Thiol-mediated processes play a key role to induce or inhibit inflammation proteins. Tailoring the reactivity of electrophiles can enhance the selectivity to address only certain surface cysteines. Fourteen 2′,3,4,4′-tetramethoxychalcones with different α-X substituents (X=H, F, Cl, Br, I, CN, Me, p-NO₂-C₆H₄, Ph, p-OMe-C₆H₄, NO₂, CF₃, COOEt, COOH) were synthesized, containing the potentially electrophilic α,β-unsaturated carbonyl unit. The assessment of their reactivity as electrophiles in thia-Michael additions with cysteamine shows a change in the reactivity of more than six orders of magnitude. Moreover, a clear correlation between their reactivity and an influence on the inflammation proteins heme oxygenase-1 (HO-1) and the inducible NO synthase (iNOS) is demonstrated. As the biologically most active compound, the α-CF₃-chalcone is shown to inhibit the NO production in RAW264.7 mouse macrophages in the nanomolar range.

α,β-Unsaturated carbonyl compounds as potential drug candidates is a controversial topic since their potential Michael acceptor activity can lead to cell damage and cytotoxicity. Nevertheless, the α,β-unsaturated carbonyl functionality can be employed as a tool to fine tune biological activity by directly manipulating this entity. Depending on their electronic properties, α,β-unsaturated carbonyl functionalities display different reactivities, namely Michael addition, radical scavenging, oxidation or double bond isomerization. Modifying the α-position of the α,β-unsaturated carbonyl system, a concept that has not been widely explored, could produce new, very interesting derivatives. Currently in drug development, irreversible binding in active sites has proven to be one answer to drug resistance in cancer treatment. Overall, natural products containing the α,β-unsaturated carbonyl unit possess multiple biological activities that could be transferred into novel pharmaceutical agents.