2. Academic Validation
  3. Design and synthesis of dual-activity biphenyl inhibitors against SARS-CoV-2 and bladder cancer

Design and synthesis of dual-activity biphenyl inhibitors against SARS-CoV-2 and bladder cancer

  • Eur J Med Chem. 2026 Mar 15:306:118581. doi: 10.1016/j.ejmech.2026.118581.
Lin Lin Shang 1,  Teng Long Hu 2,  Situ Xiong 3,  Songhui Xu 4,  Li Ping Cheng 5
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; Faculty of Chemical Engineering and Energy Technology, Shanghai Institute of Technology, Shanghai, 201418, China.
  • 2 Faculty of Chemical Engineering and Energy Technology, Shanghai Institute of Technology, Shanghai, 201418, China.
  • 3 Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; Jiangxi Institute of Urology, Nanchang, Jiangxi, China. Electronic address: [email protected].
  • 4 Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; Jiangxi Institute of Urology, Nanchang, Jiangxi, China. Electronic address: [email protected].
  • 5 Faculty of Chemical Engineering and Energy Technology, Shanghai Institute of Technology, Shanghai, 201418, China. Electronic address: [email protected].
PMID: 41558060 DOI: 10.1016/j.ejmech.2026.118581
Abstract

Targeting the crucial SARS-CoV-2 therapeutic target 3CLpro, a natural product MOL007703 was identified from Stellariae Radix. Through systematic optimization, a series of novel biphenyl derivatives were designed to enhance target engagement. Among them, compound L3 shows superior 3CLpro inhibition with an IC50 of 0.15 μM, which is 13.6-fold more potent than the reference drug ebselen (IC50 = 2.04 μM). L3 also exhibits potent Antiviral activity against SARS-CoV-2 (EC50 = 2.82 μM), comparable to remdesivir (EC50 = 1.47 μM). Molecular docking revealed that the para-trifluoromethyl-substituted benzene ring occupies the hydrophobic S4 pocket of 3CLpro. The electron-withdrawing fluorine atoms promote electrostatic and dipole interactions and act as hydrogen-bond acceptors with residues in the polar S1 pocket, synergistically enhancing inhibitory potency. Furthermore, L3 displays favorable therapeutic potential with low cytotoxicity in HK-2 fibroblasts (CC50 > 50 μM) and potent concentration-dependent suppression of T24 bladder Cancer cell proliferation (IC50 = 10.99 μM), outperforming the reference drug mitomycin (IC50 = 16.95 μM). These results highlight fluorinated biphenyl scaffolds as privileged chemotypes for multitarget drug development, enabling concurrent inhibition of viral protease and Cancer cell growth. This work provides a rational strategy for repurposing traditional medicine-derived scaffolds into dual-function therapeutics through structural hybridization.

Keywords

3CL(pro) inhibitor; Bladder cancer; Dual-functional bioactivity; SARS-CoV-2; Stellariae Radix.

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