Transition-Metal-Free One-Pot Synthesis of (Hetero)chalcones with Cysteine Protease Inhibitory Activity
Thais Rodrigues Arroio, Franco Jazon Caires, Gabriela de Oliveira Almeida, Victor Hugo Catricala Fernandes, Isabela Wada Ferreira Pinto, Luíz Vinícius Santos de Oliveira, Paulo Cezar Vieira, Giuliano Cesar Clososki
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.
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…
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Taxonomy
TopicsSynthesis and biological activity · Synthesis and Characterization of Pyrroles · Synthesis of Organic Compounds