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

• Published in: Journal of molecular structure Vol. 1282; p. 135223
• Main Authors: Szafrański, Przemysław W., Siwek, Agata, Smaga-Maślanka, Irena, Pomierny-Chamioło, Lucyna, Ilnicki, Piotr, Żuchowski, Grzegorz, Nevalainen, Tapio, Filip, Małgorzata, Zajdel, Paweł, Cegła, Marek T.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15.06.2023
• Subjects: Azide-alkyne cycloaddition; Cannabinoid CB1 receptor; Click chemistry; NMR; Relative configuration; Triazole; Azide-alkyne cycloaddition; Triazole; NMR; Click chemistry; Relative configuration; Cannabinoid CB1 receptor
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2023.135223

•Exploration of 1,2,3-triazoles as potential CB1 receptor ligands - CB1 affinity tested for 19 compounds.•Efficient synthesis of 1,2,3-triazoles using a ligand-assisted CuAAC protocol.•C5-modification of 1,2,3-triazoles: lithiation and reaction with epoxide or other electrophiles.•3 diastereoisomeric pairs of 3-triazolyl cyclohexanol derivatives obtained and separated.•Relative configuration assignment using 1D/2D NMR, supported with DFT-based chemical shift prediction. Extending the click chemistry concept, 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 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 electrophile. 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 (CB1R). 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. [Display omitted]