Synthesis and anti-HSV-1 activity of quinolonic acyclovir analogues

Several 1-[(2-hydroxy-ethoxy)methyl]-3-carbethoxy-4(1H)quinolones (2a–l) and l-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxylic acids (3a–j and 3l) were synthesized and 2a–j, 2l and 3a–j, 3l were evaluated against herpes simplex virus type 1 (HSV-1), employing a one-pot reaction: silylation of the desired quinolone (BSTFA 1% TMCS) followed by equimolar amount addition of 1,3-dioxolane, chlorotrimethylsilane and KI, at room temperature. The acyclonucleosides 2a–l were obtained in 40–77% yields. The esters 2a–j and 2l were subsequently converted into the corresponding hydroxyacids 3 in 40–70% yields. Attempts of hydrolysis of 2k produced only a mixture of degradation products. Antiviral activity of 2 and 3 on HSV-1 virus infection was assessed by the virus yield assay. Except for compounds 2i and 3e, the acyclonucleosides were found to reduce the virus yield by 70–99% at the concentration of 50 μM, being the acids, in general, more effective inhibitors than their corresponding esters. Compounds 3j and 2d exhibited antiviral activity against HSV-1 virus with EC50 of 0.7 ± 0.04 and 0.8 ± 0.09 μM, respectively. Both compounds were not toxic towards the Vero cell line.

Several new acyclonucleosides, 1-[(2-hydroxy-ethoxy)methyl]-3-carbethoxy-4(1H)quinolones (2a–l) and 1-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxylic acids (3a–j and 3l), were synthesized and evaluated against herpes simplex virus type 1 (HSV-1).Figure optionsDownload as PowerPoint slide