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The molecular hybridization approach has been used to develop compounds with improved efficacy by combining two or more pharmacophores of bioactive scaffolds. In this context, hybridization of various relevant pharmacophores with phenothiazine derivatives has resulted in pertinent compounds with diverse biological activities, interacting with specific or multiple targets. In fact, the development of new drugs or drug candidates based on phenothiazine system has been a promising approach due to the diverse activities associated with this tricyclic system, traditionally present in compounds with antipsychotic, antihistaminic and antimuscarinic effects. Actually, the pharmacological actions of phenothiazine hybrids include promising antibacterial, antifungal, anticancer, anti-inflammatory, antimalarial, analgesic and multi-drug resistance reversal properties. The present review summarizes the progress in the development of phenothiazine hybrids and their biological activity.

In order to improve the performance of organic luminescent materials, lots of studies have been carried out at the molecular level. However, these materials are mostly applied as solids or aggregates in practical applications, in which the relationship between aggregation structure and luminescent property should be paid more attention. Here, we obtained five phenothiazine 5,5‐dioxide (O‐PTZ) derivatives with distinct molecular conformations by rational design of chemical structures, and systematically studied their room‐temperature phosphorescence (RTP) effect in solid state. It was found that O‐PTZ dimers with quasi‐equatorial (eq) conformation tended to show stronger π‐π interaction than quasi‐axial (ax) conformers in crystal state, which was more conducive to the generation of RTP. Based on this result, a multi‐level structural model of organic solids was proposed to draw the relationship between aggregation structure and RTP effect, just like the research for the structure‐property relationship of proteins. Using this structural model as the guide, boosted RTP efficiency from 1% to 20% was successfully achieved in the corresponding host‐guest doping system, showing its wide applicability. Five phenothiazine 5,5‐dioxide (O‐PTZ) derivatives with distinct molecular conformations were obtained, and their room‐temperature phosphorescence (RTP) effects were studied. It was found that O‐PTZ dimers with quasi‐equatorial (eq) conformation were more conducive to generate RTP than quasi‐axial (ax)‐ones in crystal state. Accordingly, a multi‐level structural model of organic solids was proposed to draw the relationship between aggregation structure and RTP effect.

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.

Interactions between U2AF homology motifs (UHMs) and U2AF ligand motifs (ULMs) play a crucial role in early spliceosome assembly in eukaryotic gene regulation. UHM-ULM interactions mediate heterodimerization of the constitutive splicing factors U2AF65 and U2AF35 and between other splicing factors that regulate spliceosome assembly at the 3′ splice site, where UHM domains of alternative splicing factors, such as SPF45 and PUF60, contribute to alternative splicing regulation. Here, we performed high-throughput screening using fluorescence polarization assays with hit validation by NMR and identified phenothiazines as general inhibitors of UHM-ULM interactions. NMR studies show that these compounds occupy the tryptophan binding pocket of UHM domains. Co-crystal structures of the inhibitors with the PUF60 UHM domain and medicinal chemistry provide structure-activity-relationships and reveal functional groups important for binding. These inhibitors inhibit early spliceosome assembly on pre-mRNA substrates in vitro. Our data show that spliceosome assembly can be inhibited by targeting UHM-ULM interactions by small molecules, thus extending the toolkit of splicing modulators for structural and biochemical studies of the spliceosome and splicing regulation. So far only a few compounds have been reported as splicing modulators. Here, the authors combine high-throughput screening, chemical synthesis, NMR, X-ray crystallography with functional studies and develop phenothiazines as inhibitors for the U2AF Homology Motif (UHM) domains of proteins that regulate splicing and show that they inhibit early spliceosome assembly on pre-mRNA substrates in vitro.

Cancer is one of the biggest challenges for health concerns in the world. There are so many drugs available, but they have a lack of specificity, poor safety, side effects, and the development of resistance. Therefore, there is an urgent need for much safer and more targeted anticancer treatments. Nitrogen-containing heterocycles play an important role in the development of drugs. Recently, imidazole and phenothiazine rings are well known for their antiproliferative and anticancer activities. This study employs the molecular hybridisation method to link these bioactive scaffolds and develop novel N -substituted imidazole-phenothiazine ( N -IPTZ) hybrids. All the synthesised hybrids were characterised by using analytical techniques such as 1 H-NMR, 13 C-NMR, mass spectrum, and FT-IR. Furthermore, the DFT analysis under the B3LYP/6-311G(d, p) level in gas phase to optimise and correlate the structures of the synthesised hybrids was also performed. The optimised structure was used to determine the energies of frontier molecular orbitals (HOMO-LUMO), quantum chemical descriptors (QCD), and molecular electrostatic potentials (MEP). Additionally, in silico approaches such as ADMET, BOILED-Egg, and bioactivity radar were also performed to evaluate the oral bioavailability of the synthesised hybrids. Molecular docking and MD simulation studies were also conducted to assess the interaction profile of the synthesised hybrids with cancer target receptors like EGFR, IGF, VEGFR1, VEGFR2, and PARP-2. It was found through docking studies that the synthesised N -IPTZ(a-c) hybrids might interact with amino acids such as GLY695, SER696, GLY697, ALA698, PHE699, LYS721, GLY772, CYS773, THR766, GLN767, LEU768, MET769, ARG817, ASN818, and THR830. Additionally, it reveals hydrogen bonding with ASP831, with binding energies of − 7.23, − 6.11, and − 5.93 kcal/mol. Moreover, all the synthesised hybrids were also analysed for their anti-cancer activity against the human liver cancer cell line (HepG2) by MTT assay. Obtained results revealed that N -IPTZ(c) exhibited anticancer activity with an IC 50 value of 35.3 µg/mL.

The flavin adenine dinucleotide-dependent glucose dehydrogenase (FAD-GDH) from Aspergillus species require suitable redox mediators to transfer electrons from the enzyme to the electrode surface for the application of bioelectrical devices. Although several mediators for FAD-GDH are already in use, they are still far from optimum in view of potential, kinetics, sustainability, and cost-effectiveness. Herein, we investigated the efficiency of various phenothiazines and quinones in the electrochemical oxidation of FAD-GDH from Aspergillus terreus. At pH 7.0, the logarithm of the bimolecular oxidation rate constants appeared to depend on the redox potentials of all the mediators tested. Notably, the rate constant of each molecule for FAD-GDH was approximately 2.5 orders of magnitude higher than that for glucose oxidase from Aspergillus sp. The results suggest that the electron transfer kinetics is mainly determined by the formal potential of the mediator, the driving force of electron transfer, and the electron transfer distance between the redox active site of the mediator and the FAD, affected by the steric or chemical interactions. Higher k2 values were found for ortho-quinones than for para-quinones in the reactions with FAD-GDH and glucose oxidase, which was likely due to less steric hindrance in the active site in the case of the ortho-quinones.

Organic luminogens with persistent room temperature phosphorescence (RTP) have attracted great attention for their wide applications in optoelectronic devices and bioimaging. However, these materials are still very scarce, partially due to the unclear mechanism and lack of designing guidelines. Herein we develop seven 10-phenyl-10H-phenothiazine-5,5-dioxide-based derivatives, reveal their different RTP properties and underlying mechanism, and exploit their potential imaging applications. Coupled with the preliminary theoretical calculations, it is found that strong π–π interactions in solid state can promote the persistent RTP. Particularly, CS-CF 3 shows the unique photo-induced phosphorescence in response to the changes in molecular packing, further confirming the key influence of the molecular packing on the RTP property. Furthermore, CS-F with its long RTP lifetime could be utilized for real-time excitation-free phosphorescent imaging in living mice. Thus, our study paves the way for the development of persistent RTP materials, in both the practical applications and the inherent mechanism. Organic luminogens with persistent room temperature phosphorescence will find wide applications in optoelectronic devices and bioimaging, but they are still scarce. Here, the authors synthesize seven organic luminogens and investigate their different properties and potential imaging applications.

Nucleophilic aromatic substitution (SNAr) reactions can provide metal-free access to synthesize monosubstituted aromatic compounds. We developed efficient SNAr conditions for p-selective substitution of polyfluoroarenes with phenothiazine in the presence of a mild base to afford the corresponding 10-phenylphenothiazine (PTH) derivatives. The resulting polyfluoroarene-bearing PTH derivatives were subjected to a second SNAr reaction to generate highly functionalized PTH derivatives with potential applicability as photocatalysts for the reduction of carbon–halogen bonds.