Synthesis of variously substituted 1,8-naphthyridine derivatives and evaluation of their antimycobacterial activity

Article abstract of DOI:10.1016/S0014-827X(02)01235-1

A series of 1,8-naphthyridine derivatives variously substituted in the 2, 3, 4 and 7 positions were synthesized for in vitro evaluation of antimycobacterial activity in accordance with an international program with the tuberculosis antimicrobial acquisition and coordinating facility (TAACF). Several compounds 4, 8, 12, 14, 19, 29 and 30, when tested at a concentration of 6.25 μg/ml against Mycobacterium tuberculosis H₃₇Rv, showed an interesting activity with % inhibition in the range 38-96%. The most effective substituent in position 2, 4 or 7 of the 1,8-naphthyridine nucleus seem to be the piperidinyl group.

Full text of DOI:10.1016/S0014-827X(02)01235-1

Il Farmaco 57 (2002) 631–639
www.elsevier.com/locate/farmac
Synthesis of variously substituted 1,8-naphthyridine derivatives and
evaluation of their antimycobacterial activity
Muwaffag Badawneh a, Clementina Manera b,*, Claudio Mori b, Giuseppe Saccomanni b,
Pier Luigi Ferrarini b
a Philadelphia Uni6ersity, PO Box 1101, Sweileh, Jordan
b Dipartimento di Scienze Farmaceutiche, Uni6ersita´ di Pisa, 6ia Bonanno 6, 56126 Pisa, Italy
Received 13 October 2001; accepted 18 February 2002
Abstract
A series of 1,8-naphthyridine derivatives variously substituted in the 2, 3, 4 and 7 positions were synthesized for in vitro
evaluation of antimycobacterial activity in accordance with an international program with the tuberculosis antimicrobial
acquisition and coordinating facility (TAACF). Several compounds 4, 8, 12, 14, 19, 29 and 30, when tested at a concentration of
6.25 mg/ml against Mycobacterium tuberculosis H37R6, showed an interesting activity with % inhibition in the range 38–96%. The
´
most effective substituent in position 2, 4 or 7 of the 1,8-naphthyridine nucleus seem to be the piperidinyl group. © 2002 Editions
scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Tuberculostatic agents; 1,8-Naphthyridines; Morpholinyl; Piperazinyl; Piperidinyl
benzimidazole [7–10], benzotriazole [11],triazolothiadia-
zole [12], isothiazolopyridines [13], quinoline [14–17],
quinazoline [18–24] and quinoxaline [25].
1. Introduction
Tuberculosis today can be considered one of the
major problems for public health worldwide. In the last
few years an unexpected return of this disease has taken
place [1]. The World Health Organization has estimated
that every year about eight million new cases of tuber-
culosis occur and about three million individuals die of
this disease. This infection is present both in developing
countries, where it is endemic, and in industrialized
countries. Today the drugs used in the therapy of
tuberculosis are still isoniazid, pyrazinamide, ethambu-
tol, rifampin and streptomycin, generally used in com-
bination [2]. However, the protracted use in time of
these molecules represents the main cause of the out-
break of new resistant strains. For this reason, in the
last few years, the search for new antitubercular agents
has become very important. Among a large amount of
molecules tested for this purpose the heterocyles benzo-
furane [3], benzothiazole [4,5], benzoisothiazole [6],
In collaboration with an international program with
the tuberculosis antimicrobial acquisition and coordi-
nating facility (TAACF) we initiated a program of
synthesis and antiinfective screening of a series of 1,8-
naphthyridine derivatives structurally correlated to
quinoline and phenyl-substituted quinazoline deriva-
tives which possess tuberculostatic activity [14,15,18–
20].
In a previous paper [26], we reported the preparation
and the antimycobacterial activity of some 4-phenyl-
1,8-naphthyridine derivatives variously substituted in
positions 2 and 7 tested in vitro at a concentration of
12.5 mg/ml against Mycobacterium tuberculosis H37R6.
Some of these compounds showed a marked activity
with an inhibition \50%.
In this paper we describe the synthesis and biological
results of some 1,8-naphthyridine derivatives substi-
tuted in positions 2, 3, 4 and 7 with some of the
substituents present in the previous series [26] and with
new substituents.
* Corresponding author
E-mail address: manera@farm.unipi.it (C. Manera).
´
0014-827X/02/$ - see front matter © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S0014-827X(02)01235-1

632
M. Badawneh et al. / Il Farmaco 57 (2002) 631–639
treatment with morpholine or piperidine in toluene at
2. Chemistry
reflux afforded the corresponding derivatives 15 and 16
(Scheme 2, Tables 1 and 2). These compounds were
allowed to react with morpholine or piperidine in a
sealed tube at 160 °C to give the 4-substituted deriva-
tives 17–19. Under these conditions the 4-chloro
derivative 13 was converted into the 4-morpholino and
4-piperidino derivatives 20 and 21, respectively, which
afforded the corresponding 2-chloro derivatives 22 and
23 by reaction with phosphoryl chloride. The 2-mor-
pholino derivative 24 was obtained from 22 in
analogous conditions, as reported above for com-
pounds 16 (Scheme 2, Tables 1 and 2). The reaction of
the 7-acetamido-2,4-dichloro-1,8-naphthyridine (25)
[27] with morpholine or piperidine in toluene at reflux
afforded the corresponding derivatives 26 and 27,
which by acid hydrolysis gave the 7-amino derivatives
28 [27] and 29, respectively (Scheme 3, Tables 1 and 2).
The 4-chloro derivative 29 was converted into the 4-
piperidino derivative 30 by reaction with piperidine in a
The 3-methyl- and 3-benzyl-2,4-dihydroxy-7-methyl-
1,8-naphthyridines (1 and 2) were obtained from 2-
amino-6-methylpyridine and diethyl methylmalonate or
diethyl benzylmalonate, respectively by reflux in
Dowtherm A. The reaction of 1 and 2 with phosphoryl
chloride afforded the dichloro derivatives 3 and 4 which
were allowed to react with morpholine or piperidine in
toluene under reflux to give the corresponding 2-mono-
substituted derivatives 5, 6 and 7, 8, respectively be-
cause of the high reactivity of the chloro group in the 2
position [27]. When the 4-chloro derivatives 7 and 8
were treated with morpholine or piperidine in a sealed
tube at 160 °C, the 2-piperidino-4-substituted deriva-
tives 9, 10 and 11, 12, respectively were obtained
(Scheme 1, Tables 1 and 2).
The reaction of the 4-chloro-7-hydroxy-2-mor-
pholino-1,8-naphthyridine (13) [27] with phosphoryl
chloride afforded the dichloro derivative 14, which by
Scheme 1. Synthetic route to variously substituted 3,7-dimethyl- and 3-benzyl-7-methyl-1,8-naphthyridine derivatives. Morph, morpholin-1-yl; Pip,
piperidin-1-yl.

M. Badawneh et al. / Il Farmaco 57 (2002) 631–639
633
Table 1
Physical data of 1,8-napthyridine derivatives
Comp.
R
R1
R2
R3
Crystallization solvent
M.p. (°C)
Yield (%)
Mass m/z
(M+
)
(Base)
1
2
3
4
5
6
7
8
9
10
11
12
14
15
16
17
18
19
20
21
OH
OH
Cl
Cl
Morph
Morph
Pip
Pip
Pip
CH3
OH
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Cl
Morph
Pip
Morph
Pip
Pip
OH
EtOH
EtOH
\300
53
43
81
84
88
76
88
98
70
70
10
10
66
98
86
84
46
49
34
50
190
268
266
302
277
353
275
351
326
326
324
400
283
334
332
385
383
381
316
314
190
266
266
231
157
231
157
160
158
158
241
316
163
277
249
328
326
41
C6H5CH2 OH
CH3 Cl
C6H5CH2 Cl
CH3 Cl
C6H5CH2 Cl
CH3 Cl
C6H5CH2 Cl
267–270
205–207
115–118
128–131
115–118
108–110
95–98
145–147
102–105
(oil)
118–120
200–205
260–262
155–157
250–253
172–175
197–200
268–270
247–250
EtOH–H2O
EtOH–H2O
Petr. Ether 100–140°
Petr. Ether 100–140°
EtOH–H2O
EtOH–H2O
Toluene a
CH3
Morph
Pip
Pip
Pip
C6H5CH2 Morph
CH3
C6H5CH2 Pip
Toluene a
Pip
a
Toluene a
Morph
Morph
Morph
Morph
Morph
Morph
Morph
Morph
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Morph
Morph
Pip
Morph
Pip
EtOH–H2O
Toluene
Benzene–Petr. Ether 40–60°
Toluene
Petr. Ether 100–140°
Petr. Ether 100–140°
Petr. Ether 100–140°
Toluene
316
314
OH
22
23
24
26
27
29
30
31
32
34
35
Morph
Morph
Morph
Morph
Pip
Pip
Pip
Morph
Morph
OH
H
H
H
H
H
H
H
H
Morph
Pip
Pip
Cl
Cl
Cl
Pip
Morph
Pip
H
Cl
Cl
Petr. Ether 100–140°
Petr. Ether 100–140°
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
208–210
145–148
205–208
250–253
215–218
230–235
262–265
272–275
251–253
224–226
235–237
78
85
95
79
84
81
96
67
52
77
82
334
332
383
306
304
262
311
315
313
378
306
277
275
326
144
144
144
228
258
256
250
250
Morph
NHAc
NHAc
NH2
NH2
NH2
NH2
Cep
H
C6H5
C6H5
Toluene
Benzene
OH
H
Pipz
Morph=Morpholinyl, Pip=Piperidinyl, Pipz=Piperazinyl, Cep=Nꢀethoxycarbonylpiperazinyl.
a Previously purified by flash chromatography [AcOEt–Petr. Ether (2:1)].
their antitubercular activity at the GWl Hansen’s Di-
sease Center (Colorado State University) within the
TAACF screening program for the discovery of novel
drugs for treatment of tuberculosis. The purpose of the
screening program is to provide a resource whereby
new experimental compounds can be tested for their
capacity to inhibit the growth of M. tuberculosis H37R6
according to the method described by Collins and
Franzblau [29].
sealed tube at 160 °C. In analogous conditions com-
pound 28, by reaction with morpholine or piperidine,
gave the 4-substituted derivatives 31 and 32 (Scheme 3,
Tables 1 and 2).
Starting from the 7-hydroxy-2-chloro-3-phenyl-1,8-
naphthyridine (33) [28] by treatment with N-ethoxycar-
bonylpiperazin in a sealed tube at 160 °C was obtained
the corresponding derivatives 34 which by alkaline hy-
drolysis gave the 7-piperazinyl derivative 35 (Scheme 4,
Tables 1 and 2).
4. Results and discussion
3. Pharmacology
Results of the in vitro evaluation of antitubercular
activity of the tested compounds are reported in Table
All described compounds were tested in vitro for

634
M. Badawneh et al. / Il Farmaco 57 (2002) 631–639
Table 2
1H-NMR chemical shifts (l ppm/TMS)

M. Badawneh et al. / Il Farmaco 57 (2002) 631–639
635
Scheme 2. Synthetic route to variously substituted 2-(morpholin-1-yl)-1,8-naphthyridine derivatives. Morph, morpholin-1-yl; Pip, piperidin-1-yl.
3 and they show an interesting activity for several
compounds. Compounds 4, 8, 12, 14, 19, 29 and 30
exhibited a growth inhibition against M. tuberculosis
H37R6 at a concentration of 6.25 mg/ml in the range
38–96%. These data were compared with those of
rifampicin, as reference drug, that showed an inhibition
activity of 98% at a concentration of 0.25 mg/ml.
In spite of the restricted number of compounds tested
in this study, some preliminary consideration of
structure–activity relationships can be put forward.
Before all, the biological results indicate that
1,8-naphthyridine derivatives reported in this study
exhibited a greater antimycobacterial activity than that
of 4-phenyl-naphthyridine derivatives tested at
concentration of 12.5 mg/ml [26].
From analysis of biological results reported in Table 3,
the 3-benzyl derivatives 4, 6, 8 and 10 are more active
than the corresponding 3-methyl derivatives 3, 5, 7 and
9, consequently it can be deduced that the benzyl group
in the position 3 of the heterocyclic ring seem to be
more effective than the methyl group in the same
position.
Furthermore, the comparison of compounds 6 (20%)
versus 8 (41%), 10 (20%) versus 12 (96%), 19 (43%)

636
M. Badawneh et al. / Il Farmaco 57 (2002) 631–639
Scheme 3. Synthetic route to variously substituted 7-acetamido- and 7-amino-1,8-naphthyridine derivatives. Morph, morpholin-1-yl; Pip,
piperidin-1-yl.
versus 24 (11%) and 30 (72%) versus 31 (0%) and 32
(6%) clearly indicate that the morpholino group either
in the position 2, 4 or 7 of the heterocyclic ring cause a
decrease of activity.
possessed a very poor activity. More probably the
inactivity of these last compounds is due to the pre-
sence of the morpholinyl group on the heterocyclic
ring.
When a hydroxy group was introduced into position
2, 4 or 7 of the 1,8-naphthyridine nucleus, inactive
compounds (1, 2, 13, 20 and 21) were obtained, as also
reported in a previous paper for the analogous 4-phenyl
derivatives [26].
The influence of the amino group, in position 7 of the
heterocyclic ring on the antimycobacterial activity is
not clear at this time; in fact the 7-amino derivative 29
and 30 showed an inhibition activity of 38 and 72%,
respectively, whereas the 7-amino derivatives, 31 and 32
However, on the basis of the biological results, it is
interesting to point out that the most effective subs-
tituent in the positions 2, 4 or 7 of the 1,8-naph-
thyridine nucleus seem to be the piperidinyl group.
Furthermore, the above data of biological activity
and those previous reported [26] seem to show that a
balance between both lipophilic and electronegative
effects is necessary to determine an appreciable antimy-
cobacterial activity.
In the light of the above results we can conclude that

M. Badawneh et al. / Il Farmaco 57 (2002) 631–639
637
Scheme 4. Synthetic route to substituted 2-hydroxy-3-phenyl-1,8-naphthyridine derivatives. Cep, N-ethoxycarbonylpiperazin-1-yl; Pipz, piperazin-
1-yl.
the 1,8-naphthyridine ring appears to be a useful subs-
trate for antitubercular agents.
5.1.2. General procedure for the preparation of mono-
and dichloro-1,8-naphthyridine deri6ati6es 3, 4, 14, 22
and 23
A mixture of 5 mmol of the appropriate hydroxy-1,8-
naphthyridine 1, 2, 13 [27], 20 or 21 POCl3 (10 ml for
13, 20 and 21 or 15 ml for 1 and 2) was heated at 90 °C
for 40 min. After cooling, the solution obtained was
treated with ice and water and then alkalinized
with concd. NH4OH (pH$8). The solid was collected
by filtration, washed with water and purified by
crystallization to give the title compounds (Tables 1
and 2).
5. Experimental
5.1. Chemistry
All compounds were routinely checked for their
structure by IR and H NMR spectroscopy. M.p.s were
1
determined on a Ko¨fler hot-stage apparatus and are
uncorrected. The IR spectra were measured with a
Genesis Series FTIR ATI Mattson. The 1H NMR
spectra were determined in DMSO-d6 or CDCl3 with
TMS as the internal standard, on a Varian CFT-20
NMR spectrometer. Analytical TLC was carried out on
Merck 0.2 mm precoated silica gel glass plates (60
F-254) and location of spots was detected by illumina-
tion with a UV lamp. Elemental analyses of all com-
pounds synthesized for C, H and N were within
90.4% of theoretical values and were performed by
our analytical laboratory.
5.1.3. General procedure for the preparation of (mor-
pholin-1-yl)-5, 6, 15, 24 and 26 and (piperidin-1-yl)-7, 8,
16 and 27-1,8-naphthyridine deri6ati6es.
A mixture of 2 mmol of appropriate chloro-1,8-naph-
thyridine 3, 4, 14, 23 or 25 and 5 mmol of morpholine
or piperidine in 20 ml of C6H5CH3 was refluxed for 6 h.
The solvent was evaporated to dryness in vacuo and the
residue was treated with water, filtered and purified by
crystallization to give the title compounds. Only the
compound 26 was purified by flash chromatography
(Tables 1 and 2).
5.1.1. General procedure for the preparation of
5.1.4. 7-Amino-4-chloro-2-(morpholin-1-yl) (28) [27]
and 7-amino-4-chloro-2-(piperidin-1-yl)-1,8-
naphthyridine (29)
A solution of 5.0 mmol of the 7-acetamido-4-chloro-
1,8-naphthyridine 26 or 27 in 20 ml of 10% H2SO4 was
refluxed for 2 h and then, after cooling, the pH was
adjusted to 9 with concd. NH4OH. The solid was
separated by filtration and purified by crystallization
(Tables 1 and 2).
2,4-dihydroxy-1,8-naphthyridine deri6ati6es 1 and 2
A mixture of 2-amino-6-methylpyridine (9.0 mmol)
and diethyl benzylmalonate or diethyl methylmalonate
(10.0 mmol) in 10 ml of Dowtherm A was refluxed for
15 min. The solution was allowed to rest at r.t. and
after 24 h the precipitate formed was collected by
filtration and washed with petroleum ether to obtain
the title compounds (Tables 1 and 2).

638
M. Badawneh et al. / Il Farmaco 57 (2002) 631–639
5.1.5. General procedure for the preparation of (mor-
pholin-1-yl)- 9, 10, 17, 18, 20 and 31, (piperidin-1-yl)-
11, 12, 19, 21, 30 and 32 and (N-ethoxycarbonylpiper-
azin-1-yl)- 34 -1,8-naphthyridine deri6ati6es
A mixture of 5 mmol of appropriate 4-chloro-1,8-
naphthyridine (7, 8, 13, 15, 16, 28, 29) or 7-hydroxy-2-
chloro-3-phenyl-1,8-naphthyridine (33) and 20 mmol of
appropriate amine was kept for 16 h in a sealed tube, at
160 °C. After cooling, the crude residue was treated
with water and the solid obtained was collected by
filtration, washed with water, and purified by
crystallization or by flash chromatography (Tables 1
and 2).
vacuo to a small volume. The pH of the solution was
adjusted to 8–9 with 10% HCl and the solution was
extracted twice with CHCl3: the combined extracts were
dried (magnesium sulfate) and evaporated to dryness in
vacuo to obtain the piperazin-1-yl derivative 35, which
was purified by crystallization (Tables 1 and 2).
5.2. Pharmacology
Primary screening was conducted at 6.25 mg/ml
against the virulent strain M. tuberculosis H37R6 M.
tuberculosis was grown in BACTEC 12B medium con-
taining radiolabelled substrate [29]. Labelled CO2 pro-
duced was detected and quantified by the automatic
BACTEC 460-radiometric system. Compounds effec-
ting 596% inhibition in the primary screening (MIC\
6.25 mg/ml) were not evaluated further. The standard
compound used in this primary assay was rifampicin
(MIC=0.25 mg/ml).
5.1.6. 2-methoxy-3-phenyl-7-(piperazin-1-yl)-1,8-naph-
thyridine (35)
A solution of 1 mmol of the 7-carbethoxypiperazinyl
derivative 34 in 25 ml of EtOH and 25 ml of 10% aq.
NaOH was refluxed for 16 h and then concentrated in
Table 3
Antimycobacterial in vitro activity of the tested compounds expressed
as % inhibition of M. tuberculosis H37R6 at a concentration of 6.25
mg/ml
Acknowledgements
The in vitro evaluation of the antituberculosis acti-
vity was carried out in the Tuberculosis Antimicrobial
Acquisition and Coordinating Facility (TAACF) at the
National Institute of Allergy and Infectious Disease,
Southern Research Institute, GWL Hansen’s Disease
Center and Colorado State University, USA; we thank
J.A. Maddry, Ph.D. for his collaboration.
Comp.
R
R1
R2
R3
% Inhibition
1
2
3
4
5
6
7
8
9
OH
OH
Cl
CH3
OH
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
0
0
1
55
0
20
17
41
11
20
96
2
38
0
27
C6H5CH2 OH
CH3 Cl
C6H5CH2 Cl
Cl
Morph C6H5CH2 Cl
Cl
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RMP
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Pip
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Morph Morph 11
Morph Pip
Pip Pip
Morph OH
Pip OH
Morph Cl
Pip
Pip
Cl
0
43
9
0
1
Cl
8
Morph 11
AcNH
NH2
8
38
72
0
H
H
H
H
C6H5
C6H5
Cl
Pip
NH2
Morph NH2
Pip
H
NH2
Cep
Pipz
6
16
11
98
OH
H

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