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

We report a new and efficient one-pot methodology for the synthesis of (hetero)-chalcones via direct C-H functionalization. The protocol employs directed organolithiation of aromatic and heteroaromatic substrates, followed by in situ formylation using inexpensive DMF, which not only serves as the formylating agent but also generates lithium dimethylamide as the base for the subsequent aldol condensation with (hetero)-aryl ketones. This transition-metal-free and additive-free approach enables the preparation of 23 chalcone derivatives with broad structural diversity, varying both aromatic and heteroaromatic units, in isolated yields up to 85%. To demonstrate the synthetic utility of the obtained chalcones, a model chalcone was further transformed into two different derivatives, including a pyrazole and a thioacetic acid derivative. The synthesized chalcones were evaluated through enzymatic inhibition assays against cysteine proteases papain and Cathepsin B (CatB), with compound <b>3c</b> (bearing a <i>para</i>-chloro substituent) showing the highest potency (IC₅ ₀ = 7.54 ± 0.99 μM) against papain. These results were supported by molecular docking studies, which highlighted key interactions between (hetero)-chalcones, especially compound <b>3c</b>, and catalytic residues, reinforcing its potential as a fragment-like starting point for drug design.