TRICYCLIC ANALOGS 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-ox o-5H-imidazo[1,2-alpha]purine (1,N-2-ethenoguanine) analogues of acycl ovir (1) and ganciclovir (2) on their physical properties and antiherp etic activity was investigated by synthesizing a series of compounds s ubstituted in the 2, 6, or 7 position (6-14). Substitution in the 6-po sition with phenyl or 4-biphenylyl resulted in fluorescent compounds ( 7, 9, 13, 14). In general, the substituent in the 6 position potentiat ed the antiviral activity. The fluorescent 6-phenyl derivatives: ihydr o-3-[(2-hydroxyethoxy)methyl]-9-oxo-6-phenyl- 5H-imidazo[1,2-alpha]pur ine (7) and its 3-[( 1,3-dihydroxy-2-propoxy)methyl] congener (13) wer e the most potent tricyclic analogues of 1 and 2, respectively. Compou nd 7 was inhibitory to TK+ HSV-1, TK+ HSV-2, and TK+ VZV within the co ncentration range of 0.2-2.0 mu g/mL, well below the cytotoxicity thre shold (50 to > 100 mu g/mL). Compound 13 was inhibitory to TK+ HSV-1 a nd TK+ HSV-2 within the concentration range of 0.005-0.3 mu g/mL and t o TK+ and TK- VZV within the concentration range of 0.4-3 mu g/mL (cyt otoxicity threshold > 200 mu g/mL). Both 7 and 13 seem to be promising candidate compounds for the noninvasive diagnosis of herpesvirus infe ctions.