EFFECT OF ACYLATION ON THE OCULAR DISPOSITION OF ACYCLOVIR .1. SYNTHESIS, PHYSICOCHEMICAL PROPERTIES, AND ANTIVIRAL ACTIVITY OF 2'-ESTERS

A series of aliphatic 2'-esters of acyclovir ([9-(2-hydroxyethoxymethy l)guanine]) were synthesized by direct acylation in a pyridine-N,N-dim ethylformamide solution. The prodrugs were characterized as to their a queous solubility in phosphate buffer (pH 7.4), partition coefficients in 1-octanol/phosphate buffer (pH 7.4), bioreversion kinetics by the soluble ocular esterases, and in vitro effectiveness against Herpes gr oup viruses. The compounds exhibit an expected decrease in aqueous sol ubility upon esterification with a corresponding increase in the 1-oct anol/water partition coefficient. The butyrate ester shows good aqueou s stability in the neutral pH ranges. The apparent first order rate co nstants of bioreversion varied with the steric nature and polarity of the acyl substituent. The butyrate and pivalate esters were evaluated for their anti-herpesvirus activity and cellular toxicity. The butyrat e ester possesses similar anti-herpesvirus activity to acyclovir and h as a very high selectivity index. The pivalate ester shows poor anti-h erpes simplex virus activity; however, it is unique in its effectivene ss against the Epstein-Barr virus.