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

作者：Shaobo Wang, Qiao‐Yun Song, Dong‐Lin Zhong, Jie Jiao, Lei Zhang, Lu-Ming Deng, Zhi‐Zhang Duan, Guan‐Qiu Qin, Jian‐Guo Song, Wei Tang, Wen‐Cai Ye, Ying Wang, Lijun Hu · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00256 · 被引用次数：1 · 研究领域：Carbohydrate Chemistry and Synthesis、Synthesis and biological activity、Synthesis of Organic Compounds

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.