Synthesis, ADME, docking studies and in vivo anti-hyperglycaemic potential estimation of novel Schiff base derivatives from octadec-9-enoic acid

Bioorg Chem. 2019 Mar:84:478-492. doi: 10.1016/j.bioorg.2018.12.004. Epub 2018 Dec 4.

Abstract

A new series of octadec-9-enoic acid schiff base entities (S1-S30) were designed and synthesized targeting peroxisome proliferator activated receptor-gamma for agonist action. Molinspiration software (online) was used to estimate drug like molecular properties of the metabolites. Docking disquisition on co-crystallized protein of PPAR-γ (PDB ID 1FM9) was carried out which showed S21, S10 and S7 as best situated in the vital sites of receptor having docking scores -9.19, -8.68 and -8.64 respectively. Free binding energy measured using model of Maestro 9.0 and was in range of from -40.01 and -80.54 kcal/mol, significant when compared with pioglitazone (-51.58 Kcal/mol). Seven best docked derivatives were assessed for in-vivo oral glucose tolerance on normal rats and anti-hyperglycaemic activity by streptozotocin induced diabetes model. S21 unveiled to be the best measured analogue among all the synthesized entities. Encouraging outcomes motivates fatty acids for further development of more effective and safer compounds.

Keywords: Fatty acids; Hyperglycaemia; Molecular docking; PPAR; STZ; Schiff base.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / drug therapy
  • Drug Design
  • Female
  • Glucose Tolerance Test
  • Half-Life
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / metabolism
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Molecular Docking Simulation*
  • Oleic Acid / chemistry*
  • Oleic Acid / metabolism
  • Oleic Acid / therapeutic use
  • PPAR gamma / chemistry
  • PPAR gamma / metabolism
  • Rats
  • Rats, Wistar
  • Schiff Bases / chemistry*
  • Structure-Activity Relationship

Substances

  • Hypoglycemic Agents
  • PPAR gamma
  • Schiff Bases
  • Oleic Acid