Modifications on the heterocyclic base of acyclovir: syntheses and antiviral properties

Abstract

A group of compounds was prepared in which variations of the ring portion of the acyclovir (ACV) structure were made. These modifications included monocyclic (isocytosine, triazole, imidazole), bicyclic (8-azapurine, pyrrolo[2,3-d]pyrimideine, pyrazolo [3,4-d]pyrimidine) and tricyclic (linear benzoguanine) congeners. The derivatives were evaluated against herpes simplex virus type 1 (HSV-1) by the plaque-inhibition and plaque-reduction methods with only the 8-azapurine analog 28 [5-amino-3,6-dihydro-3[(2-hydroxyethoxy)methyl]-7H-1,2,3-triazolo [4,5-d]pyrimidin-7-one] showing some activity. In a test measuring the ability of these compounds to inhibit the HSV-1 thymidine kinase 28 and the tricyclic derivative [6-amino-3,7-dihydro-3-[(2-hydroxyethoxy)methyl]-8H-imidazo[4,5-g]quinazolin-8-one] exhibited competition with ACV for binding to the enzyme. The inability of the group to exert significant antiherpetic action is attributed to their lack of antiherpetic action is attributed to their lack of phosphorylation to the requisite triphosphate stage.