Discovery of Phloroglucinol Derivatives as a New Type of Nonnucleoside Inhibitors with Anti-herpes Simplex Virus Type 1 Activity

Herpes
simplex virus type 1 (HSV-1) causes keratoconjunctivitis
and encephalitis, with nucleoside analogues such as acyclovir (ACV)
serving as standard treatments. However, rising drug resistance underscores
the need for agents with novel mechanisms. In this study, phytochemical
investigation led to the obtainment of several phloroglucinol derivatives
from Rhodomyrtus tomentosa. Subsequent
phenotypic screening demonstrated compound 6 as the most
promising HSV-1 inhibitor. To facilitate lead optimization, we synthesized
44 analogues of 6 to elucidate the structure–activity
relationships, and 24 analogues exhibited comparable potency to 6 against both HSV-1 and ACV-resistant viruses. Preliminary
mechanistic studies revealed that 6 can inhibit viral
replication by blocking host cell factors involved in serine 5-phosphorylated
RNA polymerase expression. Furthermore, 6 also showed
efficacy in vivo against HSV-1 infection via topical administration.
These findings highlight a new type of anti-HSV-1 inhibitors with
a mechanism distinct from that of ACV, offering new avenues for anti-HSV-1
drug development.