Fluorinated 1,3-benzothiazin-4-ones containing fluoroquinolone fragment

Article abstract of DOI:10.1007/s10593-019-02499-1

[Figure not available: see fulltext.] We have developed an efficient synthetic approach to potential antibacterial agents with double mechanism of action through the combination of antibacterial fluoroquinolones with 1,3-benzothiazin-4-ones.

Full text of DOI:10.1007/s10593-019-02499-1

DOI 10.1007/s10593-019-02499-1
Chemistry of Heterocyclic Compounds 2019, 55(6), 578–582
Fluorinated 1,3-benzothiazin-4-ones containing
fluoroquinolone fragment
Emiliya V. Nosova1,2*, Olga A. Batanova1,
Nataliya N. Mochulskaya1, Valery N. Charushin1,2
1 Department of Organic and Biomolecular Chemistry,
Ural Federal University named after the first President of Russia B. N. Yeltsin,
19 Mira St., Yekaterinburg 620002, Russia; e-mail: emily74@rambler.ru
2 Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22 S. Kovalevskoi St. / 20 Akademicheskaya St., Yekaterinburg 620137, Russia
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(6), 578–582
Submitted April 1, 2019
Accepted April 24, 2019
We have developed an efficient synthetic approach to potential antibacterial agents with double mechanism of action through the combi-
nation of antibacterial fluoroquinolones with 1,3-benzothiazin-4-ones.
Keywords: fluorobenzothiazin-4-ones, o-fluorobenzoyl isothiocyanates, 7-hydrazinoquinolone-3-carboxylic acid, quinolone-3-carboxylic
acid hydrazides, cyclocondensation.
Design of dual action antibiotics is an important
approach in the search for new promising drugs.1 Fluoro-
quinolones demonstrate high activity toward tuberculosis
(TB) mycobacteria and are of considerable interest as
agents for the combined chemotherapy of multidrug-
resistant tuberculosis.2 Notably, that nowadays the creation
of 4-quinolone hybrids is considered as one of the most
promising ways for the design of antibacterial agents.3
A large number of fluoroquinolone hybrid compounds, in
which the fluoroquinolone fragment is covalently con-
nected with such antibacterial agents as oxazolidinones,
macrolides, rifamycin, tetracycline, benzylpyrimidines,
anilinouracils, cephalosporines, aminoglycosides, is
described in literature.1 Recently, new 2-oxo-2H-chromen-
3-yl-substituted bi- and tricyclic fluoroquinolones, which
are of interest due to inhibition of GyrA and GyrB subunits
of DNA girase and the potential expansion of the spectrum
of action on pathogens, were obtained.4
into its epimere, the corresponding arabinose, and
this conversion proved to be the key step in biosynthesis
of arabinan, as a building block for TB mycobacteria
cell wall.5 Obviously, other mechanisms of action can
exist for benzothiazinоnes not containing nitro group at
position 8.
Earlier we demonstrated that interaction of tetrafluoro-
benzoyl isothiocyanates with aminoazines and aminoazoles
as N-nucleophiles represents an effective approach to
2-heterylamino-6,7,8-trifluoro-1,3-benzothiazin-4-ones.6
Some of the synthesized 6,7,8-trifluoro-1,3-benzothiazin-
4-ones derivatives possess high antitubercular activity.7
This year we reported fluorinated 2-cycloalkylamino-
1,3-benzothiazin-4-ones exhibiting antitubercular acti-
vity.8
In present work, we studied the reaction of o-fluoro-
benzoyl isothiocyanates with hydrazino and hydrazido
derivatives of fluoroquinolones and found convenient
conditions leading to the formation of molecules containing
covalently bound fluoroquinolone and fluorobenzothia-
zinone fragments. It worth noting that hydrazide spacer
was previously used for fluoroquinolone modifications, for
example, in the design of N'-(aldehydoglycosylquinolon-
Benzothiazinone derivatives are of particular interest
due to their recently discovered ability to be active against
TB mycobacteria by blocking decaprenylphosphoryl-
β-D-ribose-2'-epimerase (DprE1), the enzyme catalyzing
transformation of decaprenylphosphoryl-substituted ribose
0009-3122/19/55(6)-0578©2019 Springer Science+Business Media, LLC
578

Chemistry of Heterocyclic Compounds 2019, 55(6), 578–582
Scheme 1
3-yl)carbohydrazides.9 Condensation of 3-formylrifamycin SV
and 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methylpiperazin-1-yl)-
4-oxoquinoline-3-carboxylic acid hydrazide led to the
compound active toward Gram-positive microorganisms
and TB micobacteria.10
We demonstrated that 2,3,4,5-tetra- and 2,6-difluoro-
benzoyl isothiocyanates 1а,b, obtained by interaction of the
corresponding benzoyl chlorides with ammonium isothio-
cyanate, smoothly react with hydrazine 2 and hydrazides
5a,b in MeCN at 80°С for 1 h, and addition products 3,
6a,b were obtained with 78–90% yields (Scheme 1).
Compound 3 was found to undergo intramolecular
cyclization into 1,3-benzothiazin-4-one 4 under reflux in
MeCN in the presence of DBU for 1 h, treatment with
AcOH allowed to transform salt 4·DBU into the target
product 4. Intermediates 6а,b underwent intramolecular
cyclization into 1,3-benzothiazin-4-ones 7а,b under reflux
in DMF in the presence of Et3N for 4 h.
fluoroquinolone fragment at –130.89 ppm. 1H NMR
spectrum of compound 4 contains one two-proton
broadened signal of NHNH fragment.
1
One-proton multiplet at 7.62–7.68 ppm in the H NMR
spectra of addition products 6a,b is typical for the tetra-
fluorobenzoyl moiety. In 1H NMR spectra of benzo-
thiazinone derivatives 7a,b, the multiplicity of H-5 signal has
changed to a double doublet of doublets (7.94–7.95 ppm),
while one NH signal has expectedly disappeared.
The molecular ion peak in mass spectrum of benzo-
thiazinone 4 has 100% intensity. The molecular ion peaks
in mass spectra of compounds 7a,b have relative intensities
of 15–21%. The ions with m/z 287 and m/z 259 with 100%
intensity were observed for pyrrolidine-containing derivative
7a and thiomorpholine-containing one 7b, respectively.
Earlier11 we have demonstrated that p-nitrophenyl-
hydrazine smoothly reacts with tetrafluorobenzoyl isothio-
cyanate upon boiling in MeCN (reaction time 30 min) to
give thiosemicarbazide, which was subjected to cyclization
by boiling in DMSO for 15 min; as a result, 1,3-benzo-
thiazinone was isolated. By boiling tetrafluorobenzoyl
isothiocyanate 1a with (4,6-dimethylpyrimidin-2-yl)hydrazine
in MeCN for 1 h we directly obtained fluorine-containing
2-(4,6-dimethylpyrimidin-2-yl)-4H-1,3-benzothiazin-4-one.
4,6-Diphenylpyrimidin-2-ylhydrazine reacted with isothio-
cyanate 1a in boiling MeCN in a different way, and the
product was substituted [1,2,4]triazolo[4,3-a]pyrimidine.
As for benzoylthiosemicarbazides obtained from aryl-
Structure of compounds 3–7 was confirmed by the data
1
of Н, 13C, 19F NMR spectra and mass spectra. 19F NMR
spectrum of compound 3 proved to exhibit two signals,
from two fluorine atoms of C6H3F2 fragment at
–113.54 ppm and from atom F-6' of fluoroquinolone
fragment at –131.78 ppm. In 1H NMR spectrum of
compound 3, signals of three NH groups were observed. As
for cyclization product 4, signals from two fluorine atoms
were observed in 19F NMR spectrum: atom F-5 of benzo-
thiazinone fragment at –110.87 ppm and atom F-6' of
579

Chemistry of Heterocyclic Compounds 2019, 55(6), 578–582
hydrazides and isothiocyanate 1a, they failed to cyclize
Tetrafluorobenzamides 6а,b were synthesized by the
method used for compound 3 synthesis. Tetrafluorobenzoyl
chloride, ammonium isothiocyanate, and hydrazides 5a,b
were taken in ratio 1.03:1.03:1, solvent – MeCN. After
addition of hydrazine 5a,b, mixture was stirred at 80°C
for 1 h.
into 2-substituted benzothiazinones in the presence of base,
their thermal cyclization in Dowtherm A led to thia-
diazoloquinazolines.12
The hybrid fluorinated benzothiazinones 4, 7a,b were
screened to estimate the level of their activity against
Mycobacterium tuberculosis H37Rv strain. Derivatives 4,
7a,b demonstrated low activity (MIC 12.5 mg/ml).
To sum up, we have developed an effective approach for
the design of molecules combining antibacterial fluoro-
quinolones and benzothiazine derivatives in one core
structure.
N-{2-[1-Ethyl-6-fluoro-4-oxo-7-(pyrrolidin-1-yl)-1,4-di-
hydroquinoline-3-carbonyl]hydrazine-1-carbonothioyl}-
2,3,4,5-tetrafluorobenzamide (6а). Yield 0.49 g (79%),
colorless crystals, mp 320–322°C. 1Н NMR spectrum,
δ, ppm (J, Hz): 1.48 (3Н, t, J = 7.4, СН3); 2.03−2.06 (4Н,
m, (СН2)2); 3.60−3.62 (4Н, m, N(СН2)2); 4.47 (2Н, q,
4
J = 7.4, СН2); 6.58 (1Н, d, JHF = 7.4, Н-8'); 7.63−7.68
3
Experimental
(1Н, m, C6НF4); 7.84 (1Н, d, JHF = 11.5, Н-5'); 8.74 (1H,
1H, 13C, and 19F NMR spectra were obtained on a Bruker
Avance II DMX400 spectrometer (400, 100, and 376 MHz,
respectively) in DMSO-d6. TMS was used as internal
s, H-2'); 12.02 (1Н, br. s, NH); 13.33 (1H, br. s, NH); 13.51
(1H, br. s, NH). 13C NMR spectrum, δ, ppm (J, Hz): 13.5
((CH2)2); 14.6 (CH3); 45.5 (N(CH2)2); 49.4 (NCH2); 110.8
(d, 2JCF = 24.0, C-5'); 112.1 (d, 2JCF = 19.9, C-6); 122.3 (d,
1
standard for H and 13C NMR spectra, CFCl3 (C6F6 as a
secondary reference, F –162.9 ppm) for 19F NMR spectra.
Assignments in 13C NMR spectra were made based on a
literature data.4,8 Mass spectra were recorded on a Shimadzu
GCMS-QP2010 Ultra instrument (EI). Elemental analyses
were performed on a PerkinElmer 2400 elemental analyzer.
Melting points were determined on a Stuart SMP3
instrument.
3JCF = 3.5, C-8'); 127.1 (d, JCF = 7.8, C-4a'); 128.2 (C-3');
3
2
129.8 (d, JCF = 18.1, C-7'); 129.7–130.0 (m, C-1); 135.6
(d, 4JCF = 1.5, C-8a'); 139.8 (dt, 1JCF = 249.8, 2JCF = 15.0, C
1
2
-3); 141.4 (dt, JCF = 253.6, JCF = 13.4, C-4); 145.1 (dd,
2
1
1JCF = 246.6, JCF = 13.4, C-2); 146.0 (dd, JCF = 246.6,
2JCF = 11.8, C-5); 149.4 (C-2'); 157.2 (d, JCF = 250.4,
1
4
C-6'); 159.2 (C=O); 161.7 (CONH); 176.6 (d, JCF = 2.4,
7-Hydrazinylquinoline-3-carboxylic acid 213 and quinoline-
3-carboxylic acid hydrazides 5a,b14 were synthesized by
reported procedures.
C-4'); 178.5 (CS). 19F NMR spectrum, δ, ppm (J, Hz):
3
3
–128.16 (1F, dd, JFH = 11.5, JFH = 7.4, F-6'); –136.80 ÷
–136.85 (1F, m); –138.35 ÷ –138.40 (1F, m); –150.65 ÷
–150.70 (1F, m); –155.10 ÷ –155.15 (1F, m). Found, %:
C 52.19; H 3.61; N 12.72. C24H20F5N5O3S. Calculated, %:
C 52.08; H 3.64; N 12.65.
7-(2-{[(2,6-Difluorophenyl)carbonyl]carbamothioyl}-
hydrazinyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-
3-carboxylic acid (3). A solution of ammonium isothio-
cyanate (0.09 g, 1.17 mmol) in MeCN (7 ml) was added to
2,6-difluorobenzoyl chloride (0.205 g, 1.17 mmol). The
reaction mixture was stirred at 40°C for 5 min, the preci-
pitate of NH4Cl was filtered off, and hydrazine 2 (0.3 g,
1.13 mmol) was added to resulting solution of 2,6-difluoro-
benzoyl isothiocyanate 1b. The mixture was stirred at 80°C
for 1 h and then cooled. The precipitate was filtered off,
washed with hexane, and recrystallized from DMSO. Yield
N-{2-[1-Ethyl-6-fluoro-4-oxo-7-(thiomorpholin-4-yl)-
1,4-dihydroquinoline-3-carbonyl]hydrazine-1-carbono-
thioyl}-2,3,4,5-tetrafluorobenzamide (6b). Yield 0.51 g
1
(78%), colorless crystals, mp 279–281°C. Н NMRspectrum,
δ, ppm (J, Hz): 1.50 (3Н, t, J = 7.3, СН3); 2.81−2.83 (4Н,
m, S(СН2)2); 3.57−3.59 (4Н, m, N(СН2)2); 4.55 (2Н, q, J = 7.3,
4
СН2); 7.14 (1Н, d, JHF = 7.1, Н-8'); 7.62−7.66 (1H, m,
3
C6HF4); 7.96 (1Н, d, JHF = 13.0, Н-5'); 8.87 (1Н, s, Н-2');
1
0.47 g (90%), colorless crystals, mp 328–330°C. Н NMR
12.0 (1H, br. s, NH); 13.4 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm (J, Hz): 14.5 (CH3); 26.4 (S(CH2)2); 45.5
(N(CH2)2); 49.3 (NCH2); 110.6 (d, 2JCF = 23.8, C-5'); 112.1
spectrum, δ, ppm (J, Hz): 1.47 (3Н, t, J = 7.2, СН3); 4.46
4
(2Н, q, J = 7.2, СН2); 7.02 (1Н, d, JHF = 7.0, Н-8');
2
3
7.15−7.17 (2Н, m, Н-3,5); 7.55−7.59 (1Н, m, Н-4); 7.92
(1H, d, 3JHF = 11.6, H-5'); 8.91 (1Н, s, Н-2'); 9.3 (1Н, br. s,
NH); 10.8 (1Н, br. s, NH); 15.3 (2Н, br. s, COОН,
C(O)NHC(S)). 13C NMR spectrum, δ, ppm (J, Hz): 14.6
(CH3); 49.4 (NCH2); 110.8 (d, 2JCF = 23.8, C-5'); 112.0 (dd,
(d, JCF = 19.9, C-6); 122.2 (d, JCF = 3.5, C-8'); 127.1 (d,
3JCF = 7.8, C-4a'); 128.2 (C-3'); 129.8 (d, JCF = 18.1, C-7',
2
4
1
C-1); 135.6 (d, JCF = 1.5, C-8a'); 139.8 (dt, JCF = 247.9,
2JCF = 14.8, C-3); 141.4 (dt, 1JCF = 253.6, 2JCF = 12.9, C-4);
1
2
145.1 (dd, JCF = 246.3, JCF = 12.9, C-2); 146.0 (dd,
4
2
2
2JCF = 23.8, JCF = 4.6, C-3,5); 114.0 (t, JCF = 21.8, C-1);
1JCF = 246.3, JCF = 11.6, C-5); 149.4 (C-2'); 156.9 (d,
3
3
122.3 (d, JCF = 2.7, C-8'); 127.3 (d, JCF = 7.8, C-4a');
1JCF = 250.4, C-6'); 159.2 (C=O); 161.6 (CONH); 176.6 (d,
127.7 (C-3'); 129.3 (d, 2JCF = 18.1, C-7'); 132.6 (t, 3JCF = 10.6,
4JCF = 2.4, C-4'); 178.4 (CS). 19F NMR spectrum, δ, ppm
4
3
3
C-4); 135.5 (d, JCF = 1.3, C-8a'); 149.5 (C-2'); 157.2 (d,
(J, Hz): –123.16 (1F, dd, JFH = 12.5, JFH = 7.4, F-6');
1JCF = 250.7, C-6'); 158.8 (dd, JCF = 253.4, JCF = 8.7,
–136.60 ÷ –136.65 (1F, m); –138.30 (1F, dd, JFF = 21.1,
1
3
3
3
4
3
C-2,6); 164.9 (d, JCF = 5.9, C=O); 165.7 (COO); 168.6
3JFH = 13.2, JFF = 8.0, F-2); –150.55 (1F, td, JFF = 20.8,
(C(O)Ar); 178.2 (C=S). 19F NMR spectrum, δ, ppm
(J, Hz): –113.50 ÷ –113.55 (2F, m, F-2,6); –131.78 (dd,
3JFH = 14.9, JFF = 6.2, F-5); –155.06 (1F, t, JFF = 21.1,
F-4). Found, %: C 49.31; H 3.45; N 11.99. C24H20F5N5O3S2.
Calculated, %: C 49.23; H 3.44; N 11.96.
4
3
4
3JFH = 11.5, JFH = 7.0, F-6'). Found, %: C 51.53; H 3.33;
N 12.12. C20H15F3N4O4S. Calculated, %: C 51.72; H 3.26;
N 12.06.
1-Ethyl-6-fluoro-7-[2-(5-fluoro-4-oxo-4H-1,3-benzo-
thiazin-2-yl)hydrazinyl]-4-oxo-1,4-dihydroquinoline-
580

Chemistry of Heterocyclic Compounds 2019, 55(6), 578–582
3-carboxylic acid (4). DBU (0.24 ml, 1.448 mmol) was
(1F, m, F-7). Mass spectrum, m/z (Irel %): 533 [M]+ (21),
288 (18), 287 (100), 260 (11), 259 (12). Found, %:
C 54.13; H 3.52; N 13.21. C24H19F4N5O3S. Calculated, %:
C 54.03; H 3.59; N 13.13.
added to a suspension of compound 3 (0.336 g, 0.724 mmol)
in MeCN (12 ml) . Reaction mixture was refluxed for 1 h,
and then cooled. The precipitate was filtered off, suspended
in H2O, and рН was adjusted to 5 by addition of diluted
AcOH. The precipitate was filtered off and recrystallized
from EtOH. Yield 0.26 g (81%), light-yellow crystals,
1-Ethyl-6-fluoro-4-oxo-7-(thiomorpholin-4-yl)-N'-(6,7,8-
trifluoro-4-oxo-4H-benzo[e][1,3]thiazin-2-yl)-1,4-dihydro-
quinoline-3-carbohydrazide (7b). Yield 0.29 g (86%),
1
1
mp 276–278°C. Н NMR spectrum, δ, ppm (J, Hz): 1.20
light-yellow crystals, mp 309–311°C. Н NMR spectrum,
(3Н, t, J = 7.1, СН3); 4.41 (2Н, q, J = 7.1, СН2); 6.77 (1Н, d,
δ, ppm (J, Hz): 1.19 (3Н, t, J = 7.2, СН3); 2.94−2.97 (4Н,
m, S(СН2)2); 3.57−3.60 (4Н, m, N(СН2)2); 4.55 (2Н, q,
J = 7.2, СН2); 7.13−7.15 (1Н, m, Н-8'); 7.95 (1H, ddd,
3
4JHF = 6.8, Н-8'); 7.08 (1Н, dd, 3JHF = 10.1, JHH = 8.7, Н-6);
3
3
7.30 (1Н, d, JHH = 8.5, Н-8); 7.68 (1H, td, JHH = 8.4,
4JHF = 5.4, H-7); 8.03 (1Н, dd, 3JHF = 11.5, JHH = 1.5, Н-5');
8.83 (1Н, s, Н-2'); 10.9 (2Н, br. s, 2NH); 13.2 (1Н, br. s,
COОН). 13C NMR spectrum, δ, ppm (J, Hz): 14.6 (CH3);
4
5
3JHF = 9.9, JHF = 7.5, JHF = 2.1, H-5); 7.97−8.01 (1Н, m,
Н-5'); 8.87 (1Н, s, Н-2'); 12.32 (1Н, br. s, NH); 12.86 (1Н,
br. s, NH). 13C NMR spectrum, δ, ppm (J, Hz): 14.5 (CH3);
26.4 (S(CH2)2); 45.5 (N(CH2)2); 49.3 (NCH2); 110.6 (d,
2
49.4 (NCH2); 110.8 (d, JCF = 23.8, C-5'); 112.4 (d,
2
2JCF = 13.0, C-4a); 116.3 (d, 2JCF = 24.2, C-6); 122.3 (two d,
2JCF = 23.8, C-5'); 111.3 (d, JCF = 22.6, C-5); 113.1 (d,
4JCF = 5.4, C-8 and JCF = 2.7, C-8'); 127.3 (d, JCF = 7.8,
3JCF = 24.9, C-4a); 118.1–118.3 (m, C-8a); 122.2 (d,
3
3
C-4a'); 127.7 (C-3'); 129.3 (d, JCF = 18.1, C-7'); 133.6 (d,
3JCF = 3.5, C-8'); 127.1 (d, JCF = 7.8, C-4a'); 128.2 (C-3');
2
3
4
2
4
3JCF = 7.8, C-7); 134.4 (C-8a); 135.5 (d, JCF = 1.3, C-8a');
129.8 (d, JCF = 18.1, C-7'); 135.6 (d, JCF = 1.5, C-8a');
1
1
2
149.5 (C-2'); 154.5 (C-2); 157.1 (d, JCF = 250.7, C-6');
141.5 (dt, JCF = 252.6, JCF = 12.4, C-7); 145.3 (dd,
161.8 (d, JCF = 262.3, C-5); 165.0 (d, JCF = 5.9, C=O);
1JCF = 242.9, JCF = 12.7, C-8); 149.4 (C-2' and dd,
1
3
2
4
2
165.7 (COO); 176.6 (d, JCF = 2.4, C-4). 19F NMR spectrum,
1JCF = 247.8, JCF = 12.3, C-6); 154.4 (C-2); 156.9 (d,
δ, ppm: –110.87 (1F, s); –130.89 (1F, s). Mass spectrum,
m/z (Irel, %): 444 [M]+ (7), 374 (66), 401 (10), 400 (45),
250 (19), 207 (13), 206 (99), 205 (12), 196 (91), 191
(42), 178 (17), 163 (35), 150 (14), 149 (14), 138 (100),
137 (75), 122 (23), 110 (76), 109 (26), 108 (33), 94 (13),
83 (11), 82 (26), 81 (16). Found, %: C 54.28; H 3.41;
N 12.25. C20H18F2N4O4S. Calculated, %: C 54.05; H 3.18;
N 12.61.
Synthesis of 6,7,8-trifluorobenzothiazin-4-ones 7a,b
(General method). Et3N (0.1 ml, 0.546 mmol) was added to
a suspension of compound 6а,b (0.273 mmol) in DMF
(2 ml). The reaction mixture was refluxed for 4 h and then
cooled. The precipitate was filtered off, washed with H2O
(15 ml) and EtOH (3 ml).
1JCF = 250.4, C-6'); 161.6 (CONH); 164.4 (C=O); 176.6 (d,
4JCF = 2.4, C-4'). 19F NMR spectrum, δ, ppm: –123.36 (1F,
s); –132.75 ÷ –132.80 (1F, m); –135.03 (1F, dd, 3JFF = 21.6,
4JFF = 4.6); –151.54 ÷ –151.59 (1F, m). Mass spectrum, m/z
(Irel, %): 565 [M]+ (15), 507 (11), 336 (21), 334 (14), 333
(64), 320 (14), 319 (86), 293 (14), 292 (85), 287 (26), 286
(11), 262 (11), 261 (71), 260 (27), 259 (100), 258 (13), 245
(19), 244 (39), 243 (21), 233 (19), 232 (12), 231 (13), 219
(10), 218 (52), 217 (15), 216 (21), 203 (32), 190 (47), 188
(11), 175 (15), 174 (11), 162 (40), 161 (19), 160 (12), 148
(12), 147 (12), 146 (13), 134 (15), 133 (14), 132 (11), 130
(11), 120 (11), 107 (15), 93 (18), 87 (17), 75 (14), 74 (10),
46 (34), 44 (92), 38 (12), 36 (29). Found, %: C 50.89;
H 3.40; N 12.43. C24H19F4N5O3S2. Calculated, %: C 50.97;
H 3.39; N 12.38.
1-Ethyl-6-fluoro-4-oxo-7-(pyrrolidin-1-yl)-N'-(6,7,8-
trifluoro-4-oxo-4H-benzo[e][1,3]thiazin-2-yl)-1,4-dihydro-
quinoline-3-carbohydrazide (7а). Yield 0.072 g (80%),
Antibacterial activity tests of compounds 4, 7a,b were
performed as previously reported.4,8
1
light-yellow crystals, mp 330–332°C. Н NMR spectrum,
δ, ppm (J, Hz): 1.49 (3Н, t, J = 7.3, СН3); 2.05−2.07 (4Н,
m, (СН2)2); 3.61−3.63 (4Н, m, N(СН2)2); 4.47 (2Н, q,
J = 7.3, СН2); 6.57 (1Н, d, 4JHF = 7.3, Н-8'); 7.94 (1H, ddd,
3JHF = 10.5, 4JHF = 7.5, 5JHF = 2.2, H-5); 7.98−8.00 (1Н, m,
Н-5'); 8.77 (1Н, s, Н-2'); 12.28 (1Н, br. s, NH); 12.98 (1H,
br. s, NH). 13C NMR spectrum, δ, ppm (J, Hz): 13.5 ((CH2)2);
14.6 (CH3); 45.5 (N(CH2)2); 49.4 (CH2); 111.4 (d, 2JCF = 22.3,
The work was carried out with financial support from
the Russian Scientific Foundation (grant 15-13-00077-P)
and from the Ministry of Education of Russian Federation
(State Assignment 4.6351.2017/8.9).
Antibacterial activity tests were performed at the Ural
Research Institute for Phthisiopulmonology.
2
3
References
C-5); 110.8 (d, JCF = 24.0, C-5'); 113.1 (d, JCF = 25.1,
3
C-4a); 118.2 (m, C-8a); 122.3 (d, JCF = 3.5, C-8'); 127.1
1. Tevyashova, A. N.; Olsufyeva, E. N.; Preobrazhenskaya, M. N.
Russ. Chem. Rev. 2015, 84, 61. [Usp. Khim. 2015, 84, 61.]
2. Caminero, J. A.; Sotgiu, G.; Zumla, A.; Migliori, G. B. Lancet
Infect Dis. 2010, 10, 621.
3. (a) Zhang, G.-F.; Zhang, S.; Pan, B.; Liu, X.; Feng, L.-S. Eur.
J. Med. Chem. 2018, 143, 710. (b) Hu, Y.-Q.; Zhang, S.; Xu, Z.;
Lv, Z.-S.; Liu, M.-L.; Feng, L.-S. Eur. J. Med. Chem. 2017,
141, 335.
3
2
(d, JCF = 7.8, C-4a'); 128.2 (C-3'); 129.8 (d, JCF = 18.1,
4
1
C-7'); 135.6 (d, JCF = 1.5, C-8a'); 141.4 (dt, JCF = 252.6,
2JCF = 12.6, C-7); 145.4 (dd, 1JCF = 244.2, 2JCF = 13.9, C-8);
1
2
149.4 (C-2'); 149.5 (dd, JCF = 248.4, JCF = 12.6, C-6);
1
157.2 (d, JCF = 250.4, C-6'); 154.5 (C-2); 161.7 (CONH);
164.5 (C=O); 176.6 (d, JCF = 2.4, C-4'). 19F NMR
4
3
spectrum, δ, ppm (J, Hz): –128.30 (1F, dd, JFH = 11.8,
4. Charushin, V. N.; Mochulskaya, N. N.; Antipin, F. V.;
Kotovskaya, S. K.; Nosova, E. V.; Ezhikova, M. A.; Kodess, M. I.;
Kravchenko, M. A. J. Fluorine Chem. 2018, 208, 15.
3JFH = 7.4, F-6'); –132.75 ÷ –132.80 (1F, m, F-8); –135.17
3
4
(1F, dd, JFF = 21.5, JFF = 4.6, F-6); –151.62 ÷ –151.67
581

Chemistry of Heterocyclic Compounds 2019, 55(6), 578–582
5. Pasca, M. R.; Degiacomi, G.; Ribeiro, A. L. J. L.; Zara, F.;
10. Lakhina, V. V; Zinchenko, E. Ya.; Jarotskij, S. V.;
Charushin, V. N.; Chupakhin, O. N.; Tsoj, E. V.;
Shorshnev, S. V. RU Patent 95101820A1.
11. Nosova, E. V.; Lipunova, G. N.; Laeva, A. A; Sidorova, L. P.;
Charushin, V. N. Russ. J. Org. Chem. 2007, 43, 68. [Zh. Org.
Khim. 2007, 43, 67.]
12. Nosova, E. V.; Poteeva, A. D.; Slepukhin, P. A. Russ. J. Org.
Chem. 2019, 55, 83. [Zh. Org. Khim. 2019, 55, 111.]
13. Ziegler, C. B., Jr.; Kuck, N. A.; Harris, S. M.; Lin, Y.-I.
J. Heterocycl. Chem. 1988, 25, 1543.
14. Nosova, E. V.; Sidorova, L. P.; Lipunova, G. N.;
Mochul'skaya, N. N; Chasovskikh, O. M.; Charushin, V. N.
Chem. Heterocycl. Compd. 2002, 38, 922. [Khim. Geterotsikl.
Soedin. 2002, 1060.]
De Mori, P.; Heym, B.; Mirrione, M.; Brerra, R.; Pagani, L.;
Pucillo, L.; Troupioti, P.; Makarov, V.; Cole, S. T.; Riccardi, G.
Antimicrob. Agents Chemother. 2010, 54, 1616.
6. Nosova, E. V.; Lipunova, G. N.; Laeva, A. A.; Charushin, V. N.
Russ. J. Org. Chem. 2006, 42, 1544. [Zh. Org. Khim. 2006, 42, 1555.]
7. Nosova, E. V.; Lipunova, G. N.; Kravchenko, М. А.;
Laeva, А. А.; Charushin, V. N. Pharm. Chem. J. 2008, 42,
169. [Khim.-Pharm. Zh. 2008, 42(4), 14.]
8. Nosova, E. V.; Batanova, O. A., Lipunova, G. N.;
Kotovskaya, S. K.; Slepukhin, P. A.; Kravchenko, M. A.;
Charushin, V. N. J. Fluorine Chem. 2019, 220, 69.
9. Al-Soud, Y. A.; Al-Masoudi, N. A. J. Braz. Chem. Soc. 2003,
14, 790.
582