Mollugin Derivatives as Anti-Inflammatory Agents: Design, Synthesis, and NF-κB Inhibition.

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Immunology

Background:

• Nuclear factor κB (NF-κB) is a critical transcription factor regulating inflammatory and immune responses.
• Inhibition of the NF-κB signaling pathway represents a key therapeutic strategy for managing inflammatory conditions.
• Mollugin derivatives were explored for their potential to modulate NF-κB activity.

Purpose of the Study:

• To design and synthesize novel mollugin derivatives.
• To evaluate the anti-inflammatory activity of these derivatives by assessing their ability to inhibit NF-κB transcription.
• To investigate the mechanism of action and pharmacokinetic properties of promising compounds.

Main Methods:

• Synthesis of 27 mollugin derivatives.
• In vitro evaluation of anti-inflammatory activity targeting NF-κB transcription.
• In vivo assessment of compound 5k's efficacy via intraperitoneal administration.
• Mechanism of action studies, including p65 protein expression analysis.
• ADMET prediction for pharmacokinetic properties.
• Molecular docking simulations to correlate structure with activity.

Main Results:

• Most synthesized mollugin derivatives displayed potent anti-inflammatory activity.
• Compound 5k exhibited the highest efficacy (81.77% inhibition), surpassing mollugin, ibuprofen, and mesalazine.
• Compound 5k was found to down-regulate NF-κB expression, potentially by inhibiting LPS-induced p65 protein expression.
• ADMET predictions suggested favorable pharmacokinetic profiles for compounds 5h and 5k.
• Molecular docking provided insights into structure-activity relationships.

Conclusions:

• Novel mollugin derivatives possess significant anti-inflammatory potential.
• Compound 5k is a highly potent inhibitor of NF-κB signaling.
• Compounds 5h and 5k demonstrate promising characteristics for further development as anti-inflammatory agents.