Benzo[f]naphtyridones: A new family of topical antibacterial agents active on multi-resistant Gram-positive pathogens

Article abstract of DOI:10.1016/S0960-894X(03)00057-X

The synthesis and antibacterial activity of benzo[f][1,7]naphtyridone derivatives are reported. These compounds are potent antibacterial agents with a Gram-positive spectrum of activity. They are active against multi-resistant cocci, especially Staphyloco

Full text of DOI:10.1016/S0960-894X(03)00057-X

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1329–1331
Benzo[f]naphtyridones: A New Family of Topical Antibacterial
Agents Active on Multi-Resistant Gram-Positive Pathogens
Michel Tabart,* Guy Picaut, Marc Lavergne, Sylvie Wentzler, Jean-Luc Malleron,
Sylvie Dutka-Malen and Nadine Berthaud
Aventis Pharma, Centre de Recherche de Vitry Alfortville, 13 Quai Jules Guesde, 94403 Vitry sur Seine, France
Received 17 October 2002; revised 10 January 2003; accepted 10 January 2003
Abstract—The synthesis and antibacterial activity of benzo[f][1,7]naphtyridone derivatives are reported. These compounds are
potent antibacterial agents with a Gram-positive spectrum of activity. They are active against multi-resistant cocci, especially Sta-
phylococcus aureus strains. Their physico-chemical and biological properties make them particularly suitable for topical anti-
bacterial use.
# 2003 Elsevier Science Ltd. All rights reserved.
Introduction
We describe now the synthesis and the biological eval-
uation of RPR203246 (Fig. 1), a new topical antibacterial
agent active against multi-resistant Gram-positive patho-
gens, representative of the benzo[f][1,7]naphtyridone
series. Some representative compounds of this series
were first described by Lesher13 but with no activity
against resistant strains.
The introduction and increasing use of antibacterial
agents such as b-lactams, macrolides, vancomycin or
quinolones for antibacterial therapy has resulted in the
emergence of multi-resistant pathogens, especially in
Gram-positive bacteria.1,2
During the last decade, Gram-positive infections have
become a major problem, particularly in the hospital
setting, creating a need for new antibacterial drugs
effective against bacteria resistant to multiple anti-
biotics,3 especially methicillin-resistant Staphylococcus
aureus (MRSA)4,5 which are endemic in many hospitals.
Chemistry
RPR203246 is obtained in
a
10-step synthesis14
(Scheme 1): nitro benzene 1 is reduced by tin chloride
into the corresponding aniline 2. Bromination of this
aniline is performed with N-bromosuccinimide, which
leads to compound 3, which is then treated by n-butyl-
lithium and formylated with DMF. The amino benzal-
The prevention of nasal carriage6 and topical treatment
or prophylaxis of infections caused by these pathogens
in hospitals are important aspects of the battle against
bacterial resistance. Mupirocin7 and fusidic acid8 are
used in these indications, but resistance to these agents
has become a concern.9,10
We had previously described11,12 the synthesis and
antibacterial activity of RP60556A, a representative
compound of benzo[b]naphtyridone series which is
active against multi-resistant strains (especially resistant
to mupirocin) and could be used in these indications.
*Corresponding author. Tel.: +33-1-5571-87709; fax: +33-1-5573-
8770; e-mail: michel.tabart@aventis.com
Figure 1.
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00057-X

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M. Tabart et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1329–1331
Scheme 2.
Table 1.
Compd
Compd
no
MIC
S.A.Sa
MIC
S.A.Rb
MIC
S.P.Sc
Pefloxacin
Muprirocin
RP60556A
0.5
0.5
0.25
64
1
2
8
0.12
0.5
Scheme 1. (a) HCl 12 N, Et2O, SnCl2, 40 ꢀC, O.5 h, 90%; (b) NBS,
DMF, À2 ꢀC, 1 h, 74%; (c) BuLi, THF, À75 ꢀC, then DMF, À70 ꢀC,
3 h, 59%; (d) EtOH, metazonic acid, HCl 12 N, 20 ꢀC, 16 h, 73%; (e)
EtOH, Ni Raney, H2 1 atm, 20 ꢀC, 1 h, 85%; (f) diethyl ethoxy-
methylenemalonate, 120 ꢀC, 1 h, 89%; (g) diphenyl ether, 240 ꢀC,
0.5 h, 90%; (h) DMF, K2CO3, MeI, 110 ꢀC, 1 H, 85%; (i) DMSO,
80 ꢀC, 28 h, separation of regioisomers by flash chromatography,
compd 10: 7%, compd 11: 46%; (j) EtOH, KOH 1 N, 11 h, 100 ꢀC,
then aqueous AcOH 1 N, 69%.
12
13
14
15
16
17
1
2
2
2
4
4
1
2
1
4
2
4
2
4
dehyde 4 obtained is condensed on metazonic acid
(nitroacetaldehyde oxime, freshly prepared by reacting
nitromethane with aqueous sodium hydroxide, then
quenching with concentrated aqueous hydrochloric acid
and filtrating the precipitate) to get nitro quinoline 5
which is reduced into amino quinoline 6 using hydrogen
and Raney–Nickel as catalyst. Compound 6 is reacted
with diethyl ethoxymethylenemalonate to obtain enamine
7. The key step of this synthesis, formation of the tri-
cyclic structure benzo[f][1,7]naphtyridine is a Gould–
Jacob cyclisation of 7 in diphenyl ether at 240 ꢀC with a
good yield (90%). The N-alkylation of compound 8 is
performed with methyl iodide, and the benzo[f]naph-
tyridone 9 obtained is reacted with 4-(3-fluoro-4-
methyl-phenyl) piperazine in DMSO. Only the fluorine
atoms are substituted by the N-aryl piperazine in this
nucleophilic aromatic substitution, leading to a mixture
of regioisomers 10 and 11 in a 1:6 ratio. This mixture is
separated by flash chromatography, and ethyl ester 11 is
subjected to saponification with potassium hydroxide in
ethanol to obtain compound 12, RPR203246.
16
16
16
4
aS.A.S, Staphylococcus aureus RN4220, quinolone sensitive, MIC in
mg/L.
A series of benzo[f]naphtyridones has been synthesized
according to Scheme 2, in which a fluorine atom of a
polyhalogenated benzo[f]naphtyridine is substituted by
various cyclic amines, leading to a mixture of regio-
isomers which is separated by flash chromatography
before saponification.
bS.A.R, Staphylococcus aureus AS5155, MRSA and resistant to qui-
nolone, MIC in mg/L.
cS.P.S, Streptococcus pyogenes Dig 7, quinolone sensitive, MIC in mg/L.
positive strains. Enterococcus species, which are not
relevant strains to study for a topical antibacterial use,
were not tested. The results are summarized in Table 1
for a selection of three representative Gram-positive
strains, one S. aureus quinolone sensitive, one S. aureus
quinolone and methicillin resistant, and one Strepto-
coccus Pyogenes quinolone sensitive.
Biological Evaluation
Minimal inhibitory concentrations (MICs) of a set of
compounds were determined against a range of Gram-

M. Tabart et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1329–1331
1331
The characteristic of this series of benzo[f][1,7]naphtyr-
idones, just like in benzo[b]naphtyridone previous series,
is that the MICs of the compounds tested are identical
against quinolone-resistant and quinolone-sensitive S.
aureus strains. This result suggests that the mechanism
of action of these derivatives in the Gram-positive
strains tested is different from that of quinolones.
antibacterial agents with a Gram positive spectrum of
activity that could be developed for topical use. They
show no cross resistance with major classes of anti-
biotics, especially with quinolones. Their antibacterial
and physico-chemical properties make them particularly
suitable for topical antibacterial use.
Structure–activity relationship analysis in this series
shows that a combination of a lipophilic cyclic amine
and a fluorine (or a fluorine and a chlorine) as sub-
stituants in positions 7, 8 and 9 of the tricycle gives rise
to the desired property, that is antibacterial activity on
quinolone-resistant strains. A non-basic N-phenyl sub-
stituted piperazine such as in compounds 12, 14, 153
and 16 gives good results (like in RP60556A, benzo[b]-
naphtyridone series), but a piperazine is not mandatory
for the activity against resistant strains since lipophilic
cyclic amines such as 3,3-dimethylpiperidine in com-
pound 17 or 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane
(commercially available from Aldrich) in compound 13
give similar results.
References and Notes
1. Witte, W. J. Antimicrob. Chemother. 1999, 14, 1.
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101.
5. Herwaldt, L. A. American Journal of Medicine 1999, 106,
11S.
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eno, S.; Cruz Menarguez, M.; Cercenado, E. Antimicrob.
Agents Chemother. 1995, 39, 175.
7. Ward, A.; Campoli-Richards, D. M. Drugs 1986, 32, 425.
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S23.
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10. Turnidge, J.; Collignon, P. Int. J. Antimicrob. Agents
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11. Tabart, M.; Picaut, G.; Desconclois, J. F.; Dutka-Malen,
S.; Huet, Y.; Berthaud, N. Bioorg. Med. Chem. Lett. 2001, 11,
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The compounds from Table 1 are active against Gram-
positive cocci (staphylococci and steptococci, MIC
range 1–16 mg/L) without cross-resistance with quino-
lones, b-lactams, MLSB (macrolides, lincosamides,
streptogramin Bgroup), mupirocin and fusidic acid,
and are active against anaerobes.
12. Desconclois, J. F.; Girard, P.; Picaut, G.; Tabart, M.;
Wentzler, S. Patent WO 0037 467 A1, June 29, 2000.
13. Lesher, G., Patent US 3 300 499, Jan 24, 1967.
14. Desconclois, J. F.; Genevois-Borella, A.; Girard, P.; Kry-
venko, M.; Lavergne, M.; Malleron, J.; Picaut, G.; Tabart,
M.; Wentzler, S. Patent WO 0102396 A1, Jan 11, 2001.
Conclusion
This new series of benzo[f][1,7] derivatives shows many
similarities with the benzo[b]naphtyridone series pre-
viously described: the compounds are interesting new