Synthesis, relative configuration and CB1 receptor affinity studies for a set of 1,2,3-triazole derivatives

Extending the click chemistry concept, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reac-tion was used to synthesize a series of 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles using 1-(2-hydroxycyclohexyl)-4-dimethylaminomethyl 1,2,3-triazole (AMTC) as the Cu-binding ligand. The 1,4,5-trisubstituted 1,2,3-triazoles were obtained through 5-lithiation followed by a reaction with an elec-trophile. This study also showed, that a 1,4-disubstituted 5-lithiotriazole can be acylated using N,N-dimethylbenzamide, as an extension of the dimethylformamide formylation. The synthesized compounds, designed to mimic the bicyclic non-classical cannabinoids, were evaluated for their affinity to the cannabinoid type 1 receptor (CB1 R). For a subset of 4-(3-hydroxycyclohexyl) 1,2,3-triazoles, the cis/trans relative configuration was determined, using 1D and 2D NMR combined with DFT-based chemical shift prediction.(c) 2023 Published by Elsevier B.V.

Automated summary

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction was used to synthesize a series of 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles. The synthesized compounds were evaluated for their affinity to the cannabinoid type 1 receptor (CB1 R). The relative configuration of a subset of 4-(3-hydroxycyclohexyl) 1,2,3-triazoles was determined using NMR and DFT-based chemical shift prediction.