Quinolone analogs 11: Synthesis of novel 4-quinolone-3-carbohydrazide derivatives with antimalarial activity

Article abstract of DOI:10.1002/jhet.774

The reaction of the 6-substituted 1-methyl-4-quinolone-3-carboxylates 10a,b with hydrazine hydrate gave the 3-carbohydrazides 7a,b, respectively, whose reaction with 2-, 3-, and 4-pyridinecarbaldehydes afforded the 3-(N ²-pyridylmethylene)carbohydrazides 8a-c and 9a-c. The Curtius rearrangement of compound 7b provided the N,N'-bis(4-quinolon-3-yl)urea 14 presumably via the 3-carboazide 11 and then 3-isocyanate 12. Compounds 7a, 8a, and 9a were found to possess antimalarial activity from the in vitro screening data. Copyright

Full text of DOI:10.1002/jhet.774

288
Quinolone Analogs 11: Synthesis of Novel 4-Quinolone-3-
carbohydrazide Derivatives with Antimalarial Activity
Vol 49
Yoshihisa Kurasawa,a* Kiminari Yoshida,a Naoki Yamazaki,a Eisuke Kaji,b
Kenji Sasaki,c* Yoshito Zamami,c Yasuhiro Sakai,c Takatoshi Fujii,c
and Hideyuki Itoc
aSchool of Pharmacy, Iwakli Meisei University, Iino, Chuodai, Iwaki-shi,
Fukushima 970-8551, Japan
bSchool of Pharmaceutical Sciences, Kitasato University, Shirokane, Minato-ku,
Tokyo 108-8641, Japan
cGraduate School of Medicine, Dentistory, and Pharmaceutical Sciences, Okayama University,
Tsushimanaka, Okayama-shi, Okayama 700-8530, Japan
*E-mail: kura77@iwakimu.ac.jp or ksasaki@pheasant.pharm.okayama-u.ac.jp
Received July 15, 2010
DOI 10.1002/jhet.774
Published online 21 November 2011 in Wiley Online Library (wileyonlinelibrary.com).
The reaction of the 6-substituted 1-methyl-4-quinolone-3-carboxylates 10a,b with hydrazine hydrate
gave the 3-carbohydrazides 7a,b, respectively, whose reaction with 2-, 3-, and 4-pyridinecarbaldehydes
afforded the 3-(N2-pyridylmethylene)carbohydrazides 8a–c and 9a–c. The Curtius rearrangement of
compound 7b provided the N,N0-bis(4-quinolon-3-yl)urea 14 presumably via the 3-carboazide 11 and
then 3-isocyanate 12. Compounds 7a, 8a, and 9a were found to possess antimalarial activity from the
in vitro screening data.
J. Heterocyclic Chem., 49, 288 (2012).
INTRODUCTION
zyl)]carboxamide 5 is an antiviral agent for the treatment
of infections caused by viruses belonging to the herpesvi-
rus family [14].
In previous papers [1–9], we reported the synthesis of
the 1-alkyl-4-oxopyridazino[3,4-b]quinoxalines 1 (Chart 1)
as candidates of antibacterial quinolone analogs [1–10],
which were found to have antibacterial, antifungal, and/
or algicidal activities [3–6]. Thereafter, we changed the
target ring system from the pyridazino[3,4-b]quinoxalin-
4(1H)-one to 4-quinolone such as new quinolones 2 to
search for novel biologically active compounds. In litera-
ture [11], quinolones and new quinolones 2 have been
known as antibacterial agents inhibiting DNA gyrase and
clinically used in the world. In addition, quinolones have
also been studied on the application to antiviral agent, as
quinolones interact with DNA topoisomerase. In fact, the
4-quinolone-3-carboxamide 3 was reported to show anti-
viral activity [12]. This is an example for the activity
conversion by the substituent change of the 3-carboxyl
into 3-carboxamide group in quinolones. Moreover, the
4-quinolone-3-[N-(4-chlorobenzyl)]carboxamide 4 is a
non-nucleoside antiviral agent inhibiting herpesvirus po-
lymerase [13], and the 4-quinolone-3-[N-(4-chloroben-
In this context, we also tried to modify the structure
of new quinolones 2, following the above examples for
the activity conversion. At first, we transferred the base
moiety of new quinolones 2 from the C7-position to the
N1-side chain, leading to the production of the quino-
lones 6 [10] (Chart 2). As the result, we found that the
4-pyridyl derivative of quinolones 6 (X ¼ H, R1 ¼ R2
¼ C2H5) exhibited antimalarial activity. Some antima-
larial quinolones [15–17] as well as quinine and chloro-
quin have been introduced in a recent review [18],
which also includes 4-aminoquinolines, 8-aminoquino-
lines, isoquinolines, 9-aminoacridines, and many other
related compounds. Moreover, pyridinium dimers [19–
21] and carbocyclic adenine nucleosides [22–25] were
synthesized as candidates of antimalarial agents.
In continuation of our works, we further synthesized
the quinolones 8 and 9 via the quinolone-3-carbohydra-
zides 7 based on the concept shifting a pyridyl moiety
from the N1-side chain to C3-side chain. Subsequently,
C
V
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March 2012
Quinolone Analogs 11: Synthesis of Novel 4-Quinolone-3-carbohydrazide
Derivatives with Antimalarial Activity
289
Chart 2.
Chart 1.
works, this antimalarial activity was clarified to diminish
remarkably when the N1-methyl group of compounds
7a, 8a, and 9a was substituted with the acrylate moiety
included in compounds 6 [26]. Thus, we have accom-
plished the serial synthesis of antimalarial quinolones by
shifting the basic moiety from the C6-position of new
we evaluated the in vitro antimalarial activity for com-
pounds 7, 8, and 9, wherein compounds 7a, 8a, and 9a
(Scheme 1) were found to possess inhibitory activity to
Plasmodium falciparum (Table 2). In our extended
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

290
Y. Kurasawa, K. Yoshida, N. Yamazaki, E. Kaji, K. Sasaki, Y. Zamami,
Y. Sakai, T. Fujii, and H. Ito
Vol 49
Table 1
13C-NMR spectral data for compounds 7a and 8a.a
Antimalarial activity. The in vitro screening to anti-
malarial activity was carried out for compounds 7a,b,
8a–c, 9a–c, and 14 according to a method described in
previous papers [10,29], and the data are shown in Table
2. The IC50 values in micromolar concentraton for our
3-carbohydrazides 7a, 8a, and 9a, and reference com-
pounds (quinine and chloroquin) are 8.7, 3.3, 6.2, and
(0.110, 0.018) to P. falciparum FCR-3 strain, respec-
tively, and the above values of our 3-carbohydrazides
are referred as effective level. The 2-pyridyl moiety
results in a good antimalarial activity. The IC50 values
in micromolar concentration for compounds 8b and 9b
(3-pyridyl), 8c and 9c (4-pyridyl), and 14 (dimer) are
above 100, which is referred as not effective level.
Compound
Carbon
2-C
3-C
7a
8a
148.2
109.7
174.1
128.3
110.2
159.2
121.3
120.6
136.6
163.5
41.3
–
149.7
109.5
174.7
128.6
110.6
159.8
121.9
121.2
137.0
161.5
41.9
4-C
4a-C
5-C
6-C
7-C
8-C
8a-C
3-CONN
CH3
Pyridyl 2-C
Pyridyl 3-C
Pyridyl 4-C
Pyridyl 5-C
Pyridyl 6-C
154.3
120.6
136.9
124.6
149.7
–
–
EXPERIMENTAL
–
–
All melting points were determined on a Yazawa micro melting
point BY-2 apparatus and are uncorrected. The IR spectra (potas-
sium bromide) were recorded with a JASCO FT/IR-200 spectrom-
eter. The NMR spectra were measured with a Varian XL-400
spectrometer at 400 MHz. The gHSQC and gHMBC spectra were
measured with Varian INOVA 600 spectrometer. The chemical
shifts are given in the d scale. The mass spectra (ms) were deter-
mined with a JEOL JMS-01S spectrometer. Elemental analyses
were performed on a Perkin-Elmer 240B instrument.
a Measured in deuteriodimethyl sulfoxide.
quinolone to N1-position of compound 6 and then to
C3-position of compounds 7, 8, and 9 (Chart 2), succes-
sively. This article describes the synthesis and antima-
larial activity of the 4-quinolones 7a,b, 8a–c, and 9a–c.
6-Fluoro-1,4-dihydro-1-methyl-4-oxoquinoline-3-carbohy-
drazide 7a. A solution of compound 10a (5.0 g) and an
excess amount of hydrazine hydrate (100% purity, 10.0 g) in
ethanol (150 mL) was refluxed with stirring for 5 h to precipi-
tate colorless needles 7a, which were collected by filtration
and washed with ethanol to give an analytically pure samꢁpl1e
RESULTS AND DISCUSSION
Synthesis of quinolone derivatives. The 6-substi-
tuted 1-methyl-4-quinolone-3-carboxylates 10a,b were
synthesized from 6-substituted 4-hydroxyquinoline-3-
carboxylates by known methods [27,28]. The reaction of
compounds 10a,b with hydrazine hydrate gave the
3-carbohydrazides 7a,b, whose reaction with 2-, 3-, and
4-pyridinecarbaldehydes afforded the 3-[N2-(2-, 3-, and
4-pyridylmethylene)]carbohydrazides 8a–c and 9a–c,
respectively (Scheme 1).
(4.2 g, 89%); mp 273–274ꢀ; IR: m 3220, 3040, 1660 cm
;
ms: m/z 235 (Mþ); NMR (deuteriodimethyl sulfoxide): 10.56
(s, 1H, NH), 8.83 (s, 1H, 2-H), 7.95 (dd, J ¼ 3.0, 9.0 Hz, 1H,
5-H), 7.90 (dd, J ¼ 4.5, 10.0 Hz, 1H, 8-H), 7.75 (ddd, J ¼
3.0, 8.0, 10.0 Hz, 1H, 7-H), 5.57 (s, 2H, NH2), 4.01 (s, 3H,
CH3). Anal. Calcd. For C11H10FN3O2: C, 56.17; H, 4.29; N,
17.86. Found: C, 56.28; H, 4.47; N, 17.80.
Table 2
In vitro antimalarial activity of compounds 7, 8, 9, and 14.a
The Curtius rearrangement of compound 7b provided
the N,N0-bis(6-trifluoromethyl-4-quinolon-3-yl)urea 14,
wherein 3-amino intermediate 13 was not isolated pre-
sumably due to the slow hydrolysis of 3-isocyanate
intermediate 12 and due to the fast addition of 3-amino
intermediate 13 to 3-isocyanate intermediate 12. The
isolation of the N,N0-bis(6-trifluoromethyl-4-quinolon-3-
yl)urea 14, but not the 3-amino derivative 13, may be
attributed to an electron donating character of the N1
moiety.
Compound
R
Base position
IC50 (lmol)
Quinine
Chloroquin
0.110
0.018
8.7
7a
7b
8a
8b
8c
9a
9b
9c
14
F
CF3
F
–
–
>100
3.3
2-Pyridyl
3-Pyridyl
4-Pyridyl
2-Pyridyl
3-Pyridyl
4-Pyridyl
–
F
F
>100
>100
6.2
>100
>100
>100
CF3
CF3
CH3
CH3
The structural assignment of new compounds 7, 8, 9,
and 14 was based on the analytical and spectral data.
Table 1 shows the carbon chemical shifts for our typical
quinolones 7a and 8a assigned by the gHSQC and
gHMBC spectral data.
a Antimalarial activity was examined to chloroquin-sensitive P. falcipa-
rum FCR-3 strain.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2012
Quinolone Analogs 11: Synthesis of Novel 4-Quinolone-3-carbohydrazide
Derivatives with Antimalarial Activity
291
8.49 (dd, J ¼ 8.0, 8.0 Hz, 1H, pyridine 4-H), 8.45 (s, 1H, hy-
drazone CH), 8.10 (d, J ¼ 8.0 Hz, 1H, pyridine 3-H), 8.02 (d,
J ¼ 9.0 Hz, 1H, 7-H), 7.89 (dd, J ¼ 8.0, 7.0 Hz, 1H, pyridine
5-H), 7.82 (d, J ¼ 9.0 Hz, 1H, 8-H), 4.07 (s, 3H, CH3). Anal.
Calcd. For C18H13F3N4O2: C, 57.76; H, 3.50; N, 14.97. Found:
C, 57.67; H, 3.57; N, 14.85.
3-Pyridyl derivative 9b was obtained in 80% yield (1.05 g);
mp above 300ꢀ; IR: m 3050, 1670 cmꢁ1; ms: m/z 374 (Mþ);
NMR (deuteriotrifluoroacetic acid): 9.21 (s, 1H, 2-H), 9.05 (s,
1H, pyridine 2-H), 9.00 (d, J ¼ 8.0 Hz, 1H, pyridine 6-H),
8.63 (d, J ¼ 8.0 Hz, 1H, pyridine 4-H), 8.62 (d, J ¼ 2.0 Hz,
1H, 5-H), 8.44 (s, 1H, hydrazone CH), 8.06 (dd, J ¼ 9.0, 2.0
Hz, 7-H), 7.95 (dd, J ¼ 8.0, 8.0 Hz, 1H, pyridine 5-H), 7.87
(d, J ¼ 9.0 Hz, 1H, 8-H), 4.11 (s, 3H, CH3). Anal. Calcd. For
C18H13F3N4O2: C, 57.76; H, 3.50; N, 14.97. Found: C, 57.69;
H, 3.57; N, 14.69.
4-Pyridyl derivative 9c was obtained in 82% yield (1.08 g);
mp above 300ꢀ; IR: m 3060, 1680 cmꢁ1; ms: m/z 374 (Mþ);
NMR (deuteriotrifluoroacetic acid): 9.19 (s, 1H, 2-H), 8.60 (d,
J ¼ 2.0 Hz, 1H, 5-H), 8.59 (d, J ¼ 7.0 Hz, 2H, pyridine 2,6-
H), 8.42 (s, 1H, hydrazone CH), 8.34 (d, J ¼ 7.0 Hz, 2H, pyri-
dine 3,5-H), 8.04 (d, J ¼ 9.0, 2.0 Hz, 1H, 7-H), 7.84 (d, J ¼
9.0 Hz, 1H, 8-H), 4.09 (s, 3H, CH3). Anal. Calcd. For
C18H13F3N4O2: C, 57.76; H, 3.50; N, 14.97. Found: C, 57.66;
H, 3.57; N, 14.86.
N,N0-Bis(1,4-dihydro-1-methyl-4-oxo-6-trifluoromethylquinolin-
3-yl) urea 14. A solution of sodium nitrite (0.36 g, 5.26 mmol)
in water (10 mL) was added to a solution of compound 7b
(1.0 g, 3.50 mmol) in acetic acid (20 mL) with stirring for 30
min at room temperature to precipitate colorless crystals.
Then, the reaction mixture was refluxed for 1 h to precipitate
pale yellow needles 14, which were collected by filtration and
washed with ethanol to afford an analytically pure sample
(0.51 g, 57%). Herein, compounds 11, 12, and 13 were not
isolated from the above filtrate. Compound 14 had mp above
300ꢀ; IR: m 3450, 3320, 3100, 1640, 1580 cmꢁ1; ms: m/z 510
(Mþ); NMR (deuteriotrifluoroacetic acid): 8.97 (s, 2H, 2-H),
8.83 (d, J ¼ 2.0 Hz, 2H, 5-H), 8.17 (dd, J ¼ 9.0, 2.0 Hz, 2H,
7-H), 8.09 (d, J ¼ 9.0 Hz, 2H, 8-H), 4.33 (s, 6H, CH3). Anal.
Calcd. For C23H16F6N4O3ꢂ1.5H2O: C, 51.40; H, 3.56; N,
10.43. Found: C, 51.66; H, 3.56; N, 10.41.
1,4-Dihydro-1-methyl-4-oxo-6-trifluoromethylquinoline-3-
carbohydrazide 7b. A solution of compound 10b (5.0 g) and
an excess amount of hydrazine hydrate (100% purity, 10.0 g)
in ethanol (150 mL) was refluxed with stirring for 5 h. Cooling
of the solution to room temperature precipitated colorless nee-
dles 7b, which were collected by filtration and washed with
ethanol to give an analytically pure sample (4.4 g, 92%); mp
262–263ꢀ; IR: m 3320, 3280, 1680, 1655 cmꢁ1; ms: m/z 285
(Mþ); NMR (deuteriodimethyl sulfoxide): 10.46 (s, 1H, NH),
8.90 (s, 1H, 2-H), 8.52 (d, J ¼ 2.0 Hz, 1H, 5-H), 8.13 (dd, J
¼ 9.0, 2.0 Hz, 1H, 7-H), 8.01 (d, J ¼ 9.0 Hz, 1H, 8-H), 4.62
(s, 2H, NH2), 4.03 (s, 3H, CH3). Anal. Calcd. For
C12H10F3N3O2: C, 50.53; H, 3.53; N, 14.73. Found: C, 50.27;
H, 3.64; N, 14.44.
6-Fluoro-1,4-dihydro-1-methyl-4-oxoquinoline-3-[N2-(2-, 3-,
and 4-pyridylmethylene)]carbohydrazides 8a–c and 1,4-dihy-
dro-1-methyl-4-oxo-6-trifluoromethylquinoline-3-[N2-(2-, 3-,
and 4-pyridylmethylene)]carbohydrazides 9a–c.
General
procedure. A solution of the 3-carbohydrazide 7a (1.0 g, 4.26
mmol) or 7b (1.0 g, 3.51 mmol) and 2-, 3-, or 4-pyridinecar-
baldehyde (0.68 g, 6.30 mmol for 7a; 0.56 g, 5.27 mmol for
7b) in N,N-dimethylformamide (30 mL) was refluxed for 2 h.
Cooling of the solution to room temperature precipitated color-
less crystals 8a–c or 9a–c, which were collected by filtration
and washed with ethanol to give an analytically pure sample.
Evaporation of the filtrate in vacuo afforded additional prod-
uct, which was recrystallized from N,N-dimethylformamide to
provide colorless needles.
2-Pyridyl derivative 8a was obtained in 80% yield (1.10 g);
mp 263–264ꢀ; IR: m 3060, 1665 cmꢁ1; ms: m/z 324 (Mþ);
NMR (deuteriotrifluoroacetic acid): 9.20 (s, 1H, 2-H), 8.67 (d,
J ¼ 8.0, 1H, pyridine 6-H), 8.58 (dd, J ¼ 8.0, 8.0 Hz, 1H, pyr-
idine 4-H), 8.54 (s, 1H, hydrazone CH), 8.03 (dd, J ¼ 8.0, 3.0
Hz, 1H, 5-H), 8.20 (d, J ¼ 8.0 Hz, 1H, pyridine 3-H), 7.98
(dd, J ¼ 8.0, 8.0 Hz, 1H, pyridine 5-H), 7.88 (dd, J ¼ 9.0, 3.5
Hz, 1H, 8-H), 7.69 (ddd, J ¼ 9.0, 8.0, 3.0 Hz, 1H, 7-H), 4.18
(s, 3H, CH3). Anal. Calcd. For C17H13FN4O2ꢂH2O: C, 59.65;
H, 4.42; N, 16.37. Found: C, 59.81; H, 4.35; N, 16.23.
3-Pyridyl derivative 8b was obtained in 97% yield (1.34 g);
mp above 300ꢀ; IR: m 3060, 1675 cmꢁ1; ms: m/z 324 (Mþ);
NMR (deuteriotrifluoroacetic acid): 9.24 (s, 1H, 2-H), 9.08
(s, 1H, pyridine 2-H), 9.02 (d, J ¼ 8.0 Hz, 1H, pyridine 6-H),
8.67 (d, J ¼ 6.0 Hz, 1H, pyridine 4-H), 8.49 (s, 1H, hydrazone
CH), 8.05 (dd, J ¼ 8.0, 2.5 Hz, 1H, 5-H), 7.99 (dd, J ¼ 8.0,
6.0 Hz, 1H, pyridine 5-H), 7.91 (dd, J ¼ 9.0, 4.0 Hz, 1H, 8-
H), 7.72 (ddd, J ¼ 9.0, 7.0, 2.5 Hz, 1H, 7-H), 4.21 (s, 3H,
CH3). Anal. Calcd. For C17H13FN4O2: C, 62.96; H, 4.04; N,
17.28. Found: C, 63.02; H, 4.11; N, 17.18.
4-Pyridyl derivative 8c was obtained in 93% yield (1.29 g);
mp above 300ꢀ; IR: m 3065, 1680 cmꢁ1; ms: m/z 324 (Mþ);
NMR (deuteriotrifluoroacetic acid): 8.80 (s, 1H, 2-H), 8.47
(d, J ¼ 7.0 Hz, 2H, pyridine 2,6-H), 8.23 (s, 1H, hydrazone
CH), 8.09 (d, J ¼ 7.0 Hz, 2H, pyridine 3,5-H), 7.68 (dd, J ¼
10.0, 3.5 Hz, 1H, 5-H), 7.59 (dd, J ¼ 11.0, 5.0 Hz, 1H, 8-H),
7.72 (ddd, J ¼ 11.0, 9.0, 3.5 Hz, 1H, 7-H), 3.87 (s, 3H, CH3).
Anal. Calcd. For C17H13FN4O2: C, 62.96; H, 4.04; N, 17.28.
Found: C, 63.13; H, 4.21; N, 17.15.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet