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

Targeting the crucial SARS-CoV-2 therapeutic target 3CL^pro, 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 3CL^pro 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 3CL^pro. 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.