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

Izabela Muszalska-Kolos,Agnieszka Klupczyńska,Szymon Plewa,Monika A Lesniewska-Kowiel

doi:10.3390/molecules25092156

Izabela Muszalska-Kolos, Agnieszka Klupczyńska + Show 2 more

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https://doi.org/10.3390/molecules25092156

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Abstract

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.

Highlights

Since the 1960s, there has been a steady increase in interest in the preparation and use of prodrugs.The purpose of the prodrug design is to optimize the properties of the compounds exerting the desired pharmacological action that cause problems with the further development of the drug
The tricyclic acyclovir derivative (3,9-Dihydro-3-[(2-hydroxyethoxy)methyl]-6-(4-methoxyphenyl)-9-oxo5H-imidazo[1,2-a]–purine; 6-(4-MeOPh)-TACV) and its esters were obtained from the Poznan
Acyclovir esters were synthesized at the Chair and Department of Pharmaceutical Chemistry (Poznan University of Medical Sciences), in a laboratory scale, according to the literature [40]

Summary

Introduction

The purpose of the prodrug design is to optimize the properties of the compounds exerting the desired pharmacological action that cause problems with the further development of the drug. This applies mainly to the solubility or lipophilicity of the active substance. The vast majority of prodrugs undergo enzymatic activation, most often with the participation of hydrolases or cytochrome P450 [1,2] enzymes. In the case of systemically acting systemic drugs, the resulting prodrug is usually intended to be a substrate for hydrolases that commonly occur and accept a variety of substances, such as peptidases, phosphatases, and especially esterases

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