G.C. Muscia et al. / European Journal of Medicinal Chemistry 73 (2014) 243e249
247
Table 2
MIC values of compounds 9, 13 and 14.
Compound
MIC H37Rv (
m
g/mL)
% Inhib.a
MIC INH-Rb
(
m
g/mL)
% Inhib.
MIC RMP-Rc
(
m
g/mL)
% Inhib.
MIC OFX-Rd
(
m
g/mL)
% Inhib.
9
13
14
12.5
12.5
75
0.049
NA
88
52
76
65
NA
6.25
6.25
37.5
0.02
NA
69
41
52
74
NA
6.25
3.125
37.5
NAe
83
69
72
NA
85
12.5
3.125
37.5
1.56
NA
81
50
70
71
NA
Rifampin (pos control)
Isoniazid (pos control)
0.02
a
Percent inhibition at the MIC concentration.
INH-R ¼ isoniazid resistance.
b
c
RMP-R ¼ rifampin resistance.
d
e
OFX-R ¼ ofloxacin resistance.
NA ¼ not applicable: compound not used in assay.
128.7,129.0,130.6,130.7,134.3,137.2,139.2,139.8,140.1,142.6,146.1,
159.3. Calcd analysis for C22H14ClN, %: C, 80.61; H, 4.30; N, 4.27.
Found, %: C, 80.58; H, 4.38; N, 4.33.
white solid, mp (179e181)ꢁC, yield 44%. 1H NMR (DCCl3):
d 1.05e
1.08 (2H, m, CH2), 1.52e1.56 (2H, m, CH2), 1.58e1.67 (2H, m, CH2),
2.87e2.97 (2H, m, CH2), 3.01e3.08 (2H, m, CH2), 7.33e7.54 (5H, m,
PheH), 8.13 (1H, d, J ¼ 9.0 Hz, HeteH), 8.25 (1H, d, J ¼ 2.1 Hz, Hete
H), 8.42 (1H, dd, J ¼ 2.1 and 9.0 Hz, HeteH). 13C NMR (DCCl3):
d 21.3,
4.1.1.6. 8-Chloro-10-phenyl-11H-indeno[1,2-b]quinoline
Reaction time 2 min, it was triturated at rt with EtOH, white solid,
mp (250e251)ꢁC, yield 92%. 1H NMR (DCCl3):
4.09 (2H, s, CH2),
11.
22.1, 24.7, 28.8, 36.3, 120.9, 121.4, 125.2, 127.5, 128.4, 129.3, 130.1,
130.6, 136.7, 143.2, 148.4, 165.7. MS (m/z): 322 (Mþ, 70.0), 272
([Mþ ꢂ NO2], 37.0), 245 ([Mþ ꢂ C6H5], 19.0), 198 ([Mþ ꢂ C5H10],
100.0). Calcd analysis for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80.
Found, %: C, 75.63; H, 5.90; N, 8.73.
d
7.51e7.84 (5H, m, PheH), 7.67e7.70 (3H, m, PheH), 7.76 (1H, d,
J ¼ 2.0 Hz, HeteH), 7.82 (1H, dd, J ¼ 2.0 and 9.0 Hz, HeteH), 9.16
(1H, d, J ¼ 9.0 Hz, HeteH), 9.34 (1H, d, J ¼ 7.7 Hz, PheH). 13C NMR
(DCCl3):
d 35.6, 124.3, 126.1, 127.7, 128.6, 129.5, 129.8, 130.2, 131.0,
133.4, 133.8,134.2, 135.0,135.6,136.4, 137.4, 147.9, 151.7, 156.4. Calcd
analysis for C22H14ClN, %: C, 80.61; H, 4.30; N, 4.27. Found, %: C,
80.63; H, 4.36; N, 4.30.
4.1.1.10. 3,3-Dimethyl-7-nitro-9-phenyl-3,4-dihydroacridin-1(2H)-
one 15. Reaction time 4 min, it was crystallized from acetone,
yellow solid, mp (167e169)ꢁC, yield 76%. 1H NMR (DMSO-d6):
d 1.12
(2H, s, CH2), 2.51 (6H, s, CH3), 3.35 (2H, s, CH2), 7.28e7.29 (2H, m,
PheH), 7.55e7.56 (3H, m, PheH), 8.21 (1H, d, J ¼ 2.5 Hz, HeteH),
8.25 (1H, d, J ¼ 9.2 Hz, HeteH), 8.54 (1H, dd, J ¼ 2.5 and 9.2 Hz, Hete
4.1.1.7. 8-Chloro-10-phenyl-11H-indeno[1,2-b]quinolin-11-one
Reaction time 4.5 min, it was crystallized from EtOH, yellow solid,
mp (239e241)ꢁC, yield 93%. 1H NMR (DMSO-d6):
7.40-7.43 (3H, m,
12.
d
H). 13C NMR (DMSO-d6):
d 28.3, 32.3, 48.0, 53.7, 124.5, 124.6, 125.3,
PheH), 7.46e7.51 (6H, m, PheH), 8.45 (1H, d, J ¼ 9.1 Hz, HeteH),
126.4, 128.5, 128.7, 128.8, 130.9, 136.5, 145.5, 150.6, 151.9, 165.9,
197.4. Calcd analysis for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09.
Found, %: C, 72.90; H, 5.30; N, 8.12.
8.67 (1H, d, J ¼ 9.1 Hz, HeteH), 8.82 (1H, s, HeteH). 13C NMR
(DMSO-d6):
d 118.4, 121.0, 121.4, 123.4, 124.1, 125.8, 127.1, 128.4,
129.6, 130.1, 130.6, 131.1, 133.6, 136.2, 137.0, 142.3, 145.2, 148.1, 150.4,
194.4. Calcd analysis for C22H12ClNO, %: C, 77.31; H, 3.54; N, 4.10.
Found, %: C, 77.38; H, 3.50; N, 4.15.
4.1.1.11. 8-Nitro-10-phenyl-11H-indeno[1,2-b]quinoline
Reaction time 2.50 min, it was triturated at rt with EtOH, yellow
solid, mp > 300 ꢁC, yield 70% 1H NMR (CDCl3):
3.96 (2H, s, CH2),
16.
d
4.1.1.8. 7-Nitro-9-phenyl-1,2,3,4-tetrahydroacridine
Reaction time 6 min, it was crystallized from water, yellow solid,
mp (156e158)ꢁC, yield 52%. 1H NMR (DCCl3):
1.77e1.85 (2H, m,
13.
7.52 (2H, d, J ¼ 6.5 Hz, PheH), 7.57e7.68 (6H, m, PheH), 8.37 (1H, d,
J ¼ 9.0 Hz, HeteH), 8.39 (1H, d, J ¼ 2.7 Hz, PheH), 8.49e8.51 (1H,
dd, J ¼ 2.5 and 9.3 Hz, HeteH), 8.69 (1H, d, J ¼ 2.5 Hz, PheH). 13
C
d
CH2), 1.95e2.04 (2H, m, CH2), 2.64 (2H, t, J ¼ 6.4 Hz, CH2), 3.23 (2H,
t, J ¼ 6.7 Hz, CH2), 7.22e7.26 (2H, m, PheH), 7.53e7.58 (3H, m, Phe
H), 8.10 (1H, d, J ¼ 9.2 Hz, HeteH), 8.29 (1H, d, J ¼ 2.6 Hz, HeteH),
NMR (CDCl3):
d 34.1, 122.4, 122.8, 122.9, 125.4, 125.5, 127.9, 129.1,
129.2, 130.7, 131.3, 134.8, 134.9,144.9, 145.4, 145.8. Calcd analysis for
22H14N2O2: C, 78.09; H, 4.17; N, 8.28. Found, %: C, 78.13; H, 4.22; N,
C
8.31.
8.36 (1H, dd, J ¼ 2.6 Hz and 9.2 Hz). 13C NMR (DCCl3):
d 22.5, 22.6,
28.1, 34.5, 121.9, 122.9, 125.7, 128.6, 128.9, 129.0, 130.1, 130.8, 135.3,
144.9, 148.3, 148.4, 163.5. MS (m/z): 304 (Mþ, 100.0), 257
([Mþ ꢂ NO2], 33.3), 227 ([Mþ ꢂ C6H5], 5.4). Calcd analysis for
4.1.1.12. 8-Nitro-10-phenyl-11H-indeno[1,2-b]quinolin-11-one
17.
Reaction time 2.5 min, it was crystallized from acetone-water,
C
19H16N2O2: C, 74.98; H, 5.30; N, 9.20. Found, %: C, 72.63; H, 5.10; N,
yellow solid, mp (297e299)ꢁC, yield 65%. 1H NMR (DMSO-d6):
9.41.
d
7.37e7.42 (4H, m, PheH), 7.44e7.57 (5H, m, PheH), 8.51 (1H, d,
J ¼ 9.2 Hz, HeteH), 8.58 (1H, d, J ¼ 9.2 Hz, HeteH), 8.62 (1H, s, Hete
H). 13C NMR (DMSO-d6):
118.1, 121.3, 121.4, 123.6, 124.2, 125.7,
4.1.1.9. 2-Nitro-11-phenyl-7,8,9,10-tetrahydro-6H-cyclohepta[b]
quinoline 14. Reaction time 3 min, it was triturated at rt with EtOH,
d
127.4, 128.5, 129.7, 130.4, 130.7, 131.3, 133.7, 136.3, 137.1, 142.4, 145.5,
148.3, 150.7, 193.8. Calcd analysis for C22H12N2O3: C, 74.99; H, 3.43;
N, 7.95. Found, %: C, 75.12; H, 3.50; N, 8.00.
Table 3
MBC results for compounds 9, 13 and 14.
4.2. Antituberculosis tests
Compound
CBM (
m
g/mL)
Colony count (CFU)
9
13
14
Rifampin
50
ea
e
0
4.2.1. In vitro activity against M. tuberculosis (Mtb)
All manipulations of Mtb H37Rv were conducted in accordance
with the Biosafety in Microbiological and Biomedical Laboratories
(BMBL) 5th Edition in Biosafety Level 3 containment laboratories
[14].
TNTCb
TNTC
39
1.56
a
MBC above the established rejection value of ꢄ40 colonies.
TNTC ¼ too numerous to count.
b