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Malaria and cancer are chronic diseases. The challenge with drugs available for the treatment of these diseases is drug toxicity and resistance. Ferrocene is a potent organometallic which have been hybridized with other compounds resulting in compounds with enhanced biological activity such as antimalarial and anticancer. Drugs such as ferroquine were developed from ferrocene and chloroquine. It was tested in the 1990s as an antimalarial and is still an effective antimalarial. Many researchers have reported ferrocene compounds as potent compounds useful as anticancer and antimalarial agents when hybridized with other pharmaceutical scaffolds. This review will be focused on compounds with ferrocene moieties that exhibit either an anticancer or antimalarial activity.

It has been known since the 1990s that the introduction of a ferrocenyl–type substituent into compounds with proven biological activity can improve their properties. More recently, it was also shown that a carbon bridge connecting the two cyclopentadienyl rings in ferrocene derivatives could enhance the biological properties of the new compounds compared to those without them. However, the synthesis of ferrocenes with this additional linker, known as ansa–ferrocenes, is more difficult due to advanced synthetic protocols and the phenomenon of planar chirality in ring–substituted compounds. As a result, research into the formation of hybrids, conjugates and other ansa–ferrocene derivatives has not been widely conducted. This review discusses the potential biological properties of these units, covering scientific articles published between 1980 and 2024.

In this study, a series of (Z)- and (E)-2-substituted-3-ferrocene-acrylonitrile derivatives were synthesized, characterized, and evaluated in vitro for their anticancer and anti-migration properties. The compounds were synthesized via the Knoevenagel condensation of the appropriate benzyl cyanide or benzoyl acetonitrile with ferrocenecarboxaldehyde 1, producing isolated yields of 99 to 23%. The structures of the compounds were analyzed using IR, 1H NMR, 13C1H NMR, GC-MS, and UV/Vis spectroscopic methods. Single-crystal X-ray diffraction analysis of representative compounds 21, 27, and 29 demonstrated that the geometry of the double bond was that of the (Z)-isomer. For representative compound 33, the geometry of the double bond was that of the (E)-isomer. Additionally, the electrochemistry of the compounds was investigated using cyclic voltammetry. The cytotoxic and anti-migratory effects of these compounds were evaluated in the MCF-7 and MDA-MB-231 breast cancer cell lines, providing insight into the structure–activity relationships. Preliminary investigations of their anticancer activity revealed that several compounds exhibit moderate antiproliferative effects on cancer cell lines, with GI50 values ranging from 23 to 44 μM for the MCF-7 cell line and from 9 to 41 μM for the MDA-MB-231 cell line. Moreover, compound (Z)-25 inhibited 13% of the migration activity of the metastatic MDA-MB-231 cell line.

In this study, ferrocene-containing thiazolidine-2,4-dione derivatives were screened against triple-negative breast cancer (TNBC) cell lines, which represent an aggressive subtype of the disease predominant in women of African descent. The lack of key receptors in TNBC poses a therapeutic challenge as there are limited targeted treatment options available for this subtype. The ferrocene thiazolidine-2,4-dione derivatives displayed toxicity against HCC70 TNBC cells in the low-moderate micromolar range (5–46 μM) and two compounds were selected for further study, with IC 50 values of 7.54 ± 1.07 μM (OY25) and 5.59 ± 1.24 μM (OY29). Additionally, compounds OY25 and OY29 were screened against other cancer and non-tumourigenic cell lines and found to be less toxic against non-cancerous breast epithelial cell line MCF-12A (SI = 2.2188 and 4.4359, respectively) compared to the HCC70 TNBC cell line. Compounds OY25 and OY29 show a dual mode of action involving increased reactive oxygen species generation and induction of DNA damage. In silico docking analysis and competitive DNA binding fluorescence-based assays revealed that the compounds disrupt key DNA damage phosphoprotein levels through binding to the minor groove of DNA. In a combination assay, the compounds acted synergistically and antagonistically with DNA damage-inducing drugs, camptothecin and etoposide, respectively. Meanwhile, in combination with PARP-1 inhibitor, OY25 and OY29 acted synergistically and antagonistically, respectively. Furthermore , in silico results, using the SwissADME web tool, showed that the compounds OY25 and OY29 display desirable ADME (absorption, distribution, metabolism, and excretion) profile with parameters within acceptable range.

Neurodegenerative and oncological disorders, such as Alzheimer’s disease (AD) and glioblastoma (GBM), are major global health challenges. Recent evidence indicates shared molecular mechanisms between these diseases, including dysregulated oxidative stress, mitochondrial dysfunction, and protein aggregation. We hypothesized that ferrocene-containing curcumin derivatives could exert dual-functional effects by simultaneously modulating amyloid-β (Aβ) aggregation and inhibiting glioblastoma cell proliferation. This study explores organometallic ferrocene compounds linked to four pyrazole and two pyrimidine analogues of curcumin with different substituents for their effects on amyloid-β-peptide (Aβ) aggregation and glioblastoma. To test this, pyrazole ( FcPy-Cur-H , FcPy-Cur-COPh , FcPy-Cur-COFc , FcPy-Cur-Me ) and pyrimidine ( FcPyn-Cur-O , FcPyn-Cur-S ) analogues were synthesized and evaluated. Thioflavin T fluorescence, atomic force microscopy, and single-molecule localization microscopy revealed structure-dependent inhibition of Aβ fibrillogenesis, with FcPyn-Cur-O , FcPyn-Cur-S , and FcPy-Cur-H showing the strongest anti-amyloidogenic activity. Concurrently, these derivatives reduced U87MG glioblastoma cell viability in a dose-dependent manner, inducing apoptotic features, mitochondrial disruption, and α-tubulin destabilization. Our results demonstrate that specific structural modifications of ferrocene-curcumin analogues enhance their dual anti-amyloidogenic and anticancer activities, highlighting the therapeutic potential of multifunctional compounds. This study provides a conceptual advance by combining neurodegenerative and oncological targets within a single chemical framework, offering a promising strategy for the development of multitargeted therapeutics for complex brain disorders.

Ferrocene (Fc), a redox-active organometallic scaffold, has attracted significant attention in medicinal chemistry due to its favorable physicochemical and pharmacological properties. The present study explores the therapeutic potential of novel Fc-functionalized analogues of imatinib and nilotinib, aimed at targeting BCR-ABL1+ chronic myeloid leukemia (CML) cells. A series of Fc-based derivatives (compounds 6, 9, 14, and 18) were synthesized by systematically substituting key pharmacophoric regions of the parent tyrosine kinase inhibitors with Fc units. The antiproliferative activity of these compounds was evaluated against four BCR-ABL1-positive leukemia cell lines (K-562, BV-173, AR-230, and LAMA-84), with imatinib serving as a reference drug. Biological assays revealed distinct structure–activity relationships. Compounds 6 and 9 demonstrated superior activity against the K-562 cell line, while compounds 14 and 18 exhibited enhanced potency and higher ligand efficiencies (LEs) against BV-173 and AR-230 cells compared to imatinib. Selectivity assays further indicated favorable toxicity profiles of compounds 9 and 14 toward malignant versus non-malignant cells. Molecular docking studies supported these findings, showing that Fc substitution alters binding interactions within the c-Abl kinase ATP-binding site while retaining key stabilizing contacts. Computationally predicted LEs showed strong correlation with experimental data, especially for K-562 and LAMA-84 cells, confirming the kinase as a relevant target.

Ce-MOFs with ferrocenedicarboxylic acid ligands (Ce-FcDC) as a bifunctional nanozyme exhibited high peroxidase (POD)-mimicking activity and superoxide dismutase (SOD)-mimicking activity. H 2 O 2 was produced from catalytic hydrolysis of peroxymonosulfate (PMS) using Ce-FcDC as a catalyst. The growth of E. coli and S. aureus were synergistically and more effectively suppressed by PMS in the presence of Ce-FcDC, in comparison with the sole use of PMS or Ce-FcDc. Under the catalysis of Ce-FcDC as the POD-mimicking nanozyme, PMS could be activated by Ce-FcDC to produce SO 4 •− and •OH and H 2 O 2 from the hydrolysis of PMS was further derivatized to O 2 •− and •OH. Ce-FcDC as the SOD-mimicking nanozyme causes O 2 •−  to form H 2 O 2 . The generation of O 2 •− and •OH were confirmed using p-benzoquinone and isopropanol alcohol as the scavengers. The resulted SO 4 •− , O 2 •− , and •OH from combination of PMS with Ce-FcDC as an activator may have key roles for suppressing the growth of E. coli and S. aureus . This strategy could be an effective approach for suppressing the growth and preventing infections or pollutions of some other microbial cells as well. Graphical abstract

A novel chrysin-ferrocene Schiff base (CFSB) was synthesised as a potential anticancer agent. CFSB demonstrated high cytotoxicity against cancer cells with HepG2 (liver) being the most susceptible (IC = 3.11 µM). The compound was less toxic towards normal MRC5 cells and exhibited ∼5-fold selectivity towards most cancer cells. CFSB caused G1-phase arrest, induced caspase-dependent apoptosis by increasing Bax/Bcl2 ratio and reduced metastasis by decreasing MMP9 in HepG2. Furthermore, CFSB was inactive against CDK2, EGFR, TrkA and VEGFR, but it strongly inhibited topoisomerase II (IC = 20 µM) with potency comparable to etoposide (IC = 15 µM), while weak inhibition was observed against tubulin (IC = 76 µM). DFT calculations revealed that CFSB had desirable reactivity, while docking indicated high binding affinity with topoisomerase II. Molecular dynamics and MM-GBSA analyses showed that CFSB-topoisomerase II complex was stable with favourable binding energies, while ADMET studies showed drug-like properties for CFSB.

The poor prognosis of glioblastoma multiforme, inadequate treatment options, and growing drug resistance urge the need to find new effective agents. Due to the significant anti-cancer potential of harmicens, hybrid compounds which comprise harmine/β-carboline and ferrocene moiety, we investigated their antiglioblastoma potential and mechanism of action (inhibition of DYRK1A, Hsp90, anti-oxidative activity). The results have shown that triazole-type harmicens, namely , with a ferrocene moiety in C-3 position of the β-carboline ring ( = 3.7 ± 0.1 µmol L–1, SI = 12.6) and ., the C-6 substituted harmicene ( = 7.4 ± 0.5 µmol L–1, SI = 5.8) exert remarkable activity and selectivity against human malignant glioblastoma cell line (U251) . On the other hand, amide-type harmicens , , and exhibited strong, but non-selective activity, in the low micro-molar range. Mechanistic studies revealed that among active compounds, amide-type harmicens and inhibit DYRK1A and Hsp90 CTD, whereas compound showed pronounced antioxidative activity. Therefore, the antiproliferative activity of harmicens might be a combination of complex molecular interactions.

Cancer and malaria are both global health threats. Due to the increase in the resistance to the known drugs, research on new active substances is a priority. Here, we present the design, synthesis, and evaluation of the biological activity of harmicens, hybrids composed of covalently bound harmine/β-carboline and ferrocene scaffolds. Structural diversity was achieved by varying the type and length of the linker between the β-carboline ring and ferrocene, as well as its position on the β-carboline ring. Triazole-type harmicens were prepared using Cu(I)-catalyzed azide-alkyne cycloaddition, while the synthesis of amide-type harmicens was carried out by applying a standard coupling reaction. The results of in vitro biological assays showed that the harmicens exerted moderate antiplasmodial activity against the erythrocytic stage of P. falciparum (IC50 in submicromolar and low micromolar range) and significant and selective antiproliferative activity against the MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range, SI > 5.9). Cell localization experiments showed different localizations of nonselective harmicene 36 and HCT116-selective compound 28, which clearly entered the nucleus. A cell cycle analysis revealed that selective harmicene 28 had already induced G1 cell cycle arrest after 24 h, followed by G2/M arrest with a concomitant drastic reduction in the percentage of cells in the S phase, whereas the effect of nonselective compound 36 on the cell cycle was much less pronounced, which agreed with their different localizations within the cell.