Synthesis and antitubercular activity of lipophilic moxifloxacin and gatifloxacin derivatives

Article abstract of DOI:10.1016/j.bmcl.2007.07.073

Fluoroquinolone (FQ) has a broad spectrum of activity against several bacteria, mycobacteria, parasites, and other diseases. Moxifloxacin and gatifloxacin are a new generation of fluoroquinolone agents with improved activity against Gram-negative and positive bacteria. As lipophilicity is an important consideration in the design and activity of novel antibacterial agents, we report in this work the synthesis and biological evaluation of 12 lipophilic moxifloxacin or gatifloxacin derivatives, by reaction of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid 13 with severals N-monoalkyl 1,2-ethanediamine or 1,3-propanediamine.

Full text of DOI:10.1016/j.bmcl.2007.07.073

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5661–5664
Synthesis and antitubercular activity of lipophilic moxifloxacin
and gatifloxacin derivatives
a
b
Mauro V. de Almeida,a, Maurıcio F. Saraiva, Marcus V. N. de Souza,
*
´
Cristiane F. da Costa,a Felipe R. C. Vicenteb and Maria C. S. Lourenc¸ob
a
ˆ
Departamento de Quı´mica, Instituto de Ciencias Exatas, Universidade Federal de Juiz de Fora, Cidade Universitaria,
´
36036-330 Juiz de Fora, MG, Brazil
bInstituto de Tecnologia em Fa´rmacos-Far Manguinhos, Fundac¸a˜o Oswaldo Cruz, 21041-250 Rio de Janeiro, RJ, Brazil
Received 20 June 2007; revised 17 July 2007; accepted 18 July 2007
Available online 21 August 2007
Abstract—Fluoroquinolone (FQ) has a broad spectrum of activity against several bacteria, mycobacteria, parasites, and other dis-
eases. Moxifloxacin and gatifloxacin are a new generation of fluoroquinolone agents with improved activity against Gram-negative
and positive bacteria. As lipophilicity is an important consideration in the design and activity of novel antibacterial agents, we report
in this work the synthesis and biological evaluation of 12 lipophilic moxifloxacin or gatifloxacin derivatives, by reaction of 1-cyclo-
propyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid 13 with severals N-monoalkyl 1,2-ethanediamine or
1,3-propanediamine.
Ó 2007 Elsevier Ltd. All rights reserved.
The discovery of the FQs during the 1980s improved the
treatment of infectious diseases, due to their fewer toxic
side effect. This class of compounds has, when compared
to the previous existing bactericidal drugs, enhanced
pharmacokinetics properties and extensive and potent
activity against various parasites, bacteria, and myco-
bacteria, including resistant strains.1 This class of antibi-
otics is the first-line therapy for complicated urinary
tract and bacterial diarrhea. They are also alternative
agents for the treatment of many sexually transmitted
diseases, as well as osteomyelitis, some cases of wound
infection, and selected respiratory infections.1 The
history of quinolones began in 1962,2 when Lesher
accidentally discovered the nalidixic acid, 1-ethyl-1,4-
dihydro-7-methyl-1,8-naphthylidine-3-carboxylic acid,
as by-product of the synthesis of the antimalarial com-
pound chloroquine. In 1963, the nalidixic acid was
approved by The Food and Drug Administration
(FDA) for the treatment of urinary tract infection.
However, the importance of the FQs started in the early
1980s with the discovery that a combination of a fluo-
rine atom at position 6 and a piperazinyl group at posi-
tion 7 resulted in a broad and potent antimicrobial
activity, producing the norfloxacin, the first of a new
generation of FQs antibacterials.3 This combination
produced a broad spectrum of activity and better phar-
macokinetic profile against Gram-negative, Gram-posi-
tive bacteria, and mycobacteria with antibacterial
activities 1000 times more potent than those observed
in the nalidixic acid.
After the discovery of the norfloxacin, structure–activity
relationships (SAR) analysis of the fluoroquinolonic nu-
cleus led to the development of new derivatives with bet-
ter solubility, higher antimicrobial activity, prolonged
serum half-life, fewer adverse side effects, and both oral
and parenteral routes of administration.1,4 The quino-
lones can be classified in four generations. The first gen-
eration is represented by nalidixic acid and cinoxacin,
the second one by norfloxacin, ciprofloxacin (Fig. 1),
ofloxacin, enoxacin, and lomefloxacin, the third one by
levofloxacin, sparfloxacin, and gatifloxacin (Fig. 1)
and, finally, the fourth generation is represented by
moxifloxacin (Fig. 1) and trovafloxacin.4 The bacterici-
dal activity generated by FQs is caused by the inhibition
of two bacterial enzymes: DNA gyrase and topoisomer-
ase IV enzymes. DNA gyrase (topoisomerase II) is an
Keywords: Fluoroquinolones; M. tuberculosis; Moxifloxacin; Gatiflox-
acin; Diamines; N-Alkyl chains; Antitubercular; Structure–activity
relationships.
*
Corresponding author. Tel./fax: +55 32 3229 3310; e-mail: mauro.
almeida@ufjf.edu.br
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.07.073

5662
M. V. de Almeida et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5661–5664
O
O
O
O
N
O
O
F
F
F
OH
OH
OH
H3C
H
N
N
N
N
N
HN
HN
OMe
OMe
Gatifloxacin
H
NH
Ciprofloxacin
Moxifloxacin
Figure 1. Structure of some fluoroquinolones.
essential enzyme involved in the replication, transcrip-
tion, and reparation of the bacterial DNA and topoiso-
merase IV is an enzyme responsible for the separation of
daughter DNA strands during bacterial cell division. In
Gram-negative organisms DNA gyrase is the primary
target, in the case of topoisomerase IV the Gram-posi-
tive bacteria are the most affected ones.1
ships.10 Mycobacteria have lipid-rich cell walls and lipo-
philicity is an important consideration in the design of
novel analogs.11
In this context, this work describes the synthesis and
antitubercular evaluation of 12 lipophilic moxifloxacin
or gatifloxacin analogs. We recently described the syn-
thesis and anti-TB activity of some N-acyl diamine
derivatives.12 Furthermore, Shoaa described the anti-
bacterial activity of 1,3-propanediamine fluoroquino-
lone derivatives.13
It was observed that C-8 halogen and methoxy FQs
derivatives are more active against resistant M. tubercu-
losis than the C-8 H compound ciprofloxacin.1,5–10
Moxifloxacin and gatifloxacin are 8-methoxy-fluoro-
quinolones with enhanced anti-Gram-positive activity
in vitro compared with other fluoroquinolones of second
generation such as ciprofloxacin and ofloxacin.5–8 Moxi-
floxacin was recently suggested by the American Tho-
racic Society to be used against tuberculosis.1,9
Modification of the substituents at the C-7 position of
fluoroquinolone ring could affect the pharmacokinetic
profile and the spectrum of activity of this class of anti-
biotics. A vast number of quinolones differing by the C-
7 substituent were prepared aiming at the establishment
of structure/antibacterial and antituberculosis relation-
In this work, we plained the substitution of the 1,2-dia-
mine moiety present in the moxifloxacin or gatifloxacin
structure by N-alkylated 1,2-ethanediamine or 1,3-prop-
anediamine. The new compounds were prepared by
reaction of fluoride 13 with different N-alkyl-1,2-ethane-
diamine or 1,3-propanediamine (Schemes 1 and 2).
The synthesis of different moxifloxacin or gatifloxacin
derivatives has been achieved by a simple method de-
scribed in the general procedure.14,15 The N-alkyl-dia-
mines were prepared in 44–56% yields by reaction of
EtOH
CH3(CH2)nCH(R)CH2Cl
+
NH2(CH2)mNH2
CH3(CH2)nCH(R)CH2NH(CH2)mNH2
reflux, 20h
1 m = 2 n = 3 R = H
2 m = 2 n = 3 R = Et
3 m = 2 n = 5 R = H
4 m = 2 n = 7 R = H
5 m = 2 n = 9 R = H
6 m = 2 n = 11 R = H
44%
53%
48%
56%
45%
52%
7
8
9
m = 3 n = 3 R = H
m = 3 n = 3 R = Et
m = 3 n = 5 R = H
45%
48%
44%
52%
53%
52%
10 m = 3 n = 7 R = H
11 m = 3 n = 9 R = H
12 m = 3 n = 11 R = H
Scheme 1.
O
O
N
F
COOH
CH3(CH2) CH(R)CH2NH(CH2) NH2
m
n
COOH
F
Et3N
CH CN,
3
80-82˚C
N
F
CH3(CH2) CH(R)CH2NH(CH2) NH
n
m
OMe
OMe
13
14 m = 2 n = 3 R = H
15 m = 2 n = 3 R = Et
16 m = 2 n = 5 R = H
17 m = 2 n = 7 R = H
18 m = 2 n = 9 R = H
19 m = 2 n = 11 R = H
20 m = 3 n = 3 R = H
21 m = 3 n = 3 R = Et
22 m = 3 n = 5 R = H
23 m = 3 n = 7 R = H
24 m = 3 n = 9 R = H
25 m = 3 n = 11 R = H
67%
64%
65%
68%
66%
68%
61%
63%
61%
63%
66%
62%
Scheme 2.

M. V. de Almeida et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5661–5664
5663
Table 1. In vitro antitubercular activities
the antitubercular activity depends on the alkyl chains,
size or ramification. Ideal chain contains 10 carbon
atoms, which could be a good starting point to find
new lead compounds.
Compound
MIC (lg/mL)
14
15
5
0.62
12.5
0.62
1.25
6.25
50
16
17
Acknowledgments
18
19
20
21
M.F.S., C.F.C., and M.V.A. gratefully acknowledge
CAPES and CNPq for fellowships. This research was
supported by FAPEMIG.
2.5
22
23
1.25
0.31
0.62
0.62
1.0
24
25
Supplementary data
Rifampicin
Gatifloxacin
0.1
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2007.07.073.
different alkyl chlorides with 1,2-ethanediamine or 1,3-
propanediamine (Scheme 1).14 The low yield in the prep-
aration of N-alkyl-diamines is due to the formation of
the corresponding N,N0-dialkyl-diamines. The reaction
between fluoroquinolone intermediate 13, which was
furnished by Xiamen Mchem Pharma group (Xiamen,
China), and the respective N-alkyl-diamines 1–12 affor-
ded the desired fluoroquinolone derivatives 14–25 in
61–68% yields (Scheme 2).15
References and notes
1. (a) De Souza, M. V. N. Mini-Rev. Med. Chem. 2005, 5,
1009; (b) Anquetin, G.; Greiner, J.; Mahmoud, N.;
Santillana-Hayat, Maud; Gozalbes, R.; Farhati, K.; Der-
ouin, F.; Aubry, A.; Cambau, E.; Vierling, P. Eur. J. Med.
Chem. 2006, 41, 1478.
2. Lesher, G. Y.; Froelich, E. D.; Gruet, M. D.; Bailey, J. H.;
Brundage, R. P. J. Med. Pharm. Chem. 1962, 5, 1063.
3. Da Silva, A. D.; De Almeida, M. V.; De Souza, M. V. N.;
Couri, M. R. C. Curr. Med. Chem. 2003, 10, 21.
4. De Souza, M. V. N.; Vasconcelos, T. A.; Cardoso, S. H.;
De Almeida, M. V. Curr. Med. Chem. 2006, 13, 455.
5. (a) Tobin, C. M.; Sunderland, J.; White, L. O.; MacGo-
wan, A. P.; Reeves, D. S. J. Antimicrob. Chemother. 1998,
42, 278; (b) Drlica, K.; Zhao, X. Microbiol. Mol. Biol. Rev.
1997, 61, 377.
The activity of the compounds against M. tuberculosis
virulent strain H37Rv was determined in vitro as previ-
ously described16 (Table 1). The minimum inhibitory
concentration (MIC), concentration that inhibits the
colony, forming ability of M. tuberculosis, was deter-
mined by incorporating decreasing concentrations of
the test compound in Middle brook 7H9 agar medium.
MIC values represent means of three separate experi-
ments. Compound 23 inhibited bacterial growth at
0.31 lg/mL, whereas compounds 15, 17, 24, and 25
inhibited growth at a concentration of 0.62 lg/mL.
6. Woodcock, J. M.; Andrews, J. M.; Boswell, F. J.;
Brenwald, N. P.; Wise, R. J. Antimicrob. Chemother.
1997, 41, 101.
7. Aldrige, K. E.; Ashcraft, D. S. J. Antimicrob. Chemother.
1997, 41, 709.
The size of the spacer seems to be important: all 1,3-
propanediamine derivatives had higher MIC than the
1,2-ethanediamine derivatives with the same alkyl chain.
In the two series the best activity was displayed by com-
pounds 17 (MIC 0.62 lg/mL) and 23 (MIC 0.31 lg/mL),
both having a 10 carbon alkyl chain, which would be the
ideal length. Compounds 14 and 20, with shorter alkyl
chains, exhibited moderate activities (MIC = 50 lg/
mL). Ramificated compound 15 showed a better activity
(MIC 0.62 lg/mL) than its linear analog 16 (MIC
12.5 lg/mL), maybe due to its volume. In the propanedi-
amine series, the linear compound 22 was more active
than the ramificated analog 21.
8. (a) Zhao, B.-Y.; Pine, R.; Domagala, J.; Drlica, K.
Antimicrob. Agents Chemother. 1999, 43, 661; (b) Lu, T.;
Zhao, X.; Li, X.; Drlica-Wagner, A.; Wang, J.-Y.;
Domagala, J.; Drlica, K. Antimicrob. Agents Chemother.
2001, 45, 2703.
9. Pletz, M. W. R.; De Roux, A.; Roth, A.; Neuman, K.-H.;
Mauch, H.; Lode, H. Antimicrob. Agents Chemother. 2004,
48, 780.
10. (a) Renau, T. E.; Sanchez, J. P.; Gage, J. W. J. Med. Chem.
1996, 39, 729; (b) Shindikar, A. V.; Viswanathan, C. L.
Bioorg. Med. Chem. Lett. 2005, 15, 1803; (c) Gutierrez-
Zufiaurre, N. Rev. Esp. Quimioter. 2004, 17, 232; (d) Aubry,
A.; Pan, X. S.; Fisher, L. M.; Jarlier, V.; Cambau, E.
Antimicrob. Agents Chemother. 2004, 48, 1281.
In summary, this work describes the synthesis, charac-
terization, and anti-TB evaluation of 12 lipophilic moxi-
floxacin or gatifloxacin derivatives, by reaction of
1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-
quinoline-3-carboxylic acid 13 with severals N-alkyl-1,2-
ethanediamine or 1,3-propanediamine. The minimum
inhibitory concentration (MIC) against M. tuberculosis
demonstrated that compound 23 inhibited growth at
0.31 lg/mL, whereas compounds 15, 17, 24, and 25 inhib-
ited growth at 0.62 lg/mL concentration. It seems that
11. Brennan, P. J.; Nikaido, H. Annu. Rev. Biochem. 1995, 64,
29.
12. Almeida, M. V.; Le Hyaric, M.; Amarante, G.; Silva
Lourenc¸o, M. C.; Lima Branda˜o, M. L. Eur. J. Med.
Chem. 2007, in press. doi:10.1016/j.ejmech.2007.01.00.
13. Shoaa, A. -R. U.S. Patent 6,967,205, 2001.
14. General procedure for the preparation of N-alkyl-1,2-
ethanediamine and N-alkyl-1,3-propanediamine. To a
solution of 1,2-ethanediamine or 1,3-propanediamine
(100 mmol) in 50 mL of ethanol at reflux was slowly
added the alkyl chloride (50 mmol). The reaction mixture

5664
M. V. de Almeida et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5661–5664
was maintained under reflux during 24 h. The solvent was
in 5 mL of CH3CN was refluxed for 24 h. The white
precipitate was removed by filtration, washed with
CH3CN, recriystallized, and dried in vacuo to give the
desired compounds 14–25 in 61–68% yield.
evaporated under reduced pressure and the residue was
purified by column chromatography on silica gel (eluent:
dichloromethane:methanol) furnishing compounds 1–12
in 44–56% yield.
16. (a) Collins, L. A.; Franzblau, S. G. J. Antimicrob.
Chemother. 1997, 41, 1004; (b) De Souza, A. O.; Hemerly,
F. P.; Busollo, A. C.; Melo, P. S.; Machado, G. M. C.;
Miranda, C. C.; Santa-Rita, R. M.; Haun, M.; Leon, L.
L.; Sato, D. N.; Castro, S. L.; Duran, N. J. Antimicrob.
Chemother. 2002, 50, 629.
15. General procedure for the preparation of fluoroquinolone
derivatives. A solution of 1-cyclopropyl-6,7-difluoro-1,4-
dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid 13
(1.0 mmol), N-alkyl-1,2-ethanediamine or N-alkyl-1,3-
propanediamine (1.0 mmol), and triethylamine (1 mmol)