Synthesis of Novel Heterocyclic Ferrocenyl Chalcones and Their Biological Evaluation.

Breast cancer is currently the most commonly diagnosed cancer, with 287,850 new cases estimated for 2022 as reported by the American Cancer Society. Therefore, finding an effective treatment for this disease is imperative. Chalcones are α,ß-unsaturated systems found in nature. These compounds have shown a wide array of biological activities, making them popular synthetic targets. Chalcones consist of two aromatic substituents connected by an enone bridge; this arrangement allows for a large number of derivatives. Given the biological relevance of these compounds, novel ferrocene-heterocycle-containing chalcones were synthesized and characterized based on a hybrid drug design approach. These heterocycles included thiophene, pyrimidine, thiazolyl, and indole groups. Fourteen novel heterocyclic ferrocenyl chalcones were synthesized and characterized. Herein, we also report their cytotoxicity against triple-negative breast cancer cell lines MDA-MB-231 and 4T1 and the noncancer lung cell line MRC-5. System 3 ferrocenyl chalcones displayed superior anticancer properties compared to their system 1 analogues. System 3 chalcones bearing five-membered heterocyclic substituents (thiophene, pyrazole, pyrrole, and pyrimidine) were the most active toward the MDA-MB-231 cancer cell line with IC50 values from 6.59 to 12.51 µM. Cytotoxicity of the evaluated compounds in the 4T1 cell line exhibited IC50 values from 13.23 to 213.7 µM. System 3 pyrazole chalcone had consistent toxicity toward both cell lines (IC50 ∼ 13 µM) as well as promising selectivity relative to the noncancer MRC-5 control. Antioxidant activity was also evaluated, where, contrary to anticancer capabilities, system 1 ferrocenyl chalcones were superior to their system 3 analogues. Antioxidant activity comparable to that of ascorbic acid was observed for thiophene-bearing ferrocenyl chalcone with EC50 = 31 µM.

Crystal structure of 1-ferrocenyl-2-(4-nitro-phen-yl)ethyne.

The title ferrocene derivative, [Fe(C5H5)2(C8NO2)], including an alkyne bonded to a para-nitro-phenyl substituent, which was synthesized from a copper-free Sonogashira cross-coupling reaction between ethynylferrocene and 4-bromo-1-nitro-benzene, crystallizes in the P21/n space group. In the ferrocene unit, the penta-dienyl (Cps) rings are in an eclipsed conformation. The angle of rotation between the substituted cyclo-penta-dienyl ring and the p-nitro-phenyl group is 6.19 (10)°, yielding a quasi-linear extension of the ferrocenyl substitution. Important inter-molecular inter-actions arise from π-π stacking between the Cp rings and the p-nitro-phenyl, from corners of the Cp rings that are perpendicularly aligned, and between the O atoms from the nitro substituent and carbons at the corners of the Cp rings, propagating along all three crystallographic axes.

Synthesis and characterization of novel ferrocenyl chalcone ammonium and pyridinium salt derivatives.

A novel series of ferrocenyl chalcone ammonium and pyridinium salt derivatives were synthesized in order to improve their solubility in aqueous media. Substituted ferrocenyl chalcones with amines and pyridines were synthesized using the base-catalyzed Claisen-Schmidt reaction, and their corresponding salts were prepared by a nucleophilic quaternization reaction at the nitrogen atom. Most of the synthesized ferrocenyl chalcone salts were soluble in water at room temperature. They were fully characterized by IR, NMR spectroscopy and HRMS spectrometry, and their electrochemistry was studied. The salt derivatives presented chemical reversibility, electrochemical quasi reversibility, and the slope of a plot of Log Ipc (or Ipa) versus Log v were almost 0.5 suggesting that their redox process was controlled by diffusion.