Design, Synthesis, Anti-Inflammatory Activity, DFT Modeling and Docking Study of New Ibuprofen Derivatives

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Materials Science

Background:

• Inflammation and pain management often rely on non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen.
• Developing novel NSAID derivatives with improved efficacy and safety profiles is a key research area.
• Understanding the structure-activity relationship of metal complexes with NSAIDs can lead to enhanced therapeutic properties.

Purpose of the Study:

• To synthesize a new ibuprofen derivative, (E)-2-(4-isobutylphenyl)-N'-(4-oxopentan-2-ylidene) propane hydrazide (IA).
• To prepare and characterize metal complexes of IA with Cobalt (Co), Copper (Cu), Nickel (Ni), Gadolinium (Gd), and Samarium (Sm).
• To evaluate the anti-inflammatory efficacy and cyclooxygenase-2 (COX-2) inhibition potential of the synthesized compounds.

Main Methods:

• Synthesis of the ibuprofen derivative (IA) and its metal complexes.
• Structural characterization using 1H NMR, Mass Spectrometry (MS), Fourier-Transform Infrared (FTIR) spectroscopy, and UV-Vis spectroscopy.
• Computational analysis including Density Functional Theory (DFT) and molecular docking with the COX-2 enzyme (PDB: 5IKT).
• Pharmacokinetic assessments using SwissADME for parameters like Blood-Brain Barrier (BBB) permeability and gastrointestinal absorption.

Main Results:

• Successful synthesis and comprehensive structural characterization of the ibuprofen derivative (IA) and its metal complexes.
• Determination of unique coordination geometries for different metal ions: octahedral for Cu/Ni/Co and capped square antiprismatic/tricapped trigonal prismatic for Gd/Sm.
• Molecular docking revealed superior binding energies of the compounds to the COX-2 enzyme compared to ibuprofen.
• Pharmacokinetic profiling indicated favorable properties, including potential BBB permeability and gastrointestinal absorption.
• Significantly lower IC50 values demonstrated enhanced anti-inflammatory and COX-2 inhibitory activity.

Conclusions:

• The novel ibuprofen derivative (IA) and its metal complexes exhibit promising anti-inflammatory and COX-2 inhibitory activities.
• These compounds possess improved binding affinities and pharmacokinetic profiles over traditional ibuprofen.
• The findings support the potential of this new generation of ibuprofen derivatives for therapeutic applications in inflammation treatment.