S. Barman et al. / European Journal of Medicinal Chemistry 71 (2014) 81e90
89
HRMS (TOF, ESI) m/z: calculated for C25H27N2O2: 387.20670, found:
(s, 1H, OH). 13C NMR (75 MHz, mixture of chloroform-d and
methanol-d4, intensity ratio 4): 10.29, 22.59, 22.67, 28.63, 28.87,
28.89, 110.67, 120.88, 123.64, 123.88, 125.67, 126.94, 127.24, 128.23,
128.91, 129.04, 132.36, 133.83, 135.69, 136.66, 138.34, 152.50, 156.51,
161.21. LCeMS (ESIþ): tR ¼ 9.29 min (acetonitrile and water in 1:1
ratio was used as an eluent), m/z 373.2, purity 96%; [M þ 1]þ; HRMS
(TOF, ESI) m/z: calculated for C24H25N2O2: 373.19105, found:
373.19095.
387.20645.
1H NMR (300 MHz, DMSO-d6)
d ppm (intensity ratio 1): 0.87 (t,
3H, J ¼ 4.9 Hz, CH), 1.42 (sx, 2H, J ¼ 9.9 Hz, CH), 1.75 (m, 4H, CH),
2.58 (t, 2H, J ¼ 5.6 Hz, CH), 2.80 (m, 4H, CH), 7.06 (d, 1H, J ¼ 7.9 Hz,
CH), 7.17 (s,1H, CH), 7.18 (d,1H, J ¼ 4.2 Hz, CH), 7.29 (t,1H, J ¼ 5.2 Hz,
CH), 7.44 (t, 1H, J ¼ 7.9 Hz, CH), 7.56 (s, 1H, CH), 7.65 (d, 1H,
J ¼ 3.9 Hz, CH), 7.90 (d, 1H, J ¼ 7.9 Hz, CH), 8.56 (s, 1H, CH). 13C NMR
(75 MHz, DMSO-d6)
d
ppm: 13.53, 19.59, 22.49, 22.53, 28.75, 28.84,
1H NMR (300 MHz, mixture of chloroform-d and methanol-d4,
intensity ratio 1): 1.04 (t, 3H, J ¼ 5.9 Hz, CH), 1.77 (m, 4H, CH), 2.60
(q, 2H, J ¼ 8.0 Hz, CH), 2.77 (m, 4H, CH), 7.03 (m, 1H, CH), 7.19 (s, 1H,
CH), 7.24 (d, 1H, CH), 7.32 (m, 1H, CH), 7.47 (m, 1H, CH), 7.68 (s, 1H,
CH), 7.69 (d, 1H, CH), 7.98 (d, 1H, CH), 8.62 (s, 1H, CH), 10.94 (bs, 1H,
OH). 13C NMR (75 MHz, mixture of chloroform-d and methanol-d4,
intensity ratio 1): 11.15, 22.45, 22.48, 28.69, 28.71, 31.11, 110.38,
120.57, 123.75, 123.91, 125.96, 127.12, 128.14, 128.20, 128.90, 129.71,
131.10, 132.68, 135.60, 137.70, 137.96, 152.20, 160.64.
28.91, 110.38, 120.51, 123.75, 125.60, 125.72, 127.19, 127.26, 128.19,
128.92, 129.76, 131.19, 132.75, 135.67, 137.77, 138.04, 157.78, 160.80,
161.31.
6.1.15. (E)-N0-(Cyclopentyl(5,6,7,8-tetrahydronaphthalen-2-yl)
methylene)-3-hydroxy-2-naphthohydrazide (14)
A mixture of 3-hydroxy-2-naphthohydrazide (0.42 g, 2.1 mmol)
and 1-(5,6,7,8-tetrahydronaphthalen-2-yl)butan-1-one (0.48 mL,
2.1 mmol) were refluxed for 20 h in ethanol under nitrogen at-
mosphere. The reaction mixture was filtered and washed with
warm ethanol to afford a light yellow solid product (yield 70%). 1H
NMR (300 MHz, mixture of chloroform-d and methanol-d4): 1.41e
1.92 (bm, 12H, CH), 2.68e2.86 (bm, 4H, CH), 3.10 (m, 1H, CH), 6.83e
6.96 (m, 2H, CH), 7.13e7.30 (m, 3H, CH), 7.40 (m, 1H, CH), 7.47e7.70
(m, 3H, CH). 13C NMR (75 MHz, mixture of chloroform-d and
methanol-d4): 23.80, 24.37, 26.17, 29.35, 30.00, 30.73, 31.05, 46.24,
48.44, 113.05, 117.98, 124.91, 125.00, 126.02, 126.93, 127.32, 128.68,
129.01, 129.97, 130.55, 130.94, 132.47, 137.78, 138.79, 139.11, 143.32,
156.00. LCeMS (ESIþ): tR ¼ 9.29 min (acetonitrile and water in 1:1
ratio was used as an eluent), m/z 413.2, purity 96%; [M þ 1]þ; HRMS
(TOF, ESI) m/z: calculated for C27H29N2O2: 413.22235, found:
413.22221.
6.1.18. (E)-N0-(4-Chloro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)
butylidene)-3-hydroxy-2-naphthohydrazide (16)
A mixture of 3-hydroxy-2-naphthohydrazide (0.42 g, 2.1 mmol)
and 4-chloro-1-(5,6,7,8-tetrahydronaphthalen-2-yl)butan-1-one
(0.49 mL, 2.1 mmol) were refluxed for 20 h in ethanol under ni-
trogen atmosphere. The reaction mixture was filtered and washed
with warm ethanol to afford a light yellow solid product (yield
71%). 1H NMR (400 MHz, DMSO-d6): 1.71 (m, 4H, CH), 2.49 (m, 2H,
CH), 2.68 (m, 2H, CH), 2.72 (m, 2H, CH), 4.65 (m, 4H, CH), 7.13 (d, 1H,
J ¼ 7.8 Hz, CH), 7.25 (s, 1H, CH), 7.27 (t, 1H, CH), 7.45 (t, 1H, CH), 7.62
(d, 1H, J ¼ 7.8 Hz, CH), 7.70 (s, 1H, CH), 7.76 (d, 1H, J ¼ 3.9 Hz, CH),
7.87 (d, 1H, J ¼ 3.9 Hz, CH), 8.73 (s, 1H, CH). 13C NMR (100 MHz,
DMSO-d6): 17.47, 17.58, 22.10, 22.28, 29.07, 29.92, 62.11, 111.69,
122.35, 124.12, 125.92, 127.17, 127.18, 127.31, 129.30, 129.55, 130.36,
131.77, 131.79, 131.98, 137.50, 138.93, 148.49, 154.73, 166.76. LCeMS
(ESIþ): tR ¼ 9.10 min (acetonitrile and water in 1:1 ratio was used as
an eluent), m/z 385.2, purity 98%; [M þ 1]þ; HRMS (TOF, ESI) m/z:
calculated for C25H25N2O2: 385.19105, found: 385.19085.
6.1.16. (E)-3-Hydroxy-N0-(2-methyl-1-(5,6,7,8-
tetrahydronaphthalen-2-yl)propylidene)-2-naphthohydrazide (12)
A mixture of 3-hydroxy-2-naphthohydrazide (0.42 g, 2.1 mmol)
and 2-methyl-1-(5,6,7,8-tetrahydronaphthalen-2-yl)propan-1-one
(0.42 mL, 2.1 mmol) were refluxed for 20 h in ethanol under ni-
trogen atmosphere. The reaction mixture was filtered and washed
with warm ethanol to afford a light yellow solid product (yield
76%). 1H NMR (300 MHz, mixture of chloroform-d and methanol-
d4): 1.21 (d, 6H, J ¼ 3.2 Hz, CH), 1.90 (m, 4H, CH), 2.83 (m, 4H, CH),
3.04 (m, 1H, CH), 6.93e7.01 (m, 2H, CH), 7.20e7.38 (m, 3H, CH),
7.41e7.56 (m, 2H, CH), 7.62e7.71 (d, 1H, J ¼ 3.2 Hz, CH), 9.22 (s, 1H,
CH). 13C NMR (75 MHz, mixture of chloroform-d and methanol-d4):
19.23, 20.04, 22.89, 29.27, 29.39, 35.11, 36.64, 112.43, 123.96, 124.02,
125.39, 126.25, 126.60, 126.92, 127.19, 127.59, 128.63, 129.19, 129.30,
130.36, 133.66, 138.88, 139.28, 142.85, 156.44. LCeMS (ESIþ):
tR ¼ 9.39 min (acetonitrile and water in 1:1 ratio was used as an
eluent), m/z 387.20, purity 95%; [M þ 1]þ; HRMS (TOF, ESI) m/z:
calculated for C25H27N2O2: 387.20670, found: 387.20663.
6.1.19. (E)-N0-(4-(Dimethylamino)-1-(5,6,7,8-
tetrahydronaphthalen-2-yl)butylidene)-3-hydroxy-2-
naphthohydrazide (17)
A mixture of 3-hydroxy-2-naphthohydrazide (0.42 g, 2.1 mmol)
and
4-(dimethylamino)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)
butan-1-one (0.51 mL, 2.1 mmol) were refluxed for 20 h in ethanol
under nitrogen atmosphere. The reaction mixture was filtered and
washed with warm ethanol to afford a light yellow solid product
(yield 61%). 1H NMR (400 MHz, DMSO-d6): 1.80 (s, 3H, CH), 2.00 (m,
2H, CH), 2.17 (m, 6H, CH), 2.33 (m, 2H, CH), 2.79 (m, 4H, CH), 3.05
(m, 2H, CH), 7.09 (d, 1H, J ¼ 3.9 Hz, CH), 7.34 (t, 1H, J ¼ 4.2 Hz, CH),
7.40 (s, 1H, CH), 7.50 (t, 1H, J ¼ 4.2 Hz, CH), 7.60 (d, 1H, J ¼ 3.9 Hz,
CH), 7.69 (s, 1H, CH), 7.72 (d, 1H, J ¼ 3.9 Hz, CH), 7.79 (d, 1H,
J ¼ 3.9 Hz, CH), 8.21 (s, 1H, CH). 13C NMR (100 MHz, DMSO-d6):
22.72, 23.01, 23.10, 23.52, 24.17, 29.33, 29.47, 44.19, 55.62, 112.15,
118.03, 123.42, 123.90, 126.19, 127.04, 126.77, 127.55, 128.28, 128.32,
129.23, 133.08, 136.93, 137.43, 139.73, 156.45, 158.12, 167.45. LCeMS
(ESIþ): tR ¼ 6.10 min (acetonitrile and water in 1:1 ratio was used as
an eluent), m/z 430.2, purity 98%; [M þ 1]þ; HRMS (TOF, ESI) m/z:
calculated for C27H32N3O2: 430.24890, found: 430.24887.
6.1.17. (E)-3-Hydroxy-N0-(1-(5,6,7,8-tetrahydronaphthalen-2-yl)
propylidene)-2-naphthohydrazide (10)
A mixture of 3-hydroxy-2-naphthohydrazide (0.42 g, 2.1 mmol)
and 1-(5,6,7,8-tetrahydronaphthalen-2-yl)propan-1-one (0.39 mL,
2.1 mmol) were refluxed for 20 h in ethanol under nitrogen at-
mosphere. The reaction mixture was filtered and washed with
warm ethanol to afford a light yellow solid product (yield 76%). The
1H NMR showed similar peaks with 4:1 intensity ratio due to the
presence of the E and the Z isomers. 1H NMR (300 MHz, mixture of
chloroform-d and methanol-d4, intensity ratio 4): 1.16 (t, 3H,
J ¼ 6.2 Hz, CH), 1.76e1.82 (m, 4H, CH), 2.65e2.84 (m, 6H, CH), 7.12
(d, 1H, J ¼ 6.4 Hz, CH), 7.36 (d, 1H, J ¼ 7.9 Hz, CH), 7.51 (t, 1H,
J ¼ 6.4 Hz, CH), 7.56 (s, 1H, CH), 7.57 (d, 1H, J ¼ 5.9 Hz, CH), 7.76 (d,
1H, J ¼ 7.9 Hz, CH), 8.00 (d, 1H, J ¼ 5.9 Hz, CH), 8.64 (s, 1H, CH), 11.62
6.2. Biology
6.2.1. RT-PCR assay
An RT-qPCR assay was employed to measure the concentration
of viral particles in aliquots of the supernatant surrounding cells
infected with Influenza A (strain A/Udorn/307/1972 H3N2). The
primer/probe set detects segment 6 of Influenza A. The probe is