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G. A. Silva et al. / Bioorg. Med. Chem. 12 (2004) 3149–3158
ꢁ
1
reflux for 4 h. After concentration of the reaction mix-
ture under reduced pressure, 30 mL of cold water was
added to the residue giving the formation of a yellow
precipitate, which was collected by filtration, washed
with cold water and dried under vacuum to furnish
(C@O); IR (KBr) cm : 3328 (m N–H), 1631 (m C@O);
UV (nm): 395 (n ! p), 315 (p ! p); MS (70 eV) m=z
(relative abundance): 423 (28%), 225 (100%), 197 (80%).
0
1
1
.78 g of the desired hydrazide (12) (89% yield). mp 113–
ꢁ
4.1.9. (4 -Methoxybenzylidene) 10H-phenothiazine-1-car-
bohydrazide (6c). The derivative (6b) was obtained as a
1
1
14 ꢁC. IR (KBr) cm : 3293 (m N–H), 1690 (m C@O); H
): d 7.0 (dd, H-2, J ¼ 1:1 and
NMR (300 MHz, CDCl
3
yellow solid by condensation of (12) with 4-methoxy-
1
9
7
1
.1 Hz), 6.7 (t, H-3, J ¼ 7:7 Hz), 6.9 (dd, H-4, 1.4 and
benzaldehyde (HPLC retention time ¼ 4.64 min).
H
.6 Hz), 6.9 (dd, H-6, J ¼ 1:5 and 7.7 Hz), 6.8 (td, H-7,
.2 and 7.4 Hz), 6.9 (td, H-8, J ¼ 1:2 and 7.4 Hz), 6.6
NMR (200 MHz, DMSO-d
6
): d 11.9 (s, N–H), 9.9 (s, N–
H), 8.3 (s, C–H), 7.3 (d, H-12, J ¼ 7 Hz), 7.0 (d, H-13,
13
(dd, H-9, J ¼ 7:8 and 1.1 Hz), 7.4 (s, N–H), 9.8 (s,
CONH), 4.0 (broad, NH ); C NMR (75 MHz, CDCl ):
J ¼ 7 Hz), 3.8 (s, OCH ); C NMR (50 MHz, DMSO-
3
13
d ): 55.4 (OCH ), 119.8 (C-1), 128.0 (C-2), 121.0 (C-3),
2
3
6
3
1
1
1
1
2
13.61 (C-1), 127.60 (C-2), 120.76 (C-3), 130.01 (C-4),
20.93 (C-4a), 117.44 (C-6a), 124.51 (C-6), 123.03 (C-7),
27.40 (C-8), 115.66 (C-9), 140.49 (C9a), 144.08 (C10a),
69.57 (C@O); MS (70 eV) m=z (relative abundance):
57 (63%), 225 (82%), 197 (100%).
129.6 (C-4), 115.6 (C-4a), 116.8 (C-6a), 126.5 (C-6),
123.2 (C-7), 127.0 (C-8), 115.8 (C-9), 140.6 (C-9a), 143.4
(C-10a), 148.7 (C-11), 126.8 (C-12), 129.0 (C-13), 114.5
(C-14), 161.1 (C15), 164.4 (C@O); IR (KBr) cm : 3429
(m N–H), 1631 (m C@O), 1442 (m C–N); UV (nm):
ꢁ
1
437(n ! p), 317.254 (p ! p); MS (70 eV) m=z (relative
abundance): 375 (67%), 225 (100%), 197 (75%).
4
.1.6. General procedure for preparation of the 10H-
phenothiazine-1-acylhydrazone derivatives (6a–i). To a
solution of 0.150 g (0.58 mmol) of hydrazide (12) in
absolute ethanol (15 mL) containing two drops of 37%
hydrochloric acid, was added 0.60 mmol of corre-
sponding aromatic aldehyde derivative previously di-
luted in absolute ethanol (5 mL). The mixture was
stirred at room temperature for 30 min, until extensive
precipitation was visualized. Next, the solvent was par-
tially concentrated at reduced pressure and the resulting
mixture was poured into cold water. After neutralization
with 10% aqueous sodium bicarbonate solution, the
precipitate formed was filtered out and dried under
vacuum to give desired acylhydrazone derivatives (6a–i).
0
4.1.10. (4 -Nitrobenzylidene) 10H-phenothiazine-1-carbo-
hydrazide (6d). The derivative (6d) was obtained as a red
solid by condensation of (12) with 4-nitrobenzaldehyde
1
(HPLC retention time ¼ 4.87 min). H NMR (200 MHz,
13
DMSO-d ): d 12.0 (s, N–H), 9.9 (s, N–H), 8.2 (s, C–H),
6
7.5 ( d, H-12, J ¼ 7 Hz), 6.7 (d, H-13, J ¼ 7 Hz);
C
NMR (50 MHz, DMSO-d ): d 114.5 (C-14), 115.6 (C-
6
4a), 115.8 (C-9), 116.8 (C-6a), 119.8 (C-1), 121.0 (C-3),
123.2 (C-7), 126.5 (C-6), 126.8 (C-12), 127.0 (C-8), 128.0
(C-2), 129.0 (C-13), 129.6 (C-4), 140.6 (C-9a), 143.4 (C-
10a), 145.81 (C-11), 147.9 (C15), 164.6 (C@O); IR (KBr)
ꢁ
1
cm : 3409 (m N–H), 1632 (m C@O); UV (nm): 407
(
dance): 390 (65%), 225 (100%), 197 (80%).
n ! p), 329 (p ! p); MS (70 eV) m=z (relative abun-
4
.1.7. Benzylidene 10H-phenothiazine-1-carbohydrazide
6a). The derivative (6a) was obtained as a yellow solid
(
by condensation of (12) with benzaldehyde (HPLC
0
4.1.11. (4 -Dimethylaminobenzylidene) 10H-phenothia-
1
retention time ¼ 4.54 min). H NMR (200 MHz, DMSO-
13
zine-1-carbohydrazide (6e). The derivative (6e) was ob-
tained as an orange solid by condensation of (12) with 4-
dimethylaminobenzaldehyde (HPLC retention time-
d ): d 12.01 (s, N–H), 8.3 (s, C–H) 7.8 (m, H-12), 7.7 (m,
6
H-13), 7.4 (m, H-14); C NMR (50 MHz, DMSO-d ): d
6
1
1
(
8
1
19.8 (C-1), 128.0 (C-2), 121.0 (C-3), 129.6 (C-4), 115.6
C-4a), 116.8 (C-6a), 126.5 (C-6), 123.2 (C-7), 127.0 (C-
¼ 4.98 min). H NMR (200 MHz, DMSO-d
6
): d 11.9 (s,
N–H), 9.9 (s, N–H), 8.3 (s, C–H), 7.5 (d, H-12,
13
), 115.8 (C-9), 140.6 (C-9a), 143.4 (C-10a), 147.75 (C-
1), 127.60 (C-12), 128.52 (C-13), 127.01 (C-14), 130.9
J ¼ 7 Hz), 6.7 (d, H-13, J ¼ 7 Hz), 3.0 (CH ); C NMR
3
(50 MHz, DMSO-d
6
3
): d 39.8 (NCH ), 119.8 (C-1), 128.0
ꢁ
1
(
1
C-15), 167.45 (C@O); IR (KBr) cm : 3467 (m N–H),
(C-2), 121.0 (C-3), 129.6 (C-4), 115.6 (C-4a), 116.8 (C-
6a), 126.5 (C-6), 123.2 (C-7), 127.0 (C-8), 115.8 (C-9),
140.6 (C-9a), 143.4 (C-10a), 151.5 (C-11), 126.8 (C-12),
129.0 (C-13), 114.5 (C-14), 161.1 (C15), 164.0 (CO); IR
697 (m C@O), 1474 (d C–O); UV (nm): 393 (n ! p), 321
(
(
p ! p); MS (70 eV) m=z (relative abundance): 345
70%), 225 (100%), 197 (72%).
ꢁ
1
(
(
KBr) cm : 3448 (m N–H), 1631 (m C@O); UV (nm): 482
n ! p), 372 and 336 (p ! p); MS (70 eV) m=z (relative
0
4.1.8. (4 -Bromobenzylidene) 10H-phenothiazine-1-carbo-
hydrazide (6b). The derivative (6b) was obtained as a
yellow solid by condensation of (12) with 4-bromo-
abundance): 388 (96%), 225 (100%), 197 (80%).
1
0
0
0
benzaldehyde (HPLC retention time ¼ 5.76 min).
NMR (200 MHz, DMSO-d
H), 8.3 (s, C–H), 7.5 (d, H-12, J ¼ 7 Hz), 6.7 (d, H-13,
H
4.1.12. (3 ,5 -Ditertbutyl-4 -hydroxybenzylidene) 10H-
phenothiazine-1-carbohydrazide (6f). The derivative (6f)
was obtained as a green solid by condensation of (12)
with 3,5-ditertbutyl-4-hydroxybenzaldehyde (HPLC
6
): d 12.0 (s, N–H), 9.9 (s, N–
13
J ¼ 7 Hz); C NMR (50 MHz, DMSO-d
6
): d 114.5 (C-
4), 115.6 (C-4a), 115.8 (C-9), 116.8 (C-6a), 119.8 (C-1),
21.0 (C-3), 123.2 (C-7), 126.5 (C-6), 126.8 (C-12), 127.0
1
1
1
retention time ¼ 6.50 min). H NMR (200 MHz, DMSO-
d ): d 9.9 (s, N–H), 8.3 (s, C–H), 7.5 (d, H-12, J ¼ 7 Hz),
6
13
(
9
C-8), 128.0 (C-2), 129.0 (C-13), 129.6 (C-4), 140.6 (C-
a), 143.4 (C-10a), 147.2 (C-11), 161.1 (C-15), 164.4
6.7 (d, H-13, J ¼ 7 Hz), 2.5 (CH ); C NMR (50 MHz,
3
DMSO-d
6
3
): d 30.1 (CH ), 114.5 (C-14), 115.6 (C-4a),