The alpha-substitution of chalcones as a tool to modulate the reactivity and biological activity
Year: 2014
Type: dissertation
Abstract: The chalcone motif can be a privileged structure in drug design if the reactivity is modulated to reach a suitable range. Chalcones are relatively easily synthesized and they have a structural versatility that can affect their reactivity as Michael acceptors. Since the reactivity of chalcones as Michael acceptors is essential for their biological activity, the assessment of this reactivity is of great interest. Hence, a new simple kinetic assay was developed to study the electrophilicity of chalcones upon reaction with thiols by determining the second-order rate constants. The solvent system used in the assay permits inclusion of compounds with quite diverse electrophilicity. A clear structure-activity relationship was shown within 16 alpha-H-chalcones. After that, the reactivity of chalcones was fine-tuned by modifying the alpha-position, a strategy which is not that common in literature for this aim. A library of alpha-X-2',3,4,4'-tetramethoxychalcones (alpha-X-TMCs) with different X- substituents (H, F, CN, Me, Br, Cl, I, p-NO2-C6H4, Ph, p-OMe-C6H4, NO2, COOEt, COOH, CF3) of diverse electronic properties was prepared. Then the reactivity of these chalcones was assessed utilizing the developed kinetic assay. The anti-inflammatory activity of alpha-X-TMCs was evaluated based on their ability to inhibit the production of NO by the proinflammatory enzyme iNOS. A strong correlation was found between Michael acceptor activity and inhibition of NO production of the alpha-X-TMCs for X = H, F, Cl, Br, I, CF3. The chemical reactivity-biological activity order is: CF3 > Br > Cl > I > H > F. The data prove that it is essential to find a certain reactivity window in order to retain activity. This reactivity window was identified by the kinetic assay to be in the range of 2-20 M-1 s-1 for the k2 values. So, it was proven chemically and biologically that a single simple modification on the structure of chalcones has a tremendous effect on their activity. Finally, it was tried to enhance the activity of 2’-OH chalcones which are proven to be more active than their 2’-alkoxy analogues by alpha-substitution. Seven alpha-X-HCs (X = CN, Me, F, Cl, Br, CF3, p-NO2-C6H4) were synthesized and their biological activity was compared with the corresponding alpha-X-TMCs. The conversion of these chalcones to flavanones was proven by LC-MS analysis. It was found that this isomerization is affected by the electron-withdrawing ability if the X-substituent, i.e. the more this ability, the higher is the tendency of the alpha-X-HCs to cyclize. This cyclization made it difficult to get clean kinetics for the reaction of alpha-X-HCs with thiols and led to loss of activity that was supposed to be enhanced by the 2’-OH group. A gain in activity was observed only for alpha-CN-HC.
DOI: 10.5283/epub.29627
Author: Al-Rifai, Nafisah
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W76515573