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

  • J Med Chem. 2025 Jul 10;68(13):13321-13334. doi: 10.1021/acs.jmedchem.4c03034.
Lei Zhang  1  2 ,  Yuhang Xiang  3 ,  Zhanhao Zeng  1 ,  Bo Peng  1 ,  Shanshan Chen  1 ,  Zhenying Wu  1 ,  Yiping Zhong  1 ,  Mengya Wang  1 ,  Juncheng Zhang  3 ,  Dongli Pan  3 ,  Yongping Yu  1  4  5 ,  Wenteng Chen  1  4
Affiliations
  • 1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 2. School of Pharmacy, Air Force Medical University, Xi'an 710032, China.
  • 3. Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
  • 4. Jinhua Institute of Zhejiang University, Jinhua, Zhejiang 321299, China.
  • 5. School of Pharmacy, Xinjiang Medical University, Urumqi 830054, China.
PMID: 40530737 DOI: 10.1021/acs.jmedchem.4c03034
Abstract

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.

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