Influence of the spatial configuration of 2-(2,4-dioxopyrimidin-1-yl)-5-hydroxymethyl-5-(trifluoromethyl)tetrahydrothiophene stereoisomers on their antiherpetic activity

Introduction. The efficacy of antiviral agents is determined by their ability to interact with biological targets, such as viral DNA, replication enzymes, or viral envelope proteins. A crucial aspect of this interaction is the spatial arrangement of the drug molecules and their structural characteristics.  Methods. The substances investigated were a diastereomeric mixture of compounds 10S-46  -  2-(2,4-dioxopyrimidin-1-yl)-5-hydroxymethyl-5-(trifluoromethyl)tetrahydrothiophene and the four possible enantiomers. Cytotoxicity was evaluated using MTT dye. Activity against herpes simplex virus type 1 (HSV-1/Us) was determined by the reduction in the titer of virus synthesized in Vero cells in the presence of the compounds at concentrations ranging from 340 to 1.3 μM.  Results. The compounds showed no toxic effect on Vero cells: CC₅₀ > 3400 μM. In the antiviral activity study, the greatest reduction in viral titer—2.43 lg —was observed with isomer 10S‑46 ((2R,5S)-2-(2,4-dioxopyrimidine-1-yl)-5-hydroxymethyl-5-(trifluoromethyl)tetrahydrothiophene) at a concentration of 1.3 μM; this indicates an atypical dose-response relationship, with the maximum effect occurring at the lowest concentration tested. A low concentration may maintain a more stable and sustained intracellular level of the compound—avoiding rapid saturation and elimination—thereby better covering critical phases of viral replication, whereas high concentrations might undergo faster metabolism or induce adaptive cellular changes.  

 Conclusions. Preliminary results indicate that the new compounds exhibit pronounced antiviral activity with low cytotoxicity, making them promising candidates for further study as antiviral agents.