Search Results (29)

The rapid emergence of antimicrobial resistance has intensified the search for alternative antimicrobial scaffolds that target both planktonic bacteria and biofilm-associated infections. In this study, a series of hydroxylated phosphonium ionic liquids derived from triphenylphosphonium (TPP⁺) and trihexylphosphonium (THP⁺) cations bearing C3, C6, C7, and C10 ω-hydroxyalkyl chains were synthesized and evaluated for their antibacterial and anti-biofilm activities. Antibacterial activity was determined using broth microdilution assays against Staphylococcus aureus and Escherichia coli, while anti-biofilm activity was assessed by disrupting preformed biofilms using a 96-pin microtiter plate system and crystal violet staining. The results showed that antibacterial activity was strongly influenced by the amphiphilic balance of the compounds, particularly the alkyl chain length and the nature of the phosphonium core. Derivatives bearing C6OH–C10OH chains exhibited the highest antibacterial activity, whereas short-chain analogs displayed markedly reduced potency. THP derivatives were notably more active against E. coli bacteria, consistent with their higher hydrophobicity and activity consistent with membrane interaction. In addition, THP derivatives demonstrated greater biofilm disruption, achieving up to ~90% biomass removal in E. coli biofilms, with C6OH–C7OH derivatives showing the most favorable activity profile. Hemolysis assays indicated low erythrocyte toxicity at concentrations close to antibacterial MIC values, indicating a favorable selectivity window. Overall, these findings highlight phosphonium ionic liquids as promising antimicrobial agents with activity consistent with membrane interaction and provide structure–activity insights for the rational design of new antibacterial and anti-biofilm compounds. Full article

Radiation-induced liver injury (RILI) is a major complication of abdominal radiotherapy, originating from mitochondrial oxidative stress, and effective radioprotectants are lacking. We designed an antioxidant intended to target mitochondria, TPP-C6-NIT, by conjugating a triphenylphosphonium cation to an imidazole nitroxide radical. Its protective effects were evaluated through in vitro assays, studies on irradiated L-02 and Huh-7 cells, a mouse model of whole-body irradiation, combined with metabolomics, molecular docking, and assessments of mitochondrial function, apoptosis, and inflammation. TPP-C6-NIT exhibited potent radical scavenging activity in vitro. In L-02 cells, it reduced oxidative stress, preserved mitochondrial function (membrane potential, ATP, respiratory capacity), and improved viability. In mice, pretreatment with TPP-C6-NIT significantly improved survival, alleviated liver injury (reduced serum ALT/AST and histopathological damage), and suppressed systemic inflammation. Mechanistic exploration suggested TPP-C6-NIT treatment was associated with increased Nrf2/GPX4 expression and reversal of lipid metabolic changes. Notably, TPP-C6-NIT did not confer significant protection in Huh-7 cells, indicating selective cytoprotection. By reducing oxidative stress and preserving mitochondrial function, TPP-C6-NIT demonstrates potent protection against radiation-induced liver injury in a whole-body irradiation mouse model, presenting a promising candidate for further development. Full article

Background: Cancer is a major health concern that significantly impacts the global population. Selective chemotherapeutic delivery is needed to improve the efficacy of cancer therapy while minimizing side effects in healthy cells. This study investigated the potential of gold nanoclusters (AuNCs) functionalized with poly(amidoamine) dendrimers (PAMAM) and folic acid (FA) to selectively deliver doxorubicin (DOX) to cancer cells that express the folate receptor (FR). Methods: AuNC synthesis was confirmed via UV–visible and Fourier transform infrared spectroscopy, nanoparticle tracking analysis, and transmission electron microscopy. Folic acid (FA) was incorporated for cell surface receptor targeting, while the triphenylphosphonium cation (TPP⁺) was added to improve mitochondrial localization. Cytotoxicity (MTT), apoptosis, caspase 3/7, mitopotential, and oxidative stress assays were assessed using human MCF-7 (breast adenocarcinoma), HeLa (cervical carcinoma), Caco-2 (colon adenocarcinoma), MDA-MB-231 (epithelial breast cancer), and the embryonic kidney (HEK293) cells. Results: Favorable DOX loading (>78%), with more than 90% of the drug released at pH 4.5, was achieved. A dose-dependent increase in cytotoxicity was observed, with IC50 values lower in cancer cells than HEK293 cells, indicating selective toxicity and minimal off-target effects. Targeting nanocomplexes produced the best responses in the mitopotential, caspase, and oxidative stress assays in HeLa and MCF-7 cells. Conclusions: The improved cytotoxicity in cancer cells may be due to folate-receptor-mediated cellular uptake, as well as the mitochondrial uptake of TPP⁺ nanocomplexes. This highlighted the potential of the drug–AuNC nanocomplexes to limit systemic side effects, proposing a potential novel strategy for drug delivery to cancer cells. Full article

Aging and neurodegenerative diseases are characterized by common features involving bioenergetics deficiencies, oxidative stress and alterations of calcium buffering. Mechanisms of mitochondrial-targeted drugs include the modulation of electron transport chain and oxidative phosphorylation, the binding to mitochondrial lipids, free-radical scavenging, calcium signaling, and possible effects on mitochondrial biogenesis and dynamics and on the regulation of mitophagic pathways. One of the main sites of action of mitochondria-targeted drugs is the interaction with respiratory chain components. Mitochondrial-targeted compounds such as Mito-Q, and Mito-apocynin have been developed by conjugating triphenylphosphonium (TPP⁺) lipophilic cation group with natural molecules, therefore obtaining promising drugs for reestablishing the correct functioning of the mitochondrial respiratory chain. Stabilization of cardiolipin at the inner mitochondrial membrane by elamipretide or SkQ1 and mitochondria-targeted ROS scavengers can also offer a therapeutic approach to prevent bioenergetic impairment associated with several diseases. In addition, the modulation of calcium signaling can be achieved using both MCU agonists and antagonists representing another mitochondrial target for drug therapies development. Finally, potential strategies for treating neurodegenerative diseases based on the modulation of mitochondrial biogenesis, dynamics and/or mitophagic pathways are discussed. Full article

Oxidative stress, caused by an imbalance between the production of reactive oxygen species and endogenous antioxidant capacity, is a key etiological factor in numerous pathologies, including neurodegenerative and cardiovascular diseases. The limited clinical efficacy of conventional antioxidants is primarily due to their insufficient accumulation within the mitochondria, the main site of intracellular ROS generation. This article reviews the design and application of Mitochondria-Targeted Antioxidants, which represent a major advance in precision medicine. The design of these compounds involves linking an antioxidant “payload” to a lipophilic cation, such as the triphenylphosphonium group. This positive charge leverages the negative electrochemical gradient across the inner mitochondrial membrane to drive the antioxidant into the organelle. This mechanism allows the drug to reach concentrations over 100 times higher than non-targeted alternatives. The discussion encompasses the structure-activity analysis of the carrier, the payload (e.g., quinone derivatives), and the linker, which determine optimal subcellular partitioning and scavenging efficiency. Preclinical data highlight the therapeutic potential of this approach, showing strong neuroprotection in models of Parkinson’s and Alzheimer’s diseases, as well as improved outcomes in cardiovascular and ocular health. By restoring redox balance specifically within the mitochondria, these targeted therapies offer a more effective way to treat chronic oxidative damage. Full article

Poly(lactic acid) (PLA)-based nanocomposites containing a mixture of graphene nanoplatelets (GNP) and carbon nanotube (CNT) as hybrid fillers were prepared using a solution-assisted sonication process followed by melt processing. The effects of the filler dispersion on dielectric properties and microwave absorbing (MWA) performance were systematically investigated. Two ionic liquids (ILs), trihexyl-(tetra-decyl)phosphonium bis (trifluoromethanesulfonyl)imide (IL1) and 11-carboxyundecyl-triphenylphosphonium bromide (IL2), were employed as dispersing agents for the carbonaceous fillers. Incorporation of IL-treated fillers resulted in enhanced dielectric permittivity and improved MWA performance of the PLA composites. The MWA properties were evaluated in X- band and Ku-band. A minimum reflection loss (RL) of −34 dB and an effective absorption bandwidth (EAB) of 2.1 GHz were achieved for the composite containing GNP/CNT/IL2 (HB3) at a weight ratio of 2.5:0.5:0.5 wt% with one 3 mm thick layer. The superior performance of IL2 is attributed to π-π and π-cation interactions between its phenyl-containing cation and the carbonaceous fillers, as well as improved compatibility with the PLA matrix due to carboxyl groups. Additionally, three-layered composite structures, combining PLA/GNP as the outer layer with IL-assisted hybrid fillers in the core and PLA/CNT at the bottom layer, achieved an extended EAB of 4.5 GHz for GNP/HB2/CNT arrangement and 4.35 GHz for the GNP/HB3/CNT arrangement, driven by enhanced scattering and internal reflection of microwaves. These results demonstrate the potential of IL-assisted hybrid filler dispersion in PLA for developing biodegradable materials with multifunctional applications as charge storage capacitors and microwave absorbing materials for sustainable electronics. Full article

Salinomycin and monensin represent a class of natural ionophore antibiotics with strong anticancer properties. In this paper we report on chemical modification of these compounds by conjugation with phosphonium cations for targeting conjugates to the mitochondria of cancer cells. Our findings indicate that this approach yields conjugates with enhanced anticancer activity and selectivity, outperforming not only the parent compounds but also the widely used chemotherapeutic agent, doxorubicin. Comprehensive biological and biophysical analyses proved that the conjugates target the mitochondria in cancer cells, with some of the derivatives additionally promoting generation of mitochondrial reactive oxygen species (mtROS). This targeted strategy holds significant promise for the development of effective mitochondrial-targeted novel anticancer agent. Full article

Polymeric antibacterial agents are attracting attention due to their increased bactericidal efficiency and low probability of causing drug resistance. Their activity, usually attributed to electrostatic interactions and subsequent disruption of cell membranes, is attributed to the number and chemical structure of their functional groups. In this study, hyperbranched polyethyleneimines (PEIs) of two different molecular weights were functionalized with amphiphilic alkyltriphenylphosphonium groups, which are known to induce membrane penetration, especially in cells with high membrane potential. The obtained nanoparticles were chemically and physicochemically characterized, and their inhibition potential against Gram (−) E. coli and Gram (+) S. aureus bacteria was determined. The effects of polymer molecular weight, alkyl chain length, and the number of triphenylphosphonium groups on their antimicrobial efficacy were studied. All compounds exhibited antibacterial properties, especially against S. aureus (MIC < 50 μg/mL). Low-molecular-weight polymeric derivatives and longer alkyl chains proved more efficient against both E. coli (MIC = 20 μg/mL) and S. aureus (MIC = 0.25 μg/mL). SEM images depicted changes in cell morphology, bacterial membrane disruption, and leakage of intracellular contents, signifying loss of cell viability. Minimal cytotoxicity against three mammalian cell lines at relevant antibacterial concentrations demonstrated the potential of a structure–property relationship approach for novel potent antibacterial polymers. Full article

Neurodegenerative diseases are a major public health problem due to the aging population and multifaceted pathology; therefore, the search for new therapeutic alternatives is of the utmost importance. In this sense, a series of six 1-(3-phenoxypropyl)piperidines alkyl-linked to a triphenylphosphonium cation derivative were synthesized as H₃R ligands with antioxidant properties to regulate excessive mitochondrial oxidative stress and contribute to potential new therapeutic approaches for neurodegenerative diseases. Radioligand displacement studies revealed high affinity for H₃R with Ki values in the low to moderate two-digit nanomolar range for all compounds. Compound 6e showed the highest affinity (Ki H₃R = 14.1 nM), comparable to that of pitolisant. Antioxidative effects were evaluated as radical-scavenging properties using the ORAC assay, in which all derivatives showed low to moderate activity. On the other hand, cytotoxic effects in SH-SY5Y neuroblastoma cells were investigated using the colorimetric alamar blue assay, which revealed significant effects on cell viability with an unequivocally structure–toxicity relationship. Finally, docking and molecular simulation studies were used to determine the H₃R binding form, which will allow us to further modify the compounds to establish a robust structure-activity relationship and find a lead compound with therapeutic utility in neurodegenerative diseases. Full article

Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC—such as 5-fluorouracil (5FU)—remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP⁺C₁₀), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP⁺C₁₀), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP⁺C₁₀ with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP⁺C₁₀ and TPP⁺C₁₀ using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP⁺C10 and TPP⁺C₁₀, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP⁺C₁₀ and GA-TPP⁺C₁₀ increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity. Full article

The triphenylphosphonium (TPP) cation has been widely used as a carrier for mitochondria-targeting molecules. We synthesized two commonly employed targeting systems, namely, ω-triphenylphosphonium fatty acids (group 2) and ω-triphenylphosphonium fatty alcohols (group 3), to assess the impact of the TPP module on the biological efficacy of mitochondria-targeting molecules. We evaluated their fungicidal activities against nine plant pathogenic fungi in comparison to alkyl-1-triphenylphosphonium compounds (group 1). All three compound groups exhibited fungicidal activity and displayed a distinct “cut-off effect”, which depended on the length of the carbon chain. Specifically, group 1 compounds showed a cut-off point at C₁₀ (compound 1–7), while group 2 and 3 compounds exhibited cut-off points at C₁₅ (compound 2–12) and C₁₄ (compound 3–11), respectively. Notably, group 1 compounds displayed significantly higher fungicidal activity compared to groups 2 and 3. However, group 2 and 3 compounds showed similar activity to each other, although susceptibility may depend on the pathogen tested. Initial investigations into the mechanism of action of the most active compounds suggested that their fungicidal performance may be primarily attributed to their ability to damage the membrane, as well as uncoupling activity and inhibition of fungal respiration. Our findings suggest that the TPP module used in delivery systems as aliphatic acyl or alkoxyl derivatives with carbon chains length < 10 will contribute negligible fungicidal activity to the TPP-conjugate compared to the effect of high level of accumulation in mitochondria due to its mitochondria-targeting ability. These results provide a foundation for utilizing TPP as a promising carrier in the design and development of more effective mitochondria-targeting drugs or pesticides. Full article

Pancreatic ductal adenocarcinoma (PDAC)’s resistance to therapies is mainly attributed to pancreatic cancer stem cells (PCSCs). Mitochondria-impairing agents can be used to hamper PCSC propagation and reduce PDAC progression. Therefore, to develop an efficient vector for delivering drugs to the mitochondria, we synthesized tris(3,5-dimethylphenyl)phosphonium-conjugated palmitic acid. Triphenylphosphonium (TPP) is a lipophilic cationic moiety that promotes the accumulation of conjugated agents in the mitochondrion. Palmitic acid (PA), the most common saturated fatty acid, has pro-apoptotic activity in different types of cancer cells. TPP-PA was prepared by the reaction of 16-bromopalmitic acid with TPP, and its structure was characterized by ¹H and ¹³C NMR and HRMS. We compared the proteomes of TPP-PA-treated and untreated PDAC cells and PCSCs, identifying dysregulated proteins and pathways. Furthermore, assessments of mitochondrial membrane potential, intracellular ROS, cardiolipin content and lipid peroxidation, ER stress, and autophagy markers provided information on the mechanism of action of TPP-PA. The findings showed that TPP-PA reduces PDAC cell proliferation through mitochondrial disruption that leads to increased ROS, activation of ER stress, and autophagy. Hence, TPP-PA might offer a new approach for eliminating both the primary population of cancer cells and PCSCs, which highlights the promise of TPP-derived compounds as anticancer agents for PDAC. Full article

The most important area of modern pharmacology is the targeted delivery of drugs, and one of the most promising classes of chemical compounds for creating drugs of this kind are the photochromic spiropyrans, capable of light-controlled biological activity. This work is devoted to the synthesis and study of the photochromic properties of new triphenylphosphonium salts of spiropyrans. It was found that all the synthesized cationic spiropyrans have high photosensitivity, increased resistance to photodegradation and the ability for photoluminescence. Full article

Antibacterial resistance poses a critical public health threat, challenging the prevention and treatment of bacterial infections. The search for innovative antibacterial agents has spurred significant interest in quaternary heteronium salts (QHSs), such as quaternary ammonium and phosphonium compounds as potential candidates. In this study, a library of 49 structurally related QHSs was synthesized, varying the cation type and alkyl chain length. Their antibacterial activities against Staphylococcus aureus, including antibiotic-resistant strains, were evaluated by determining minimum inhibitory/bactericidal concentrations (MIC/MBC) ≤ 64 µg/mL. Structure–activity relationship analyses highlighted alkyl-triphenylphosphonium and alkyl-methylimidazolium salts as the most effective against S. aureus CECT 976. The length of the alkyl side chain significantly influenced the antibacterial activity, with optimal chain lengths observed between C₁₀ and C₁₄. Dose–response relationships were assessed for selected QHSs, showing dose-dependent antibacterial activity following a non-linear pattern. Survival curves indicated effective eradication of S. aureus CECT 976 by QHSs at low concentrations, particularly compounds 1e, 3e, and 5e. Moreover, in vitro human cellular data indicated that compounds 2e, 4e, and 5e showed favourable safety profiles at concentrations ≤ 2 µg/mL. These findings highlight the potential of these QHSs as effective agents against susceptible and resistant bacterial strains, providing valuable insights for the rational design of bioactive QHSs. Full article

This research is based on the concept that mitochondria are a promising target for anticancer therapy, including thatassociated with the use of oxidative phosphorylation blockers (mitochondrial poisons). Liposomes based on L-α-phosphatidylcholine (PC) and cholesterol (Chol) modified with cationic surfactants with triphenylphosphonium (TPPB-n, where n = 10, 12, 14, and 16) and imidazolium (IA-n(OH), where n = 10, 12, 14, and 16) head groups were obtained. The physicochemical characteristics of liposomes at different surfactant/lipid molar ratios were determined by dynamic/electrophoretic light scattering, transmission electron microscopy, and spectrophotometry. The hydrodynamic diameter of all the systems was within 120 nm with a polydispersity index of no more than 0.24 even after 2 months of storage. It was shown that cationization of liposomes leads to an increase in the internalization of nanocontainers in pancreatic carcinoma (PANC-1) and duodenal adenocarcinoma (HuTu 80) cells compared with unmodified liposomes. Also, using confocal microscopy, it was shown that liposomes modified with TPPB-14 and IA-14(OH) statistically better colocalize with the mitochondria of tumor cells compared with unmodified ones. At the next stage, the mitochondrial poison rotenone (ROT) was loaded into cationic liposomes. It was shown that the optimal loading concentration of ROT is 0.1 mg/mL. The Korsmeyer–Peppas and Higuchi kinetic models were used to describe the release mechanism of ROT from liposomes in vitro. A significant reduction in the IC₅₀ value for the modified liposomes compared with free ROT was shown and, importantly, a higher degree of selectivity for the HuTu 80 cell line compared with the normal cells (SI value is 307 and 113 for PC/Chol/TPPB-14/ROT and PC/Chol/IA-14(OH)/ROT, respectively) occurred. It was shown that the treatment of HuTu 80 cells with ROT-loaded cationic liposomal formulations leads to a dose-dependent decrease in the mitochondrial membrane potential. Full article