T. Gao, Z. Zeng, G. Wang, S. Sun, and Y. Liu
Vol 000
Calcd (%) for C22H20N2O5: C, 67.34; H, 5.14; N, 7.14;
Found: C, 67.21; H, 5.01; N, 7.03.
3-(Ethoxyimino)-5-fluoro-1-(2-((4-methyl-2-oxo-2H-
The general procedure for preparing targets 5c–j. To a
solution of substituted amine hydrochlorides (15 mmol)
and NaHCO3 (15 mmol) dissolved in water (10 mL) and
methanol (50 mL) was added 5a,b (5 mmol). The
reaction mixture was stirred at room temperature for
24 h. After removal of the solvent, the residue was
diluted with water (20 mL) and then filtered. The solid
crude product was purified by column chromatography
chromen-7-yl)oxy)ethyl)indolin-2-one (5h).
Yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 1.35 (3H, t,
NOCH2CH3), 2.36 (3H, s, Me), 4.12 (2H, t, ─CH2─),
4.32 (2H, t, ─CH2─), 4.42 (2H, q, NOCH2CH3), 6.21
(1H, s, Ar─H), 6.96 (1H, dd, Ar─H), 6.99 (1H, d,
Ar─H), 7.35 (1H, dd, Ar─H), 7.47 (1H, dd, Ar─H),
7.63 (1H, dt, Ar─H), 7.74 (1H, d, Ar─H). ESI-MS m/z:
(silica gel) eluted with DCM to PE:EA = 1:1 to give the
title targets 5c–j.
411 [M
+
H]+. Elemental Anal. Calcd (%) for
3-(Hydroxyimino)-1-(2-((4-methyl-2-oxo-2H-chromen-7-yl)
oxy)ethyl)indolin-2-one (5c).
Yellow solid. 1H NMR
C22H19FN2O5: C, 64.39; H, 4.67; N, 6.83; Found: C,
64.19; H, 4.52; N, 6.61.
2-(1-(2-((4-Methyl-2-oxo-2H-chromen-7-yl)oxy)ethyl)-2-
oxoindolin-3-ylidene)hydrazinecarbothioamide (5i). Yellow
(400 MHz, DMSO-d6) δ 2.35 (3H, s, Me), 4.13 (2H, t,
─CH2─), 4.32 (2H, t, ─CH2─), 6.21 (1H, s, Ar─H), 6.87
(1H, dd, Ar─H), 6.91 (1H, d, Ar─H), 7.15 (1H, t, Ar─H),
7.32 (1H, d, Ar─H), 7.51 (1H, d, Ar─H), 7.74 (1H, d,
Ar─H), 13.40 (1H, brs, NOH). ESI-MS m/z: 365
solid. 1H NMR (400 MHz, DMSO-d6) δ 2.36 (3H, s,
Me), 4.12 (2H, t, ─CH2─), 4.34 (2H, t, ─CH2─), 6.22
(1H, s, Ar─H), 6.80 (1H, dd, Ar─H), 6.88 (1H, d,
Ar─H), 7.14 (1H, t, Ar─H), 7.25 (1H, d, Ar─H), 7.52
(1H, d, Ar─H), 7.74 (1H, d, Ar─H), 8.76, 9.08 (1H, s,
NNHCSNH2), 12.18 (1H, s, NNHCSNH2). ESI-MS m/z:
[M + H]+. Elemental Anal. Calcd (%) for C20H16N2O5: C,
65.93; H, 4.43; N, 7.69; Found: C, 65.82; H, 4.27; N, 7.46.
5-Fluoro-3-(hydroxyimino)-1-(2-((4-methyl-2-oxo-2H-
chromen-7-yl)oxy)ethyl)indolin-2-one (5d).
Yellow solid.
+
H]+. Elemental Anal. Calcd (%) for
1H NMR (400 MHz, DMSO-d6) δ 2.34 (3H, s, Me), 4.12
(2H, t, ─CH2─), 4.34 (2H, t, ─CH2─), 6.21 (1H, s,
Ar─H), 6.92 (1H, dd, Ar─H), 6.98 (1H, d, Ar─H), 7.37
(1H, dd, Ar─H), 7.46 (1H, dd, Ar─H), 7.61 (1H, dt,
Ar─H), 7.68 (1H, d, Ar─H), 13.36 (1H, brs, NOH). ESI-
MS m/z: 383 [M + H]+. Elemental Anal. Calcd (%) for
C20H15F2NO5: C, 62.83; H, 3.95; N, 7.33; Found: C,
423 [M
C21H18N4O4S: C, 59.70; H, 4.29; N, 13.26; Found: C,
59.59; H, 4.07; N, 13.11.
2-(5-Fluoro-1-(2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)
ethyl)-2-oxoindolin-3-ylidene)hydrazinecarbothioamide (5j).
Yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.36
(3H, s, Me), 4.13 (2H, t, ─CH2─), 4.32 (2H, t, ─CH2─),
6.21 (1H, s, Ar─H), 6.97 (1H, dd, Ar─H), 7.01 (1H, d,
Ar─H), 7.36 (1H, dd, Ar─H), 7.45 (1H, dd, Ar─H), 7.66
(1H, dt, Ar─H), 7.76 (1H, d, Ar─H), 8.78, 9.10 (1H, s,
NNHCSNH2), 12.16 (1H, s, NNHCSNH2). ESI-MS m/z:
62.71; H, 3.74; N, 7.21.
3-(Methoxyimino)-1-(2-((4-methyl-2-oxo-2H-chromen-7-yl)
oxy)ethyl)indolin-2-one (5e).
Yellow solid. 1H NMR
(400 MHz, DMSO-d6) δ 2.31 (3H, s, Me), 4.12 (2H, t,
─CH2─), 4.21 (3H, s, NOMe), 4.33 (2H, t, ─CH2─), 6.21
(1H, s, Ar─H), 6.86 (1H, dd, Ar─H), 6.90 (1H, d, Ar─H),
7.18 (1H, t, Ar─H), 7.30 (1H, d, Ar─H), 7.52 (1H, d,
Ar─H), 7.76 (1H, d, Ar─H). ESI-MS m/z: 379 [M + H]+.
Elemental Anal. Calcd (%) for C21H18N2O5: C, 66.66; H,
4.79; N, 7.40; Found: C, 66.52; H, 4.57; N, 7.23.
5-Fluoro-3-(methoxyimino)-1-(2-((4-methyl-2-oxo-2H-
chromen-7-yl)oxy)ethyl)indolin-2-one (5f). Yellow solid. 1H
NMR (400 MHz, DMSO-d6) δ 2.36 (3H, s, Me), 4.12 (2H,
t, ─CH2─), 4.21 (3H, s, NOMe), 4.34 (2H, t, ─CH2─), 6.21
(1H, s, Ar─H), 6.94 (1H, dd, Ar─H), 6.98 (1H, d, Ar─H),
7.38 (1H, dd, Ar─H), 7.48 (1H, dd, Ar─H), 7.61 (1H, dt,
Ar─H), 7.72 (1H, d, Ar─H). ESI-MS m/z: 397 [M + H]+.
Elemental Anal. Calcd (%) for C21H17FN2O5: C, 63.63;
441 [M
+
H]+. Elemental Anal. Calcd (%) for
C21H17FN4O4S: C, 57.27; H, 3.89; N, 12.72; Found: C,
57.07; H, 3.71; N, 12.53.
MIC determination. Hybrids 5a–j together with RIF
and INH were evaluated for their in vitro activities
against MTB H37Rv and MDR-TB via rapid direct
susceptibility test technique [19]. The wells of a sterile
48-well plate were filled with 100 mL twofold diluted
tested compounds and 100 mL MTB H37Rv or MDR-TB
suspension containing 4 × 10–3 mg cells. Pure medium
replaced the diluted compounds in two wells as the
positive control of growth, and deionized water instead of
the culture in other two wells as the negative control of
growth in the plates. The plates were covered and sealed,
then incubated at 37°C in a wet box. The positive and
negative control wells should show obvious difference
after 3 days. The MIC was determined by observing the
quantity and state of the cells in each test well by a
continuous visual high magnification system, and
redetermined 7 days later. The MIC is defined as the
concentration of the compound required to give complete
inhibition of bacterial growth.
H, 4.32; N, 7.07; Found: C, 63.50; H, 4.14; N, 7.01.
3-(Ethoxyimino)-1-(2-((4-methyl-2-oxo-2H-chromen-7-yl)
oxy)ethyl)indolin-2-one (5g).
Yellow solid. 1H NMR
(400 MHz, DMSO-d6) δ 1.34 (3H, t, NOCH2CH3), 2.35
(3H, s, Me), 4.12 (2H, t, ─CH2─), 4.32 (2H, t, ─CH2─),
4.41 (2H, q, NOCH2CH3), 6.21 (1H, s, Ar─H), 6.84 (1H,
dd, Ar─H), 6.90 (1H, d, Ar─H), 7.16 (1H, t, Ar─H),
7.27 (1H, d, Ar─H), 7.51 (1H, d, Ar─H), 7.76 (1H, d,
Ar─H). ESI-MS m/z: 393 [M + H]+. Elemental Anal.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet