One-pot synthesis and antimicrobial activity of novel naphthyridine derivatives

Article abstract of DOI:10.3184/030823410X12890461346708

A one-pot synthetic route was developed to synthesise novel naphthyridine derivatives from amino acids and a series of new naphthyridines was prepared and characterised by IR, 1H NMR, MS and elemental analysis. The preliminary bioassay results reveal that they have medium antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Aspergillus, Escherichia coli and Monilia albican. The compounds containing aliphatic amino acids have greater bioactivity than that of those containing aromatic amino acids against Bacillus subtilis and Staphylococcus aureus.

Full text of DOI:10.3184/030823410X12890461346708

658 RESEARCH PAPER
NOVEMBER, 658–660
JOURNAL OF CHEMICAL RESEARCH 2010
One-pot synthesis and antimicrobial activity of novel naphthyridine
derivatives
Hui Zheng, Juan Liu and Pengfei Zhang*
College of Material, Chemistry & Chemical Engineering, Hangzhou Normal University, Hangzhou, 310036, P. R. China
A one-pot synthetic route was developed to synthesise novel naphthyridine derivatives from amino acids and a
series of new naphthyridines was prepared and characterised by IR, 1H NMR, MS and elemental analysis. The pre-
liminary bioassay results reveal that they have medium antimicrobial activity against Bacillus subtilis, Staphylococ-
cus aureus, Aspergillus, Escherichia coli and Monilia albican. The compounds containing aliphatic amino acids have
greater bioactivity than that of those containing aromatic amino acids against Bacillus subtilis and Staphylococcus
aureus.
Keywords: naphthyridines, amino acids, antimicrobial activity, antifungal activity
Interest in heterocyclic compounds,1–3 especially the naphthy-
against the above bacteria. The synthetic route is shown in
ridines, has continued for many years, largely based on their
widespread use as anti-asthmatic, anti-bacterial, and anti-
malarial agents. 4–7 As part of our ongoing interests to find new
naphthyridine derivatives, we have focused our attention on
introducing natural amino acids into naphthyridines at the
N1-position.
Scheme 1.
Experimental
All the reagents were purchased commercially and used without
further purification. The melting points were determined using a XT-4
melting-point apparatus and uncorrected. IR spectra were recorded
on a Bruker Equinox-55 spectrophotometer using KBr discs in the
4000–400 cm−1 region. The 1H NMR data were obtained on a Bruker
AC-400 (400 MHz) instrument in DMSO-d6 using TMS as internal
standard. Chemical shifts (δ) are expressed in ppm and coupling con-
stants J are given in Hz. Mass spectra were obtained on an Agilent
5973N mass spectrometer operating at 70 eV by electron ionisation
technique (EI/MS). Elemental analyses were performed on an
EA-1110 instrument.
1-(Carboxymethyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naph-
thyridine-3-carboxylic acid (6a): 2,6-Di- chloro-5-fluoronicotinic
acid 1 (4.18 g, 0.02 mol) was dissolved in thionyl chloride (23 mL) in
a 50 mL round-bottomed flask, stirred and refluxed for 3 h, The excess
thionyl chloride was removed on a rotary evaporator. (E)-Ethyl-3-
(dimethylamino) acrylate (2.85 g, 0.02 mol) was added dropwise to
the toluene solution, and it was stirred at 50–60 °C, monitoring with
TLC (PE/EA=1/1 (v/v)) to show at the end of reaction the absence of
reactants. Then the amino acid ethyl ester hydrochloride (0.02 mol)
was added directly and stirring was continued for about 5–8 h at
room temperature, checking the reaction via TLC. After completion,
potassium carbonate (3.08 g, 0.025 mol) was added and the reaction
Often, several steps and much complicated post-treatment
and purification processes are necessary to synthesise the
naphthyridine derivatives. For example, Okada and Kimura
et al. reported a muti-step reaction to synthesise some of these
heterocyclicderivatives.8,9Wepreparedaseriesofnaphthyridine
heterocyclic derivatives by a multistep reaction from an analo-
gous compound 1 to give, via the intermediates 2–4, the com-
pound 5. We wish to develop a concise route with simple
work-up procedures to synthesise a series of these novel het-
erocyclic compounds. We now report that this procedure goes
well and via steps a–d shown in Scheme 1 we can merge the
different steps into a one-pot procedure. The title compounds
1
were characterised by H NMR, IR spectra, mass spectra and
elemental analyses. In order to investigate their preliminary
antimicrobial bioactivities, all the compounds were screened
against Bacillus subtilis, Staphylococcus aureus, Aspergillus,
Escherichia coli and Monilia albican. The preliminary bioas-
say results reveal that they have medium antimicrobial activity
Scheme 1 The synthetic route to novel naphthyridine derivatives.
* Correspondent. E-mail: zhenghui86@gmail.com

JOURNAL OF CHEMICAL RESEARCH 2010 659
was stirred for 8–10 h at 110 °C. When the reaction was over (deter-
mined by TLC), the cold mixture was acidified with dilute hydrochlo-
ric acid (5%) to pH=1–2. The reaction mixture was poured into a
separating funnel and separated. The organic layer was concentrated
under reduced pressure and the residue was chromatographed on silica
gel (PE/EA=2/1 (v/v)) to give compound 5a. Compound 5a was added
to 20% sulfuric acid solution, refluxed for about 6–8 h, then cooled to
room temperature and the mixture was filtered. The filter cake was
recrystallised using 15% alcohol aqueous solution to afford com-
pounds 6a in 50% yield; m.p. 259–261 °C. IR (KBr) vmax: 3487 (–OH),
(KBr) vmax: 3494 (-OH), 2970 (CH2), 1746 (C=O), 1650 (Ar), 1470
1
(C=C) cm−1; H NMR (DMSO-d6, 400 MHz): δ 3.43–3.49 (m, 2H,
CH2), 3.92–3.99 (m, 1H, CH), 7.29–7.41 (m, 5H, ArH), 8.27 (d,
J = 7.60 Hz, 1H, ArH), 9.31 (s, 1H, C=CH), 13.56 (br s, 1H, COOH),
14.25 (br s, 1H, COOH); MS (70 eV): m/z (%) = 390 (M+). Anal.
Calcd for C18H12ClFN2O5: C, 55.33; H, 3.10; N, 7.17. Found: C, 55.39;
H, 2.99; N, 7.24%.
All the target compounds were tested for their antibacterial and
antifungal activity by a broth dilution method with Bacillus subtilis,
Staphylococcus aureus, Aspergillus, Escherichia coli and Monilia
albican according to the literature.10,11 The antimicrobial discs (diam-
eter, 0.55 cm) were prepared at concentrations of 1 mg mL−1, 0.2 mg
mL−1 and 0.1 mg mL−1, and applied to each of the culture plates previ-
ously seeded with the test bacteria. These culture plates were then
incubated at 37 °C for 24 h. The preliminary antimicrobial activity
was determined by the diameter of the inhibition zone. For each com-
pound, three replicate trials were conducted against each organism.
1
2929 (CH2), 1746 (C=O), 1634 (Ar), 1489 (C=C) cm−1; H NMR
(DMSO-d6, 400 MHz): δ 5.33 (s, 2H, CH2), 8.74 (d, J = 7.60 Hz, 1H,
ArH), 9.29 (s, 1H, C=CH), 14.12 (br s, 2H, COOH); MS (70 eV): m/z
(%) = 300 (M+). Anal. Calcd for C11H6ClFN2O5: C, 43.95; H, 2.01; N,
9.32. Found: C, 44.02; H, 2.05; N, 9.44%.
1-(1-Carboxy-2-methylpropyl)-7-chloro-6-fluoro-4-oxo-1,4-dihy-
dro-1,8-naphthyridine-3-carboxylic acid (6b): This compound was
obtained in similar manner to 6a with 52% yield; m.p. 254–256 °C. IR
(KBr) vmax: 3469 (-OH), 2972 (CH3), 1754 (C=O), 1611 (Ar), 1474
(C=C) cm−1; 1H NMR (DMSO-d6, 400 MHz): δ 0.91 (d, J = 7.20 Hz,
6H, CH3), 2.02–2.04 (m, 1H, CH), 3.65–3.67 (m, 1H, CH), 8.77 (d,
J = 7.60 Hz, 1H, ArH), 9.22 (s, 1H, C=CH), 13.53 (br s, 1H, COOH),
14.22 (br s, 1H, COOH); MS (70 eV): m/z (%) = 342 (M+). Anal.
Calcd for C14H12ClFN2O5: C, 49.07; H, 3.53; N, 8.17. Found: C, 49.21;
H, 3.55; N, 8.24%.
Results and discussion
The structures of these novel naphthyridine heterocyclic com-
pounds 6a–f were confirmed by IR, 1H NMR, MS and elemen-
tal analysis. The IR spectra of all compounds showed easily
distinguishable stretching vibration peaks, such as carboxylic
group (1746–1754 cm−1), aromatic ring (1611–1688 cm−1) and
1
carbon-carbon double bond (1470–1489 cm−1). In H NMR
1-(1-Carboxy-3-methylbutyl)-7-chloro-6-fluoro-4-oxo-1,4-dihy-
dro-1,8-naphthyridine-3-carboxylic acid (6c): This compound was
obtained in similar manner to 6a with 49% yield; m.p. 271–273 °C.
IR (KBr) vmax: 3313 (–OH), 2972 (CH3), 1753 (C=O), 1611 (Ar), 1473
spectrum, two kind of carboxylic group signals appear at
13.53–13.65 ppm and 14.12–14.25 ppm, which demonstrate
the existence of amino acids. All the MS spectral data and
elemental analyses agree well with the target molecule
structures.
(C=C) cm−1; 1H NMR (DMSO-d6, 400 MHz):
δ 0.93 (d,
J = 7.20 Hz, 6H, CH3), 1.41–1.43 (m, 1H, CH), 2.31–2.33 (m, 2H,
CH2), 3.71–3.74 (m, 1H, CH), 8.68 (d, J = 8.00 Hz, 1H, ArH), 9.27 (s,
1H, C=CH), 13.65 (br s, 1H, COOH), 14.13 (br s, 1H, COOH); MS
(70 eV): m/z (%) = 356 (M+). Anal. Calcd for C15H14ClFN2O5: C,
50.50; H, 3.96; N, 7.85. Found: C, 50.56; H, 4.00; N, 7.94%.
It should be noted that, after confirmation by IR, 1H NMR,
MS and elemental analysis, the structures of compounds 6a–f
prepared by one-pot method were exactly the same as those
prepared by a four-step method.
1-(1-Carboxy-2-methylbutyl)-7-chloro-6-fluoro-4-oxo-1,4-dihy-
dro-1,8-naphthyridine-3-carboxylic acid (6d): This compound was
obtained in similar manner 6a with 48% yield; m.p. 282–284 °C. IR
(KBr) vmax: 3387 (-OH), 2963 (CH3), 1751 (C=O), 1630 (Ar), 1472
All the title compounds were tested for their antibacterial
and antifungal activities. From the screening results, it was
discovered that these compounds have medium bioactivity
against Bacillus subtilis and Staphylococcus aureus, and
compounds 6b and 6c have some bioactivity against Aspergil-
lus, Escherichia coli and Monilia albican. The detailed results
are listed in Table 1.
From the preliminary biological results, all the new com-
pounds have medium antibacterial and antifungal bioactivity.
Generally speaking, the compounds containing aliphatic amino
acids have greater bioactivities than that of those containing
aromatic amino acids against Bacillus subtilis and Staphylo-
coccus aureus. Although the series of compounds have less
bioactivity with regard to the control, it is a preliminary
research to develop new bioactive compounds and it gives
valuable information. These results can evoke our keen inter-
ests to design better compounds. Especially, the compound 6b
has a wider antimicrobial spectrum than other compounds, and
it has the anti-Aspergillus and anti-Monilia albican activities
1
(C=C) cm−1; H NMR (DMSO-d6, 400 MHz): δ 0.85-0.89 (m, 6H,
CH3), 0.93–0.96 (m, 2H, CH2), 2.21–2.24 (m, 1H, CH), 3.79–3.82 (m,
1H, CH), 8.42 (d, J = 8.00 Hz, 1H, ArH), 9.29 (s, 1H, C=CH), 13.62
(br s, 1H, COOH), 14.18 (br s, 1H, COOH); MS (70 eV): m/z (%) =
356 (M+). Anal. Calcd for C15H14ClFN2O5: C, 50.50; H, 3.96; N, 7.85.
Found: C, 50.55; H, 4.02; N, 7.96%.
1-(Carboxy(phenyl)methyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-
1,8-naphthyridine-3-carboxylic acid (6e): This compound was obtai-
ned in similar manner with 50% yield; m.p. 172–174 °C. IR (KBr)
v
max: 3435 (–OH), 1747 (C=O), 1688 (Ar), 1470 (C=C) cm−1; 1H NMR
(DMSO-d6, 400 MHz): δ 4.19 (s, 1H, CH), 7.52–7.61 (m, 5H, ArH),
8.36 (d, J = 7.60 Hz, 1H, ArH), 9.26 (s, 1H, C=CH), 13.58 (br s, 1H,
COOH), 14.23 (br s, 1H, COOH); MS (70 eV): m/z (%) = 376 (M+).
Anal. Calcd for C17H10ClFN2O5: C, 54.20; H, 2.68; N, 7.44. Found: C,
54.29; H, 2.55; N, 7.47%.
1-(1-Carboxy-2-phenylethyl)-7-chloro-6-fluoro-4-oxo-1,4-dihy-
dro-1,8-naphthyridine-3-carboxylic acid (6f): This compound was
obtained in similar manner with 51% yield; m.p. 247–249 °C. IR
Table 1 The preliminary antimicrobial activity of title compounds
Conc. (mg mL−1)
6a
6b
6c
6d
6e
6f
Controlc
Bacillus subtilis
1
1.60a
1.00
2.00
1.15
1.00
1.75
0.95
0.65
0.75
0.60
0.65
1.90
1.50
0.70
2.10
1.50
1.15
0.75
0.65
–
1.10
0.65
–
0.90
0.60
–
0.65
–
–
0.75
0.65
0.60
1.10
0.65
0.60
–
0.65
4.60
3.80
3.60
3.30
2.90
2.60
–
0.2
0.1
1
–
b
–
–
0.75
0.60
–
Staphylococcus aureus
1.15
1.00
–
–
–
–
0.2
0.1
1
1
1
Aspergillus
Escherichia coli
Monilia albican
–
–
–
2.70
–
–
–
a Diameter of inhibition zone (cm).
b No inhibition.
c Levofloxacin hydrochloride.

660 JOURNAL OF CHEMICAL RESEARCH 2010
which the commercial control drug Levofloxacin Hydrochlo-
ride does not possess. The results intrigued us to study its
QSAR further and synthesise higher activity compounds in our
following study and in-depth research work is ongoing.
Received 15 March 2010; accepted 4 September 2010
Paper 101053 doi: 10.3184/030823410X12890461346708
Published online: 24 November 2010
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ing naphthyridine heterocyclic compounds and synthesised a
series of novel heterocyclic derivatives which contain natural
amino acids. The preliminary bioassays results reveal that they
have medium antimicrobial activity against Bacillus subtilis,
Staphylococcus aureus, Aspergillus, Escherichia coli and
Monilia albican. Generally speaking, the compounds contain-
ing aliphatic amino acids have greater bioactivities than that of
those containing aromatic amino acids against Bacillus subtilis
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