Synthesis and biological evaluation of benzo[b]naphthyridones, a series of new topical antibacterial agents

Article abstract of DOI:10.1016/S0960-894X(01)00091-9

We describe here the synthesis and biological evaluation of a series of benzo[b]naphthyridones, a new family of tricyclic antibacterial compounds that have a Gram-positive spectrum of activity. RP60556A, one of the most potent of these compounds, is bactericidal against multiresistant cocci, especially multiresistant Staphylococcus aureus strains. Its physico-chemical and biological properties make it particularly suitable for topical antibacterial use.

Full text of DOI:10.1016/S0960-894X(01)00091-9

Bioorganic & Medicinal Chemistry Letters 11 (2001) 919–921
Synthesis and Biological Evaluation of Benzo[b]naphthyridones,
a Series of New Topical Antibacterial Agents
Michel Tabart,* Guy Picaut, Jean-Franc¸ ois Desconclois,
Sylvie Dutka-Malen, Yvette Huet and Nadine Berthaud
Aventis Pharma, Centre de Recherche de Vitry Alfortville, 13 Quai Jules Guesde, 94403 Vitry sur Seine, France
Received 5 December 2000; revised 5 February 2001; accepted 7 February 2001
Abstract—We describe here the synthesis and biological evaluation of a series of benzo[b]naphthyridones, a new family of tricyclic
antibacterial compounds that have a Gram-positive spectrum of activity. RP60556A, one of the most potent of these compounds, is
bactericidal against multiresistant cocci, especially multiresistant Staphylococcus aureus strains. Its physico-chemical and biological
properties make it particularly suitable for topical antibacterial use. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
In recent years, emergence of resistance to most com-
mon antimicrobial agents such as b-lactams, macro-
lides, vancomycin or quinolones has become a major
1
,2
worldwide health problem. Therefore the search for
new antibacterial drugs effective against bacteria resis-
tant to multiple antibiotics is a key objective for many
3
pharmaceutical companies. The spread of resistant
nosocomial pathogens, and especially methicillin-resis-
4
,5
tant Staphylococcus aureus (MRSA)
specific need in hospital for prevention of nasal car-
has created a
6
Figure 1.
riage and topical treatment or prophylaxis of infections
7
8
caused by these pathogens. Mupirocin and fusidic acid
are used in these indications, but resistance to these
9
,10
agents
need for alternative treatments.
has become a concern. Therefore there is a
Chemistry
RP60556A is obtained in a 10-step synthesis12 (Scheme
1) with a global yield of 14%. The tricyclic structure of
the benzo[b]naphthyridone is obtained by a Friedel–Craft
cyclisation followed by a Grohe-type ring closure. Thus
We had previously described the synthesis11 of a series
of benzo[b]naphthyridones studied as systemic anti-
bacterial agents.
3,4-difluoro aniline 1 is condensed on 3-chloropropionyl
We have found now that a modification of the sub-
stitution of the heterocycle led us to a new series of
topical antibacterial agents particularly active against
multiresistant Gram-positive pathogens, especially against
MRSA. RP60556A is the most potent representative
compound of this series (Fig. 1).
chloride to form the corresponding anilide 2 which is
cyclised using aluminium chloride as Lewis acid cata-
lyst. Compound 3 is formylated and chlorinated with
the Vilsmeier reagent. The 1,4-dihydroquinoline 4
obtained is oxidized into quinoline 5 by potassium per-
manganate. Then the magnesium chelate of mono-
malonic ethyl ester is condensed on the acid chloride
of 5 to get b-keto ester 6 which is reacted with dimethyl
formamide dimethyl acetal to obtain enamine 7. The key
step of the synthesis, i.e., the cyclization of quinoline 7
1
3
*Corresponding author. Fax: +33-1-55-71-87-70; e-mail: michel.
tabart@aventis.com
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00091-9

920
M. Tabart et al. / Bioorg. Med. Chem. Lett. 11 (2001) 919–921
ꢀ
ꢀ
ꢀ
Scheme 1. (a) Pyridine, acetone, 55 C, 3 h, 95%; (b) AlCl
ꢀ
3
, 110 C, 2 h, 78%; (c) DMF, CHCl
3
, POCl
3
, 60 C, 2 h, 85%; (d) KOH, KMnO
ꢀ
4
, H
2
O,
then magnesium chelate of monomalonic ethyl ester, THF, 65%; (f) DMFDMA, ethyl acetate, 75 C, 1 h, 91%;
1
0 C, 1 h, 66%; (e) CHCl
ꢀ
3
, SOCl
2
ꢀ
ꢀ
(
g) MeNH
ꢀ
2
, EtOH, 25 C, 16 h, 83%; (h) HCl 6 N, AcOH, 100 C, 1.5 h, 89%; (i) DMSO, 90 C, 4 h, 98%; (j) choline hydroxide 45% in MeOH, 2 h,
25 C, 79%.
into tricyclic benzo[b]naphthyridone 8 is performed in
good yield (83%) with methylamine in methanol. Ethyl
Table 1.
Amine or ref cmpd
Cmpd no.
MIC G+QSa MIC G+QRb
ester 8 is hydrolyzed with a mixture of hydrochloric acid
ꢀ
6
Nand acetic acid at 100 C to obtain acid 9. The
Pefloxacin
Muprirocin
Pefloxacin
Mupirocin
0.5
0.5
128
0.5
nucleophillic aromatic substitution of the fluorine in
position 8 of the benzo[b]naphthyridone 9 by a sub-
stituted piperazine is performed in DMSO in high yield
1
1 (RP60556A)
0.25
0.5
1
0.5
(
98%). It is interesting to note that the fluorine in
position 7 of the tricycle is not substituted even in the
presence of a large excess of nucleophile, just as in
the quinolone chemistry. The obtained acid 10 is very
insoluble in water and in most organic solvents, there-
fore it is transformed into its cholinate salt 11 with
choline hydroxide in methanol. The cholinate salt 11,
RP60556A is readily soluble in water.
1
1
2a
2b
1
1
1
2c
1
1
A series of benzo[b]naphthyridones was synthesized
according to Scheme 2, in which fluorine in the position
1
2d
4
4
8
of intermediate 9 was replaced by various amines.
aG+QS=Staphylococcus hominis IP8203, quinolone sensitive, MIC in
mg/L.
b
G+QR=Staphylococcus aureus LF11C128B, quinolone resistant,
MIC in mg/L.
Scheme 2.

M. Tabart et al. / Bioorg. Med. Chem. Lett. 11 (2001) 919–921
921
Biological Evaluation
which shows no cross-resistance with major classes of
antibiotics, especially with quinolones. RP60556A is a
very potent antibacterial agent with a Gram-positive spec-
trum of activity, it is bactericidal against multiresistant
strains such as Staphylococcus aureus, and its in vivo
activity in a cutaneous model of infection is close to that
of mupirocin. RP60556A physico-chemical and biologi-
cal properties make it particularly suitable for topical
antibacterial use.
Minimal inhibitory concentrations (MICs) were deter-
mined on two Gram-positive strains, one quinolone
sensitive, one quinolone resistant, for a set of com-
pounds corresponding to representative amines. The
results are summarized in Table 1.
The analysis of these results shows that MICs of deri-
vatives tested are identical against quinolone-resistant
and quinolone-sensitive strains: this suggests that these
derivatives could have a mechanism of action in these
strains different from that of quinolones.
Substituted piperazine is not mandatory for activity: sec-
ondary amines such as N-methyl N-cyclohexyl amine (12b)
or aza-cyclooctane (12c) maintain a good level of activity.
References
The presence of a basic centre (12a) or not (11, 12b, 12c,
12d) does not seem to have an influence on the spectrum
of activity.
1
3
2
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3
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The best amine is 4-fluorophenyl piperazine (RP60556A).
This compound is active against Gram-positive cocci
(
0
staphylococci, streptococci and enterococci, MIC range
.25 to 2 mg/L) without cross-resistance with quinolones,
4
b-lactams, MLSB (macrolides, lincosamides, strepto-
gramin B group), mupirocin and fusidic acid, and
against anaerobes. RP60556A is generally bactericidal
within 3–6 h at 4ÂMIC against Gram-positive strains
tested. RP60556A is also active in vivo: in a guinea-pig
model of Staphylococcus aureus cutaneous infection, a
formulation containing 2% of active compound has
shown in vivo activity close to that of mupirocin.
7
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Conclusion
The RP60556A series is a unique family of antibacterial
agents, developed only for topical, not systemic, use,