Novel chalcone/aryl carboximidamide hybrids as potent anti-inflammatory via inhibition of prostaglandin E2 and inducible NO synthase activities: design, synthesis, molecular docking studies and ADMET prediction

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1067-1078. doi: 10.1080/14756366.2021.1929201.

Abstract

Two series of chalcone/aryl carboximidamide hybrids 4a-f and 6a-f were synthesised and evaluated for their inhibitory activity against iNOS and PGE2. The most potent derivatives were further checked for their in vivo anti-inflammatory activity utilising carrageenan-induced rat paw oedema model. Compounds 4c, 4d, 6c and 6d were proved to be the most effective inhibitors of PGE2, LPS-induced NO production, iNOS activity. Moreover, 4c, 4d, 6c and 6d showed significant oedema inhibition ranging from 62.21% to 78.51%, compared to indomethacin (56.27 ± 2.14%) and celecoxib (12.32%). Additionally, 4c, 6a and 6e displayed good COX2 inhibitory activity while 4c, 6a and 6c exhibited the highest 5LOX inhibitory activity. Compounds 4c, 4d, 6c and 6d fit nicely into the pocket of iNOS protein (PDB ID: 1r35) via the important amino acid residues. Prediction of physicochemical parameters exhibited that 4c, 4d, 6c and 6d had acceptable physicochemical parameters and drug-likeness. The results indicated that chalcone/aryl carboximidamides 4c, 4d, 6c and 6d, in particular 4d and 6d, could be used as promising lead candidates as potent anti-inflammatory agents.

Keywords: Chalcone; PGE2; amidoxime; anti-inflammatory; carboximidamide; iNOS inhibitors.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Carrageenan
  • Cells, Cultured
  • Chalcone / chemical synthesis
  • Chalcone / chemistry
  • Chalcone / pharmacology*
  • Dinoprostone / antagonists & inhibitors*
  • Dinoprostone / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Edema / chemically induced
  • Edema / drug therapy*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Mice
  • Molecular Docking Simulation*
  • Molecular Structure
  • Nitric Oxide Synthase Type II / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / metabolism
  • RAW 264.7 Cells
  • Structure-Activity Relationship

Substances

  • Amides
  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Chalcone
  • Carrageenan
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II
  • Dinoprostone

Grants and funding

This project was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, under Grant no. RG-8-166-41. The authors, therefore, gratefully acknowledge DSR technical and financial support.