A series of bis- N -substituted tetrandrine derivatives carrying different aromatic substituents attached to both nitrogen atoms of the natural alkaloid were studied with double-stranded model DNAs (dsDNAs) to examine the binding properties and mechanism. Variable-temperature molecular recognition studies using UV–vis and fluorescence techniques revealed the thermodynamic parameters, Δ H , Δ S , and Δ G , showing that the tetrandrine derivatives exhibit high affinity toward dsDNA ( K ≈ 10 5 –10 7 M –1 ), particularly the bis(methyl)anthraquinone (BAqT) and bis(ethyl)indole compounds (BInT). Viscometry experiments, ethidium displacement assays, and molecular modeling studies enabled elucidation of the possible binding mode, indicating that the compounds exhibit a synergic interaction mode involving intercalation of one of the N -aryl substituents and interaction of the molecular skeleton in the major groove of the dsDNA. Cytotoxicity tests of the derivatives with tumor and nontumor cell lines demonstrated low cytotoxicity of these compounds, with the exception of the bis(methyl)pyrene (BPyrT) derivative, which is significantly more cytotoxic than the remaining derivatives, with IC 50 values against the LS-180, A-549, and ARPE-19 cell lines that are similar to natural tetrandrine. Finally, complementary electrochemical characterization studies unveiled good electrochemical stability of the compounds.

This work reports on the antibacterial activity of two tetrandrine derivatives, with acridine (MAcT) and anthracene (MAnT) units, against Gram-positive and Gram-negative bacteria of clinical importance by the broth microdilution method as well as their antioxidant activity against ABTS •+ and DPPH •+ radicals. Unlike natural tetrandrine, its derivatives inhibited bacterial growth, showing selectivity against Staphylococcus aureus with notable activity of MAnT (MIC = 0.035 μg/mL); this compound also has good activity against the ABTS •+ radical (IC 50 = 4.59 μg/mL). Cell membrane integrity studies and reactive oxygen species (ROS) detection by fluorescent stains helped to understand possible mechanisms related to antibacterial activity, while electrophoretic mobility assays showed that the derivatives can bind to bacterial DNA plasmid. The results indicate that MAnT can induce a general state of oxidative stress in S. aureus and Escherichia coli, while MAcT induces an oxidative response in S. aureus. Complementary electrochemical studies were included.

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