrave-
nously (thirty minute infusion) and after oral admini-
stration of 100 mgkg of biphenyl acetic acid. N o
convulsions or deaths were recorded up to 100 mgkg
MF 5137 0.008 1.3 for WQ 2128 and levofloxacin compared to ciproflox-
acin and enoxacin [71.

0 Ashley Publications Ltd. All rights reserved. Exp. Opin. Invest. Drugs (1995) 4(7)
 Anti-infectives - Monthly Update 653

E-4904, E-4884, E-4874, E-4749

Table 8: In vitro activity of WQ 2128 against Gram-positivc
These compounds belong to a new series of 7-azetidi- cocci.
nylquinoline derivatives. They differ by the substi-
tuents on the azetidinyl ring and the side-chain mc50 (4)
appended at N-1 (N-1 cyclopropyl or 2,4-di-
fluorophenyl moieties) (Figure 6). The antibacterial
I N I WQ2128 1 Sparfloxacin
activity of these compounds is comparable to that of S. aureus 39 0.39 0.10
ciprofloxacin and sparfloxacin. E4094 was the least
active analogue. It should be noted that Sevutiu S. epidermidis 27 0.39 0.20
marcescens is resistant to these compounds (MIC50 2 S. pneumoniae 13 0.20 0.20
8 mg/l) and cross-resistance is shared between these
derivatives and ciprofloxacin. S. pyogenes 35 0.39 0.39

They are inactive against P. aeruginosa, non-aermgi- E.faecalis 26 0.78 0.78

nosa Pseudomonas, S. maltophilaa and Acinetobacter
E. faecium 27 3.13 1.56
sp. They exert good activity against Aeromonas spp.
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and Pleisiomonas spp. The four compounds are active

against S. uureu~strains susceptible to methicillin, but
are two to eight times less active than ciprofloxacin
and sparfloxacin.They are inactive against MRSA. Most
of the strains of E. faeculis are resistant (MIC50 4 - MICso
mg/l). E4904, E-4874 and sparfloxacinwere four times
more active than ciprofloxacin against S.pneumoniae. N WQ 2128 Ciprofloxacin
E4874 was four-fold more active than other com-
pounds tested against L . monocytogenes (MIC50 0.5 - E. coli 56 0.025 0.025
mg/l). These compounds are poorly active against
K. pneunwniae 60 0.05 0.05
anaerobes [ll.
E. cloacae 30 0.05 0.05
New tetracvclic fluoroquinolone derivatives E. aerogenes 27 0.05 0.05
A new series of tetracyclic-pyridone-f3-carboxylicacid S. marcescens 30 0.39 0.20
analogues was reported by Jinbo et al. [8],with differ-
ent morpholino groups at the C-8 position instead of C.ji-eundii 30 0.20 0.10
an 8-piperazinyl moiety such as KB-5246 or KB-5290.
P. mirabilis 25 0.20 0.05
These compounds are thiazolopyrazine incorporated
tetracyclic pyridone-kcarboxylic analogues. In a pre- M.morganii 27 0.05 0.05
vious study, a morpholino derivative (Figure 7)
showed good antibacterial activity against Gram-posi- P. vulgaris 27 0.10 0.05
tive bacteria and against MRSA isolates, but insufficient P. rettgeri 15 0.05 0.05
in vim activity because of low oral absorption [91.
P. aeruginosa 58 0.39 0.39
Against Gram-positive bacterial, compounds with
methyl, chloromethyl, fluoromethyl or hydroxymethyl
functional groups at the C-2 position of the mor-
pholino moiety exhibit good and equivalent activity
against Gram-positive cocci and are more active than
ofloxacin. Compounds with an ethyl methoxymethyl Micro- Cells/ MIC EDSO
group or a 2,6 dimethyl group are less active than the organisms mouse (mgn) (mg/kg)
original compound. Compounds with an aminomethyl
S. aureus 1.1 x lo6 WQ 2121 0.10 1.20
group fixed at the C-2 position are four- to eight-fold Smith Levofloxacin 0.10 1.33
less potent against Gram-positive cocci than the first
morpholino derivative. S.pneumoniae 5 x lo2 WQ 2121 0.10 35.36
W1466 Levofloxacin 0.78 35.36
Against Gram-negative bacteria, the introduction of
functional groups on the morpholino moiety tended P. aeruginosa 4.6 x lo4 WQ 2121 0.76 41.58
to weaken the antibacterial activity as compared to the E-2 Levofloxacin 1.56 24.71
unsubstituted compound. I1 I I I I

0 Ashley Publications Ltd.All rights reserved Exp. Opin. Invest. Drugs (1995) 4(7)
 654 New fluoroquinolones bsued In 1994 - Bryskier

E-4904 - NH, -H

E-4884 - NH, -H
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E-4874 - NH, - CH, -H 4 CI

E-4749 - NH, -H -H ( F t F H

Figure 6: New azetidinyl derivatives.

0 In the piperazinyl series, only analogues with an alkyl

group at the N 4 ' position of the piperazinyl ring
showed oral efficacy. Introduction of functional
groups at the C-2 'position of the 8-morpholino moiety
enhanced the antibacterial activity after oral dosing.
The introduction of a methoxymethyl group at the C-2'
R position of the &morpholino moiety resulted in good
S. aureus I1 D803
bioavailability after oral administration. This com-
pound has an asymmetric centre on the morpholino
moiety. However, the stereochemical properties have
no influence on either in vitro or in yivo antibacterial
activity.
-H 0.006 > 12 0.05

-CH3 0.006 3.5

References
-2',6'-CH3 0.12 > 12
1. GARCIA-RODRIGUEZ JA, GARCIA-SANCHEZ JE, GARCIA-
-C2H5 0.02 > 12 GARCIA MI, FRESNADILLO MJ, TRUJILLANO I, GARCIA-
SANCHEZ E: In u i t r o activity of four new
-CH2CI 0.006 fluoroquinobnes./. Antimicmb. Chaotber. (1994)3453-
64.
-CH2F 0.006 1.9 0.63
2. PARK KH, M O M, LEE JM, KANG JA, KIM YG, HONG KH,
-CH20H 0.006 5.1 0.25 KIM JH, NISHINO T, KIM JW:In Vttm and fn ufuo antibac-
terial activity of CFC-222, a novel broad spectrum
-CH20CH3 0.12 1.7 2.63 f l u o ~ o k m e 5th
. Intern. Symposium on New Qui-
nobnes, Singapore, 1994. Abstract 87.
-CH2NHCH3 0.05 3. JUNG YH, LEE KS, YEON KJ, KIM DH, KIM JH, LEE KH, KIM
JW,PARK KH: Pharmacokinetics ofCPC-222 in animals.
-CH2N(CH2)2 0.02 4.8 5thIntern. Symposium on New Quinolones, Singapore, 19%.
Abstract 86.
Ofloxacin 0.39 4.4
4. HAN KO, LEE DK, MOON EY, LEW CW, JUNG YH, YOON
SJ, YANG SI, GONG JY,TAMAOKA N, DOMORI K, OBANA
Y Phaimacolcinetics studies of a new qulnolone DW-
Figure 7: In vitro and in vivo activity of 8-morpholinotetracyclic 116. 5th Intent. Symposium on New QuinoZone, Stngapore,
fluoroquinolones. 1994. Abstract 175.

0 Ashley PublicationsLtd. All rights reserved. Exp. Opin. Invest. Drugs (1995) 4(7)

5. WISE R, PAGELLA PG, CECCHETFI V, FRAVOLINI A, TABAR-
RINI 0:In ultm activity of MF5137, a new potent 6-amlno
quinobne. 5th Intern. Symposium on New Quinolones,
Singapore, 1994. Abstract 9.
6. ALLEMAND1 DA, ALOVERO FL, M A N 2 0 RH:In vfWO acthr-
ityof-sulphonilllfluomqufnolon=~ againststapby-
lococcus aureus. J . Antimicrob. Chemother. (1994)
34:261-265.
7. OHSITA Y, HIRAO Y, HAGASHI N, AMANO H, MURUYAMA
S, NODA S, K W O T O Y, YAZAKI A: WQ-2128,apotent
~t~~~ q b o b n e : biobdcal ~ u a t i o n J4th
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tersci. ConJ Antimicrob. Agents Chemother., Orlando
(1994):F-32.
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0 Ashley Publications Ltd. All rights reserved.
Anti-idectives - Monthlv Uodate 655
8. JINBO Y, KONDO H, TAGUCHI M, WOUE Y, SAKAMOTO
F, TSUKAMOTO G: SyntheSL and blobgical activity of
thtazolopyrazine-lporated tetracyclic quholone
antibacterlal agents (a.
J. Med. Chem. (1994) 37:2791-
27%.
9. INom y, H, TAGUCHl M, JNBo sAKAMoTo
F, TUKAMOTO G: Synthesis and antibacterial activity of
thiazolopyrazine-incorporatedtetracyclic qufnolone
antibactetlals. J. Med. Chem. (1994) 37:586-592.
Andre Bryskier, R o w e l Uclaf, Hoechst-Roussel Anti-infectives, Clini-
cal Pharmacology Department, 102, Route de Noisy, 93230 Romain-
ville, France (Tel: 33 1 49 91 51 21; Fax: 33 1 49 91 50 20).
Exp, Opin. Invest. Drugs (1995)4(7)