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Q. Tang et al. / European Journal of Medicinal Chemistry 202 (2020) 112310
4.2.4.10. N-(2-(Dimethylamino)ethyl)-2-(pentyloxy)quinoline-4-
5.62e5.52 (m, 1H), 3.25 (t, J ¼ 6.5 Hz, 2H), 1.91e1.80 (m, 1H), 1.41 (d,
J ¼ 6.2 Hz, 6H), 0.96 (d, J ¼ 6.7 Hz, 6H). 13C NMR (100 MHz, CDCl3)
carboxamide (6j). White solid, 21.8% solid, mp 125e126 ꢀC. 1H NMR
(400 MHz, CDCl3)
d
8.10 (d, J ¼ 8.3 Hz, 1H), 7.84 (d, J ¼ 8.3 Hz, 1H),
d 167.3, 160.8, 147.3, 145.1, 129.9, 127.5, 125.2, 124.5, 121.3, 111.5,
7.63 (s, 1H), 7.40 (t, J ¼ 7.6 Hz, 1H), 6.97 (s, 1H), 6.85 (s, 1H), 4.47 (t,
J ¼ 6.7 Hz, 2H), 3.58 (q, J ¼ 5.6 Hz, 2H), 2.55 (t, J ¼ 5.9 Hz, 2H), 2.26
(s, 6H), 1.88e1.77 (m, 2H), 1.53e1.36 (m, 4H), 0.95 (t, J ¼ 7.0 Hz, 3H).
68.4, 47.2, 28.6, 22.0, 20.1. HRMS (ESI) calcd for C17H22N2O2 [MþH]þ
287.1754, found 287.1751.
13C NMR (100 MHz, CDCl3)
d 167.2, 161.5, 147.3, 144.8, 129.9, 127.6,
4.2.4.17. 2-Butoxy-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-4-
carboxamide (6q). Yellow thick liquid, 26.8% yield. 1H NMR
125.3, 124.6, 121.5, 111.3, 66.3, 57.5, 45.0, 37.1, 28.7, 28.3, 22.5, 14.1.
HRMS (ESI) calcd for C19H27N3O2 [MþH]þ 330.2176, found 330.2171.
(400 MHz, CDCl3)
d
8.11 (d, J ¼ 8.3 Hz, 1H), 7.84 (d, J ¼ 8.4 Hz, 1H),
7.64 (t, J ¼ 7.7 Hz,1H), 7.40 (t, J ¼ 7.7 Hz,1H), 7.20 (s, 1H), 7.01 (s, 1H),
4.48 (t, J ¼ 6.6 Hz, 2H), 3.71e3.62 (m, 2H), 2.84 (t, J ¼ 5.6 Hz, 2H),
2.76e2.63 (m, 4H), 1.88e1.77 (m, 6H), 1.65e1.41 (m, 2H), 1.01 (t,
4.2.4.11. N-(2-(Dimethylamino)ethyl)-2-(hexyloxy)quinoline-4-
carboxamide (6k). White solid, 11.8% yield, mp 116e118 ꢀC. 1H NMR
J ¼ 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d
167.3,161.6, 147.3, 144.7,
(400 MHz, CDCl3)
d
8.12 (d, J ¼ 8.0 Hz,1H), 7.85 (d, J ¼ 8.3 Hz, 1H),
7.64 (t, J ¼ 7.6 Hz,1H), 7.41 (t, J ¼ 7.6 Hz,1H),6.98 (s, 1H), 6.77 (s, 1H),
4.48 (t, J ¼ 6.6 Hz, 2H), 3.66e3.50 (m, 2H), 2.58e2.50 (m, 2H), 2.26
(s, 6H), 1.91e1.74 (m, 2H), 1.49 (d, J ¼ 7.8 Hz, 2H), 1.43e1.31 (m, 4H),
129.9, 127.6, 125.3, 124.6, 121.6, 111.4, 66.0, 54.5, 53.9, 38.1, 31.0,
23.4, 19.3, 13.9. HRMS (ESI) calcd for C20H27N3O2 [MþH]þ 342.2176,
found 342.2168.
0.93 (t, J ¼ 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 167.2, 161.5,
147.3144.9, 129.9, 127.6, 125.3, 124.6, 121.6, 111.3, 66.3, 57.5, 45.1,
37.2, 31.6, 28.9, 25.8, 22.6, 14.1. HRMS (ESI) calcd for C20H29N3O2
[MþH]þ 344.2333, found 344.2325.
4.2.4.18. 2-Butoxy-N-(2-(piperidin-1-yl)ethyl)quinoline-4-
carboxamide (6r). Yellow solid, 45.9% yield, mp 100e103 ꢀC. 1H
NMR (400 MHz, CDCl3)
d
8.09 (d, J ¼ 8.3 Hz, 1H), 7.84 (d, J ¼ 8.3 Hz,
1H), 7.62 (t, J ¼ 7.7 Hz, 1H), 7.38 (t, J ¼ 7.6 Hz, 1H), 6.95 (s, 1H), 6.89
(s, 1H), 4.47 (t, J ¼ 6.7 Hz, 2H), 3.56 (q, J ¼ 5.7 Hz, 2H), 2.53 (t,
J ¼ 6.1 Hz, 2H), 2.40 (s, 4H), 1.91e1.69 (m, 2H), 1.62e1.48 (m, 6H),
1.48e1.32 (m, 2H),1.01 (t, J ¼ 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
4.2.4.12. 2-Ethoxy-N-propylquinoline-4-carboxamide
(6l).
White solid, 67.2% yield, mp 163e165 ꢀC. 1H NMR (400 MHz, CDCl3)
d
8.04 (d, J ¼ 7.7 Hz, 1H), 7.83 (d, J ¼ 8.4 Hz, 1H), 7.64 (t, J ¼ 7.7 Hz,
1H), 7.39 (t, J ¼ 7.3 Hz, 1H), 6.90 (s, 1H), 6.26 (s, 1H), 4.53 (q,
J ¼ 7.0 Hz, 2H), 3.57e3.35 (m, 2H), 1.69e1.64 (m, 2H), 1.46 (t,
J ¼ 7.1 Hz, 3H), 1.01 (t, J ¼ 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d
167.1,161.6, 147.3,145.0,129.9,127.6,125.3,124.5, 121.5,111.3, 66.0,
57.0, 54.3, 36.6, 31.0, 25.9, 24.3, 19.3, 13.9. HRMS (ESI) calcd for
C
21H29N3O2 [MþH]þ 356.2333, found 356.2325.
d
167.2,161.3, 147.2, 145.1, 130.0,127.6,125.2,124.6,121.5, 111.0, 62.0,
41.7, 22.8, 14.5, 11.4. HRMS (ESI) calcd for C15H18N2O2 [MþH]þ
259.1441, found 259.1441.
4.2.4.19. 2-Butoxy-N-(3-(dimethylamino)propyl)quinoline-4-
carboxamide (6s). White solid, 18.4% yield, mp 91e94 ꢀC. 1H NMR
4.2.4.13. 2-Propoxy-N-propylquinoline-4-carboxamide
(6m).
(400 MHz, CDCl3)
d
8.14 (d, J ¼ 8.5 Hz, 1H), 8.11 (s, 1H), 7.84 (d,
White solid, 72.2% yield, mp 157e159 ꢀC. 1H NMR (400 MHz, CDCl3)
J ¼ 8.3 Hz, 1H), 7.63 (t, J ¼ 8.2 Hz, 1H), 7.39 (t, J ¼ 7.2 Hz, 1H), 6.94 (s,
1H), 4.48 (t, J ¼ 6.7 Hz, 2H), 3.59 (q, J ¼ 5.8 Hz, 2H), 2.50 (t,
J ¼ 6.2 Hz, 2H), 2.22 (s, 6H), 1.86e1.77 (m, 4H), 1.58e1.39 (m, 2H),
d
8.05 (d, J ¼ 8.8 Hz, 1H), 7.83 (d, J ¼ 8.3 Hz, 1H), 7.64 (t, J ¼ 8.3 Hz,
1H), 7.39 (t, J ¼ 8.1 Hz, 1H), 6.92 (s, 1H), 6.22 (s, 1H), 4.43 (t,
J ¼ 6.7 Hz, 2H), 3.49e3.43 (m, 2H), 1.91e1.81 (m, 2H), 1.72e1.62 (m,
2H), 1.08 (t, J ¼ 7.4 Hz, 3H), 1.02 (t, J ¼ 7.4 Hz, 3H). 13C NMR
1.00 (t, J ¼ 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 167.0, 161.6,
147.3, 145.2, 129.9, 127.5, 125.4, 124.5, 121.6, 111.1, 66.0, 58.7, 45.2,
40.1, 31.0, 25.5, 19.3, 13.9. HRMS (ESI) calcd for C19H27N3O2 [MþH]þ
330.2176, found 330.2169.
(100 MHz, CDCl3)
d 167.2, 161.5, 147.2, 145.1, 130.0, 127.6, 125.2,
124.6, 121.5, 111.0, 67.8, 41.7, 22.9, 22.3, 11.4, 10.6. HRMS (ESI) calcd
for C16H20N2O2 [MþH]þ 273.1598, found 273.1596.
4.2.4.20. 2-Butoxy-N-(3-(diethylamino)propyl)quinoline-4-
carboxamide (6t). Yellow thick liquid, 20.1% yield. 1H NMR
4.2.4.14. 2-Ethoxy-N-isobutylquinoline-4-carboxamide
Yellow solid, 46.0% yield, mp 166e168 ꢀC. 1H NMR (400 MHz,
CDCl3)
(6n).
(400 MHz, CDCl3)
d
8.50 (s, 1H), 8.14 (d, J ¼ 8.2 Hz, 1H), 7.84 (d,
d
8.05 (d, J ¼ 8.2 Hz, 1H), 7.84 (d, J ¼ 8.3 Hz, 1H), 7.71e7.57
J ¼ 8.3 Hz, 1H), 7.63 (t, J ¼ 7.7 Hz, 1H), 7.39 (t, J ¼ 7.6 Hz, 1H), 6.97 (d,
J ¼ 2.1 Hz,1H), 4.47 (t, J ¼ 6.6 Hz, 2H), 3.62 (d, J ¼ 6.1 Hz, 2H), 2.72 (s,
2H), 2.63e2.51 (m, 4H), 1.92e1.84 (m, 2H), 1.80 (q, J ¼ 7.0 Hz, 2H),
(m, 1H), 7.40 (t, J ¼ 7.6 Hz, 1H), 6.92 (s, 1H), 6.23 (s, 1H), 4.54 (q,
J ¼ 7.1 Hz, 2H), 3.33 (t, J ¼ 6.5 Hz, 2H), 1.98e1.86 (m, 1H), 1.46 (t,
J ¼ 7.1 Hz, 3H), 1.01 (d, J ¼ 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3)
1.53e1.48 (m, 2H), 1.01 (d, J ¼ 7.4 Hz, 3H), 0.97 (t, J ¼ 5.4 Hz, 6H). 13
C
d
167.2, 161.3, 147.3, 145.2, 130.0, 127.6, 125.2, 124.7, 121.5, 110.9,
NMR (100 MHz, CDCl3)
d 167.2, 161.6, 147.3, 145.0, 129.9, 127.5,
62.0, 47.2, 28.6, 20.1, 14.5. HRMS (ESI) calcd for C16H20N2O2 [MþH]þ
125.4, 124.5, 121.6, 111.2, 65.9, 46.4, 39.9, 31.0, 24.6, 19.3, 13.9, 10.6.
21H31N3O2 [MþH]þ 358.2489, found
273.1598, found 273.1596.
HRMS (ESI) calcd for
358.2480.
C
4.2.4.15. N-Isobutyl-2-propoxyquinoline-4-carboxamide
(6o).
White solid, 19.2% yield, mp 158e160 ꢀC. 1H NMR (400 MHz, CDCl3)
4.3. Biological assays
d
8.06 (d, J ¼ 8.2 Hz, 1H), 7.84 (d, J ¼ 8.4 Hz, 1H), 7.64 (t, J ¼ 8.2 Hz,
1H), 7.40 (t, J ¼ 7.6 Hz, 1H), 6.94 (s, 1H), 6.22 (s, 1H), 4.44 (t,
4.3.1. Cells, antibodies and viruses
J ¼ 6.7 Hz, 2H), 3.34 (t, J ¼ 6.5 Hz, 2H), 1.94 (dd, J ¼ 13.5, 6.8 Hz, 1H),
1.90e1.81 (m, 2H), 1.08 (t, J ¼ 7.4 Hz, 3H), 1.01 (d, J ¼ 6.6 Hz, 6H). 13
C
RD cells, Vero cells, EV-A71, EV-A71 VP1 antibody (10F0) and
Tubulin (T5168) were used in this study as previously reported [33].
An anti-dsRNA antibody (MABE1134) and an EV-A71 2C polyclonal
antibody (GTX132354) for immunofluorescence assay or Western
blot were purchased from Merck and GeneTex, respectively.
NMR (100 MHz, CDCl3) d 167.2,161.5, 147.2,145.3,130.1, 127.5, 125.2,
124.7, 121.5, 110.9, 67.9, 47.3, 28.6, 22.3, 20.2, 10.6. HRMS (ESI) calcd
for C17H22N2O2 [MþH]þ 287.1754, found 287.1752.
4.2.4.16. N-Isobutyl-2-isopropoxyquinoline-4-carboxamide
Yellow solid, 28.6% yield, mp 126e128 ꢀC. 1H NMR (400 MHz,
CDCl3)
8.00 (d, J ¼ 8.2 Hz, 1H), 7.81 (d, J ¼ 8.3 Hz, 1H), 7.61 (t,
J ¼ 7.7 Hz, 1H), 7.35 (t, J ¼ 8.0 Hz, 1H), 6.86 (s, 1H), 6.40 (s, 1H),
(6p).
4.3.2. Cytotoxicity assay
A CCK8 kit (YEASEN, China) was applied to evaluate the cell
viability as previously reported [33].
d