Reactivity Studies and Synthetic Strategies Towards the Preparation of New Hydrophilic Indirubin-Triazole-Based Compounds

Abstract

Indirubin is an isomer of the blue dye indigo. It is widely used in Chinese medicine as part of therapy against many diseases and, thus, its skeleton becomes a promising candidate for new drug prototypes. Since it has low solubility, its properties could be improved through the insertion of hydrophilic and pharmacophoric groups, such as sugars bridged to 1,2,3-triazoles. Here, we report the synthesis of indirubin-based compounds evaluating two different routes: via the aldol condensation reaction of triazole-isatin derivatives with 3-acetoxyindole (pathway A) and reductive coupling of isatin, followed by N-propargylation of indirubin. We also performed reactivity studies guided by density functional theory (DFT) calculations (pathway B). As a demonstration, we simulate interactions with the glycogen synthase kinase 3β enzyme, which is associated with neurodegenerative diseases, through both molecular docking and molecular dynamics simulations.

Keywords:
indirubin reactivity; isatin functionalization; CuAAC reactions; molecular docking