From 1,4- to 1,5-Disubstituted Triazoles: Enhanced Three-Dimensionality and Aqueous Solubility

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) is a representative click reaction with practical applications in various fields, including medicinal chemistry. Its product, 1,4-disubstituted triazoles, has an elongated, rod-like shape. The continued proliferation of 1,4-disubstituted triazole-based drug candidates is concerning because existing bioactive compounds are heavily biased toward rod-like shapes with limited structural diversity, even though three-dimensional compounds generally possess more favorable druglike properties. Replacing this triazole ring with a 1,5-disubstituted counterpart is expected to bend the molecular shape and address these limitations. Here, to evaluate this possibility, we constructed a new library in which the triazole rings of our previously established 7-azanorbornane-based 1,4-disubstituted triazole library were replaced with 1,5-disubstituted counterparts. We then assessed the effects of this change on molecular shape, aqueous solubility, and membrane permeability. Ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC), the most common synthetic method for 1,5-disubstituted triazoles, failed to produce the designed compounds, likely due to steric hindrance around the bicyclic scaffold. We therefore employed the reaction between acetylides and azides, which is relatively tolerant to steric hindrance, and successfully obtained the target 1,5-disubstituted triazoles, although not all designed compounds were produced. The 1,5-disubstituted triazoles synthesized here exhibited more three-dimensional shapes, greater structural diversity, and improved aqueous solubility than their 1,4-disubstituted counterparts, although no clear difference was observed in membrane permeability. These results suggest that replacing the triazole rings in CuAAC-derived libraries with 1,5-disubstituted counterparts is a promising strategy to construct libraries that exhibit greater three-dimensional structural diversity, and are more soluble in aqueous media.