Tricyclic Derivative of Acyclovir and Its Esters in Relation to the Esters of Acyclovir Enzymatic Stability: Enzymatic Stability Study.

The 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-6-(4-methoxyphenyl)-9-oxo-5H-imidazo[1,2-a]-purine (6-(4-MeOPh)-TACV) was selected to assess the enzymatic stability of the tricyclic acyclovir derivatives from the imidazo[1,2-a]-purine group. The parent compound and its esters (acetyl, isobutyryl, pivaloyl, nicotinic, ethoxycarbonyl) were subjected to kinetic studies and compared with the stability of analogous acyclovir (ACV) esters. The enzymatic hydrolysis was observed in vitro in a medium of 80% human plasma in the absence and presence of porcine liver esterase (PLE). The tests were carried out at 37 °C. To determine the kinetic parameters (kobs., t0.5) of the observed reaction, the validated HPLC-UV method in the reversed phase was used. The HPLC-MS/MS method was used to identify the degradation products under the tested conditions. In summary, it was found that 6-(4-MeOPh)-TACV esters are more susceptible to esterase metabolism than ACV esters. It was confirmed by HPLC-MS/MS that in the plasma, the main product of their hydrolysis is 6-(4-MeOPh)-TACV and not ACV, which confirms that their antiviral activity observed in vitro does not result from ring degradation.

Strategies in the designing of prodrugs, taking into account the antiviral and anticancer compounds.

Prodrugs are a wide group of substances of low or no pharmacological activity. The search for prodrugs is aimed at obtaining drugs characterized by better pharmacokinetic properties, pharmaceutical availability and selective activity of the active substance. Prodrug strategies involve chemical modifications and syntheses of new structures as well as the establishment of systems that deliver active substances for therapeutic aims that is prodrug-based treatments. The paper describes decisive factors in prodrug designing, such as enzymes participating in their activation, concepts of chemical modifications in the group of antiviral drugs and new anticancer treatments based on prodrugs (ADEPT, GDEPT, LEAPT). Prodrugs are seen as a possibility to design medicines which are selective for their therapeutic aim, for example a tumorous cell or a microorganism. Such an approach is possible thanks to the knowledge on: pathogenesis of diseases at molecular level, metabolism of healthy and affected cells as well as metabolism of microorganisms (bacteria, fungi, protozoa, etc.). Many drugs which have been used for years are still studied in relation to their metabolism and their molecular mechanism of operation, providing new knowledge on active substances. Many of them meet the criteria of being a prodrug. The paper indicates methods of discovering new structures or modifications of known structures and their synthesis as well as new therapeutic strategies using prodrugs, which are expected to be successful and to broaden the knowledge on what is happening to the drug in the body, in addition to providing a molecular explanation of xenobiotics activity.