Partitioning and complexation study of bioactive tricyclic acyclovir derivative with cyclodextrins

Abstract

Tricyclic acyclovir derivative 6-Ph-O-Me-TACV (6-(4-methoxyphenyl)-3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxy-5H-imidazol [1,2-a] purine) 1 which was obtained by modification of guanine moiety in acyclovir molecule 2 showed good bioactivity towards HSV viruses. Because aqueous solubility of acyclovir derivative 1 is very low, we used different cyclodextrins for enhancing solubility of the studied compound by inclusion of hydrophobic part of 6-Ph-O-Me-TACV into cyclodextrin cavity. Solubility method has been used to study the inclusion complex formation of acyclovir derivative with following cyclodextrins: β-cyclodextrin (β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), methyl-β-cyclodextrin (M-β-CD) and hydroxypropyl-γ-cyclodextrin (HP-γ-CD). Additionally 1H NMR measurements have been done to study the complexation of 6-Ph-O-Me-TACV with the selected cyclodextrins. The obtained results showed that acyclovir derivative 1 forms 1:1 complexes with the all investigated cyclodextrins. The solubility of 6-Ph-O-Me-TACV in buffered cyclodextrins solutions (pH=5.5 and pH=7.0) at different temperatures (298.15 to 318.15)K and partition coefficients between 1-octanol and aqueous buffered cyclodextrin solutions were also determined. The thermodynamic parameters, such as apparent binding constants, free energies, enthalpies and entropies were calculated and analyzed in terms of influence of cavity size and availability of cyclodextrins substituents on the complex formation.