tetano
Editor, Senior Moderator
Eur J Med Chem
. 2025 May 2:293:117681.
doi: 10.1016/j.ejmech.2025.117681. Online ahead of print. Novel benzamide derivatives with indole moiety as dual-target antiviral agents: Rational design, efficient synthesis, and potent anti-influenza activity through concurrent binding to PA[SUB]C[/SUB] terminal domain and viral nucleoprotein
Chao Zhang[SUP] 1 [/SUP], Jia-Bin Li[SUP] 1 [/SUP], Yi-Wen Zhang[SUP] 1 [/SUP], Yun-Sang Tang[SUP] 2 [/SUP], Xiao-Fei Yu[SUP] 1 [/SUP], Qing-Guang Zhang[SUP] 1 [/SUP], Zhe Jin[SUP] 1 [/SUP], Shi-Cheng Hou[SUP] 3 [/SUP], Pang-Chui Shaw[SUP] 4 [/SUP], Chun Hu[SUP] 5 [/SUP]
Affiliations
In this study, a series of benzamide derivatives with an indole moiety as dual-target inhibitors were designed, synthesized and evaluated against the RNA-dependent RNA polymerase (RdRp) complex of influenza viruses. The target compounds can simultaneously disrupt two key molecular interactions: the PA[SUB]C[/SUB] terminal domain and the nucleoprotein (NP) oligomerization. Through efficient synthesis and structure-activity relationship (SAR) analysis, compounds 8e and 8f as highly potent inhibitors were identified. Both compounds (8e and 8f) exhibited submicromolar EC[SUB]50[/SUB] values (1.64 ± 0.05 μM and 1.41 ± 0.27 μM) against influenza A virus (H1N1, A/WSN/33) and broad-spectrum activity against other influenza strains, including influenza B virus and multiple subtypes of influenza A. Notably, their cytotoxicity was significantly reduced compared to previous benzofurazan derivatives, with CC[SUB]50[/SUB] values exceeding 100 μM. Surface plasmon resonance (SPR) experiments confirmed that 8e and 8f bound strongly to the PA C-terminal domain (KD = 8.90 μM and 4.82 μM) and NP (KD = 52.5 μM and 3.13 μM). Computational modeling approaches, including molecular docking, molecular dynamics (MD) simulations, and dynamical cross-correlation matrix (DCCM) analysis, principal component analysis (PCA) analysis and density functional theory (DFT) calculations, were employed to elucidate the putative binding modes and delineate critical interaction sites between the ligands and target proteins. These insights not only modulated subsequent structure-based lead optimization but also strengthened our understanding of the molecular determinants governing antiviral activity. This research provides a promising scaffold for developing dual-target antiviral agents with enhanced potency and safety, offering new strategies to combat influenza viruses.
Keywords: Antiviral inhibitors; Benzamide derivatives; Dual molecular targets; Indole moiety; Influenza virus; RNA-dependent RNA polymerase; RNP.
. 2025 May 2:293:117681.
doi: 10.1016/j.ejmech.2025.117681. Online ahead of print. Novel benzamide derivatives with indole moiety as dual-target antiviral agents: Rational design, efficient synthesis, and potent anti-influenza activity through concurrent binding to PA[SUB]C[/SUB] terminal domain and viral nucleoprotein
Chao Zhang[SUP] 1 [/SUP], Jia-Bin Li[SUP] 1 [/SUP], Yi-Wen Zhang[SUP] 1 [/SUP], Yun-Sang Tang[SUP] 2 [/SUP], Xiao-Fei Yu[SUP] 1 [/SUP], Qing-Guang Zhang[SUP] 1 [/SUP], Zhe Jin[SUP] 1 [/SUP], Shi-Cheng Hou[SUP] 3 [/SUP], Pang-Chui Shaw[SUP] 4 [/SUP], Chun Hu[SUP] 5 [/SUP]
Affiliations
- PMID: 40367674
- DOI: 10.1016/j.ejmech.2025.117681
In this study, a series of benzamide derivatives with an indole moiety as dual-target inhibitors were designed, synthesized and evaluated against the RNA-dependent RNA polymerase (RdRp) complex of influenza viruses. The target compounds can simultaneously disrupt two key molecular interactions: the PA[SUB]C[/SUB] terminal domain and the nucleoprotein (NP) oligomerization. Through efficient synthesis and structure-activity relationship (SAR) analysis, compounds 8e and 8f as highly potent inhibitors were identified. Both compounds (8e and 8f) exhibited submicromolar EC[SUB]50[/SUB] values (1.64 ± 0.05 μM and 1.41 ± 0.27 μM) against influenza A virus (H1N1, A/WSN/33) and broad-spectrum activity against other influenza strains, including influenza B virus and multiple subtypes of influenza A. Notably, their cytotoxicity was significantly reduced compared to previous benzofurazan derivatives, with CC[SUB]50[/SUB] values exceeding 100 μM. Surface plasmon resonance (SPR) experiments confirmed that 8e and 8f bound strongly to the PA C-terminal domain (KD = 8.90 μM and 4.82 μM) and NP (KD = 52.5 μM and 3.13 μM). Computational modeling approaches, including molecular docking, molecular dynamics (MD) simulations, and dynamical cross-correlation matrix (DCCM) analysis, principal component analysis (PCA) analysis and density functional theory (DFT) calculations, were employed to elucidate the putative binding modes and delineate critical interaction sites between the ligands and target proteins. These insights not only modulated subsequent structure-based lead optimization but also strengthened our understanding of the molecular determinants governing antiviral activity. This research provides a promising scaffold for developing dual-target antiviral agents with enhanced potency and safety, offering new strategies to combat influenza viruses.
Keywords: Antiviral inhibitors; Benzamide derivatives; Dual molecular targets; Indole moiety; Influenza virus; RNA-dependent RNA polymerase; RNP.