Main Structural and Stereochemical Aspects of the Antiherpetic Activity of Nonahydroxyterphenoyl‐Containing C‐Glycosidic Ellagitannins

Antiherpetic evaluation of five nonahydroxyterphenoyl‐containing C‐glycosidic ellagitannins, castalagin (1), vescalagin (2), grandinin (3), roburin B (5), and roburin D (7), was performed in cultured cells against four HSV‐1 and HSV‐2 strains, two of which were resistant to Acyclovir. All five ellagitannins displayed significant anti‐HSV activities against the Acyclovir‐resistant mutants, but the monomeric structures 1–3 were more active than the dimers 5 and 7. Vescalagin (2) stands out among the five congeners tested as the most potent and selective inhibitor, with an IC50 value in the subfemtomolar range and a selectivity index 5×105 times higher than that of Acyclovir. Molecular modeling was used to provide a rationale for the surprisingly lower activity profile of its epimer castalagin (1). These ellagitannins have promising potential as novel inhibitors in the search for non‐nucleoside drugs active against Acyclovir‐resistant herpes viruses.