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  3. Discovery of imidazo[1,2-a]pyridine derivatives as potent anti-influenza agents: SPR affinity-based screening and structure-activity relationship study

Discovery of imidazo[1,2-a]pyridine derivatives as potent anti-influenza agents: SPR affinity-based screening and structure-activity relationship study

  • Eur J Med Chem. 2026 Feb 5:303:118399. doi: 10.1016/j.ejmech.2025.118399.
Chao Zhang 1,  Yun-Sang Tang 2,  Jian-Fei Gao 1,  Zi-Xiao Liu 1,  Shi-Shao Liang 1,  Si-Miao You 1,  Chris Ka-Pun Mok 3,  Er-Fang Huang 4,  Pang-Chui Shaw 5,  Chun Hu 6
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2 School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region of China; The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region of China.
  • 3 The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region of China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region of China; SH Ho Research Centre for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region of China; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region of China.
  • 4 Key Laboratory of Structure-based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: erfanghuang@syphu.edu.cn.
  • 5 School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region of China. Electronic address: pcshaw@cuhk.edu.hk.
  • 6 Key Laboratory of Structure-based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: chunhu@syphu.edu.cn.
PMID: 41330158 DOI: 10.1016/j.ejmech.2025.118399
Abstract

Novel imidazo[1,2-a]pyridine derivatives were designed as influenza A virus RNA-dependent RNA polymerase (RdRp) inhibitors via scaffold hybridization strategy. Forty-five synthesized compounds were screened by surface plasmon resonance (SPR) and bioactivity assays, which identified three compounds exhibiting potent Antiviral activity against A/PR/8/34(H1N1) and strong binding to the target: 14 (IC50 = 3.00 μM; KD = 1.79 μM), 19 (IC50 = 0.95 μM; KD = 0.82 μM), and 41 (IC50 = 0.29 μM; KD = 4.11 μM). Moreover, compound 41 revealed significant broad-spectrum effects on multiple Influenza Virus strains. Structure-activity relationship (SAR) analysis identified key structural features on the imidazo[1,2-a]pyridine-3-carboxamide scaffold-including specific substitution patterns, linker types, and beneficial positions-that significantly enhanced inhibitory potency, providing a clear rationale for the development of potent Influenza Virus PA-PB1 inhibitors. Surface plasmon resonance analysis confirmed enhanced binding to the PAC domain, while molecular docking studies identified key interactions with LYS643 and GLN408 in PAC protein. Further molecular dynamics simulations and dynamic cross-correlation matrix analysis demonstrated stable binding modes and correlated motions within the PAC domain. In summary, compound 41 was identified as a promising sub-micromolar RdRp inhibitor targeting the PAC-PB1N interface. This study also showcases the applicability of SPR-affinity based screening approach in anti-influenza drug discovery.

Keywords

Antiviral agents; Imidazo[1,2-a]pyridine; Influenza virus; PA-PB1 interface; RNA polymerase inhibitors; Structure-activity relationship.

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