Antiviral Selectivity Trends in Homodimers: The Role of Linker Length and Structure

Multivalent ligands containing methylene linkers have attracted considerable attention because linker structures strongly influence biological activities. In this study, previously synthesized homodimers based on triazine, boronic acid pinacol ester, boronic acid, isoquinoline, and hydantoin scaffolds were comparatively analyzed to investigate the relationships between methylene linker length and biological activity. The results demonstrated that optimal methylene linker lengths varied depending on scaffold structure and biological target. Triazine homodimers generally exhibited stronger antiviral activity with relatively short methylene linkers, whereas boronic acid pinacol ester homodimers showed enhanced antiviral activity with longer methylene linkers. In contrast, boronic acid homodimers exhibited stronger cytotoxicity accompanied by a loss of antiviral activity. Hydantoin homodimers also exhibited linker-length-dependent antiproliferative activities. These findings highlight the importance of methylene linker design in homodimeric molecules.