Substituted Phenyl Ring Research Articles

Novel diaryl dihydropyrimidines as promising anticancer agents: In silico, in vitro investigation

Due to the structural resemblance with the nucleic acid bases, Dihydropyrimidines (DHPs) gained a special attention for exploring for chemotherapeutic agents. Diaryl dihydropyrimidines (DADPs) were reported to have anticancer properties and antiviral and antibacterial activities. In an attempt to design new DADP compounds, we have come up with some novel compounds (3a–3o, 4a–4o, 5a–5o) by incorporating the piperonal to check its significance on biological activity. Initially, computational screening has been performed to shortlist the top molecules which are showing better binding interactions with the selected targets of cancer treatment such as VEGFR2, JAK1 kinase, and JAK3 kinase. Later the selected compounds were synthesized (15 compounds) and characterized by spectral analysis. In the in vitro anti-proliferative activity in the three cell lines, it was observed that the compounds have exhibited potential biological activity (IC50 values 3d – 42.67 ± 2.28 μM against MCF-7; 3n – 59.68 ± 2.81 μM against Hep G-7; 3d – 70.64 ± 3.12 μM against A-549). It was observed that the piperonal, substituted phenyl ring, secondary amine in mannich base has resulted with improved biological activity, the same has been observed in molecular docking studies.

Synthesis, spectroscopic, electrochemistry and antioxidant properties of benzofuroxan and 2H-benzimidazole 1,3-dioxide derivatives: Effects of conjugation with electron-acceptor 1,2,3-triazolyl-1,2,4-oxadiazole

A series of novel benzofuroxan and of 2,2-dimethyl-2H-benzimidazole 1,3-dioxide derivatives conjugated to the strong electron-withdrawing 1,2,4-oxadiazole ring and to the amide isostere 1,2,3-triazole were synthesized. NHeterocycle-N-oxide-bearing carboxylic acids and 1,2,3-triazole-4-carbamidoximes served as convenient reactants for the obtention of the 1,2,4-oxadiazoles. By employing O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU) as coupling reagent and 1,8-diazabicyclo[5.4.0]undec‑7-ene (DBU) as base in acetonitrile, in a one-pot sequence, at room temperature, products were obtained in generally high yields (64 – 93 %) after two 30 min steps and a simple purification process. NMR spectroscopy, X-Ray diffraction and DFT calculations helped to access the preferential tautomeric structures of selected compounds. UV–Vis spectroscopy revealed characteristic absorption peaks for 1,2,3-triazolyl-1,2,4-oxadiazoles 11aa-be, noteworthy an intramolecular charge transfer (ICT) band around 500–650 nm for benzimidazole-1,3-dioxide derivatives 11ba-be, while low fluorescence quantum yields and Stokes shifts were observed for all compounds. Both oxidation and reduction peaks were observed in Cyclic Voltammetry experiments, including irreversible reduction peaks for all 11aa-be compounds. TD-DFT calculations enabled comprehension of the molecular orbitals participation in the UV–Vis transitions, which depend on the N-oxide, the heterocycles and the substituted phenyl ring. Also, some compounds with electron withdrawing groups (Cl and CF3) also displayed good antioxidant activity in DPPH assays.

Combined computational and synthetic strategies for the development of potent pyrazolo-pyridine derivatives as anticancer agents

PI3K comprise a group of lipid kinases mainly made up of three classes and have a particular role in signal transduction. The aberration of class IA PI3K is most frequently shown in cancer. The computation techniques have been applied for the identification of potent compounds. This involved the generation of a library of novel compounds (2700) through R-group enumeration study. The screening process utilized a combination of pharmacophore-based virtual screening and various docking algorithms, leading to the discovery of ten novel compounds. The docking studies against PI3K kinase highlighted MSA6 and MSA7 as the most promising compounds, with docking scores of -9.03 and -9.0 kcal/mol, respectively. Results of docking studies of all derivatives confirmed satisfactory binding mode of the compounds within the active site of the target protein PI3K kinase. The screened pyrazolo-pyridine derivatives (MSA1-MSA10) were synthesized and evaluated as anti-cancer agents against NSCLC using A549 cell line. MSA6 showed the dose dependent enhancement in ROS production at concentration of 10 and 20 µM in A549 cells. MSA6 triggered caspase 3 cleavage in lung cancer cells in a dose-dependent manner. MSA6 treatment at 10 and 20 µM levels boosted NF-κβ expression in the cytoplasm while decreasing it in the nucleus, as demonstrated by flow cytometry with an anti-NF-κβ antibody. The modulation of PI3K activity have been observed at 10 µM and 20 µM concentration of MSA6. A549 cells treated with MSA6 with 20 µM showed significant reduction in wound healing in cancerous cell. A549 cells treated with 20 µM showed significantly reduction in number of colonies compared to control group. Compound MSA6 having a methyl group at the para position of phenyl ring at imine carbon and phenyl ring substitution at nitrogen of pyrazole ring exhibited remarkable growth inhibitory activity with IC50 value of 49.23 μM. Based on the above results, pyrazolo-pyridine derivatives can be used for the further development of novel PI3K kinase inhibitors as anticancer agents.

One-step synthesis of diaryloxadiazoles as potent inhibitors of BCRP.

Aim: BCRP plays a major role in the efflux of cytotoxic molecules, limiting their antiproliferative activity. We aimed to design and synthesize new BCRP inhibitors to render cancerous tumors more sensitive toward anticancer agents. Materials & methods: Based on our previous work, we conceived potential BCRP inhibitors derived from 1,3,4-oxadiazoles bearing two substituted phenyl rings. Results: Evaluating 19 derivatives, we found that 2,5-diaryl-1,3,4-oxadiazoles possessing methoxy groups were the most active. The highest activity was recorded with derivatives bearing three methoxy groups. The most active compound (3j) was selective in inhibiting BCRP and nontoxic as evidenced by cellular tests. Conclusion: 3j is a promising BCRP inhibitor thanks to its synthetic accessibility and biological profile.

Diaryl-substituted benzimidazole derivatives as antiproliferative agents: Design, synthesis, in vitro activity, and SAR analysis

In this study, a series of 1,2-disubstituted benzimidazoles, designed to mimic nucleotides and interact favorably with amino acids in protein active sites, were synthesized and characterized. These compounds were characterized using IR, NMR spectral data, and elemental analyses, leveraging the recognition of substituted benzimidazoles as pharmacophores in the literature due to their documented anticancer activities. The compounds involved chloro and substituted phenyl rings, known for their anticancer activities, as key pharmacophores. Cytotoxicity assessments using the MTT assay were performed against MCF7, MDA-MB-231, and normal mouse fibroblasts (L929) for all synthesized compounds (11–19). Among them, compound 13 exhibited the most significant activity, inducing cell cycle arrest at the G0/G1 phase in MCF7 cells, suggesting its potential as an antitumor agent through apoptosis. To understand the underlying mechanisms of apoptotic cell death induced by compound 13, we investigated the involvement of apoptotic proteins such as Bax, Bcl-2, and p53. Our findings highlight Compound 13 as a promising scaffold for further optimization in the development of effective anticancer drugs.

Isomeric Effect of a π Bridge in an IDT-Based Nonfused Electron Photovoltaic Acceptor.

A pair of isomers, IDT-BOF containing S⋅⋅⋅O/F⋅⋅⋅H noncovalently configurational locks and IDT-BFO containing F⋅⋅⋅H/O⋅⋅⋅H noncovalently configurational locks, with an acceptor-π-donor-π-acceptor (A-π-D-π-A) structure have been designed and synthesized by choosing 4,9-dihydro-s-indaceno[1,2-b : 5,6-b']dithiophene (IDT) as the D unit, an F/n-hexyloxy substituted phenyl ring as π bridge, and 3-(dicyanomethylidene)indan-1-one as the A unit. Owing to the S⋅⋅⋅O/F⋅⋅⋅H or F⋅⋅⋅H/O⋅⋅⋅H noncovalently configurational locks, both IDT-BOF and IDT-BFO have a completely planar structure. IDT-BOF exhibits a similar LUMO to IDT-BFO, but higher HOMO energy levels, leading to a smaller optical bandgap and red-shifted absorption. However, IDT-BOF-based bulk-heterojunction organic solar cells (BHJ-OSCs) coupled with PBDB-T, and PCE-10 as donor materials both exhibited a lower PCE than that of IDT-BFO (PBDB-T: 5.2 vs. 6.1 %; PCE-10: 1.7 vs. 3.2 %). Comprehensively comparing and investigating IDT-BOF : PBDB-T and IDT-BFO : PBDB-T OSCs suggested that the large phase separation and serious charge recombination of IDT-BOF-based OSCs contributed to its lower power conversion efficiency. Importantly, ternary solar cells based on PBDB-T : Y5 as control devices with an additional 10 % IDT-BFO exhibited a 5 % enhancement in the PCE compared to the control device (14.3 vs. 13.46 %).

2-Amino-5-arylethynyl-thiophen-3-yl-(phenyl)methanones as A1 Adenosine Receptor Positive Allosteric Modulators.

A1 adenosine receptor (A1AR) agonists have cerebroprotective, cardioprotective, antinociceptive, and other pharmaceutical applications. We explored the structure-activity relationship of 5-arylethynyl aminothiophenes as A1AR positive allosteric modulators (PAMs). The derivatives were compared in binding and functional assays at the human A1AR, indicating that some fluoro-substituted analogues have enhanced PAM activity. We identified substitution of the terminal phenyl ring in 12 (2-F-Ph), 15 (3,4-F2-Ph, MRS7935), and 21 (2-CF3-Ph) as particularly enhancing the PAM activity. 15 was also shown to act as an A1 ago-PAM with EC50 ≈ 2 μM, without activity (30 μM) at other ARs. Molecular modeling indicated that both the 5-arylethynyl and the 4-neopentyl groups are located in a region outside the receptor transmembrane helix bundle that is in contact with the phospholipid bilayer, consistent with the preference for nonpolar substitution of the aryl moiety. Although they are hydrophobic, these PAMs could provide potential drug candidate molecules for engaging protective A1ARs.

Manipulating fluorine induced bulky dipoles and their strong interaction to achieve high efficiency electric energy storage performance in polymer dielectrics

The pursuit of polymer dielectrics with elevated energy density frequently results in heightened energy loss, thereby hindering practical applications. To decouple the dependence of the high energy loss on the high energy storage performance, based on theoretical simulations, a bulky polar unit constructed from a fluorine atom substituted phenyl ring (4-FSt) is designed and copolymerized with methyl methacrylate (MMA). The fluorine atom is found to induce the dipole formation by deforming π-conjugated electrons distribution on the phenyl ring, which favors reversible polarization behaviors instead of conventional dipole orientation polarization under AC electric field and enhances the energy density of polymers. Meanwhile, the introduction of fluorine atoms possessing electron-withdrawing properties is confirmed to increase the electrons capturing ability and the dipole interactions, which significantly reduces the leakage conduction and orientation relaxation induced energy loss. As a result, the rather high energy discharging efficiency (over 88 %) could be finely maintained up to 825 MV m−1, and a discharge energy density of 16.6 J cm−3 is obtained, which exhibits significant advances over the reported polymer dielectrics. This work presents the first practice to decouple the dependence of high energy storage and energy loss in polymer dielectrics by manipulating the fluorine effect.

New 2-alkoxycyanopyridine derivatives as inhibitors of EGFR, HER2, and DHFR: Synthesis, anticancer evaluation, and molecular modeling studies

New series of substituted 2-alkoxycyanopyridine derivatives were synthesized and evaluated for their in vitro and in vivo anticancer activities. Comparing the evaluated activities against cancer cell lines to the broad-spectrum anticancer doxorubicin, and the kinase inhibitor sorafenib, compounds 3a, 4b, 4c, 7a, and 8d demonstrated superior anticancer efficacy with elevated safety profiles and selectivity indices, particularly against MCF7 breast cancer. For exploration of their mechanism of action, assays for inhibition of EGFR, HER2 kinase, and DHFR were performed. The promising synthesized compounds exhibited potent dual kinase EGFR/HER2 inhibitory activity with IC50values of 0.248/0.156 μM for 4b and 0.138/0.092 μM for 4c. Additionally, with IC50 values of 0.138 and 0.193 M, respectively, 4b and 4c had the greatest DHFR inhibitory activity that was comparable to methotrexate. In the MCF7 breast cancer cell line, they caused arrest at the S phase of the cell cycle and exhibited apoptosis induction activity. With restored caspase-3 immunoexpression, the anti-breast cancer assay performed in vivo of 4b and 4c demonstrated a substantial decrease in tumor volume. Results from molecular modeling were in agreement with biological assays proving the importance of the 3-caynopyridine, two substituted phenyl rings attached to central pyridine ring, and propoxy side chain moieties for binding with the receptors. As 4c works by inhibiting both EGFR/HER2 kinase, DHFR enzymes, in addition to cellular apoptosis, it could be viewed as a model of compounds possessing a multi-targeting anticancer activity. Collectively, compounds 4b and 4c might represent prototypes for further development as anticancer molecules.

Synthesis and biological evaluation of carboxamide and quinoline derivatives as P2X7R antagonists

P2X7 receptor (P2X7R) has a key role in different pathological conditions, importantly overexpressed and activated in cancers. We explored the structure activity relationship (SAR) of three novel pyrazines, quinoline-carboxamide and oxadiazole series. Their selective inhibitory potency in Ca2+ mobilization assay using h-P2X7R-MCF-7 cells improved with phenyl ring substitutions (–OCF3, –CF3, and –CH3) in carboxamide and oxadiazole derivatives, respectively. However, highly electronegative fluoro, chloro, and iodo substitutions enhanced affinity. 1e, 2f, 2e, 1d, 2 g and 3e were most potent and selective toward h-P2X7R (IC50 values 0.457, 0.566, 0.624, 0.682, 0.813 and 0.890 µM, respectively) and were inactive at h-P2X4R, h-P2X2R, r-P2Y6R, h-P2Y2R, t-P2Y1R expressed in MCF-7 and 1321N1 astrocytoma cells. Cell viability (MTT assay at 100 µM, cell line) for 3e was 62% (HEK-293T), 70% (1321N1 astrocytoma) and 85% (MCF-7). >75% cell viability was noted for 2 g and >80% for 2e and 1d in all non-transfected cell lines. Anti-proliferative effects, compared to control (Bz-ATP), of selective antagonists (10 µM) were 3e (11%) 1d, (19%) 1e, (70%, P = 0.005) and 2f, (24%), indicating involvement of P2X7R. Apoptotic cell death by flow cytometry showed 1e to be most promising, with 35% cell death (PI positive cells), followed by 2e (25%), 2f (20%), and 1d (19%), compared to control. Fluorescence microscopic analysis of apoptotic changes in P2X7R-transfected cell lines was established. 1e and 2f at 1X and 2X IC50 increased cellular shrinkage, nuclear condensation and PI/DAPI fluorescence. In-silico antagonist modeling predicted ligand receptor interactions, and all compounds obeyed Lipinski rules. These results suggest that pyrazine, quinoline-carboxamide and oxadiazole derivatives could be moderately potent P2X7R antagonists for in vivo studies and anti-cancer drug development.

Design, synthesis, and evaluation of new anti-inflammatory natural products amide derivatives endowed with anti-blood cancer activity towards development of potential multifunctional agents against hematological cancers

New amide derivatives of the natural product 5,6,7-trimethoxyflavanone were designed as multifunctional antiproliferative molecules against blood cancer and the associated inflammatory conditions. The targeted compounds were synthesized efficiently in three linear steps employing known chalcone starting materials. Compounds 2h, 2i, 2l, 2t, 2v and 2x having bromo or nitro substituted-phenyl rings elicited potential inhibitory effects on macrophages production of nitric oxide, PGE2 and TNF-α which are proinflammatory mediators involved in tumorigenesis and progression of blood cancer. Additionally, evaluation of direct inhibitory effects on the growth of diverse blood cancers including leukemia, lymphoma, and myeloma cell lines unveiled compound 2v as the most potential molecules eliciting at least five-folds the potency of the standard imatinib drug over the used diverse blood cancers. Furthermore, compound 2v showed good selectivity to blood cancer cells rather than normal MRC5 cells. Moreover, compound 2v triggered death of HL60 leukemia cells via apoptosis induction. In conclusion, the natural product-derived compound 2v might serve as a multifunctional lead compound for further development of agents for treatment of blood cancers.

A computational approach for screening carbazole based organic dyes as potential photosensitizers for DSSCs application

The scientific community has shown significant interest in organic materials due to their potential applications in optoelectronics. In this study, we present the design and theoretical investigation of a new class of carbazole-based organic chromogens (R1-6). These chromogens consist of a heteroaromatic carbazole unit as an electron-rich donor, connected to a substituted phenyl ring carrying various electron acceptor groups. Specifically, we analyse the structural impact of electron withdrawing moieties such as carboxylic acid (–COOH), cyano (–CN), and nitro (–NO2) on the photophysical properties of these chromogens. To gain insights into the electron density localization and charge transfer characteristics, we perform DFT, TD-DFT, and MESP calculations. The computational studies indicate that these materials exhibit promising potential as sensitizers for applications in dye-sensitized solar cells (DSSCs).

On energetics of proton and electron transfer of selected phenol derivatives: Theoretical investigation of radical and oxonium cations

AbstractIn this paper, the systematic theoretical study of phenol and 36 compounds representing various ortho, meta and para‐substituted (R‐PhOH) phenols is presented. The hydroxyl group acidity is a characteristic feature of phenol which can be modified using substitution of phenyl ring. The proton‐coupled electron transfer was investigated for parent neutral phenols, R‐PhOH, their cation radicals, R‐PhOH+•, and oxonium cations, R‐PhOH2+. Density functional theory calculations were combined with solvent continuum model for water and dimethyl sulfoxide environment. For aqueous solution, the Pourbaix diagrams (electrochemical potential vs. pH) were constructed from the theoretically predicted acidity constants and electrochemical standard potentials. From the thermodynamic point of view, the obtained theoretical results allow the estimation of the thermodynamically preferred process and alternative reaction pathways of phenolic derivatives in very acidic media.

Phenyl-substituted cibalackrot derivatives: Redox behavior, structure-properties relationships and in situ UV-vis/EPR-spectroelectrochemistry of radical ions

Redox properties and UV–vis and EPR spectroelectrochemical behavior of cibalackrot (7,14-diphenyldiindolo[3,2,1-de:3′,2′,1′-ij][1,5]naphthyridine-6,13‑dione, 1) and its six derivatives 2 - 7 carrying two substituted phenyl rings have been examined. The dyes are of potential interest for organic electronics and singlet fission for solar energy conversion. The compounds are reduced in two reversible one-electron steps under formation of a stable primary radical anion. Oxidation yields the radical cation in a first reversible step and the second step is quasireversible. The presence of radical ions was confirmed by in situ UV–vis/EPR spectroelectrochemistry. The substituents have different influence on oxidation and on reduction, as revealed using the LFER approach and interpreted with the help of calculated energies of frontier orbitals. The observed first reduction (Ered1) and first oxidation (Eox1) potentials correlate well with the calculated values and their difference (ΔE1) has photophysical relevance because it reflects the energy of HOMO-LUMO gap.

A Potential Lead for Insect Growth Regulator: Design, Synthesis, and Biological Activity Evaluation of Novel Hexacyclic Pyrazolamide Derivatives.

Ecdysone receptor (EcR) and chitinase play a critical role in the molting stage of insect pests. Each of them is considered a promising target for the development of novel insect growth regulators (IGRs). In the present paper, a total of 24 (23 novel) hexacyclic pyrazolamide derivatives were designed and synthesized by reducing the heptacycle and inserting small flexible linkers on the basis of the previously discovered dual-target compound D-27 acting simultaneously on EcR and Ostrinia furnacalis chitinase (OfChtI). Their insecticidal activities against Plutella xylostella, Spodoptera frugiperda, and Ostrinia furnacalis larvae were evaluated. The results revealed that the insecticidal activity was not significantly enhanced when the heptacycle on the pyrazole ring was reduced to a hexacycle. However, the insertion of an additional methylene spacer between the substituted phenyl ring and the amide bond can improve the insecticidal activity. Among the derivatives, the most potent compound, 6j, exhibited promising insecticidal activities against P. xylostella and S. frugiperda. Further protein binding assays and molecular docking indicated that 6j could target both EcR and OfChtI, and is a potential lead compound for IGRs. The present work provides valuable clues for the development of new dual-target IGRs.

Novel substituted 1,8-naphthyridines: Design, synthesis, radiolabeling, and evaluation of apoptosis and topoisomerase II inhibition.

A series of seventeen 1,8-naphthyridine derivatives (5a-5q) conjugated at N1 to various substituted phenyl rings were designed and synthesized as potential topoisomerase II (Topo II) inhibitors. The antiproliferative activity of the target compounds against three cancer cell lines showed that compounds 5g and 5p had the highest antiproliferative activity. In addition, 5p and 5g displayed a high selectivity index (SI) for cancer cells when tested on WI38 normal cells, whereby compound 5p showed the highest SI. Furthermore, 5g and 5p induced cell cycle arrest at the S and G1/S phases, respectively, triggering apoptosis in HepG-2 cells. The in vitro Topo II inhibitory effect (plasmid-based) of both compounds revealed that 5p had better inhibition of Topo II. In addition, 5p displayed potent topoisomerase IIβ inhibitory effect when compared to known topoisomerase inhibitors (doxorubicin and topotecan). Molecular docking proposed a unique binding pattern of 5p in the etoposide binding pocket of topoisomerase IIβ, endorsing its potential role as a Topo II poison. Accordingly, 5p was chosen for radioiodination to study the degree of tumor localization following administration in solid tumor-bearing mice. The radioiodinated 5p showed a selective localization at the tumor site, which further confirmed the value of 5p as a lead 1,8-naphthyridine anticancer agent.

N-(4-Methoxy-2-nitrophenyl)-2-(3-methyl-2-oxo-1,2-dihydroquinoxalin-1-yl)acetamide.

The quinoxaline unit in the title mol-ecule, C18H16N4O5, is slightly puckered [dihedral angle between the rings = 2.07 (12)°] while the whole mol-ecule adopts an L-shaped conformation. Intra-molecular hydrogen bonding determines the orientation of the substituted phenyl ring and the amide nitro-gen atom is almost planar. The packing in the crystal is governed by C-H⋯O hydrogen bonds and slipped π-stacking inter-actions.

A microwave-assisted and efficient reduction protocol for the synthesis of alkyl-substituted [2.2]-paracyclophanes

[2.2]-Paracyclophane derivatives have been promising platforms for applications in biology and materials science. To access pure derivatives thereof, a safe and non-toxic synthetic method for 4- n-propyl-[2.2]-paracyclophane is developed via a microwave-assisted and NH2NH2/KOH reduction route. We introduce microwave-assisted acylation for a synthesis that successfully improves the yield and reduces the reaction time. Notably, an exploration of the length and number of the alkyl chains on the [2.2]-paracyclophane ring did not significantly affect the outcome of this reaction. We synthesized 4- n-butyl-[2.2]-paracyclophane and 4,12-dipropyl-[2.2]-paracyclophane via our protocol with high yields. The regioselectivity of the second electrophilic substitution on 4- n-propyl-[2.2]-paracyclophane occurs at the para position of the less substituted phenyl ring.

Antileishmanial evaluation of triazole-butenolide conjugates: design, synthesis, in vitro screening, SAR and in silico ADME predictions.

In the quest to discover novel scaffolds with leishmanicidal effects, a series of 23 compounds containing the most promising 1,2,3-triazole and highly potent butenolide in one framework were synthesized. The synthesized conjugates were screened against Leishmania donovani parasite; five of them showed moderate antileishmanial activity against promastigotes (IC50 30.6 to 35.5 μM) and eight of them exhibited significant activity against amastigotes (IC50 ≤12 μM). Compound 10u was found to be the most active (IC50 8.4 ± 0.12 μM) with the highest safety index (20.47). The series was further evaluated against Plasmodium falciparum (3D7 strain) and seven compounds were found to be moderately active. Among them, again 10u emerged as the most active compound (IC50 3.65 μM). In antifilarial assays against adult female Brugia malayi, five compounds showed grade II inhibition (50-74%). Structure-activity relationship (SAR) analysis suggested a substituted phenyl ring, triazole and butenolide as essential structural features for bioactivity. Moreover, the results of in silico ADME parameter and pharmacokinetic studies indicated that the synthesized triazole-butenolide conjugates abide by the required criteria for the development of orally active drugs, and thus this scaffold can be used as a pharmacologically active framework that should be considered for the development of potential antileishmanial hits.

Impact of Coordination Mode and Ferrocene Functionalization on the Anticancer Activity of N-Heterocyclic Carbene Half-Sandwich Complexes.

The substitution of phenyl rings in established drugs with ferrocenyl moieties has been reported to yield compounds with improved biological activity and alternative modes of action, often involving the formation of reactive oxygen species (ROS). Translating this concept to N-heterocyclic carbene (NHC) complexes, we report here organometallics with a piano-stool structure that feature di- or tridentate ligand systems. The ligands impacted the cytotoxic activity of the NHC complexes, but the coordination modes seemed to have a limited influence, which may be related to the propensity of forming the same species in solution. In general, the stability of the complexes in an aqueous environment and their reactivity to selected biomolecules were largely dominated by the nature of the metal center. While the complexes promoted the formation of ROS, the levels did not correlate with their cytotoxic activity. However, the introduction of ferrocenyl moieties had a significant impact on the antiproliferative potency of the complexes and, in particular, some of the ferrocenyl-functionalized compounds yielded IC50 values in the low μM range.