Design, synthesis, molecular modelling and in vitro cytotoxicity analysis of novel carbamate derivatives as inhibitors of Monoacylglycerol lipase

Bioorg Med Chem. 2018 May 15;26(9):2561-2572. doi: 10.1016/j.bmc.2018.04.024. Epub 2018 Apr 12.

Abstract

Monoacylglycerol lipase (MAGL) has an essential role in the catabolic pathway of the endocannabinoid 2-arachidonoylglycerol, which makes it a potential target for highly specific inhibitors for the treatment of a number of diseases. We designed and synthesized a series of carbamate analogues of URB602. We evaluated their inhibitory activity toward human MAGL in vitro both in cell culture and lysates. The target compounds exhibited moderate to excellent inhibitory activity against MAGL. The most promising compound 2b showed good inhibitory activity with IC50 value of 4.5 ± 0.70 μM reducing MAGL activity to 82% of controls at 10 μM compared to 66% for the parent compound URB602. Interestingly, compounds 2b and 2c induce cell death through the inhibition of MAGL. Molecular modelling approaches and docking studies, used to investigate inhibitory profiles, indicated that trifluoromethyl substitutions of the aryl group and the benzene ring present at the oxygen side of the carbamate molecule had a significant impact on the activity.

Keywords: Anti-proliferative; Carbamate; Cytotoxicity; Monoacylglycerol lipase; Structure-activity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Binding Sites
  • Biphenyl Compounds / chemical synthesis
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology
  • Carbamates / chemical synthesis
  • Carbamates / chemistry
  • Carbamates / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Enzyme Assays
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Monoacylglycerol Lipases / antagonists & inhibitors*
  • Monoacylglycerol Lipases / chemistry
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Biphenyl Compounds
  • Carbamates
  • Enzyme Inhibitors
  • URB602
  • Monoacylglycerol Lipases
  • Amidohydrolases
  • fatty-acid amide hydrolase