Y.-L. Fan, M. Liu, F.-z. Zhang, and S. Zhang
Vol 000
Table 1
Structures, lipophilicity, and antitubercular activities of hybrids 5a–h.
MIC (μg/mL)
MTB H37Rv
a
b
Compd.
R
1
R
2
Log P
MDR-TB
5
5
5
5
5
5
5
5
a
b
c
d
e
f
g
h
NOH
NOH
NNHCONH
NNHCONH
NNHCSNH
NNHCSNH
NOH
H
Me
H
Me
H
Me
H
Me
2.53
3.01
1.49
1.98
2.05
2.54
3.61
4.59
1.32
À0.67
3.71
1.56
1.56
0.39
0.78
0.20
0.39
100
4.0
8.0
1.0
1.0
0.5
0.5
64
128
2.0
>128
32
2
2
2
2
NOH
50
CPFX
INH
RIF
0.78
0.05
0.39
MIC, minimum inhibitory concentration, MTB, Mycobacterium tuberculosis; INH, isoniazid; RIF, rifampicin.
a
The Log P is calculated with ChemOffice 2012 software.
MDR-TB: resistant to INH, RIF, and EMB.
b
7
-(4-(3-(3-(2-Carbamoylhydrazono)-5-methyl-2-oxoindolin-1-
2 × cyclopropyl-CH ), 1.82 (2H, t, ─CH ─), 2.25 (3H, s,
2
2
yl)propyl) piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid (5d). Yellow solid. H
NMR (400 MHz, DMSO-d ) δ 1.18–1.30 (4H, m,
× cyclopropyl-CH ), 1.81 (2H, t, ─CH ─), 2.26 (3H, s,
CH3), 2.41 (2H, t, ─CH ─), 3.28–3.30 (4H, m,
piperazine-4H), 3.57–3.60 (4H, m, piperazine-4H), 3.72
2H, t, ─CH ─), 4.10–4.12 (1H, m, cyclopropyl-CH),
.09–7.73 (4H, m, Ar─H), 8.63 (1H, s, C2─H), 8.79,
CH ), 2.42 (2H, t, ─CH ─), 3.28–3.30 (4H, m,
3
2
1
piperazine-4H), 3.58–3.60 (4H, m, piperazine-4H), 3.71
6
(2H, t, ─CH ─), 4.11–4.13 (1H, m, cyclopropyl-CH),
2
2
2
2
7.09–7.71 (4H, m, Ar─H), 8.63 (1H, s, C2─H), 8.76,
2
9.08 (2H, brs, NNHCSNH ), 12.04 (1H, s, NNHCSNH ).
2
2
+
ESI-MS m/z: 606 [M + H] . Elemental Anal. Calcd (%)
(
7
8
2
for C H FN O S: C, 59.49; H, 5.33; N, 16.19; Found:
30
32
7 4
C, 59.24; H, 5.19; N, 16.07.
3-(3-(Hydroxyimino)-2-oxoindolin-1-yl)propyl 1-cyclopropyl-
6-fluoro-7-(4-(3-(3-(hydroxyimino)-2-oxoindolin-1-yl)propyl)
.86 (2H, brs, NNHCONH2), 11.56 (1H, brs,
NNHCONH ). ESI-MS m/z: 590 [M + H] . Elemental
+
2
piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate
Anal. Calcd (%) for C H FN O : C, 61.11; H, 5.47; N,
3
0
32
7 5
1
(
5g).
Yellow solid. H NMR (400 MHz, DMSO-d ) δ
1
6.63; Found: C, 61.03; H, 5.39; N, 16.37.
6
1
.13–1.26 (4H, m, 2 × cyclopropyl-CH ), 1.82 (2H, t,
2
7
-(4-(3-(3-(2-Carbamothioylhydrazono)-2-oxoindolin-1-yl)
propyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid (5e). Yellow solid. H
─CH ─), 2.03 (2H, t, ─CH ─), 2.42 (2H, t, ─CH ─),
2
2
2
1
3
.25–3.28 (4H, m, piperazine-4H), 3.39–3.41 (4H, m,
NMR (400 MHz, DMSO-d ) δ 1.19–1.28 (4H, m,
piperazine-4H), 3.75 (2H, t, ─CH ─), 3.81–3.83 (1H, m,
6
2
2
× cyclopropyl-CH ), 1.81 (2H, t, ─CH ─), 2.42 (2H, t,
2
2
cyclopropyl-CH), 3.82 (2H, t, ─CH ─), 4.21 (2H, t,
2
─
CH ─), 3.27–3.30 (4H, m, piperazine-4H), 3.61–3.63
2
─CH ─), 7.08–7.75 (10H, m, Ar─H), 8.42 (1H, s, C2─H),
2
+
(
(
(
(
4H, m, piperazine-4H), 3.72 (2H, t, ─CH ─), 4.11–4.13
1H, m, cyclopropyl-CH), 7.07–7.72 (5H, m, Ar─H), 8.64
1H, s, C2─H), 8.78, 9.10 (2H, brs, NNHCSNH ), 12.08
1H, s, NNHCSNH ). ESI-MS m/z: 592 [M + H] .
13.44 (2H, brs, NOH). ESI-MS m/z: 736 [M + H] .
2
Elemental Anal. Calcd (%) for C H FN O : C, 63.66;
39
38
7 7
2
H, 5.21; N, 13.33; Found: C, 63.54; H, 5.11; N, 13.07.
3-(3-(Hydroxyimino)-5-methyl-2-oxoindolin-1-yl)propyl
1-cyclopropyl-6-fluoro-7-(4-(3-(3-(hydroxyimino)-5-methyl-2-
+
2
Elemental Anal. Calcd (%) for C H FN O S: C, 58.87;
2
9
30
7 4
oxoindolin-1-yl)propyl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-
H, 5.11; N, 16.57; Found: C, 58.71; H, 4.95; N, 16.32.
1
3-carboxylate (5h).
Yellow solid. H NMR (400 MHz,
7-(4-(3-(3-(2-Carbamothioylhydrazono)-5-methyl-2-oxoindolin-
DMSO-d ) δ 1.15–1.30 (4H, m, 2 × cyclopropyl-CH ), 1.84
1
-yl) propyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-
6
2
1
dihydroquinoline-3-carboxylic acid (5f). Yellow solid. H
(2H, t, ─CH ─), 2.04 (2H, t, ─CH ─), 2.45 (2H, t,
2
2
NMR (400 MHz, DMSO-d ) δ 1.16–1.27 (4H, m,
─CH ─), 3.26–3.28 (4H, m, piperazine-4H), 3.40–3.43 (4H,
6
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet