Novel Multi-Target Agents Based on the Privileged Structure of 4-Hydroxy-2-quinolinone

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Organic Synthesis

Background:

• The 4-hydroxy-2-quinolinone scaffold is a privileged structure in drug discovery.
• Lipoxygenase (LOX) enzymes are key targets for anti-inflammatory drug development.
• Developing multi-target agents with both LOX inhibitory and antioxidant properties is desirable.

Purpose of the Study:

• To synthesize and evaluate novel 4-hydroxy-2-quinolinone derivatives as potential anti-inflammatory agents.
• To investigate the LOX inhibitory and antioxidant activities of synthesized compounds.
• To explore structure-activity relationships and identify lead compounds.

Main Methods:

• Synthesis of 21 quinolinone carboxamides, 7 hybrid compounds, and 3 reverse amides.
• In vitro evaluation of soybean LOX inhibition.
• Assessment of antioxidant capacity using lipid peroxidation inhibition, hydroxyl radical scavenging, and ABTS radical cation decolorization assays.
• In silico molecular docking studies.

Main Results:

• Compounds 3h and 3s demonstrated significant LOX inhibitory activity (IC50 = 10 μM).
• Carboxamide 3g and hybrid 11e exhibited multi-target properties with combined LOX inhibition and antioxidant effects.
• Docking studies revealed similar binding modes for potent inhibitors and the reference compound at an alternative binding site.

Conclusions:

• The synthesized quinolinone derivatives hold potential as anti-inflammatory agents.
• Compounds 3h and 3s are promising leads for further development due to their potent LOX inhibition.
• Multi-target agents like 3g and 11e offer a valuable strategy for addressing inflammatory conditions.