Mechanochemical Promoted Heterocycles: A Solvent-free Route to Triazole Carbohydrates as Glycogen Phosphorylase Inhibitors

Abstract

Aims: This study aimed to recommend a novel way for the preparation of carbohydrates containing triazole derivatives.

Background: Triazoles containing derivatives have numerous biological activities. Ball milling is a fast, modest, green process with massive potential. One of the greatest interesting applications of this technique is in the arena of heterocycles.

Objective: Solvent-free click reactions are facilitated via the activation of copper powder using a ball milling mechanochemical procedure. An optimization study of parameters affecting the reaction rate, such as reaction time, size, and milling ball number, has been conducted. Different substrates have been tested using this adopted procedure considering in all cases, in high yields and purity, the corresponding chiral optically pure five-membered glycoconjugates containing 1,2,3-triazole.

Methods: Three milling balls of 10 mm in diameter were placed in the milling jar (50 mL; stainless steel). 1 mmol of alkyne, 2 mmol of azide, and 1 mmol of Cu powder (63 mg) were added, respectively, in the presented order. Milling was assured for 25 min at 650 rpm deprived of solvent.

Results: The cycloaddition results and the deprotection of the cycloadducts were affected by the selection of the protective groups. Cleavage of the acetyl protecting groups provided water-soluble triazoles. The four 1,4-di-substituted 1,2,3-triazoles synthesized via deacetylation were tested against glycogen phosphorylase. The best inhibitor of rabbit muscle glycogen phosphorylase was 2-Amino-3-{2-[1-(3,4,5,6-tetrahydroxytetrahydro- pyran-2-ylmethyl)-1H-[1,2,3]triazol-4-yl]-ethylsulfanyl}-propionic acid b (Ki = 40.8 ± 3.2 μM). This novel procedure affords an eco-friendly reaction profile (catalyst-free) affording high yields and short reaction times.

Conclusion: In this work, acetyl protective groups were used to the corresponding deprotected watersoluble triazole analogous to recognizing glycogen phosphorylase inhibitors. Triazole 6a was the most effective inhibitor of RMGP b with a Ki value of 40.8 μM.

Keywords: Mechanochemical synthesis; carbohydrate; glycogen phosphorylase; high-speed vibration milling; hydrolysis; solvent-free reaction.