title: Ester groups as carriers of antivirally active tricyclic analogue of acyclovir in prodrugs designing: synthesis, lipophilicity--comparative statistical study of the chromatographic and theoretical methods, validation of the HPLC method.
abstract: Knowledge of the lipophilicity of candidate compounds for prodrugs may predict their predetermined course/effect in the body. Acyclovir (ACV) belongs to a class of drugs with low bioavailability. Its tricyclic analogues, the derivatives of 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-5H-imidazo[1,2-a]purine (TACV) exhibit similar antiviral activities and are more lipophilic as compared with acyclovir itself. In the search for new antiviral prodrugs 6-(4- methoxyphenyl) tricyclic compound (6-(4-MeOPh)-TACV) was modified by esterification of a hydroxyl group in the aliphatic chain. Selected esters (acetyl, isobutyryl, pivaloyl, ethoxycarbonyl and nicotinoyl) were synthesized and their lipophilicity was determined by the HPLC-RP method. The study compared the log kw calculated from the linear and quadratic equations and proved the correctness of the application of the linear relationship log k as a function of the concentration of ACN in the mobile phase (30-60%). Statistical analyses of the comparative values of log kw and clogP were carried out using computational methods. It was proved that the AC logP algorithm can be useful for the analysis of these compounds, which can have a statistically justified application in the assessment of the quantitative structure- activity relationship (QSAR). The lipophilicity determined by the HPLC method appears as follows: 6-(4-MeOPh)-TACV < Ac- < Nic- < Etc- < iBut- < Piv- (log kw = 0.65-2.26). Finally, the HPLC-RP method was developed and validated for simultaneous determination of synthesized esters.
authors.forename: Monika A
authors.initials: MA
authors.lastname: Lesniewska
authors.forename: Tomasz
authors.initials: T
authors.lastname: Ostrowski
authors.forename: Joanna
authors.initials: J
authors.lastname: Zeidler
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Poznan University of Medical Sciences, 6 Grunwaldzka Str., 60-780 Poznan, Poland. imuszals@ump.edu.pl.
authors.forename: Izabela
authors.initials: I
authors.lastname: Muszalska
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D015195:Drug Design; D008055:Lipids / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry*; D012995:Solubility
chemical_list: D000998:Antiviral Agents; D008055:Lipids; D011355:Prodrugs; D000212:Acyclovir