Purine acyclic nucleosides. Nitrogen isosteres of 9-[(2-hydroxyethoxy)methyl] guanine as candidate antivirals

Abstract

A number of nitrogen analogs of 9-[(2-hydroxyethoxy)methyl]guanine [acylovir, Zovirax] containing amine functions in the side chain were synthesized and tested for antiviral activity. These purine acyclic nucleosides were prepared by reaction of tris(trimethylsilyl)guanine or 2,6-diaminopurine sodium salt with the chloromethyl ethers prepared from N-(2-hydroxyethyl)phthalimide, N-[2-(2-hydroxyethoxy)ethyl]phthalimide or N-(2-hydroxyethyl)oxazolidin-2-one to give the N-blocked intermediates 5-8. Deprotection with hydrazine or by alkaline hydrolysis gave 9-[(2-aminoethoxy)methyl]guanine (9), 9-[(2-aminoethoxy)methyl]-2,6-diaminopurine (10), 9-[[2-(2-aminoethoxy)ethoxy]methyl]guanine (11) and 9-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]guanine (12). When tested against herpes simplex virus type 1, only 9 was active. Little or no activity was observed against a range of other DNA and RNA viruses.