Table 1.
activity in enzyme assay, IC50a |
antiviral activity |
|||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
compd | R2 | R3 | R4 | R5 | R6 | X | RHb | STc | EC50d HeLa | EC50e MT-4 | CC50f | SIg |
7a | H | H | H | H | H | Et | 15 | 0.25 | 1.5 | 41 | 164 | |
7b | Me | H | H | H | H | Et | 3.0 | 32 | 1.4 | >50 | >35 | |
7c | H | Me | H | H | H | Et | 9.6 | 8.0 | 2.4 | 2.2 | 37 | 15 |
7d | H | H | Me | H | H | Et | 7.3 | >111 | 17.4 | >50 | >2 | |
7e | F | H | H | H | H | Et | 6.3 | 1.0 | 0.31 | 1.2 | >50 | >161 |
7f | H | F | H | H | H | Et | 9.0 | 11 | 2.2 | 5.4 | 42 | 19 |
7g | H | H | F | H | H | Et | 8 | 98 | <0.2 | 1.7 | >50 | >250 |
7h | H | Cl | H | H | H | Et | 19 | 6 | 0.79 | >50 | >63 | |
7i | H | H | Cl | H | H | Et | 8.0 | 42 | 26.3 | >50 | >1 | |
7j | CN | H | H | H | H | Et | 32 | 9.0 | 17 | >50 | >2 | |
7k | H | CN | H | H | H | Et | 5 | 13 | 7.1 | 48 | 7 | |
7l | H | H | CN | H | H | Et | 8 | >111 | >50 | >50 | ||
7m | OMe | H | H | H | H | Et | >100 | 23 | 0.2 | >50 | >250 | |
7n | H | H | OMe | H | H | Et | 6.7 | 110 | >50 | >50 | ||
7o | OEt | H | H | H | H | Et | >100 | 12 | 0.6 | >50 | >83 | |
7p | H | Me | H | Me | H | Et | 6 | 19 | 13.8 | >50 | >3 | |
7q | F | F | H | H | H | Et | 8 | 0.53 | <0.2 | >50 | >250 | |
7r | F | H | F | H | H | Et | 19 | 1.00 | <0.2 | >50 | >250 | |
7s | F | H | H | F | H | Et | 9 | 0.45 | 0.81 | >50 | >16 | |
7t | F | H | H | H | F | Et | 19 | 4.00 | 0.2 | >50 | >250 | |
7u | H | F | F | H | H | Et | 3 | 0.60 | 2 | >50 | >25 | |
7v | H | F | H | F | H | Et | 5 | 0.49 | 3.9 | >50 | >12 | |
7w | Cl | H | Cl | H | H | Et | 9 | >111 | >50 | >50 | ||
7x | Cl | H | H | H | Cl | Et | 22 | 1.70 | 2.5 | >50 | >20 | |
7y | H | Cl | H | Cl | H | Et | 8.0 | 3 | 30 | 10 | ||
8a | H | H | H | H | H | H | 15 | 0.09 | 0.35 | 0.83 | >50 | >142 |
8b | Me | H | H | H | H | H | 26 | 0.17 | 3.7 | 1.6 | >50 | >13 |
8c | H | Me | H | H | H | H | 4.6 | 1.3 | 1.9 | 4.7 | >50 | >26 |
8d | H | H | Me | H | H | H | 17 | 1.2 | >50 | >50 | ||
8e | F | H | H | H | H | H | 6.4 | 0.98 | 0.35 | >50 | >142 | |
8f | H | F | H | H | H | H | 14 | 0.92 | 5.1 | 2.6 | >50 | >9 |
8g | H | H | F | H | H | H | 2.5 | 0.026 | 0.63 | 1.7 | >50 | >79 |
8h | H | Cl | H | H | H | H | 9 | 0.31 | >50 | >50 | ||
8i | H | H | Cl | H | H | H | 5.0 | 4.1 | >50 | >50 | >50 | |
8j | CN | H | H | H | H | H | 6 | 6 | >50 | >50 | ||
8k | H | CN | H | H | H | H | 5 | 0.75 | >50 | >50 | ||
8l | H | H | CN | H | H | H | 6 | 1.7 | >50 | >50 | ||
8m | OMe | H | H | H | H | H | 16 | 0.53 | <0.2 | 42 | >210 | |
8n | H | H | OMe | H | H | H | 3.0 | 4.1 | 17.4 | >50 | >2 | |
8o | OEt | H | H | H | H | H | 64 | 0.31 | <0.2 | >50 | >250 | |
8p | H | Me | H | Me | H | H | 16 | 1.6 | 9.8 | 30 | 3 | |
8q | F | F | H | H | H | H | 6 | 0.059 | 0.52 | >50 | >128 | |
8r | F | H | F | H | H | H | 10 | 0.042 | 0.5 | 44 | 88 | |
8s | F | H | H | F | H | H | 5 | 0.052 | 2.5 | >50 | >20 | |
8t | F | H | H | H | F | H | 50 | 0.15 | <0.2 | >50 | >250 | |
8u | H | F | F | H | H | H | 86 | 1.60 | >50 | >50 | ||
8v | H | F | H | F | H | H | 14 | 1.2 | 1.7 | >50 | >29 | |
8w | Cl | H | Cl | H | H | H | 7 | 4.9 | 16.2 | >50 | >3 | |
8x | Cl | H | H | H | Cl | H | 28 | 0.17 | 1.4 | >50 | >35 | |
8y | H | Cl | H | Cl | H | H | 30 | 0.97 | >50 | >50 | ||
1 | 0.007 | 0.024 | 0.016 | >250 | >15000 | |||||||
2 | 3.2 | 1.9 | ND | >50 |
Inhibitory concentration 50% (μM) determined from dose–response curves.
Experiments performed against HIV-1 RT-associated RNase H activity.
Experiments performed against HIV-1 IN ST activity.
Effective concentration 50% (μM) in HIV-1 infected HeLa cells.
Effective concentration 50% (μM) in HIV-1 infected MT-4 cells.
Cytotoxic concentration 50% (μM).
Selectivity index = CC50/EC50 in HeLa cells.