Novel Ferrocene-Containing Pyrazole Analogs of Curcumin: Synthesis, Characterization, Antioxidant Activity, Cyclic Voltammetry, and In Vitro Biological Evaluation

Abstract

Structural modification is an advanced strategy to improve the biological activity of selected compounds and is effectively used to overcome the adverse properties of phytochemicals (e.g., curcumin), such as poor bioavailability and solubility, which limit their clinical use. Considering the fact that ferrocene is a very good candidate for organometallic derivatization of natural products, we have synthesized six new ferrocenylpyrazole analogs of curcumin 8–13. The new compounds were characterized by FT-IR, ¹H, and ¹³C NMR spectroscopy and mass spectrometry (ESI-MS, HRMS), and their antioxidant and electrochemical properties as well as their biological activity were investigated. The best antioxidant activity evaluated with the DPPH assay was shown by compound 13, but it was lower than the activity achieved by curcumin. The prepared compounds showed no activity against the Gram-positive and Gram-negative bacteria tested, but the pyrazoles 8, 10, and 11 and the β-diketone precursors 5, 6, and 7 caused weaker inhibition of the growth of the yeast Candida utilis compared to nystatin. The higher antiproliferative activity in tumorous Hepa 1–6, HeLa, and MCF-7 cells compared to normal HaCaT and CHO-K1 cells was achieved by 10, 12, and 13. Compound 12 showed the strongest inhibitory effect in HeLa cells with an IC₅₀ value of 25.20 μM, while the proliferation of normal cells was significantly less affected. In view of the higher selectivity index, compounds 10 and 12 could be considered for further research in the sense of therapeutic use in neoplasms of reproductive tissue.