Synthesis and application of hypochlorite mediated acylhydrazone fluorescence probes.

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.

Evaluation of the Lipophilicity of Angularly Condensed Diquino- and Quinonaphthothiazines as Potential Candidates for New Drugs.

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 Lipinski, Veber, and Egan suggests that the tested pentacyclic phenothiazine analogs have a chance to become therapeutic drugs, especially orally active drugs.

Synthesis and Photophysical Properties of Luminescent Phenothiazinyl Merocyanine Substituted Polyacetylenes.

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.

New phenothiazine conjugates as apoptosis inducing agents: Design, synthesis, In-vitro anti-cancer screening and 131I-radiolabeling for in-vivo evaluation.

Phenothiazines (PTZs) are a group of compounds characterized by the presence of the 10H-dibenzo-[b,e]-1,4-thiazine system. PTZs used in clinics as antipsychotic drugs with other diverse biological activities. The current aim of the study is to investigate and understand the effect of potent PTZs compounds using a group of In-vitro and In-vivo assays. A total of seventeen novel phenothiazine derivatives have been designed, synthesized, and evaluated primarily in-vitro for their ability to inhibit proliferation activity against NCI-60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. Almost all compounds were active and displayed promising cellular activities with GI50 values in the sub-micromolar range. Four of the most promising derivatives (4b, 4h, 4g and 6e) have been further tested against two selected sensitive cancer cell lines (colon cancer; HCT-116 and breast cancer; MDA-MB231). The apoptosis assay showed that all the selected compounds were able to induce early apoptosis and compound 6e was able to induce additional cellular necrosis. Cell cycle assay showed all selected compounds were able to induce cell cycle arrest at sub-molecular phase of G0-G1 with compound 6e induced cell cycle arrest at G2M in HCT-116 cells. Accordingly, the apoptotic effect of the selected compounds was extensively investigated on genetic level and Casp-3, Casp-9 and Bax gene were up-regulated with down-regulation of Bcl-2 gene suggesting the activation of both intrinsic and extrinsic pathways. In-vivo evaluation of the antitumor activity of compound 4b in solid tumor bearing mice showed promising therapeutic effect with manifestation of dose and time dependent toxic effects at higher doses. For better evaluation of the degree of localization of 4b, its 131I-congener (131I-4b) was injected intravenously in Ehrlich solid tumor bearing mice that showed good localization at tumor site with rapid distribution and clearance from the blood. In-silico study suggested NADPH oxidases (NOXs) as potential molecular target. The compounds introduced in the current study work provided a cutting-edge phenothiazine hybrid scaffold with promising anti-proliferation action that may suggest their anti-cancer activity.

Synthesis and Structural Characterization of Novel Dimers of Dipyridothiazine as Promising Antiproliferative Agents.

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.

14-Substituted Diquinothiazines as a New Group of Anticancer Agents.

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.

Near-IR Intramolecular Charge Transfer in Strongly Interacting Diphenothiazene-TCBD and Diphenothiazene-DCNQ Push-Pull Triads.

Three types of phenothiazines dimers (PTZ-PTZ, 1-3), covalently linked with one or two acetylene linkers, were synthesized by copper-mediated Eglinton and Pd-catalyzed Sonogashira coupling reactions in excellent yields. The dimers 1-3 were further engaged in [2+2] cycloaddition-retroelectrocyclization reactions with strong electron acceptors, tetracyanoethylene (TCNE) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) to yield tetracyanobutadiene (TCBD, 1 a-3 a), and dicyanoquinodimethane (DCNQ, 1 b-3 b) functionalized donor-acceptor (D-A) conjugates, respectively. The conjugates were examined by a series of spectral, computational, and electrochemical studies. Strong ground state polarization leading to new optical transitions was witnessed in both series of D-A conjugates. In the case of DCNQ derived D-A system 1 b, the optical coverage extended until 1200 nm in benzonitrile, making this a rare class of D-A ICT system. Multiple redox processes were witnessed in these D-A systems, and the frontier orbitals generated on DFT optimized structures further supported the ICT phenomenon. Photochemical studies performed using femtosecond pump-probe studies confirmed solvent polarity dependent excited state charge transfer and separation in these novel multi-modular D-A conjugates. The charge-separated states lasted up to 70 ps in benzonitrile while in toluene slightly prolonged lifetime of up to 100 ps was witnessed. The significance of phenothiazine dimer in wide-band optical capture all the way into the near-IR region and promoting ultrafast photoinduced charge transfer in the D-A-D configured multi-modular systems, and the effect of donor-acceptor distance and the solvent polarity was the direct outcome of the present study.

Effects of toluidine blue O and methylene blue on growth and viability of pancreatic cancer cells.

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.

Stability Studies of UV Laser Irradiated Promethazine and Thioridazine after Exposure to Hypergravity Conditions.

Pharmaceuticals carried into space are subjected to different gravitational conditions. Hypergravity is encountered in the first stage, during spacecraft launching. The stability of medicines represents a critical element of space missions, especially long-duration ones. Therefore, stability studies should be envisaged before the implementation of drugs for future deep space travel, where the available pharmaceuticals would be limited and restocking from Earth would be impossible. Multipurpose drugs should be proposed for this reason, such as phenothiazine derivatives that can be transformed by optical methods into antimicrobial agents. Within this preliminary study, promethazine and thioridazine aqueous solutions were exposed to UV laser radiation that modified their structures and generated a mixture of photoproducts efficient against particular bacteria. Subsequently, they were subjected to 20 g in the European Space Agency's Large Diameter Centrifuge. The aim was to evaluate the impact of hypergravity on the physico-chemical and spectral properties of unirradiated and laser-irradiated medicine solutions through pH assay, UV-Vis/FTIR absorption spectroscopy, and thin-layer chromatography. The results revealed no substantial alterations in centrifuged samples when compared to uncentrifuged ones. Due to their stability after high-g episodes, laser-exposed phenothiazines could be considered for future space missions.

Antipsychotic phenothiazine drugs bind to KRAS in vitro.

We used NMR to show that the antipsychotic phenothiazine drugs promazine and promethazine bind to GDP-KRAS. Promazine also binds to oncogenic GDP-KRAS(G12D), and to wild type GppNHp-KRAS. A panel of additional phenothiazines bind to GDP-KRAS but with lower affinity than promazine or promethazine. Binding is most dependent on substitutions at C-2 of the tricyclic phenothiazine ring. Promazine was used to generate an NMR-driven HADDOCK model of the drug/GDP-KRAS complex. The structural model shows the tricyclic phenothiazine ring of promazine associates with the hydrophobic pocket p1 that is bordered by the central ß sheet and Switch II in KRAS. Binding appears to stabilize helix 2 in a conformation that is similar to that seen in KRAS bound to other small molecules. Association of phenothiazines with KRAS may affect normal KRAS signaling that could contribute to multiple biological activities of these antipsychotic drugs. Moreover, the phenothiazine ring represents a new core scaffold on which to design modulators of KRAS activity.

Theoretical Study of 2-(Trifluoromethyl)phenothiazine Derivatives with Two Hydroxyl Groups in the Side Chain-DFT and QTAIM Computations.

Phenothiazines are known as synthetic antipsychotic drugs that exhibit a wide range of biological effects. Their properties result from the structure and variability of substituents in the heterocyclic system. It is known that different quantum chemical properties have a significant impact on drug behavior in the biological systems. Thus, due to the diversity in the chemical structure of phenothiazines as well as other drugs containing heterocyclic systems, quantum chemical calculations provide valuable methods in predicting their activity. In our study, DFT computations were applied to show some thermochemical parameters (bond dissociation enthalpy-BDE, ionization potential-IP, proton dissociation enthalpy-PDE, proton affinity-PA, and electrontransfer enthalpy-ETE) describing the process of releasing the hydrogen/proton from the hydroxyl group in the side chain of four 2-(trifluoromethyl)phenothiazine (TFMP) derivatives and fluphenazine (FLU). Additional theoretical analysis was carried out based on QTAIM theory. The results allowed theoretical determination of the ability of compounds to scavenge free radicals. In addition, the intramolecular hydrogen bond (H-bond) between the H-atom of the hydroxyl group and the N-atom located in the side chain of the investigated compounds has been identified and characterized.

Exploitation of a novel phenothiazine derivative for its anti-cancer activities in malignant glioblastoma.

Glioblastoma remains the most malignant of all primary adult brain tumours with poor patient survival and limited treatment options. This study adopts a drug repurposing approach by investigating the anti-cancer activity of a derivative of the antipsychotic drug phenothiazine (DS00329) in malignant U251 and U87 glioblastoma cells. Results from MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and clonogenic assays showed that DS00329 inhibited short-term glioblastoma cell viability and long-term survival while sparing non-cancerous cells. Western blot analysis with an antibody to γH2AX showed that DS00329 induced DNA damage and flow cytometry and western blotting confirmed that it triggered a G1 cell cycle arrest which correlated with decreased levels in Cyclin A, Cyclin B, Cyclin D1 and cyclin dependent kinase 2 and an increase in levels of the cyclin dependent kinase inhibitor p21. DS00329 treated glioblastoma cells exhibited morphological and molecular markers typical of apoptotic cells such as membrane blebbing and cell shrinkage and an increase in levels of cleaved PARP. Flow cytometry with annexin V-FITC/propidium iodide staining confirmed that DS00329 induced apoptotic cell death in glioblastoma cells. We also show that DS00329 treatment of glioblastoma cells led to an increase in the autophagosome marker LC3-II and autophagy inhibition studies using bafilomycin A1 and wortmannin, showed that DS00329-induced-autophagy was a pro-death mechanism. Furthermore, DS00329 treatment of glioblastoma cells inhibited the phosphatidylinositol 3'-kinase/Akt cell survival pathway. Our findings suggest that DS00329 may be an effective treatment for glioblastoma and provide a rationale for further exploration and validation of the use of phenothiazines and their derivatives in the treatment of glioblastoma.

An Air-Stable, Neutral Phenothiazinyl Radical with Substantial Radical Stabilization Energy.

The vital effect of radical states on the pharmacological activity of phenothiazine-based drugs has long been speculated. Whereas cationic radicals of N-substituted phenothiazines show high stability, the respective neutral radicals of N-unsubstituted phenothiazines have never been isolated. Herein, the 1,9-diamino-3,7-di-tert-butyl-N1 ,N9 -bis(2,6-diisopropylphenyl)-10H-phenothiazin-10-yl radical (SQH2 . ) is described as the first air-stable, neutral phenothiazinyl free radical. The crystalline dark-blue species is characterized by means of EPR and UV/Vis/near-IR spectroscopy, as well as cyclic voltammetry, spectro-electrochemical analysis, single-crystal XRD, and computational studies. The SQH2 . radical stands out from other aminyl radicals by an impressive radical stabilization energy and its parent amine has one of the weakest N-H bond dissociation energies ever determined. In addition to serving as open-shell reference in medicinal chemistry, its tridentate binding pocket or hydrogen-bond-donor ability might enable manifold uses as a redox-active ligand or proton-coupled electron-transfer reagent.

Antipsychotic drugs v. barbiturates or benzodiazepines used as active placebos for schizophrenia: a systematic review and meta-analysis.

BACKGROUND: Comparisons of antipsychotics with placebo can be biased by unblinding due to side effects. Therefore, this meta-analysis compared the efficacy of antipsychotics for acute schizophrenia in trials using barbiturates or benzodiazepines as active placebos. METHODS: Randomized controlled trials (RCTs) in acute schizophrenia with at least 3 weeks duration and comparing any antipsychotic with barbiturates or benzodiazepines were eligible. ClinicalTrials.gov, CENTRAL, EMBASE, MEDLINE, PsycINFO, PubMed, WHO-ICTRP as well as previous reviews were searched up to 9 January 2018. Two separate meta-analyses, one for barbiturates and one for benzodiazepines, were conducted using random-effects models. The primary outcome was response to treatment, and mean values of schizophrenia rating scales and dropouts were analyzed as secondary outcomes. This study is registered with PROSPERO (CRD42018086263). RESULTS: Seven barbiturate-RCTs (number of participants n = 1736), and two benzodiazepine-RCTs (n = 76) were included in the analysis. The studies were published between 1960 and 1968 and involved mainly chronically ill patients. More patients on antipsychotics in comparison to barbiturates achieved a 'good' response (36.2% v. 16.8%; RR 2.15; 95% CI 1.36-3.41; I2 = 48.9) and 'any' response (57.4% v. 27.8%; RR 2.07; 95% CI 1.35-3.18; I2 = 68.2). In a single small trial (n = 60), there was no difference between antipsychotics and benzodiazepines on 'any' response (74.7% v. 65%; RR 1.15; 95% CI 0.82-1.62). CONCLUSIONS: Antipsychotic drugs were more efficacious than barbiturates, based on a large sample size. Response ratios were similar to those observed in placebo-controlled trials. The results on benzodiazepines were inconclusive due to the small number of studies and participants.

Dopamine receptors in emesis: Molecular mechanisms and potential therapeutic function.

Dopamine is a member of the catecholamine family and is associated with multiple physiological functions. Together with its five receptor subtypes, dopamine is closely linked to neurological disorders such as schizophrenia, Parkinson's disease, depression, attention deficit-hyperactivity, and restless leg syndrome. Unfortunately, several dopamine receptor-based agonists used to treat some of these diseases cause nausea and vomiting as impending side-effects. The high degree of cross interactions of dopamine receptor ligands with many other targets including G-protein coupled receptors, transporters, enzymes, and ion-channels, add to the complexity of discovering new targets for the treatment of nausea and vomiting. Using activation status of signaling cascades as mechanism-based biomarkers to foresee drug sensitivity combined with the development of dopamine receptor-based biased agonists may hold great promise and seems as the next step in drug development for the treatment of such multifactorial diseases. In this review, we update the present knowledge on dopamine and dopamine receptors and their potential roles in nausea and vomiting. The pre- and clinical evidence provided in this review supports the implication of both dopamine and dopamine receptor agonists in the incidence of emesis. Besides the conventional dopaminergic antiemetic drugs, potential novel antiemetic targeting emetic protein signaling cascades may offer superior selectivity profile and potency.

Antifungal activity of promethazine and chlorpromazine against planktonic cells and biofilms of Cryptococcus neoformans/Cryptococcus gattii complex species.

Cryptococcus neoformans/Cryptococcus gattii are fungal pathogens that affect the central nervous system, mainly in immunocompromised individuals. Due to the limited pharmacological arsenal available for the treatment of cryptococcosis associated with cases of antifungal resistance of Cryptococcus spp. reported in some studies, the search for new compounds with antifungal potential becomes relevant. Thus, the objective of this study was to evaluate the inhibitory effect of phenothiazines (promethazine and chlorpromazine) on C. neoformans/C. gattii planktonic cells and biofilms. In vitro planktonic susceptibility testing was performed using the broth microdilution assay. The effect of phenothiazines was evaluated against biofilm formation and mature Cryptococcus biofilms. Biofilm morphology and ultrastructure were also evaluated by scanning electron microscopy. Promethazine and chlorpromazine showed antifungal activity against planktonic cells, with minimum inhibitory concentrations of 8-32 µg/ml and 4-16 µg/ml, respectively. As for biofilm formation, phenothiazines reduced biomass by 60% and metabolic activity by 90% at 64 µg/ml; while in mature biofilms, reductions of 85% and 90% in biomass and metabolic activity, respectively, were observed at 1024 µg/ml. Promethazine and chlorpromazine were also able to disrupt and fragment biofilms. In conclusion, promethazine and chlorpromazine have antifungal activity against planktonic cells and biofilms of Cryptococcus spp. These data show the potential of promethazine and chlorpromazine as antibiofilm drugs.

Safety and Effectiveness of Intravenous Chlorpromazine for Agitation in Critically Ill Patients.

BACKGROUND: Agitation is common in the intensive care unit (ICU). Although antipsychotics are frequently used as first-line therapy, chlorpromazine has fallen out of favor due to risk of cardiovascular complications and severe hypotension. Although chlorpromazine is used anecdotally, there is a lack of data regarding its safety and effectiveness. The objective of this study was to investigate the use of intravenous (IV) chlorpromazine for agitation in the ICU setting. METHODS: A retrospective review was performed at a tertiary care academic medical center. Patients were included if they received IV chlorpromazine in the ICU for agitation, infused at a rate of 1 mg/min. Primary end points were change in systolic blood pressure (SBP), heart rate (HR), and mean arterial pressure (MAP) within 4 hours of administration. Secondary end points included change in vasopressor and adjunct sedative medication requirements, achievement of Richmond-Agitation Sedation Scale (RASS) 0 to -1, and incidence of cardiac arrhythmias. RESULTS: A total of 39 patients encompassing 107 IV chlorpromazine administrations were included. The median dose was 25 mg. Median vital signs prior to infusion were SBP 129 mm Hg, HR 90 beats/minute, and MAP 88 mm Hg. Over the subsequent 4 hours, SBP and HR did not change significantly (P = .83 and P = .10, respectively). Mean arterial pressure decreased from a median of 88 to 83 mm Hg (P = .04). There were no significant changes in vasopressor requirements, adjunct sedative medication requirements, or achievement of RASS goal. No patients developed symptomatic cardiac arrhythmias. CONCLUSION: In our small retrospective study, the use of IV chlorpromazine at routine doses did not result in clinically significant hemodynamic changes when infused at a rate of 1 mg/min. Intravenous chlorpromazine may be considered as a potential treatment option for agitation in ICU patients with appropriate monitoring.

Photodermatitis from topical phenothiazines: A case series.

BACKGROUND: In Europe, contact photosensitivity to phenothiazines is well-known, particularly in southern countries. Topical phenothiazines are widely used and sold over-the-counter (OTC) for the treatment of mosquito bites and pruritus in France. OBJECTIVE: To report a series of cases with photodermatitis following use of topical phenothiazines. METHOD: A retrospective study of cases of contact dermatitis from phenothiazines seen in French photodermatology centers was performed. RESULTS: In all, 14 patients with a diagnosis of contact dermatitis from phenothiazines were included. These patients developed eczema on the application sites, and in 13 the eruption spread to photodistributed sites. Topical products containing isothipendyl were the most common cause of photodermatitis. One patient had photoaggravated eczema due to promethazine cream. All patients stopped using topical phenothiazines and were treated successfully with topical corticosteroids. One patient relapsed and developed persistent light eruption. In all of the nine cases tested, photopatch testing to the topical phenothiazine used "as is" was positive. Isothipendyl, chlorproethazine, and the excipients were not tested. Photopatch tests to chlorpromazine and promethazine were positive in 8 of 12 and 7 of 13 tested, respectively. CONCLUSION: Use of isothipendyl and promethazine as OTC (or even prescribed) drugs needs to be limited due to severe reactions and sensitization to other phenothiazines that consequently will have to be avoided.

"Tau Protein Targeting Via Radioiodinated Azure A For Brain Theranostics: Radiolabeling, Molecular Docking, in vitro And in vivo Biological Evaluation".

Azure-A is one of the phenothiazines (PTZs) derivatives which for decades have been used as antipsychotic drugs due to good lipophilic characteristics which enable them to pass through the blood brain barrier (BBB), besides the important property of enabeling investigation of the pathological forms of aggregated tau protein found in the neurons of the central nervous system. Radioiodination of Azure-A was carried out via an electrophilic substitution reaction using chloramine-T as oxidizing agent. The influence of various reaction parameters and conditions on radioiodination efficiency was investigated, and a high radiochemical yield of 92.07 ± 0.9 % was obtained. An in vitro cytotoxicity study of iodinated Azure-A on three cell lines (HCT-116, human colon carcinoma cell line; Hep-G2, liver carcinoma cell line and HFB-4, normal human melanocytes) was carried out, and the data revealed that ioiodinated Azure A has no to very low toxic effect. The in vivo biodistribution study of 131 I-Azure A showed a high brain uptake of 6.15 ± 0.09 % injected dose/g tissue organ at 30 minutes post-injection, and its retention in brain remained high up to 2 hours, whereas the clearance from the body appeared to proceed via the renal system. The experimental data were confirmed by the molecular docking studies to predict the effect of radioiodination on the binding affinity of the parent molecule (Azure A) to tau paired helical filaments (PHFs). Both ligands showed better binding to S2 and S3 pockets of (PHFs). Consequently, radioiodinated Azure A seems to be a good candidate as an imaging agent for taupathies such as Alzheimer's disease, chronic traumatic encephalopathy, and corticobasal degeneration. Furthermore, it could be a very potent theranostics agent for brain tumors.

Phenothiazines, Dihydrophenazines, and Phenoxazines: Sustainable Alternatives to Precious-Metal-Based Photoredox Catalysts.

The application of photoredox catalysis to atom-transfer radical polymerization (ATRP) has resulted in the development of strongly reducing organic photoredox catalysts (PCs) that are some of the most reducing catalysts known. The objectives of this review are to highlight these PCs with regard to their development and applications in polymer and organic synthesis, as well illuminate aspects of these PCs that remain to be studied further.