Synthesis of 2-{2-[(α/β-naphthalen-1-ylsulfonyl)amino]-1,3-thiazol-4-yl} acetamides with 11β-hydroxysteroid dehydrogenase inhibition and in combo antidiabetic activities

Gabriel Navarrete-Vázquez, Maria Guadalupe Morales-Vilchis, Samuel Estrada-Soto, Juan José Ramírez-Espinosa, Sergio Hidalgo-Figueroa, Carlos Nava-Zuazo, Hugo Tlahuext, Ismael Leon-Rivera, José L Medina-Franco, Fabian López-Vallejo, Scott P Webster, Margaret Binnie, Rolffy Ortiz-Andrade, Hermenegilda Moreno-Diaz

Research output: Contribution to journalArticlepeer-review

Abstract

Compounds 1-10 were designed using a bioisosteric approach and were prepared using a short synthetic route. The in vitro inhibitory activity of the compounds against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was evaluated. Compounds 5 (α-series) and 10 (β-series) had a moderate inhibitory enzyme activity (55.26% and 67.03% inhibition at 10 μM, respectively) and were as active as BVT.14225 (positive control). Both compounds have a piperidine ring in their structure, but the most active (10) was selected to establish its in vivo antidiabetic effect using a non insulin-dependent diabetes mellitus rat model. The antidiabetic activity of compound 10 was determined at 50 mg/kg single dose in an acute model, and also by short term sub-chronic administration for 5 days. The results indicated a significant decrease of plasma glucose levels, similar than BVT.14225. Additionally, a molecular docking of the most active compounds of each series into the ligand binding pocket of one subunit of human 11β-HSD1 was performed. In this model the oxygen atom of the sulfonamide make hydrogen bond interactions with the catalytic residues Ser170 and Ala172. We also observed important π-π interactions between the naphthyl group and Tyr177.

Original languageEnglish
Pages (from-to)179-86
Number of pages8
JournalEuropean Journal of Medicinal Chemistry
Volume74
DOIs
Publication statusPublished - 3 Mar 2014

Keywords

  • 11-beta-Hydroxysteroid Dehydrogenases
  • Acetamides
  • Animals
  • Diabetes Mellitus, Experimental
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Molecular Docking Simulation
  • Rats

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