Oxazolidinones are known as a new class of antibacterial agents. In our group, the 4,5-disubstituted oxazolidinones have been previously identified to exhibit high affinity for the T box antiterminator transcription system. Among those compounds, ANB-22 and ANB-40 emerged to be the lead compounds showing good RNA-binding activity with high affinity and specificity. In medicinal chemistry, conformationally constraining molecules is a useful approach to optimize the biological activities of drug candidates. This dissertation is devoted to the design and synthesis of the fused tricyclic piperazine analogues and tricyclic triazole analogues of ANB-22 and ANB-40.
By employing the aziridine-ring-opening and the Mitsunobu reaction, a series of fused bicyclic and tricyclic oxazolidinone-piperazine derivatives have been prepared. Using similar synthetic strategy and subsequent structural modification, the fused tricyclic piperazine analogues of ANB-22/40 have been successfully obtained as well.
The application of the intramolecular azide-alkyne cycloaddition leads to the tricyclic fused oxazolidinone-piperazine-triazole compounds. After appropriate structural modification, the triazole analogues of ANB-22/40 have been prepared. By hydrolyzing the oxazolidinone ring of these tricyclic compounds, a series of amino alcohol derivatives with a piperazine-triazole framework have been generated. In addition, the use of copper catalyst allows the occurrence of the intermolecular cycloaddition to afford four macrocyclic dimers.