tetano
Editor, Senior Moderator
Eur J Med Chem
. 2025 Nov 28:303:118399.
doi: 10.1016/j.ejmech.2025.118399. Online ahead of print. Discovery of imidazo[1,2-a]pyridine derivatives as potent anti-influenza agents: SPR affinity-based screening and structure-activity relationship study
Chao Zhang[SUP] 1 [/SUP], Yun-Sang Tang[SUP] 2 [/SUP], Jian-Fei Gao[SUP] 1 [/SUP], Zi-Xiao Liu[SUP] 1 [/SUP], Shi-Shao Liang[SUP] 1 [/SUP], Si-Miao You[SUP] 1 [/SUP], Chris Ka-Pun Mok[SUP] 3 [/SUP], Er-Fang Huang[SUP] 4 [/SUP], Pang-Chui Shaw[SUP] 5 [/SUP], Chun Hu[SUP] 6 [/SUP]
Affiliations
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 (IC[SUB]50[/SUB] = 3.00 μM; K[SUB]D[/SUB] = 1.79 μM), 19 (IC[SUB]50[/SUB] = 0.95 μM; K[SUB]D[/SUB] = 0.82 μM), and 41 (IC[SUB]50[/SUB] = 0.29 μM; K[SUB]D[/SUB] = 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 PA[SUB]C[/SUB] domain, while molecular docking studies identified key interactions with LYS643 and GLN408 in PA[SUB]C[/SUB] protein. Further molecular dynamics simulations and dynamic cross-correlation matrix analysis demonstrated stable binding modes and correlated motions within the PA[SUB]C[/SUB] domain. In summary, compound 41 was identified as a promising sub-micromolar RdRp inhibitor targeting the PA[SUB]C[/SUB]-PB1[SUB]N[/SUB] 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.
. 2025 Nov 28:303:118399.
doi: 10.1016/j.ejmech.2025.118399. Online ahead of print. Discovery of imidazo[1,2-a]pyridine derivatives as potent anti-influenza agents: SPR affinity-based screening and structure-activity relationship study
Chao Zhang[SUP] 1 [/SUP], Yun-Sang Tang[SUP] 2 [/SUP], Jian-Fei Gao[SUP] 1 [/SUP], Zi-Xiao Liu[SUP] 1 [/SUP], Shi-Shao Liang[SUP] 1 [/SUP], Si-Miao You[SUP] 1 [/SUP], Chris Ka-Pun Mok[SUP] 3 [/SUP], Er-Fang Huang[SUP] 4 [/SUP], Pang-Chui Shaw[SUP] 5 [/SUP], Chun Hu[SUP] 6 [/SUP]
Affiliations
- PMID: 41330158
- DOI: 10.1016/j.ejmech.2025.118399
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 (IC[SUB]50[/SUB] = 3.00 μM; K[SUB]D[/SUB] = 1.79 μM), 19 (IC[SUB]50[/SUB] = 0.95 μM; K[SUB]D[/SUB] = 0.82 μM), and 41 (IC[SUB]50[/SUB] = 0.29 μM; K[SUB]D[/SUB] = 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 PA[SUB]C[/SUB] domain, while molecular docking studies identified key interactions with LYS643 and GLN408 in PA[SUB]C[/SUB] protein. Further molecular dynamics simulations and dynamic cross-correlation matrix analysis demonstrated stable binding modes and correlated motions within the PA[SUB]C[/SUB] domain. In summary, compound 41 was identified as a promising sub-micromolar RdRp inhibitor targeting the PA[SUB]C[/SUB]-PB1[SUB]N[/SUB] 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.