Discovery of Novel Piperazinone-Fused Hydroxypyridinones Inhibiting Herpes Simplex Virus Gene Transcription and Viral Replication

Herpes simplex virus poses a significant public health
burden,
necessitating the development of alternative therapeutic strategies
to combat infection while addressing the growing challenge of drug
resistance observed with conventional nucleoside antivirals. Herein,
we conducted a mixture-based library screening of an in-house small
molecule library, leading to the identification of a novel piperazinone-fused
hydroxypyridinone scaffold A. Structure–activity
relationship studies initiated from hit A11 culminated
in the development of lead A50, which exhibited a significant
enhancement in the inhibitory activity against luc-HSV-1. Notably, A50 demonstrated good antiviral efficacy against both acyclovir-sensitive
and -resistant HSV strains while showing weak cytotoxicity. Preliminary
mechanistic investigations revealed that A50 inhibited
viral gene transcription at a very early stage and also inhibited
a later stage of viral replication, distinct from acyclovir. Moreover,
administration of A50 significantly suppressed viral
replication in an HSV-1 strain KOS-infected mouse model with no observable
toxicity, offering a promising pathway for further development.