Search Results (61)

Pyridine derivatives are widely distributed in nature and have valuable pharmacological properties. The pyridine core can be found in drugs such as sorafenib, zapiclone or prothipendyl. Dipyridothiazines are derivatives of phenothiazines that exhibit valuable anticancer, antioxidant and immunomodulatory activities. In this study, we present the synthesis and preliminary in vitro analysis of anticancer activity towards melanotic (COLO829, G361) and amelanotic (A375, C32) melanoma cells and normal human fibroblasts (HDF) of a series of new tricyclic diazaphenothiazines containing a pyridine scaffold in their structure. The structures of these new molecules was confirmed using spectral techniques, including ¹H NMR, ¹³C NMR, 2D NMR and HRMS. An in vitro panel of experiments was assessed using the WST-1 assay and cytometric techniques. The two most promising compounds were analyzed for their effect on intracellular GSH levels, mitochondrial membrane potential and their ability to initiate DNA fragmentation to determine the potential mechanism of both cytotoxic and proapoptotic activity. The conducted studies confirmed the ability of the new 3-methyl-1,6-diazaphenothiazines to induce apoptosis in cancer cells, especially in terms of inducing initial as well as late-phase apoptosis. Moreover, the studied compounds were found to induce redox imbalance (evidenced by GSH depletion) in the analyzed melanoma cells, which may be an important factor that directs melanoma cells towards cell death signaling pathways. Full article

Nanotechnology is transforming contemporary medicine by providing cutting-edge tools for the treatment and diagnosis of complex disorders. Advanced techniques such as bioimaging and photodynamic therapy (PDT) combine early diagnosis and targeted therapy, offering a more precise approach than conventional treatments. However, a significant obstacle for PDT is the need to selectively deliver photosensitizers to disease sites while minimizing systemic side effects. In this context, mesenchymal stem cells have emerged as promising biological carriers due to their natural tropism towards tumors, low immunogenicity, and their ability to overcome biological barriers. In this study, two push–pull compounds, NPI-PTZ and BTZ-PTZ, phenothiazine derivatives featuring aggregation-induced emission (AIE) abilities, were analyzed. These molecules proved to be excellent fluorescent probes and photosensitizing agents. When administered to human bone marrow-derived multipotent stromal cells (hBM-MSCs) and human adipose multipotent stem cells (hASCs), the compounds were efficiently internalized, maintained a stable fluorescent emission for several days, and showed phototoxicity after irradiation, without inducing major cytotoxic effects under normal conditions. These results highlight the potential of NPI-PTZ and BTZ-PTZ combined with mesenchymal stem cells as theranostic tools, bridging bioimaging and PDT, and suggest new possibilities for advanced therapeutic approaches in clinical applications. Full article

Promethazine hydrochloride (PMH) is a first-generation antipsychotic drug created from phenothiazine derivatives that is widely employed to treat psychiatric disorders in human healthcare systems. However, an overdose or long-term intake of PMH can lead to severe health issues in humans. Hence, establishing a sensitive, accurate, and efficient detection approach to detect PMH in human samples is imperative. In this study, we designed orthorhombic copper molybdate microspheres decorated on reduced graphene oxide (Cu₃Mo₂O₉/RGO) composite via the effective one-pot hydrothermal method. The structural and morphological features of the designed hybrid were studied using various spectroscopic methods. Subsequently, the electrochemical activity of the composite-modified screen-printed carbon electrode (Cu₃Mo₂O₉/RGO/SPCE) was assessed by employing voltammetric methods for PMH sensing. Owing to the uniform composition and structural benefits, the combination of Cu₃Mo₂O₉ and RGO has not only improved electrochemical properties but also enhanced the electron transport between PMH and Cu₃Mo₂O₉/RGO. As a result, the Cu₃Mo₂O₉/RGO/SPCE exhibited a broad linear range of 0.4–420.8 µM with a low limit of detection (LoD) of 0.015 µM, highlighting excellent electrocatalytic performance to PMH. It also demonstrated good cyclic stability, reproducibility, and selectivity in the presence of chlorpromazine and biological and metal compounds. Furthermore, the Cu₃Mo₂O₉/RGO/SPCE sensor displayed satisfactory recoveries for real-time monitoring of PMH in human urine and serum samples. This study delivers a promising electrochemical sensor for the efficient analysis of antipsychotic drug molecules. Full article

Background/Objectives: Mycobacterium abscessus (MAB) is a highly resilient pathogen that causes difficult-to-treat pulmonary infections, particularly in individuals with cystic fibrosis (CF) and other underlying conditions. Its ability to form robust biofilms within the CF lung environment is a major factor contributing to its resistance to antibiotics and evasion of the host immune response, making conventional treatments largely ineffective. These biofilms, encased in an extracellular matrix, enhance drug tolerance and facilitate metabolic adaptations in hypoxic conditions, driving the bacteria into a persistent, non-replicative state that further exacerbates antimicrobial resistance. Treatment options remain limited, with multidrug regimens showing low success rates, highlighting the urgent need for more effective therapeutic strategies. Methods: In this study, we employed artificial sputum media to simulate the CF lung environment and conducted high-throughput screening of 24,000 compounds from diverse chemical libraries to identify inhibitors of MAB biofilm formation, using the Crystal Violet (CV) assay. Results: The screen established 17 hits with ≥30% biofilm inhibitory activity in mycobacteria. Six of these compounds inhibited MAB biofilm formation by over 60%, disrupted established biofilms by ≥40%, and significantly impaired bacterial viability within the biofilms, as confirmed by reduced CFU counts. In conformational assays, select compounds showed potent inhibitory activity in biofilms formed by clinical isolates of both MAB and Mycobacterium avium subsp. hominissuis (MAH). Key compounds, including ethacridine, phenothiazine, and fluorene derivatives, demonstrated potent activity against pre- and post-biofilm conditions, enhanced antibiotic efficacy, and reduced intracellular bacterial loads in macrophages. Conclusions: This study results underscore the potential of these compounds to target biofilm-associated resistance mechanisms, making them valuable candidates for use as adjuncts to existing therapies. These findings also emphasize the need for further investigations, including the initiation of a medicinal chemistry campaign to leverage structure–activity relationship studies and optimize the biological activity of these underexplored class of compounds against nontuberculous mycobacterial (NTM) strains. Full article

This paper explores a novel group of D-π-A configurations that has been specifically created for organic solar cell applications. In these material compounds, the phenothiazine, the furan, and two derivatives of the thienyl-fused IC group act as the donor, the π-conjugated spacer, and the end-group acceptors, respectively. We assess the impact of substituents by introducing bromine atoms at two potential substitution sites on each end-group acceptor (EG1 and EG2). With the donor and π-bridge held constant, we have employed density functional theory and time-dependent DFT simulations to explore the photophysical and optoelectronic properties of tailored compounds (M1–M6). We have demonstrated how structural modifications influence the optoelectronic properties of materials for organic solar cells. Moreover, all proposed compounds exhibit a greater V_oc exceeding 1.5 V, a suitable HOMO-LUMO energy gap (2.14–2.30 eV), and higher dipole moments (9.23–10.90 D). Various decisive key factors that are crucial for exploring the properties of tailored compounds—frontier molecular orbitals, transition density matrix, electrostatic potential, open-circuit voltage, maximum absorption, reduced density gradient, and charge transfer length (D_index)—were also explored. Our analysis delivers profound insights into the design principles of optimizing the performance of organic solar cell applications based on halogenated material compounds. Full article

Objectives: Cancer remains one of the leading causes of death worldwide, and thus, there is a need for the development of innovative and more effective treatment strategies. The aim of the study was to evaluate two types of nanoparticles—nanospheres and micelles—obtained from PLA-based polymers to discover their potential for delivering four types of phenothiazine derivatives. Methods: The morphology, drug-loading properties, cytocompatibility, hemolytic properties and anticancer activity were analyzed. Results: The micelles exhibited significantly higher drug-loading properties, release process and cytotoxic activity against cancer cells compared to the nanospheres. The micelles containing 5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride with an OH group as a substituent in the 10-position of the quinobenzothiazine ring showed the highest drug-loading content, the most efficient drug release, the lowest hemolytic activity and the most significant cytotoxic effect against HeLa cells. Conclusions: The conducted study enabled the development of a delivery system for the new anticancer compound and showed that the choice of drug carrier has a crucial effect on its cytotoxic potential against cancer cells. Full article

Phenothiazine-based photosensitizers bear the intrinsic potential to substitute various expensive organometallic dyes owing to the strong electron-donating nature of the former. If coupled with a strong acceptor unit and the length of N-alkyl chain is appropriately chosen, they can easily produce high efficiency levels in dye-sensitized solar cells. Here, three novel D-A dyes containing 1H-tetrazole-5-acrylic acid as an acceptor were synthesized by varying the N-alkyl chain length at its phenothiazine core and were exploited in dye-sensitized solar cells. Differential scanning calorimetry showed that the synthesized phenothiazine derivatives exhibited behavior characteristic of molecular glasses, with glass transition and melting temperatures in the range of 42–91 and 165–198 °C, respectively. Based on cyclic and differential pulse voltammetry measurements, it was evident that their lowest unoccupied molecular orbital (LUMO) (−3.01–−3.14 eV) and highest occupied molecular orbital (HOMO) (−5.28–−5.33 eV) values were fitted to the TiO₂ conduction band and the redox energy of I⁻/I₃⁻ in electrolyte, respectively. The experimental results were supported by density functional theory, which was also utilized for estimation of the adsorption energy of the dyes on the TiO₂ and its size. Finally, the compounds were tested in dye-sensitized solar cells, which were characterized based on current–voltage measurements. Additionally, for the compound giving the best photovoltaic response, the efficiency of the DSSCs was optimized by a photoanode modification involving the use of cosensitization and coadsorption approaches and the introduction of a blocking layer. Subsequently, two types of tandem dye-sensitized solar cells were constructed, which resulted in an increase in photovoltaic efficiency to 6.37%, as compared to DSSCs before modifications, with a power conversion value of 2.50%. Full article

Dye-sensitized solar cells with synthesized phenothiazine derivative 3,7′-bis(2-cyano-1-acrylic acid)-10-ethyl-phenothiazine (PTZ) and commercial di-tetrabutylammonium cis-bis(isothiocyanato)bis(2,2′-bipyridyl-4,4′-dicarboxylato)ruthenium(II) (N719) dyes were fabricated and characterized based on current–voltage measurements. The effect of the utilization of individual dyes and its mixture, chenodeoxycholic acid as co-adsorbent addition, replacement of I⁻/I₃⁻ by Co^2+/3+ ions in electrolyte and platinum by semiconducting polymer mixture poly(3,4-ethylenedioxythiophene) polystyrene sulfonate in counter electrode was studied. Additionally, the effect of polymer thickness on the photovoltaic performance of the device was evaluated. Prepared photoanodes were characterized by UV–Vis spectroscopy and atomic force microscopy. The further modification of DSSCs involving the fabrication of tandem solar cells was carried out. The higher power conversion efficiency 7.60% exhibited tandem photovoltaic cell sensitized with dyes mixture containing co-adsorbent, I⁻/I₃⁻ ions in the electrolyte, and platinum in the electrode. Full article

For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists. Full article

In this study, a library of 3,7-di(hetero)aryl-substituted 10-(3-trimethylammoniumpropyl)10H-phenothiazine salts is prepared. These title compounds and their precursors are reversible redox systems with tunable potentials. The Hammett correlation gives a very good correlation of the first oxidation potentials with σ_p parameters. Furthermore, the title compounds and their precursors are blue to green-blue emissive. Screening of the salts reveals for some derivatives a distinct inhibition of several pathogenic bacterial strains (Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Aconetobacter baumannii, and Klebsiella pneumoniae) in the lower micromolar range. Full article

Phenothiazine derivatives are widely studied in various fields such as biology, chemistry, and medicine research because of their pharmaceutical effects. The first compound used successfully in the treatment of psychosis was a phenthiazine derivative, chlorpromazine. Apart from its activity in neurons, chlorpromazine has also been reported to display anticancer and antibacterial properties. In this study, we present the synthesis and research on the activity of A549, MDA, MiaPaCa, PC3, and HCT116 cancer cell lines and of S. aureus, S. epidermidis, E. coli, and P. aeruginosa bacterial strains against a series of new tetracyclic chlorpromazine analogues containing a quinoline scaffold in their structure instead of the benzene ring and various substituents at the thiazine nitrogen. The structure of these novel molecules has been determined by ¹H NMR, ¹³C NMR, and HRMS spectral techniques. The seven most active of the twenty-four new chlorpromazine analogues tested were selected to study the mechanism of cytotoxic action. Their ability to induce apoptosis or necrosis in cancer cells was assessed by flow cytometry analysis. The results obtained confirmed the proapoptotic activity of selected compounds, especially in terms of inducing late apoptosis or necrosis in cancer cell lines A549, MiaPaCa-2, and HCT-116. Furthermore, studies on the induction of cell cycle arrest suggest that the new chlorpromazine analogues exert antiproliferative effects by inducing cell cycle arrest in the S phase and, consequently, apoptosis. Full article

Nowadays, drug delivery systems (DDSs) are gaining more and more attention. Conducting polymers (CPs) are efficiently used for DDS construction as such systems can be used in therapy. In this research, a well-known CP, polypyrrole (PPy), was synthesized in the presence of the polysaccharide heparin (HEP) and chlorpromazine (CPZ) using sodium dodecyl sulfate (SDS) as electrolyte on a steel substrate. The obtained results demonstrate the successful incorporation of CPZ and HEP into the polymer matrix, with the deposited films maintaining stable electrochemical parameters across multiple doping/dedoping cycles. Surface roughness, estimated via AFM analysis, revealed a correlation with layer thickness—decreasing for thinner layers and increasing for thicker ones. Moreover, SEM images revealed a change in the morphology of PPy films when PPy is electropolymerized in the presence of CPZ and HEP, while FTIR confirmed the presence of CPZ and HEP within PPy. Due to its lower molecular mass compared to HEP, CPZ was readily integrated into the thin polymer matrix during deposition, with diffusion being unimpeded, as opposed to films with greater thickness. Finally, the resulting system exhibited the ability to release CPZ, enabling a dosing range of 10 mg to 20 mg per day, effectively covering the therapeutic concentration range. Full article

A flow-through biosensor system for the determination of uric acid was developed on the platform of flow-through electrochemical cell manufactured by 3D printing from poly(lactic acid) and equipped with a modified screen-printed graphite electrode (SPE). Uricase was immobilized to the inner surface of a replaceable reactor chamber. Its working volume was reduced to 10 μL against a previously reported similar cell. SPE was modified independently of the enzyme reactor with carbon black, pillar[5]arene, poly(amidoamine) dendrimers based on the p-tert-butylthiacalix[4]arene (PAMAM-calix-dendrimers) platform and electropolymerized 3,7-bis(4-aminophenylamino) phenothiazin-5-ium chloride. Introduction of the PAMAM-calix-dendrimers into the electrode coating led to a fivefold increase in the redox currents of the electroactive polymer. It was found that higher generations of the PAMAM-calix-dendrimers led to a greater increase in the currents measured. Coatings consisted of products of the electropolymerization of the phenothiazine with implemented pillar[5]arene and PAMAM-calix-dendrimers showing high efficiency in the electrochemical reduction of hydrogen peroxide that was formed in the enzymatic oxidation of uric acid. The presence of PAMAM-calix-dendrimer G2 in the coating increased the redox signal related to the uric acid assay by more than 1.5 times. The biosensor system was successfully applied for the enzymatic determination of uric acid in chronoamperometric mode. The following optimal parameters for the chronoamperometric determination of uric acid in flow-through conditions were established: pH 8.0, flow rate 0.2 mL·min⁻¹, 5 U of uricase per reactor. Under these conditions, the biosensor system made it possible to determine from 10 nM to 20 μM of uric acid with the limit of detection (LOD) of 4 nM. Glucose (up to 1 mM), dopamine (up to 0.5 mM), and ascorbic acid (up to 50 μM) did not affect the signal of the biosensor toward uric acid. The biosensor was tested on spiked artificial urine samples, and showed 101% recovery for tenfold diluted samples. The ease of assembly of the flow cell and the low cost of the replacement parts make for a promising future application of the biosensor system in routine clinical analyses. Full article

Among the most malignant cancers, oral squamous cell carcinoma (OSCC) stands out as the most common malignant head and neck tumor. Despite advances in the field of treatment, the prognosis of patients with OSCC remains poor. Aiming to overcome the limitations of the currently existing therapies against OSCC, the present work aims to investigate the potential of photodynamic therapy (PDT) with phenothiazine derivatives used alone or in combination. The incorporation of methylene blue (MB) and toluidine blue (TB) was evaluated in OSCC cell lines (HSC-3 and SCC-9) and a nontumor cell line (Hfib). Both compounds exhibited concentration and time-dependent incorporation, with higher rates observed in tumor cells. Regarding dark-phase cytotoxic activity, SCC-9 cells were the most sensitive cell line with an IC₅₀ value of 362.6 µM and 41.4 µM for MB and TB, respectively. Using PDT, all lineages showed greater sensitivity, presenting lower IC₅₀ values when compared to the dark phase values. The combination index values of 0.69 (dark phase) and 0.73 (clear phase) associated with concave isobolograms, in both phases, revealed that MB and TB have synergistic effects when combined against SCC-9 cells. These findings suggest that MB or TB assisted with PDT holds promise for OSCC treatment. Full article

The development of new drugs or drug candidates based on the phenothiazine system (10H-dibenzo-[b,e]-1,4-thiazine) is a promising approach in view of the diverse biological activity of this tricyclic system, which is present in traditional drugs (chlorpromazine, thioridazine, trifluoperazine, and trifluopromazine) with antipsychotropic, antihistamine and antimuscarinic activities. In practical medicine, these drugs are used as antagonists of dopamine and other neurotransmitter receptors for the treatment of schizophrenia and bipolar disorders. Ongoing studies on the synthesis and biological screening of various phenothiazine derivatives in recent years have revealed other important biological effects of these compounds, among which their antitumor effects are of great interest. This work reports the synthesis of a novel N-substituted phenothiazine analog bearing a mitochondria-directed cationic group (E)-4-(1H-indol-3-ylvinyl)-pyridinium (F16) linked to the nitrogen atom of the phenothiazine core by a butane bridge. The lipophilic cationic F16 fragment was used as a means to enhance transmembrane transport and selective delivery of the hybrid molecule into the mitochondria of cancer cells. In tests on the BT474 breast cancer cell line, the phenothiazine-F16 hybrid demonstrated significant cytotoxic activity. The cytotoxic effect of the compound was noticeable at a concentration of 5 μM and further increased dose-dependently, leading to complete tumor cell death at a concentration of 50 μM (IC₅₀ 3.3 μM). The F16-derivative of phenotzine showed marked mitochondrial targeting. In experiments on isolated rat liver mitochondria, the tested agent, already at a concentration of 5 μM, significantly decreased the membrane potential of succinate-energized organelles. Increasing the concentration of the phenothiazine hybrid to 20 μM resulted in complete dissipation of the potential. The obtained result of antitumor activity against BT-474 cell culture and significant effect on the reduction of mitochondrial membrane potential allows us to consider phenothiazine-F16 hybrid as a new promising antitumor drug. Full article