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

## TL;DR

A new method for making chalcone compounds without metals shows high efficiency and potential for drug design against cysteine proteases.

## Contribution

A transition-metal-free one-pot synthesis of (hetero)chalcones with C–H functionalization and in situ formylation using DMF.

## Key findings

- 23 chalcone derivatives were synthesized with yields up to 85% using a transition-metal-free method.
- Compound 3c showed the highest cysteine protease inhibition (IC50 = 7.54 ± 0.99 μM) against papain.
- Molecular docking studies confirmed key interactions between compound 3c and catalytic residues of proteases.

## Abstract

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 3c (bearing a para-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 3c, and catalytic residues, reinforcing its potential as a
fragment-like starting point for drug design.