TABLE 1.
Antiviral activities against human herpesviruses of 1,6-naphthyridine and 7,8-dihydroisoquinoline representatives
| Virus | Cell line | IC50 (μM)a
|
||||
|---|---|---|---|---|---|---|
| Controlb | A1 | B1 | B2 | B3 | ||
| HCMV isolates | ||||||
| AD 169 | Hs68 | 0.78 ± 0.16 | 0.02 ± 0.01 | 1.8 ± 1.3 | 0.09 ± 0.01 | 2.4 ± 1.0 |
| AD 169 | MRC-5 | 6.7 ± 2.0 | 0.03 ± 0.003 | 15.5 ± 1.1 | 1.5 ± 0.1 | 8.8 ± 1.4 |
| P8c | MRC-5 | 3.0 ± 0.9 | 0.3 ± 0.03 | 11.8 ± 2.8 | 0.3 ± 0.2 | 18.0 ± 4.4 |
| C8704c | MRC-5 | 36.9 ± 6.3 | 0.03 ± 0.01 | ND | 0.09 ± 0.01 | 5.8 ± 0.7 |
| C8805-37c | MRC-5 | 59.1 ± 11.3 | 0.02 ± 0.003 | 27.1 ± 2.8 | 0.3 ± 0.06 | 6.5 ± 0.7 |
| D16c | MRC-5 | 30.7 ± 5.5 | 0.2 ± 0.06 | 23.7 ± 8.5 | 1.6 ± 0.8 | 4.1 ± 1.7 |
| AD 169 | HFF | 3.0 ± 1.0 | 0.05 | 13.8 | 1.0 | 13.6 |
| Towne | HFF | 2.94 ± 0.98 | 0.06 ± 0.01 | 9.04 ± 0.42 | 0.41 ± 0.1 | 12.9 ± 1.7 |
| Towned | HFF | 0.9 ± 0.3 | 1.8 ± 0.01 | >28.2 | 8.9 | >34.0 |
| 4760recPolA1-1-1e | HFF | 595 | 0.04 | 5.9 | 0.3 | 6.8 |
| 1117r73-1-2e | HFF | 7.2 | 0.04 | 5.6 | 6.4 | 0.3 |
| D-10 C4e | HFF | >25.3 | 0.04 | 6.2 | 0.6 | 11.2 |
| HSV isolates | ||||||
| HSV-1 (McKrae) | MA-104 | 3.2 ± 0.6 | 1.1 ± 0.3 | 15.5 ± 7.3 | 2.3 ± 1.2 | 54.4 ± 19.4 |
| HSV-2 (E194) | MA-104 | 12.9 ± 3.6 | 0.6 ± 0.1 | 42.4 ± 9.0 | 3.1 ± 0.4 | 292 ± 65 |
The IC50 was defined as the concentration of compound that resulted in a 50% reduction in plaque number compared to the number observed in control samples without drug. For the experiments performed with the Hs68 fibroblasts, the data are presented as the averages of three or more experiments with the standard deviation. For the experiments performed with the MRC-5, HFF, and MA-104 cells, all dose-response curves for all HCMV and HSV strains were constructed by using seven and eight drug concentrations, respectively, in duplicate. ND, not determined.
Control: GCV, HCMV isolates, except for 4760recPolA1-1-1, 1117r73-1-2, and D-10 C4, where PFA, CDV, and BDCRB, respectively, were used; acyclovir, HSV isolates.
HCMV strains used to infect MRC-5 cells: P8, a low-passage clinical isolate which is GCV sensitive; C8704 and C8805-37, which are GCV resistant due to UL97 phosphotransferase gene mutation (3, 34); and D16, which is GCV resistant through a mutation within the UL54 DNA polymerase gene (35).
Virus yield reduction assay.
HCMV strains used to infect HFF cells: 4760recPolA1-1-1 (genotype unknown) is PFA resistant (2.5-fold resistance) and is derived from a clinical isolate (1), 1117r73-1-2 (genotype unknown) is CDV resistant (10-fold resistance) and is derived from the AD 169 strain, D-10 C4 (D344E and Q204R mutations within the UL89 and UL56 genes, respectively) is TCRB and BDCRB resistant (20-fold resistance) and is derived from the Towne strain (19).