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Effect of acylation on the ocular disposition of acyclovir. I: Synthesis, physicochemical properties, and antiviral activity of 2'-esters.
J Ocul Pharmacol 1993; 9(4):287-97JO

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+Show Affiliations

Department of Industrial and Physical Pharmacy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8106835

Citation

Hughes, P M., et al. "Effect of Acylation On the Ocular Disposition of Acyclovir. I: Synthesis, Physicochemical Properties, and Antiviral Activity of 2'-esters." Journal of Ocular Pharmacology, vol. 9, no. 4, 1993, pp. 287-97.
Hughes PM, Krishnamoorthy R, Mitra AK. Effect of acylation on the ocular disposition of acyclovir. I: Synthesis, physicochemical properties, and antiviral activity of 2'-esters. J Ocul Pharmacol. 1993;9(4):287-97.
Hughes, P. M., Krishnamoorthy, R., & Mitra, A. K. (1993). Effect of acylation on the ocular disposition of acyclovir. I: Synthesis, physicochemical properties, and antiviral activity of 2'-esters. Journal of Ocular Pharmacology, 9(4), pp. 287-97.
Hughes PM, Krishnamoorthy R, Mitra AK. Effect of Acylation On the Ocular Disposition of Acyclovir. I: Synthesis, Physicochemical Properties, and Antiviral Activity of 2'-esters. J Ocul Pharmacol. 1993;9(4):287-97. PubMed PMID: 8106835.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of acylation on the ocular disposition of acyclovir. I: Synthesis, physicochemical properties, and antiviral activity of 2'-esters. AU - Hughes,P M, AU - Krishnamoorthy,R, AU - Mitra,A K, PY - 1993/1/1/pubmed PY - 1993/1/1/medline PY - 1993/1/1/entrez SP - 287 EP - 97 JF - Journal of ocular pharmacology JO - J Ocul Pharmacol VL - 9 IS - 4 N2 - 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. SN - 8756-3320 UR - https://www.unboundmedicine.com/medline/citation/8106835/Effect_of_acylation_on_the_ocular_disposition_of_acyclovir__I:_Synthesis_physicochemical_properties_and_antiviral_activity_of_2'_esters_ DB - PRIME DP - Unbound Medicine ER -