Transition-Metal-Free One-Pot Synthesis of (Hetero)chalcones with Cysteine Protease Inhibitory Activity.

Area of Science:

• Organic Synthesis
• Medicinal Chemistry
• Chemical Biology

Background:

• Chalcones are versatile scaffolds in medicinal chemistry.
• Efficient synthesis of diverse chalcone libraries is crucial for drug discovery.
• Direct C-H functionalization offers a streamlined route to complex molecules.

Purpose of the Study:

• To develop a novel, efficient, one-pot synthesis of (hetero)-chalcones.
• To explore the utility of synthesized chalcones as enzyme inhibitors.
• To investigate the structure-activity relationship of chalcones against cysteine proteases.

Main Methods:

• Directed organolithiation of aromatic/heteroaromatic substrates.
• In situ formylation with DMF followed by aldol condensation.
• Enzymatic inhibition assays against papain and Cathepsin B (CatB).
• Molecular docking studies.

Main Results:

• A transition-metal-free, additive-free one-pot method for (hetero)-chalcone synthesis.
• Preparation of 23 diverse chalcone derivatives in yields up to 85%.
• Compound 3c demonstrated significant inhibitory activity against papain (IC50 = 7.54 ± 0.99 μM).
• Molecular docking confirmed favorable interactions of chalcones with enzyme active sites.

Conclusions:

• The developed methodology provides an efficient route to structurally diverse (hetero)-chalcones.
• Synthesized chalcones show potential as starting points for developing cysteine protease inhibitors.
• Compound 3c is a promising lead for further optimization in drug design targeting papain.