The design and synthesis of small molecules that target RNA is immensely important in antibacterial therapy. We had previously reported on the RNA binding of a series of 4,5-disubstituted 2-oxazolidinones that bind to a highly conserved bulge region of bacterial RNA. This biological target T box antitermination system, which is found mainly in Gram-positive bacteria, regulates the expression of several amino acid related genes. In an effort to amplify our library, we have prepared a library of 1,4-disubstituted 1,2,3-triazole analogs that entails an isosteric replacement of the oxazolidinone nucleus. The synthesis of the new analogs was enhanced via copper(I) catalysis of an azide and alkyne cycloaddition reaction. A total of 108 1,4-disubstituted 1,2,3-triazole compounds have been prepared. All compounds were evaluated as RNA binding agents.

The T box antiterminator RNA element is an important component of the T box riboswitch that controls the transcription of vital genes in many Gram-positive bacteria. A series of 1,4-disubstituted 1,2,3-triazoles was screened in a fluorescence-monitored thermal denaturation assay to identify ligands that altered the stability of antiterminator model RNA. Several ligands were identified that significantly increased or decreased the melting temperature (Tm) of the RNA. The results indicate that this series of triazole ligands can alter the stability of antiterminator model RNA in a structure-dependent manner.

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The binding of tRNA to the T box antiterminator RNA element is a critical component of the T box riboswitch mechanism that regulates essential genes in many Gram-positive bacteria. A series of 1,4-disubstituted 1,2,3-triazoles was screened for disruption of the tRNA-T box antiterminator RNA interaction using a fluorescence anisotropy-based assay. Several compounds reduced the anisotropy greater than 50% likely indicating significant competition for binding antiterminator RNA. General structure-activity trends indicated that the substituents at both N-1 and C-4 likely are involved in ligand binding. In addition, the anisotropy of the complex was significantly decreased not only by ligands with the possibility for electrostatic interactions with the RNA, but also by ligands with the potential for π-π stacking or other hydrophobic interactions indicating that these nonelectrostatic interactions could possibly be utilized in the future development of compounds that target and disrupt the function of this medicinally important riboswitch.