TABLE 1.
Activity in influenza A/H3N2 virus-infected MDCK cellsa
| Compoundb | R | R1 | R2 | Antiviral EC50c (μM) |
Cytotoxicityd |
|||||
|---|---|---|---|---|---|---|---|---|---|---|
| A/X-31 |
A/HK/7/87 |
MCC (μM) | CC50 (μM) | IC50 (μM) | ||||||
| CPE | MTS | CPE | MTS | |||||||
| Series I | ||||||||||
| 3a | Me | H | H | >100 | >100 | >100 | >100 | >100 | ND | ND |
| 3b | Et | H | H | >100 | >100 | >100 | >100 | >100 | ND | ND |
| 3c | Phe | H | H | >100 | >100 | >100 | >100 | ≥100 | ND | ND |
| 4a | H | H | Me | 100 | 100 | >100 | >100 | >100 | ND | ND |
| 4b | H | Me | Me | 32 ± 17 | 44 | 42 ± 4 | 40 | >100 | ND | ND |
| 4c | Me | H | Me | 3.3 ± 1.3 | 3.2 ± 2.0 | 5.0 ± 2.3 | 3.2 ± 2.3 | ≥100 | >100 | 93 |
| 4d | Et | H | Me | 2.4 ± 2.1 | 4.0 ± 3.8 | 4.2 ± 3.3 | 4.3 ± 3.0 | 50 | >50 | 48 |
| 4e | Phe | H | Me | >100 | >100 | >100 | >100 | 100 | ND | ND |
| Series II | ||||||||||
| 2a | Me | >100 | >100 | >100 | >100 | ≥100 | ND | ND | ||
| 2b | Et | >100 | >100 | >100 | >100 | >100 | ND | ND | ||
| 2c | Phe | >100 | >100 | >100 | >100 | >100 | ND | ND | ||
| Series III | ||||||||||
| 6a | Me | H | >300 | >300 | >300 | >300 | ≥60 | >300 | ND | |
| 6b | Me | Me | 2.6 ± 2.3 | 5.9 ± 4.3 | 2.8 ± 1.8 | 1.4 ± 0.6 | >50 | >50 | 38 | |
| Oseltamivir carboxylate | 0.0042 ± 0.0035 | 0.020 ± 0.040 | 1.7 ± 1.9 | 0.63 ± 0.23 | >100 | >100 | 80 | |||
| Ribavirin | 9.9 ± 3.3 | 11 ± 4 | 7.4 ± 2.1 | 7.2 ± 3.8 | 61 ± 30 | >100 | 18 | |||
The data shown are the means ± standard deviations of 2 to 7 independent tests. ND, not done. MDCK cells, Madin-Darby canine kidney cells; Et, ethyl; Me, methyl; Phe, phenyl.
Figure 1 shows the basic structures of the N-(1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide compounds, series I, II, and III.
Antiviral activity is expressed as the EC50, defined as the compound concentration producing 50% inhibition of virus replication, as estimated by microscopic scoring of the CPE or by measuring cell viability in the formazan-based MTS assay.
Cytotoxicity is expressed as the MCC, the compound concentration producing minimal changes in cell morphology, as estimated by microscopy; the CC50, estimated by the MTS cell viability assay; or the IC50, determined by cell counting.