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Lipophilicity is one of the principal parameters that describe the pharmacokinetic behavior of a drug, including its absorption, distribution, metabolism, elimination, and toxicity. In this study, the lipophilicity and other physicochemical, pharmacokinetic, and toxicity properties that affect the bioavailability of newly synthesized dialkylaminoalkyldiquinothiazine hybrids as potential drug candidates are presented. The lipophilicity, as RM0, was determined experimentally by the RP-TLC method using RP18 plates and acetone–TRIS buffer (pH 7.4) as the mobile phase. The chromatographic parameters of lipophilicity were compared to computationally calculated partition coefficients obtained by various types of programs such as iLOGP, XLOGP3, WLOGP, MLOGP, SILCOS-IT, LogP, logP, and milogP. In addition, the selected ADMET parameters were determined in silico using the SwissADME and pkCSM platforms and correlated with the experimental lipophilicity descriptors. The results of the lipophilicity study confirm that the applied algorithms can be useful for the rapid prediction of logP values during the first stage of study of the examined drug candidates. Of all the algorithms used, the biggest similarity to the chromatographic value (RM0) for certain compounds was seen with iLogP. It was found that both the SwissADME and pkCSM web tools are good sources of a wide range of ADMET parameters that describe the pharmacokinetic profiles of the studied compounds and can be fast and low-cost tools in the evaluation of examined drug candidates during the early stages of the development process. [ABSTRACT FROM AUTHOR]

Lipophilicity is one of the most important properties of compounds required to estimate the absorption, distribution, and transport in biological systems, in addition to solubility, stability, and acid–base nature. It is crucial in predicting the ADME profile of bioactive compounds. The study assessed the usefulness of computational and chromatographic methods (thin-layer chromatography in a reversed-phase system, RP-TLC) for estimating the lipophilicity of 21 newly synthesized compounds belonging to diquinothiazines and quinonaphthiazines. In order to obtain reliable values of the relative lipophilicities of diquinothiazines and quinonaphthiazines, the partition coefficients obtained using different algorithms such as AlogPs, AClogP, AlogP, MLOGP, XLOGP2, XLOGP3, logP, and ClogP were compared with the chromatographic RM0 values of all the tested compounds measured by the experimental RP-TLC method (logPTLC). Additionally, logPTLC values were also correlated with other descriptors, as well as the predicted ADME and drug safety profiling parameters. The linear correlations of logPTLC values of the tested compounds with other calculated molecular descriptors such as molar refractivity, as well as ADME parameters (Caco-2 substrates, P-gp inhibitors, CYP2C19, and CYP3A4) generally show poor predictive power. Therefore, in silico ADME profiling can only be helpful at the initial step of designing these new candidates for drugs. The compliance of all discussed diquinothiazines and naphthoquinothiazines with the rules of Lipiński, Veber, and Egan suggests that the tested pentacyclic phenothiazine analogs have a chance to become therapeutic drugs, especially orally active drugs. [ABSTRACT FROM AUTHOR]

Herein, the direct covalent functionalization of single‐walled carbon nanotubes (SWNT) is presented with an amino‐decorated phenyl‐phenothiazine (PTH‐NH2) organophotocatalyst through the diazonium chemistry protocol. Three different SWNT‐PTH hybrids are prepared by varying the amount of PTH‐NH2 and diazonium agent and are fully characterized. These hybrids differ not only in the degree of functionalization, but also in the chemical structure and the photophysical properties. The study shows that these features affect the photoredox activity of the materials in the photo‐debromination of aromatic halides. Thus, sample SWNT‐PTH‐5, a functionalized nanotube with a 5% wt loading of PTH, surpasses the catalytic performance of homogeneous PTH in 11 different substrates, finishing the reaction in shorter times, in a recyclable manner and without catalyst leaching. This study demonstrates the importance of controlling the functionalization degree of SWNT with photocatalysts to prepare photocatalytic materials with even higher catalytic activity than that presented by the homogeneous PTH catalyst. [ABSTRACT FROM AUTHOR]

The kinetochore links chromosomes to spindle microtubules to drive chromosome segregation at cell division. While we know nearly all mammalian kinetochore proteins, how these give rise to the strong yet dynamic microtubule attachments required for function remains poorly understood. Here, we focus on the Astrin-SKAP complex, which localizes to bioriented kinetochores and is essential for chromosome segregation but whose mechanical role is unclear. Live imaging reveals that SKAP depletion dampens the movement and decreases the coordination of metaphase sister kinetochores and increases the tension between them. Using laser ablation to isolate kinetochores bound to polymerizing versus depolymerizing microtubules, we show that without SKAP, kinetochores move slower on both polymerizing and depolymerizing microtubules and that more force is needed to rescue microtubules to polymerize. Thus, in contrast to the previously described kinetochore proteins that increase the grip on microtubules under force, Astrin-SKAP reduces the grip, increasing attachment dynamics and force responsiveness and reducing friction. Together, our findings suggest a model where the Astrin-SKAP complex effectively "lubricates" correct, bioriented attachments to help preserve them.

A new generation of soluble phenothiazinyl merocyanine substituted polyacetylenes can be readily synthesized by rhodium‐catalyzed polymerization of the corresponding 3‐ethynyl phenothiazines, accessible by Sonogashira coupling and Knoevenagel condensation. UV/Vis and fluorescence spectroscopy of 7‐acceptor‐substituted phenothiazinyl polyacetylenes reveal that these polyacetylenes with conjugatively ligated merocyanines are luminescent in solution with positive emission solvatochromism and, in some cases, with distinct solid‐state luminescence. [ABSTRACT FROM AUTHOR]

Hypochlorous acid (HClO/ClO−) is one of the important reactive oxygen species (ROS). It acts as a second signaling molecule within and between cells and is an indispensable active molecule in living organisms to regulate physiological and pathological processes. In this article, two fluorescent probes (PTF and PTA) for highly selective fluorescent recognition of ClO− were successfully synthesized based on the ICT mechanism by condensing phenothiazines with two hydrazides via the hydrazide structure (). PTF can identify different concentrations of ClO− in two steps. Due to its ClO− two site recognition, the probe exhibited good selectivity (specific recognition of ClO− over a wide concentration range), a fast time response (rapid recognition in seconds), a sufficiently low detection limit (3.6 and 11.0 nM), and large Stokes shifts (180 and 145 nm). Furthermore, the recognition of ClO− by contrasting probes with different substituents exhibited different fluorescence changes of ratiometric type and turn‐off. PTF successfully achieves the detection of exogenous and endogenous ClO− in aqueous solution and living cells. [ABSTRACT FROM AUTHOR]

The limitations of current cancer therapies, including the increasing prevalence of multidrug resistance, underscore the urgency for more effective treatments. One promising avenue lies in the repurposing of existing drugs. This review explores the impact of phenothiazines, primarily used as antipsychotic agents, on key mechanisms driving tumor growth and metastasis. The cationic and amphiphilic nature of phenothiazines allows interaction with the lipid bilayer of cellular membranes, resulting in alterations in lipid composition, modulation of calcium channels, fluidity, thinning, and integrity of the plasma membrane. This is especially significant in the setting of increased metabolic activity, a higher proliferative rate, and the invasiveness of cancer cells, which often rely on plasma membrane repair. Therefore, properties of phenothiazines such as compromising plasma membrane integrity and repair, disturbing calcium regulation, inducing cytosolic K-RAS accumulation, and sphingomyelin accumulation in the plasma membrane might counteract multidrug resistance by sensitizing cancer cells to membrane damage and chemotherapy. This review outlines a comprehensive overview of the mechanisms driving the anticancer activities of phenothiazines derivates such as trifluoperazine, prochlorperazine, chlorpromazine, promethazine, thioridazine, and fluphenazine. The repurposing potential of phenothiazines paves the way for novel approaches to improve future cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Among the most malignant cancers, oral squamous cell carcinoma stands out as the most common malignant head and neck tumor, with high prevalence around the world, mainly in developing countries. Despite advances in the field of treatment, the prognosis of patients with oral squamous cell carcinoma remains poor, with a 5-year survival rate of less than 50%. Aiming to overcome the limitations of currently existing therapies, the present work proposes to investigate the potential of photodynamic therapy with methylene blue or toluidine blue. We found higher incorporation rates of both drugs in tumor cells compared to the non-tumor cell line. In addition, photodynamic therapy increases cytotoxic activity of both compounds for all lineages evaluated. Moreover, combination of both compounds promotes a synergistic effect on the viability of oral squamous cell carcinoma, opening up possibilities for the use of photodynamic therapy against other cancer cell types using combinations of these photosensitizers. 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. [ABSTRACT FROM AUTHOR]

Many new isomeric dipyridothiazine dimers have been presented as molecules with anticancer potential. These compounds were obtained in efficient syntheses of 1,6-, 1,8-, 2,7- and 3,6-diazaphenothiazines with selected alkylaromatic linkers. The structures of these compounds has been proven with two-dimensional spectroscopic techniques (COSY, NOESY, HSQC and HMBC) and high-resolution mass spectrometry (HRMS). In silico analyses of probable molecular targets were performed using the Way2Drug server. All new dimers were tested for anticancer activity against breast cancer line MCF7 and colon cancer line SW480. Cytotoxicity was assessed on normal L6 muscle cells. The tested dimers had high anticancer potential expressed as IC50 and the selectivity index SI. The most active derivative, 4c, showed an IC50 activity of less than 1 µM and an SI selectivity index higher than 100. Moreover, the compounds were characterized by low toxicity towards normal cells, simultaneously indicating a high cytostatic potential. [ABSTRACT FROM AUTHOR]

An ultrasensitive and broad-specific monoclonal antibody recognising cyproheptadine hydrochloride and six phenothiazines was produced. The 50% inhibition concentration against cyproheptadine hydrochloride was 0.036 ng/mL, and the cross-reactivities for six phenothiazines were from 6.33% to 63.16%. Based on the developed monoclonal antibody, an immunochromatographic strip was established, with the visual detection limits (cut-off values) of seven drugs ranging from 5 to 100 ng/g in feedstuffs. With the strip reader, the 50% inhibition concentration of the developed immunochromatographic strip for seven drugs ranged from 0.570 to 7.750 ng/g. The intra-assay recoveries were from 79.8% to 103.4% with the highest coefficient of variation of 11.3%. The inter-assay recoveries were from 79.0% to 96.6% with the highest coefficient of variation of 12.7%. In summary, the proposed immunochromatographic strip was considered suitable for simultaneously monitoring cyproheptadine hydrochloride and phenothiazines in feedstuffs. [ABSTRACT FROM AUTHOR]

Lipophilicity is one of the principal parameters that describe the pharmacokinetic behavior of a drug, including its absorption, distribution, metabolism, elimination, and toxicity. In this study, the lipophilicity and other physicochemical, pharmacokinetic, and toxicity properties that affect the bioavailability of newly synthesized dialkylaminoalkyldiquinothiazine hybrids as potential drug candidates are presented. The lipophilicity, as RM0, was determined experimentally by the RP-TLC method using RP18 plates and acetone–TRIS buffer (pH 7.4) as the mobile phase. The chromatographic parameters of lipophilicity were compared to computationally calculated partition coefficients obtained by various types of programs such as iLOGP, XLOGP3, WLOGP, MLOGP, SILCOS-IT, LogP, logP, and milogP. In addition, the selected ADMET parameters were determined in silico using the SwissADME and pkCSM platforms and correlated with the experimental lipophilicity descriptors. The results of the lipophilicity study confirm that the applied algorithms can be useful for the rapid prediction of logP values during the first stage of study of the examined drug candidates. Of all the algorithms used, the biggest similarity to the chromatographic value (RM0) for certain compounds was seen with iLogP. It was found that both the SwissADME and pkCSM web tools are good sources of a wide range of ADMET parameters that describe the pharmacokinetic profiles of the studied compounds and can be fast and low-cost tools in the evaluation of examined drug candidates during the early stages of the development process.

Phenothiazine and its derivatives exhibit many properties. Hence they are the starting structures for many new potential drugs, biologically active compounds, dyes, etc. In this paper, we investigated a series of five fluphenazine analogs synthesized exhibiting inhibition of multidrug resistance (MDR) in tumor cells. During the drug discovery process, the determination of physicochemical properties of new compounds, such as dissociation constant values (pKa), is essential because it directly affects their pharmacokinetic profile. Thus, this study aimed to determine the pKa values of fluphenazine and its derivatives from the mobile phase pH dependence of the retention factor with the reverse phase liquid chromatographic method. Binary mixtures of phosphate buffer (pH 2.3-11.5) and acetonitrile (40-55%) in different percentages and the Gemini NX C18 column as the stationary phase were used in the tests. The pKa' values of fluphenazine derivatives at experimental concentrations of organic solvent were determined based on the obtained sigmoidal k curves as a function of pH. Then these values were extrapolated to 0% acetonitrile to obtain the actual pKa values. Moreover, a comparative evaluation of chromatographically obtained and computationally calculated pKa parameters was carried out.

The limitations of current cancer therapies, including the increasing prevalence of multidrug resistance, underscore the urgency for more effective treatments. One promising avenue lies in the repurposing of existing drugs. This review explores the impact of phenothiazines, primarily used as antipsychotic agents, on key mechanisms driving tumor growth and metastasis. The cationic and amphiphilic nature of phenothiazines allows interaction with the lipid bilayer of cellular membranes, resulting in alterations in lipid composition, modulation of calcium channels, fluidity, thinning, and integrity of the plasma membrane. This is especially significant in the setting of increased metabolic activity, a higher proliferative rate, and the invasiveness of cancer cells, which often rely on plasma membrane repair. Therefore, properties of phenothiazines such as compromising plasma membrane integrity and repair, disturbing calcium regulation, inducing cytosolic K-RAS accumulation, and sphingomyelin accumulation in the plasma membrane might counteract multidrug resistance by sensitizing cancer cells to membrane damage and chemotherapy. This review outlines a comprehensive overview of the mechanisms driving the anticancer activities of phenothiazines derivates such as trifluoperazine, prochlorperazine, chlorpromazine, promethazine, thioridazine, and fluphenazine. The repurposing potential of phenothiazines paves the way for novel approaches to improve future cancer treatment.

Lipophilicity is one of the most important properties of compounds required to estimate the absorption, distribution, and transport in biological systems, in addition to solubility, stability, and acid–base nature. It is crucial in predicting the ADME profile of bioactive compounds. The study assessed the usefulness of computational and chromatographic methods (thin-layer chromatography in a reversed-phase system, RP-TLC) for estimating the lipophilicity of 21 newly synthesized compounds belonging to diquinothiazines and quinonaphthiazines. In order to obtain reliable values of the relative lipophilicities of diquinothiazines and quinonaphthiazines, the partition coefficients obtained using different algorithms such as AlogPs, AClogP, AlogP, MLOGP, XLOGP2, XLOGP3, logP, and ClogP were compared with the chromatographic RM0 values of all the tested compounds measured by the experimental RP-TLC method (logPTLC). Additionally, logPTLC values were also correlated with other descriptors, as well as the predicted ADME and drug safety profiling parameters. The linear correlations of logPTLC values of the tested compounds with other calculated molecular descriptors such as molar refractivity, as well as ADME parameters (Caco-2 substrates, P-gp inhibitors, CYP2C19, and CYP3A4) generally show poor predictive power. Therefore, in silico ADME profiling can only be helpful at the initial step of designing these new candidates for drugs. The compliance of all discussed diquinothiazines and naphthoquinothiazines with the rules of Lipiński, Veber, and Egan suggests that the tested pentacyclic phenothiazine analogs have a chance to become therapeutic drugs, especially orally active drugs.

This research aims to remove two phenothiazines, promazine (PRO) and promethazine (PMT), from their individual and binary mixtures using olive tree pruning biochar (BC-OTPR). The impact of individual and combinatory effects of operational variables was evaluated for the first time using central composite design (CCD). Simultaneous removal of both drugs was maximized utilizing the composite desirability function. At low concentrations, the uptake of PRO and PMT from their individual solutions was achieved with high efficiency of 98.64%, 47.20 mg/g and 95.87%, 38.16 mg/g, respectively. No major differences in the removal capacity were observed for the binary mixtures. Characterization of BC-OTPR confirmed successful adsorption and showed that the OTPR surface was predominantly mesoporous. Equilibrium investigations revealed that the Langmuir isotherm model best describes the sorption of PRO/PMT from their individual solutions with maximum adsorption capacities of 640.7 and 346.95 mg/g, respectively. The sorption of PRO/PMT conforms to the pseudo-second-order kinetic model. Regeneration of the adsorbent surface was successfully done with desorption efficiencies of 94.06% and 98.54% for PRO and PMT, respectively, for six cycles. [ABSTRACT FROM AUTHOR]

Background: Benign paroxysmal positional vertigo (BPPV) is a common cause of acute dizziness. Medication use for its treatment remains common despite guideline recommendations against their use. Objectives: The objective was to evaluate the efficacy and safety of vestibular suppressants in patients with BPPV compared to placebo, no treatment, or canalith repositioning maneuvers (CRMs). Methods: We searched MEDLINE, Cochrane, EMBASE, and ClinicalTrials.gov from inception until March 25, 2022. for randomized controlled trials (RCTs) comparing antihistamines, phenothiazines, anticholinergics, and/or benzodiazepines to placebo, no treatment, or a CRM. Results: Five RCTs, enrolling 296 patients, were included in the quantitative analysis. We found that vestibular suppressants may have no effect on symptom resolution at the point of longest follow‐up (14–31 days in four studies) when evaluated as a continuous outcome (standardized mean difference –0.03 points, 95% confidence interval [CI] −0.53 to 0.47). Conversely, CRMs may improve symptom resolution at the point of longest follow‐up as a dichotomous outcome when compared to vestibular suppressants (relative risk [RR] 0.63, 95% CI 0.52 to 0.78). Vestibular suppressants had an uncertain effect on symptom resolution within 24 h (mean difference [MD] 5 points, 95% CI −16.92 to 26.94), repeat emergency department (ED)/clinic visits (RR 0.37, 95% CI 0.12 to 1.15), patient satisfaction (MD 0 points, 95% CI −1.02 to 1.02), and quality of life (MD −1.2 points, 95% CI −2.96 to 0.56). Vestibular suppressants had an uncertain effect on adverse events. Conclusions: In patients with BPPV, vestibular suppressants may have no effect on symptom resolution at the point of longest follow‐up; however, there is evidence toward the superiority of CRM over these medications. Vestibular suppressants have an uncertain effect on symptom resolution within 24 h, repeat ED/clinic visits, patient satisfaction, quality of life, and adverse events. These data suggest that a CRM, and not vestibular suppressants, should be the primary treatment for BPPV. [ABSTRACT FROM AUTHOR]

A series of novel double-angularly condensed diquinothiazines with aminoalkyl, amidoalkyl, sulfonamidoalkyl, and substituted phenyl groups was designed, synthesized, and evaluated for their anticancer activity against four selected human tumor cell lines (HTC116, SH-SY5Y, A549, and H1299). The cytotoxicity of the novel diquinothiazines was investigated against BEAS-2B cells. The activities of the compounds were compared to etoposide. Among them, compounds with aminoalkyl and phenyl groups showed excellent broad-spectrum anticancer activity. The most active 14-(methylthiophenyl)diquinothiazine, 3c, showed low cytotoxicity against BEAS-2B cells and high activity against tumor cell lines HTC116, SH-SY5Y, A549, and H1299, with IC50 values of 2.3 µM, 2.7 µM, 17.2 µM, and 2.7 µM, respectively (etopiside 8.6 µM, 3.9 µM, 44.8 µM, and 0.6, respectively). Live long-term microscopic observations of cell survival using the starting molecule M0 were also performed. Flow cytometry showed the proapoptotic effects of the studied diquinothiazines. Inhibition of the cell cycle in the S phase was observed, which is associated with damage to nucleic acids and connected to DNA replication arrest. [ABSTRACT FROM AUTHOR]

Many new isomeric dipyridothiazine dimers have been presented as molecules with anticancer potential. These compounds were obtained in efficient syntheses of 1,6-, 1,8-, 2,7- and 3,6-diazaphenothiazines with selected alkylaromatic linkers. The structures of these compounds has been proven with two-dimensional spectroscopic techniques (COSY, NOESY, HSQC and HMBC) and high-resolution mass spectrometry (HRMS). In silico analyses of probable molecular targets were performed using the Way2Drug server. All new dimers were tested for anticancer activity against breast cancer line MCF7 and colon cancer line SW480. Cytotoxicity was assessed on normal L6 muscle cells. The tested dimers had high anticancer potential expressed as IC50 and the selectivity index SI. The most active derivative, 4c, showed an IC50 activity of less than 1 µM and an SI selectivity index higher than 100. Moreover, the compounds were characterized by low toxicity towards normal cells, simultaneously indicating a high cytostatic potential.

Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of ether-carbon linked analogs of a constrained synthetic sphingolipid analog 3, known for its cytotoxicity, nutrient transporter down-regulation and vacuolation properties, incorporating the tricyclic neuroleptics phenoxazine and phenothiazine to represent hybrid structures with possible synergistic cytotoxic activity. While the original activity of the lead compound 3 was diminished by fusion with the phenoxazine or phenothiazine tethered moieties, the corresponding 3-pyridyltetryl ether analog 10 showed cytotoxicity and nutrient transporter down-regulation similar to the lead compound 3, although it separated these PP2A-dependent phenotypes from that of vacuolation.

Phenothiazines ˗ Antipsychotic drugs, which have been studied from centuries and attracted researcher's attention toward its antitumor activities apart from their fundamental neuroleptic properties. Hence, we have targeted different structures of phenothiazines to develop potent antitumor agents. In the present study, we have synthesized various heterocyclic derivatives incorporating phenothiazine compounds via one-pot multicomponent reaction by means of N-alkyl-3-formylphenothiazine under reflux/ultrasonic method and different spectral characterization techniques such as FT-IR, mass, 1H and 13C NMR spectroscopy were used to validate the molecular structures of the synthesized compounds. The antitumor properties of all the synthesized compounds were investigated using MTT and LDH assay against HeLa cell lines. The results shown that the compounds 4 b, 2a and 3a have maximum LDH release (57.69 ± 4.69, 57.7 ± 4.6 & 67.8 ± 4.9) at 1000 µg concentration. [ABSTRACT FROM AUTHOR]

A strategy for the design of potential drugs for the treatment of neurodegenerative diseases is considered. This strategy is based on multipharmacophore compounds combining several characteristic structural moieties (scaffolds) of different neuroactive substances within the one molecule. Various synthetic approaches to such compounds are considered and exemplified by the synthesis of conjugates of phenothiazine, tetrahydro-γ-carboline, carbazole, and aminoadamantane moieties linked through a series of spacers. Data on the biological activity of compounds acquired within the framework of complex screening system are presented. In particular, effects of the novel compounds on cholinesterase enzyme systems, glutamate receptors, mitochondrial structures, formation of microtubule systems, as well as their antioxidant properties, were evaluated. For some multipharmacophore structures, the appearance of neurobiological properties that are not characteristic of the parent compounds was observed, thus providing new opportunities for the design of original highly efficient multitarget drugs. The acquired results allowed us to select several leading compounds that have successfully passed preclinical trials. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) is a major obstacle in the therapy of infectious diseases and cancer. One of the major mechanisms of MDR is the overexpression of efflux pumps (EPs) that are responsible for extruding antimicrobial and anticancer agents. EPs have additional roles of detoxification that may aid the development of bacterial infection and the progression of cancer. Therefore, targeting EPs may be an attractive strategy to treat bacterial infections and cancer. The development and discovery of a new drug require a long timeline and may come with high development costs. A potential alternative to reduce the time and costs of drug development is to repurpose already existing drugs. Antidepressants and antipsychotic agents are widely used in clinical practice in the treatment of psychiatric disorders and some somatic diseases. Antidepressants and antipsychotics have demonstrated various beneficial activities that may be utilized in the treatment of infections and cancer. This review aims to provide a brief overview of antibacterial and anticancer effects of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and phenothiazine antipsychotics, while focusing on EPs. However, it should be noted that the antimicrobial activity of a traditionally non-antibiotic drug may have clinical implications regarding dysbiosis and bacterial MDR. [ABSTRACT FROM AUTHOR]

Persistent apical periodontitis occurs when the endodontic treatment fails to eradicate the intraradicular infection, and is mainly caused by Gram-positive bacteria and yeasts, such as Enterococcus faecalis and Candida albicans, respectively. Phenothiazines have been described as potential antimicrobials against bacteria and fungi. This study aimed to investigate the antimicrobial potential of promethazine (PMZ) and chlorpromazine (CPZ) against E. faecalis and C. albicans dual-species biofilms. The susceptibility of planktonic cells to phenothiazines, chlorhexidine (CHX) and sodium hypochlorite (NaOCl) was initially analyzed by broth microdilution. Interaction between phenothiazines and CHX was examined by chequerboard assay. The effect of NaOCl, PMZ, CPZ, CHX, PMZ + CHX, and CPZ + CHX on biofilms was investigated by susceptibility assays, biochemical and morphological analyses. Results were evaluated through one-way ANOVA and Tukey's multiple comparison post-test. PMZ, alone or in combination with irrigants, was the most efficient phenothiazine, capable of reducing cell counts, biomass, biovolume, carbohydrate and protein contents of dual-species biofilms. Neither PMZ nor CPZ increased the antimicrobial activity of CHX. Further investigations of the properties of phenothiazines should be performed to encourage their use in endodontic clinical practice. [ABSTRACT FROM AUTHOR]

Phenothiazines, a diverse class of drugs, can be used to treat multiple mental health and physical conditions. Phenothiazines have been used for decades to treat mental illnesses, including schizophrenia, mania in bipolar disorder, and psychosis. Additionally, these drugs offer relief for physical illnesses, including migraines, hiccups, nausea, and vomiting in both adults and children. Further research is needed to prove the efficacy of phenothiazines in treating physical symptoms. Phenothiazines are dopaminergic antagonists that inhibit D2 receptors with varying potency. High potency phenothiazines such as perphenazine are used to treat various psychiatric conditions such as the positive symptoms of schizophrenia, the symptoms of psychosis, and mania that can occur with bipolar disorder. Low/mid potency phenothiazines such as chlorpromazine antipsychotic drugs that have been used to treat schizophrenia and schizophrenia-like disorders since the 1950s and are utilized in numerous disease states. The present investigation aims to elucidate the effects of phenothiazines in clinical practice. [ABSTRACT FROM AUTHOR]

Novel phenothiazine-dithiocarbamate analogues were designed by molecular hybridization strategy and synthesized and evaluated for their anticancer activity in vitro against three selected cancer cell lines (EC-109, MGC-803, and PC-3). The preliminary structure-activity relationship (SAR) for this phenothiazine-dithiocarbamate hybrids is explored. Among all analogues, 2-oxo-2-(10H-phenothiazin-10-yl)ethyl 4-ethylpiperazine-1-carbodithioate (8a) showed the most potent inhibitory activity with an [Formula: see text] value of [Formula: see text] against PC-3 cells. In addition, compound 8a could arrest the cell cycle at the G1 phase and regulate the expression of G1 checkpoint-related proteins, suggesting that phenothiazine-dithiocarbamate hybrids might be useful as cell cycle blockers.

Amyloid precursor‐like protein‐2 (APLP2) and its C‐terminal fragments (CTFs) are expressed at high levels in pancreatic cancer cells and knockdown of APLP2 expression inhibits tumor growth. CTFs are released from APLP2 by beta‐secretase (BACE). In this study, our goal was to determine whether methylene blue (MethB) and toluidine blue O (TBO) could be used to slow down the growth and viability of pancreatic cancer cells (Hs 766T). We found that TBO and MethB decreased the growth and viability of Hs 766T cells in a dose‐ and time‐dependent manner compared to vehicle‐treated control, as demonstrated by MTT and trypan blue exclusion assays. Although TBO led to decreased expression of APLP2, MethB did not show any significant effect on APLP2. However, both MethB and TBO reduced BACE activity and the levels of APLP2 CTFs in Hs 766T cells. In conclusion, MethB and TBO may be valuable candidates for the treatment of pancreatic cancer by targeting APLP2 processing. [ABSTRACT FROM AUTHOR]