Table 1.
SAR study of pyrazolopyridine analogs against EV-D68, EV-A71 and CVB3.
| Structure | Anti-EV-D68 US/KY/14-18953 in RD cells (μM) |
Anti-EV-A71 Tainan/4643/1998 in RD cells (μM) |
Anti-CVB3 in Vero cells (μM) |
|---|---|---|---|
|
EC50 = 16.7 ± 3.8 CC50 = 177.7 ± 11.5 SI50 = 10.6 |
EC50 = 8.1 ± 0.7 CC50 = 177.7 ± 11.5 SI50 = 21.9 |
N.T. |
|
EC50 = 0.04 ± 0.001 CC50 = 46.5 ± 3.0 SI50 = 1162.5 |
EC50 = 0.2 ± 0.1 CC50 = 46.5 ± 3.0 SI50 = 232.5 |
EC50 = 0.2 ± 0.1 CC50 = 63.1 ± 8.4 SI50 = 315.5 |
|
EC50 = 0.4 ± 0.2 CC50 = 89.9 ± 10.8 SI50 = 224.8 |
EC50 = 0.3 ± 0.2 CC50 = 89.9 SI50 = 299.7 |
EC50 = 0.5 ± 0.1 CC50 = 53.6 ± 9.3 SI50 = 107.2 |
|
EC50 = 0.1 ± 0.03 CC50 = 200.0 ± 10.8 SI50 = 2000.0 |
EC50 = 0.8 ± 0.2 CC50 = 200.0 ± 10.8 SI50 = 250.0 |
EC50 = 0.2 ± 0.1 CC50 = 125.3 ± 18.5 SI50 = 626.5 |
|
EC50 = 1.4 ± 0.1 CC50 = 91.6 ± 22.1 SI50 = 65.4 |
N.T. | N.T. |
|
EC50 = 0.02 ± 0.001 CC50 = 72.6 ± 11.3 SI50 = 3630.0 |
EC50 = 0.1 ± 0.02 CC50 = 72.6 ± 11.3 SI50 = 726.0 |
EC50 = 0.04 ± 0.002 CC50 > 300.0 SI50 > 7500.0 |
|
EC50 = 0.02 ± 0.008 CC50 = 20.7 ± 1.9 SI50 = 1035.0 |
EC50 = 0.1 ± 0.05 CC50 = 20.7 ± 1.9 SI50 = 207.0 |
EC50 = 0.1 ± 0.04 CC50 = 33.8 ± 2.2 SI50 = 338.0 |
|
EC50 = 0.2 ± 0.1 CC50 = 236.3 ± 20.5 SI50 = 1183.0 |
EC50 = 0.2 ± 0.1 CC50 = 236.3 ± 20.5 SI50 = 1183.0 |
EC50 = 0.2 ± 0.1 CC50 > 100.0 SI50 > 500.0 |
|
EC50 = 0.4 ± 0.2 CC50 = 259.3 ± 11.3 SI50 = 648.3 |
EC50 = 0.4 ± 0.1 CC50 = 259.3 ± 11.3 SI50 = 648.3 |
EC50 = 0.9 ± 0.2 CC50 = 173.8 ± 11.3 SI50 = 193.1 |
|
EC50 = 0.3 ± 0.1 CC50 = 112.9 ± 8.7 SI50 = 376.3 |
EC50 = 0.6 ± 0.1 CC50 = 112.9 ± 8.7 SI50 = 188.2 |
EC50 = 0.3 ± 0.1 CC50 = 164.2 ± 8.2 SI50 = 547.3 |
|
EC50 = 1.9 ± 0.2 CC50 = 43.8 ± 1.3 SI50 = 23.1 |
EC50 = 6.1 ± 0.5 CC50 = 43.8 ± 1.3 SI50 = 7.2 |
EC50 = 1.7 ± 0.3 CC50 = 130.2 ± 6.4 SI50 = 76.6 |
|
EC50 = 1.2 ± 0.3 CC50 = 74.1 ± 2.5 SI50 = 61.8 |
EC50 = 1.8 ± 0.4 CC50 = 74.1 ± 2.5 SI50 = 41.2 |
EC50 = 0.4 ± 0.2 CC50 > 200 SI50 > 500 |
|
EC50 = 1.7 ± 0.2 CC50 = 183.0 ± 20.1 SI50 = 107.6 |
EC50 = 5.3 ± 0.2 CC50 = 183.0 ± 20.1 SI50 = 34.5 |
EC50 = 1.6 ± 0.3 CC50 = 281.3 SI50 = 175.8 |
|
EC50 = 0.03 ± 0.001 CC50 = 160.9 ± 12.8 SI50 = 5363.3 |
EC50 = 0.1 ± 0.03 CC50 = 160.9 ± 12.8 SI50 = 1609.0 |
EC50 = 0.04 ± 0.02 CC50 > 300.0 SI50 > 7500.0 |
|
EC50 = 9.8 ± 2.3 CC50 > 100.0 SI50 > 10.2 |
N.T. | N.T. |
|
EC50 = 0.1 ± 0.04 CC50 > 100.0 SI50 > 1000.0 |
EC50 = 1.0 ± 0.4 CC50 = 70.3 ± 1.9 SI50 = 703.0 |
EC50 = 0.1 ± 0.04 CC50 = 116.6 ± 27.8 SI50 = 1166.0 |
|
EC50 = 0.4 ± 0.2 CC50 > 100.0 SI50 > 250.0 |
EC50 = 0.1 ± 0.02 CC50 > 100.0 SI50 > 1000.0 |
EC50 = 0.3 ± 0.1 CC50 = 132.9 ± 27.9 SI50 = 443.0 |
|
EC50 = 0.6 ± 0.2 CC50 = 169.5 ± 8.6 SI50 = 282.5 |
EC50 = 0.6 ± 0.2 CC50 = 169.5 ± 8.6 SI50 = 282.5 |
EC50 = 0.9 ± 0.1 CC50 = 108.1 ± 22.7 SI50 = 120.1 |
|
EC50 = 0.2 ± 0.004 CC50 = 118.1 ± 15.4 SI50 = 590.5 |
EC50 = 0.5 ± 0.3 CC50 = 118.1 ± 15.4 SI50 = 236.2 |
EC50 = 0.6 ± 0.3 CC50 = 134.8 ± 5.9 SI50 = 224.7 |
|
EC50 = 0.1 ± 0.04 CC50 = 31.4 ± 7.1 SI50 = 314.0 |
EC50 = 0.04 ± 0.003 CC50 = 31.4 ± 7.1 SI50 = 785.0 |
EC50 = 0.1 ± 0.06 CC50 = 34.4 ± 2.2 SI50 = 344.0 |
|
EC50 = 0.04 ± 0.002 CC50 = 24.6 ± 3.1 SI50 = 615.0 |
EC50 = 0.2 ± 0.1 CC50 = 24.6 ± 3.1 SI50 = 123.0 |
EC50 = 0.1 ± 0.05 CC50 = 23.0 ± 1.5 SI50 = 230.0 |
|
EC50 = 0.4 ± 0.2 CC50 = 112.3 ± 19.6 SI50 = 280.8 |
EC50 = 0.1 ± 0.04 CC50 = 112.3 ± 19.6 SI50 = 1123.0 |
EC50 = 0.2 ± 0.03 CC50 > 300.0 SI50 > 1500.0 |
|
EC50 = 1.8 ± 0.2 CC50 > 300.0 SI50 > 166.7 |
EC50 = 0.5 ± 0.3 CC50 > 300.0 SI50 > 600.0 |
EC50 = 0.8 ± 0.2 CC50 > 300.0 SI50 > 375.0 |
|
EC50 = 11.3 ± 1.6 CC50 > 300.0 SI50 > 26.5 |
EC50 = 7.3 ± 0.3 CC50 > 300.0 SI50 > 41.1 |
EC50 = 3.8 ± 1.2 CC50 > 300.0 SI50 > 78.9 |
|
EC50 = 2.3 ± 0.2 CC50 > 300.0 SI50 > 130.4 |
EC50 = 0.5 ± 0.1 CC50 > 300.0 SI50 > 600.0 |
EC50 = 1.4 ± 0.4 CC50 > 300.0 SI50 > 214.3 |
|
EC50 = 4.7 ± 0.6 CC50 > 300.0 SI50 > 63.8 |
EC50 = 0.7 ± 0.1 CC50 > 300.0 SI50 > 428.6 |
EC50 = 3.8 ± 2.4 CC50 > 300.0 SI50 > 78.9 |
|
EC50 = 11.1 ± 0.3 CC50 = 88.4 ± 18.5 SI50 = 8.0 |
N.T. | N.T. |
|
EC50 = 48.4 ± 2.2 CC50 = 218.6 ± 25.3 SI50 = 4.5 |
N.T. | N.T. |
|
EC50 = 18.3 ± 0.5 CC50 > 300 SI50 > 16.4 |
N.T. | N.T. |
|
EC50 = 58.4 ± 1.9 CC50 > 300 SI50 > 5.1 |
EC50 > 20 μM | N.T. |
|
EC50 = 1.7 ± 0.2 CC50 = 263.2 ± 21.1 SI50 = 154.8 |
EC50 = 1.2 ± 0.3 CC50 = 263.2 ± 21.1 SI50 = 219.3 |
EC50 = 1.8 ± 0.4 CC50 > 300 SI50 > 166.7 |
|
EC50 = 9.8 ± 1.5 CC50 > 300 SI50 > 30.6 |
N.T. | N.T. |
|
EC50 = 0.8 ± 0.2 CC50 = 45.2 ± 27.6 SI50 = 56.5 |
EC50 = 3.5 ± 1.2 CC50 = 45.2 ± 27.6 SI50 = 12.9 |
EC50 = 1.8 ± 0.4 CC50 = 56.3 ± 11.2 SI50 = 31.3 |
|
EC50 = 1.1 ± 0.5 CC50 = 31.9 ± 8.2 SI50 = 29.0 |
EC50 = 8.4 ± 0.2 CC50 = 31.9 ± 8.2 SI50 = 3.8 |
EC50 = 2.9 ± 0.3 CC50 = 36.8 ± 17.8 SI50 = 12.7 |
|
EC50 = 1.0 ± 0.1 CC50 = 116.6 ± 16.1 SI50 = 116.6 |
EC50 = 7.4 ± 1.7 CC50 = 116.6 ± 16.1 SI50 = 15.8 |
EC50 = 2.1 ± 0.9 CC50 = 184.0 ± 13.2 SI50 = 88.9 |
|
EC50 = 1.2 ± 0.2 CC50 = 57.7 ± 10.1 SI50 = 48.1 |
EC50 = 2.0 ± 0.6 CC50 = 57.7 ± 10.1 SI50 = 28.9 |
EC50 = 2.0 ± 0.3 CC50 = 111.0 ± 6.8 SI50 = 55.5 |
|
EC50 = 0.2 ± 0.1 CC50 = 40.7 ± 2.8 SI50 = 203.5 |
EC50 = 0.1 ± 0.02 CC50 = 40.7 ± 2.8 SI50 = 407.0 |
EC50 = 0.1 ± 0.03 CC50 = 101.4 ± 13.6 SI50 = 1014.0 |
|
EC50 = 0.7 ± 0.2 CC50 = 28.4 ± 2.3 SI50 = 40.6 |
EC50 = 0.2 ± 0.1 CC50 = 28.4 ± 2.3 SI50 = 142.0 |
EC50 = 1.9 ± 0.4 CC50 = 51.7 ± 8.3 SI50 = 27.2 |
|
EC50 = 0.2 ± 0.03 CC50 > 50 SI50 > 250.0 |
N.T. | N.T. |
a
Antiviral potency was determined in the CPE assay with EV-D68 US/KY/14-18953 virus and EV-A71 Tainan/4643/1998 virus in RD cells. For antiviral assay with CVB3 virus Vero cells were used.
b
Cytotoxicity was determined using the neutral red uptake method.
c
N.T.= not tested. The results are the mean ± standard deviation of three repeats. SI = selectivity index (CC50/EC50).
d
JX040 also inhibited the EV-D68 US/MO/14-18947 strain with an EC50 of 0.1 ± 0.04 μM.