Click Chemistry as a Synthetic Strategy for the Preparation of Bis(indolyl)-1,2,3-triazole Analogues of Topsentin and Nortopsentin

Click chemistry is one of the most important synthetic tools developed in recent years, enabling the rapid, straightforward, regioselective, and high-yielding synthesis of chemical compounds. Among these methodologies, the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC), performed under mild conditions, provides an efficient approach to prepare privileged 1,2,3-triazole scaffolds with diverse biological activities, including antibacterial and antifungal properties.

Based on this approach, the present project focused on the synthesis of topsentin and nortopsentin analogues bearing a bis(indolyl)-1,2,3-triazole core through Cu(I)-catalyzed azide–alkyne cycloaddition reactions, following the principles of click chemistry.

The synthetic methodology involved a sequence of transformations. For the preparation of the azide derivatives, protection (Boc, Bn, and Me), reduction, and nucleophilic substitution reactions were carried out. In contrast, the synthesis of the alkyne derivatives involved electrophilic aromatic substitution, protection (Boc, Bn, and Me), Sonogashira cross-coupling, and deprotection reactions. In addition, conventional extraction and silica gel column chromatography were used to isolate and purify the starting materials and triazole derivatives.

The starting materials were obtained with yields from 19 to 83% for the azide derivatives and from 41 to 97% for the alkyne derivatives. Furthermore, five nortopsentin analogues were synthesized in yields exceeding 70%. These compounds were characterized by nuclear magnetic resonance and spectroscopy and mass spectrometry.

Finally, the synthesized compounds were evaluated for their antibacterial activity against Enterococcus faecalis and Escherichia coli bacteria. None of the compounds exhibited antibacterial activity against the tested strains over the concentration range evaluated (1, 5, 10, 50, and 100 mg/mL).