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  3. Discovery of tetrasubstituted tetrahydropyrimidines as novel inhibitors against influenza a virus

Discovery of tetrasubstituted tetrahydropyrimidines as novel inhibitors against influenza a virus

  • Bioorg Chem. 2025 Aug:163:108785. doi: 10.1016/j.bioorg.2025.108785.
Zesheng Huang 1,  Zhixuan Chen 1,  Xiaoyi Qin 1,  Qiuhua Zhu 2,  Jie Yang 3
Affiliations

Affiliations

  • 1 MPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China.
  • 2 MPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China. Electronic address: zhuqh@smu.edu.cn.
  • 3 MPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China. Electronic address: yj528@smu.edu.cn.
PMID: 40714481 DOI: 10.1016/j.bioorg.2025.108785
Abstract

A series of tetra-substituted tetrahydropyrimidines (TTHPs 501-528) was designed and synthesized by an efficient one-pot four-component reaction (4CR) to study their bioactivities as novel inhibitors against influenza A virus (H1N1) Infection. The structure-activity relationship (SAR) indicates that the Antiviral activities of TTHPs mainly depend on the combination of substituents, and three TTHPs (512, 513, and 521) show potent Antiviral activities, with IC₅₀ values equal to 1.46, 5.09 and 4.06 μM, respectively. Furthermore, the mechanism of TTHP 512 against Influenza Virus A was investigated through western blotting, qRT-PCR, and an immunofluorescence assay. The primary mechanism study indicates that the most potent TTHP 512 exerts Antiviral activity by affecting virus replication. In addition, TTHP 521 shows strong aggregation-induced emission and can target endoplasmic reticulum imaging.

Keywords

Design and synthesis; Endoplasmic reticulum imaging; Influenza a virus; Multicomponent reaction; Structure-activity relationship; Tetrahydropyrimidines.

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