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

Xiaoyu Wang; Rui Zhao; Wenming Ji; Jie Zhou; Quan Liu; Linxiang Zhao; Zhufang Shen; Shuainan Liu; Bailing Xu

doi:10.1021/acsmedchemlett.1c00613

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

ACS Med Chem Lett. 2021 Dec 20;13(1):118-127. doi: 10.1021/acsmedchemlett.1c00613. eCollection 2022 Jan 13.

Authors

Xiaoyu Wang¹, Rui Zhao^{1

2}, Wenming Ji^{3

4}, Jie Zhou¹, Quan Liu^{3

4}, Linxiang Zhao², Zhufang Shen^{3

4}, Shuainan Liu^{3

4}, Bailing Xu¹

Affiliations

¹ Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
² School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 100016, China.
³ State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
⁴ Diabetes Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.

Abstract

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.