Tricyclic Analogs of Acyclovir and Ganciclovir. Influence of Substituents in the Heterocyclic Moiety on the Antiviral Activity

Abstract

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.

Fluorescent Tricyclic Analogues of Acyclovir and Ganciclovir. A Structure−Antiviral Activity Study

“…2,3 In the case of the reaction of 1 and 2 with 2-bromopropiophenone, we isolated, in addition to the expected 6-Ph-7-Me-TACV 17 and 6-Ph-7-Me-TGCV 28, the intermediate N-1 alkylation products: 1-(1-benzoylethyl)-ACV 17′ and 1-(1-benzoylethyl)-GCV 28′. The structures of 17′ and 28′ were identified on the basis of their HR MS and 1 H and 13 C NMR spectra.…”

“…We have previously reported that linking the 2-NH 2 and N-1 positions of guanine moiety of acyclovir (ACV, 1) and ganciclovir (GCV, 2) with an etheno bridge to form derivatives of the tricyclic 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purine system, TACV (3) and TGCV (4) [For the systematic names 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-5H-imidazo[1,2-a]purine and 3,9-dihydro-3-[(1,3-dihydroxy-2-propoxy]-9-oxo-5H-imidazo-[1,2-a]purine the abbreviations TACV and TGCV, respectively, are used throughout this paper. ], allows for the modulation of physical and biological properties of the parent antivirals.…”

“…], allows for the modulation of physical and biological properties of the parent antivirals. [1][2][3] The appended ring by itself diminishes the antiherpetic activity, depending on the type and strain of the virus, from 100-to more than 2000-fold. Further substitutions in the 6 or 7 position of this ring potentiate the activity and make the compounds more selective toward particular herpes viruses.…”

“…Compound 5 is on the average approximately 15-fold less active than parent acyclovir. 3 The fact that some tricyclic analogues show selective activity against herpes virus infections suggests that they are preferentially metabolized by the virus-infected cells and/or show a preferential affinity for virus-specific enzymes. This assumption has recently been substantiated by an NMR experiment in solution which demonstrated the formation of 6-ethyl-TACV-HSV-1TK complex.…”

Unusual Tritylation Reactions of Tricyclic Analogues of Acyclovir and an Attempt to Elucidate Their Mechanism

“…± When we treated 6-aryl substituted compounds 6-Ph-TACV (1a) [6] or 6-(4-MeOPh)-TACV (1b) [7] in DMF with solid K 2 CO 3 followed by Ph 3 CCl, we found products that carried C(7)-substituents being either 4-(benzhydryl)phenyl (2a and 2b), or substituted 4-(benzydryl)phenyl (3a, 3b, and 4a) (Scheme). Their structures were assigned on the basis of 1 H-and 13 C-NMR, and mass spectra.…”