Synthesis, biological evaluation, and molecular docking investigation of benzhydrol- and indole-based dual PPAR-γ/FFAR1 agonists

• Published in: Bioorganic & medicinal chemistry letters 2018-05, Vol.28 (9), p.1595-1602
• Main Authors: Darwish, Khaled M., Salama, Ismail, Mostafa, Samia, Gomaa, Mohamed S., Khafagy, El-Sayed, Helal, Mohamed A.
• Format: Article
• Language: English
• Subjects: Benzhydryl Compounds - chemical synthesis; Benzhydryl Compounds - chemistry; Benzhydryl Compounds - pharmacology; Biological evaluation; Dose-Response Relationship, Drug; FFAR1; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Molecular Docking Simulation; Molecular Structure; PPAR gamma - agonists; PPAR-γ; Receptors, G-Protein-Coupled - agonists; Structure-Activity Relationship; Thiazolidindione; Type-2 diabetes mellitus
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.03.051

[Display omitted] •T2DM is a progressive cluster of metabolic disorders, with a global health burden.•Continuing our previous work, we report benzhydrols and indoles on FFAR1 and PPARγ.•15a, 15c, and 15d, depicted affinities in low micromolar range on both targets.•In vivo study, 15c of superior hypoglycemic/lipidemic activities to rosiglitazone.•These compounds could develop unique insulin sensitizers as well as secretagogues. Type-2 diabetes mellitus is a progressive cluster of metabolic disorders, representing a global public health burden affecting more than 366 million people worldwide. We recently reported the discovery of three series of novel agents showing balanced activity on two metabolic receptors, peroxisome proliferator activated receptor-γ (PPAR-γ) and free fatty acid receptor 1 (FFAR1), also known as GPCR40. Our designing strategy relied on linking the thiazolidinedione head with known GPCR privilege structures. To further investigate this concept, two new scaffolds, the benzhydrol- and indole-based chemotypes, were introduced here in. Our optimization campaign resulted in three compounds; 15a, 15c, and 15d, with affinities in the low micromolar range on both targets. In vivo study of selected test compounds, revealed that 15c possesses a significant anti-hyperglycemic and anti-hyperlipidemic activities superior to rosiglitazone in fat-fed animal models. Molecular docking analysis was conducted to explain the binding modes of both series. These compounds could lead to the development of the unique antidiabetic agent acting as insulin sensitizer as well as insulin secretagogue.