A series of novel furan-2-yl(phenyl)methanone derivatives were synthesized, and their structures were established on the basis of 1H-NMR, 13C-NMR and mass spectral data. All the prepared compounds were screened for their in vitro protein tyrosine kinase inhibitory activity and several new derivatives exhibited promising activity, which, in some cases, was identical to, or even better than that of genistein, a positive reference compound. The preliminary structure-activity relationships of these compounds were investigated and are discussed.
We previously reported 5,2’-dibromo-2,4’,5’-trihydroxydiphenylmethanoe (LM49), a bromophenol analogue that shows strong protection from oxidative stress injury owing to its superior anti-inflammatory, antioxidant, and anti-apoptotic properties. A series of novel nitrogen-containing heterocycle bromophenols were herein synthesized by introducing substituted piperidine, piperazine, and imidazole to modify 2-position of the lead compound LM49. By further evaluating their cytoprotective activity against H2O2 induced injury in EA.hy926 cells, 14 target bromophenols showed moderate-to-potent activity with EC50 values in the range of 0.9–6.3 μM, which were stronger than that of quercetin (EC50: 18.0 μM), a positive reference compound. Of these, the most potent compound 22b is a piperazine bromophenol with an EC50 value of 0.9 μM equivalent to the LM49. Molecular docking studies were subsequently performed to deduce the affinity and binding mode of derived halophenols toward the Keap1 Kelch domain, the docking results exhibited that the small molecule 22b is well accommodated by the bound region of Keap1-Kelch and Nrf2 through stable hydrogen bonds and hydrophobic interaction, which contributed to the enhancement of affinity and stability between the ligand and receptor. The above facts suggest that 22b is a promising pharmacological candidate for further cardiovascular drug development. Moreover, the targeting Keap1-Nrf2 protein-protein interaction may be an emerging strategy for halophenols to selectively and effectively activate Nrf2 triggering downstream protective genes defending against injury.
A series of new benzophenone and diphenylmethane halophenol derivatives were prepared. Their structures were established based on 1H NMR, 13C NMR and HRMS data. All prepared compounds were screened for their in vitro protein tyrosine kinase (PTK) inhibitory activities. The effects of modification of the linker, functional groups and substituted positions at the phenyl ring on PTK inhibitory activity were investigated. Twelve halophenols showed significant PTK inhibitory activity. Among them, compounds 6c, 6d, 7d, 9d, 10d, 11d and 13d exhibited stronger activities than that of genistein, the positive reference compound. The results gave a relatively full and definite description of the structure–activity relationship and provided a foundation for further design and structure optimization of the halophenols.
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