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 <b>A</b>. Structure-activity relationship studies initiated from hit <b>A11</b> culminated in the development of lead <b>A50</b>, which exhibited a significant enhancement in the inhibitory activity against luc-HSV-1. Notably, <b>A50</b> demonstrated good antiviral efficacy against both acyclovir-sensitive and -resistant HSV strains while showing weak cytotoxicity. Preliminary mechanistic investigations revealed that <b>A50</b> inhibited viral gene transcription at a very early stage and also inhibited a later stage of viral replication, distinct from acyclovir. Moreover, administration of <b>A50</b> significantly suppressed viral replication in an HSV-1 strain KOS-infected mouse model with no observable toxicity, offering a promising pathway for further development.