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.