Chair and Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, 6 Grunwaldzka Str., 60-780 Poznań, Poland.
Chair and Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, 6 Grunwaldzka Str., 60-780 Poznań, Poland.
Molecules. 2020 May 5;25(9):2156. doi: 10.3390/molecules25092156.
The 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-6-(4-methoxyphenyl)-9-oxo-5-imidazo[1,2-]-purine (6-(4-MeOPh)-TACV) was selected to assess the enzymatic stability of the tricyclic acyclovir derivatives from the imidazo[1,2-]-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 (k, t) 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.
3,9-二氢-3-[(2-羟乙氧基)甲基]-6-(4-甲氧基苯基)-9-氧代-5-咪唑并[1,2-]-嘌呤（6-(4-MeOPh)-TACV）被选择来评估来自咪唑并[1,2-]-嘌呤基团的三环阿昔洛韦衍生物的酶稳定性。母体化合物及其酯（乙酰基、异丁酰基、特戊酰基、烟酰基、乙氧羰基）进行了动力学研究，并与类似的阿昔洛韦（ACV）酯的稳定性进行了比较。在不存在和存在猪肝酯酶（PLE）的情况下，在 80%人血浆的介质中进行了体外酶水解。测试在 37°C 下进行。为了确定观察到的反应的动力学参数（k、t），使用反相高效液相色谱-紫外法（HPLC-UV）进行了验证。使用 HPLC-MS/MS 方法在测试条件下鉴定降解产物。总之，发现 6-(4-MeOPh)-TACV 酯比 ACV 酯更容易受到酯酶代谢的影响。通过 HPLC-MS/MS 证实，在血浆中，其水解的主要产物是 6-(4-MeOPh)-TACV，而不是 ACV，这证实了它们在体外观察到的抗病毒活性不是由于环降解引起的。
