Tricyclic analogues of acyclovir and ganciclovir. Influence of substituents in the heterocyclic moiety on the antiviral activity.
The effect of substitution in the tricyclic moiety of 3,9-dihydro-9-oxo-5H-imidazo[1,2-alpha]purine (1,N-2-ethenoguanine) analogues of acyclovir (1) and ganciclovir (2) on their physical properties and antiherpetic activity was investigated by synthesizing a series of compounds substituted in the 2, 6, or 7 position (6-14). Substitution in the 6-position with phenyl or 4-biphenylyl resulted in fluorescent compounds (7, 9, 13, 14). In general, the substituent in the 6 position potentiated the antiviral activity. The fluorescent 6-phenyl derivatives: 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-6-phenyl-5H-imidaxo[ 1,2-alpha]purine (7) and its 3-[(1,3-dihydroxy-2-propoxy)methyl] congener (13) were the most potent tricyclic analogues of 1 and 2, respectively. Compound 7 was inhibitory to TK+ HSV-1, TK+ HSV-2, and TK+ VZV within the concentration range of 0.2-2.0 micrograms/mL, well below the cytotoxicity threshold (50 to > 100 micrograms/mL). Compound 13 was inhibitory to TK+ HSV-1 and TK+ HSV-2 within the concentration range of 0.005-0.3 microgram/mL and to TK+ and TK- VZV within the concentration range of 0.4-3 micrograms/mL (cytotoxicity threshold > 200 micrograms/mL). Both 7 and 13 seem to be promising candidate compounds for the noninvasive diagnosis of herpesvirus infections.
Golankiewicz
B
B
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan.
Ostrowski
T
T
Andrei
G
G
Snoeck
R
R
De Clercq
E
E
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D015774:Ganciclovir; D000212:Acyclovir