Design and synthesis of rosiglitazone-ferulic acid-nitric oxide donor trihybrids for improving glucose tolerance

Eur J Med Chem. 2019 Jan 15;162:650-665. doi: 10.1016/j.ejmech.2018.10.006. Epub 2018 Oct 4.


Glucose intolerance is associated with metabolic syndrome and type 2 diabetes mellitus (T2DM) while some new therapeutic drugs, such as rosiglitazone (Rosi), for T2DM can cause severe cardiovascular side effects. Herein we report the synthesis of Rosi-ferulic acid (FA)-nitric oxide (NO) donor trihybrids to improve glucose tolerance and minimize the side effects. In comparison with Rosi, the most active compound 21 exhibited better effects on improving glucose tolerance, which was associated with its NO production, antioxidant and anti-inflammatory activities. Furthermore, 21 displayed relatively high stability in the simulated gastrointestinal environments and human liver microsomes, and released Rosi in plasma. More importantly, 21, unlike Rosi, had little stimulatory effect on the membrane translocation of aquaporin-2 (AQP2) in kidney collecting duct epithelial cells. These, together with a better safety profile, suggest that the trihybrids, like 21, may be promising candidates for intervention of glucose intolerance-related metabolic syndrome and T2DM.

Keywords: Ferulic acid; Glucose intolerance; Nitric oxide; Rosiglitazone; Type 2 diabetes mellitus.

MeSH terms

  • Anti-Inflammatory Agents
  • Antioxidants
  • Aquaporin 2 / metabolism
  • Cells, Cultured
  • Coumaric Acids / chemistry*
  • Coumaric Acids / pharmacology
  • Coumaric Acids / therapeutic use
  • Diabetes Mellitus, Type 2 / drug therapy
  • Drug Design
  • Glucose Intolerance / drug therapy*
  • Humans
  • Kidney Tubules, Collecting / cytology
  • Kidney Tubules, Collecting / metabolism
  • Metabolic Syndrome / drug therapy
  • Microsomes, Liver
  • Nitric Oxide Donors / chemistry*
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Donors / therapeutic use
  • Rosiglitazone / chemistry*
  • Rosiglitazone / pharmacology
  • Rosiglitazone / therapeutic use


  • Anti-Inflammatory Agents
  • Antioxidants
  • Aquaporin 2
  • Coumaric Acids
  • Nitric Oxide Donors
  • Rosiglitazone
  • ferulic acid