Discovery of Novel Indole Derivatives as Fructose-1,6-bisphosphatase Inhibitors and X-ray Cocrystal Structures Analysis

Liver fructose-1,6-bisphosphatase (FBPase) is a key enzyme in the gluconeogenesis, and its inhibitors are expected to be novel antidiabetic agents. Herein, a series of new indole and benzofuran analogues were designed and synthesized to evaluate the inhibitory activity against FBPase. As a result, the novel FBPase inhibitors bearing N-acylsulfonamide moiety on the 3-position of the indole-2-carboxylic acid scaffold (compounds 22f and 22g) were identified with IC50s at the submicromolar levels. Three X-ray crystal structures of the complexes were solved and revealed the structural basis for the inhibitory activity. The chemoinformatics analysis further disclosed the distinct binding features of this class of inhibitors, providing an insight for further modifications to create structurally distinct FBPase inhibitors with high potency and drug-like properties.

Automated summary

A series of new indole and benzofuran analogues were designed and synthesized to evaluate their inhibitory activity against FBPase. Compounds with N-acylsulfonamide moiety on the 3-position of the indole-2-carboxylic acid scaffold showed submicromolar IC50 values, providing insights for creating structurally distinct FBPase inhibitors with high potency and drug-like properties. Three X-ray crystal structures of the complexes were solved, revealing the structural basis for the inhibitory activity.