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A series of berberine-derived thiazolidinediones as novel potential artificial DNA intercalators were developed via five steps from natural berberine. The biological evaluation showed that some of the target molecules exhibited good inhibitory potencies against the tested bacteria and fungi. Noticeably, compound 6b displayed excellent antibacterial activity with a quite low MIC value of 0.008 μmol mL−1 against MRSA. This compound not only showed low toxicity to hepatocyte LO2 cells and slow development of bacterial resistance, but also displayed efficient membrane penetrability. The DNA binding efficacy was investigated using molecular modeling and UV-vis absorption experiments. The docking study pointed out the specific binding sites and non-covalent interactions of butyl derivative 6b with MRSA DNA isomerase. The active molecule 6b could block DNA replication by intercalating into MRSA DNA to form a supramolecular complex and thus suppress the growth of MRSA strain. Quantum chemical studies were also performed to understand the relationship between biological activity and molecular structure. It was found that the highly active compound 6b could be supramolecularly transported by human serum albumin through hydrophobic interactions and hydrogen bonds. Furthermore, the drug combination of compound 6b with norfloxacin and fluconazole could enhance the antimicrobial efficacy.

A series of novel unique structural organophosphorus aminopyrimidines were developed as potential DNA-targeting membrane active inhibitors through an efficient one-pot procedure from aldehydes, phosphonate and aminopyrimidine. The biological assay revealed that some of the prepared compounds displayed antibacterial activities. In particular, imidazole derivative 2c exhibited more potent inhibitory activity against MRSA with an MIC value of 4 μg mL-1 in comparison with the clinical drugs chloromycin and norfloxacin. Experiments revealed that the active molecule 2c had the ability to rapidly kill the tested strains without obviously triggering the development of bacterial resistance, showed low toxicity to L929 cells and could disturb the cell membrane. The molecular docking study discovered that compound 2c could bind with DNA gyrase via hydrogen bonds and other weak interactions. Further exploration disclosed that the active molecule 2c could also effectively intercalate into MRSA DNA and form a steady 2c-DNA supramolecular complex, which might further block DNA replication to exert powerful antibacterial effects.

Novel reactions under Pictet–Spengler conditions between tryptophan methyl ester/tryptamine and 2-oxoaldehydes have been developed and successfully utilized for the total synthesis of Merinacarboline (A and B), Eudistomin Y1, Pityriacitrin B, Pityriacitrin, Fascaplysin and analogues.