title: Effect of acylation on the ocular disposition of acyclovir. I: Synthesis, physicochemical properties, and antiviral activity of 2'-esters.
abstract: A series of aliphatic 2'-esters of acyclovir ([9-(2-hydroxyethoxymethyl)guanine]) were synthesized by direct acylation in a pyridine-N,N-dimethylformamide solution. The prodrugs were characterized as to their aqueous 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 group viruses. The compounds exhibit an expected decrease in aqueous solubility upon esterification with a corresponding increase in the 1-octanol/water partition coefficient. The butyrate ester shows good aqueous stability in the neutral pH ranges. The apparent first order rate constants 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 butyrate ester possesses similar anti-herpesvirus activity to acyclovir and has a very high selectivity index. The pivalate ester shows poor anti-herpes simplex virus activity; however, it is unique in its effectiveness against the Epstein-Barr virus.
authors.affiliation: Department of Industrial and Physical Pharmacy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana.
authors.forename: P M
authors.initials: PM
authors.lastname: Hughes
authors.forename: R
authors.initials: R
authors.lastname: Krishnamoorthy
authors.forename: A K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000215:Acylation; D000818:Animals; D000869:Anterior Eye Segment / Q000378:metabolism*; D001711:Biotransformation; D003587:Cytomegalovirus / Q000187:drug effects; D004952:Esters / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D006564:Herpesviridae / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008297:Male; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D012995:Solubility
chemical_list: D004952:Esters; D011355:Prodrugs; D000212:Acyclovir