Phenothiazine Compounds Research Articles

Sonodynamic inactivation of gram-negative and gram-positive bacteria in the presence of phenothiazine compounds toluidine blue and azurin A

BackgroundSonodynamic antimicrobial chemotherapy (SACT) is an effective antimicrobial treatment that can avoid the production of drug-resistant bacteria. Design and development of new high-efficiency sonosensitizers play a key role in the practical application of SACT. MethodsThe bacteriostatic effects of two phenothiazine compounds, toluidine blue (TB) and azure A (AA) combined with ultrasonic (US) on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were studied, and the sonodynamic antibacterial activities of TB and AA were compared. The reactive oxygen species (ROS) and the types of ROS produced in the sonodynamic system were detected and the sonodynamic mechanisms of TB and AA were proposed. ResultsThe sonodynamic bacteriostasis mediated by TB and AA increased with the increasing concentration of sonosensitizer, the extension of sonication time and the increase of reaction temperature. The production of ROS was the main reason that TB and AA had excellent sonodynamic antibacterial performance. Singlet oxygen (1O2) and hydroxyl radical (•OH) were the main ROS types in the sonodynamic antibacterial system. The ROS produced by the combined action of AA and US was higher than that of TB. ConclusionBoth TB and AA displayed excellent sonodynamic antibacterial activities. Moreover, AA had a higher sonodynamic activity than TB. The electron donation effect and steric hindrance effect of the methyl group of phenothiazine parent nucleus of TB might be the cause of the decrease of its sonodynamic activity. These results would provide a valuable reference for the further study of phenothiazines sonosensitizers and their clinical application in SACT.

Preparation, Characterization, In silico and In vitro Antimicrobial Studies of Phenothiazine-3-sulphonamide Derivatives

The antibacterial activities of phenothiazine and sulphonamide derivatives have attracted so much interest. In this study, the synthesis and characterization of phenothiazine-3-sulphonamide derivatives and evaluation of their antimicrobial activity against the following pathogenic microorganisms is reported. Two Gram-positive bacteria; (Staphylococcus aureus (ATCC: 6538) and Streptococcus pyogenes (ATCC: 27853)), two Gram-negative bacteria; (Escherichia coli(ATCC: 3008), and Salmonella typhi (ATCC: 25175)) as well as one fungus (Aspergillus fumigatus (ATCC: 10231)) were used while ciprofloxacin, gentamycin and ketoconazole served as standard drugs. The synthesis of the derivatives was achieved through a base catalyzed the reaction of 4-chloroaniline with 1-naphthylamine to form 1-(naphthalen-1-yl)benzene-1,4-diamine. This intermediate was then treated with sulphur and iodine to yield the phenothiazine derivative while subsequent treatment of the phenothiazine compound with sulphonyl chlorides gave the final products. The synthesized compounds were characterized via proton nuclear magnetic resonance (1H-NMR), carbon-13 nuclear magnetic resonance (13C-NMR) and Fourier-transform infrared (FTIR) spectroscopic techniques. The minimum inhibitory concentration (MIC) of each compound was then determined using the agar well diffusion method. To predict the binding energies and patterns of the synthesized compounds with target proteins of the above-mentioned microorganisms, molecular docking simulations were run using Autodock Vina software (version 4.2). The spectra data of the compounds for FTIR, 1H-NMR and 13C-NMR spectral data were consistent with the assigned structures of the synthesized compounds. The binding energies (kcal/mol) for in silico antimicrobial studies were in the range -5.1 to -7.6 kcal/mol. The MIC values were in the range 3.5 to 1.0 mg/L. The results of the in vitro test revealed that the synthesized compounds exhibit promising antimicrobial activity and showed excellent bactericidal and fungicidal activities. The results obtained showed that the synthesized compounds possess drug-like properties and are good starting materials for drug production.

Glucose Biosensors - State of the Art and Prospects

Rapid glucose concentration detection in technical and biological systems is an important scientific and technical task of modern chemistry, engineering and technology. The article provides an overview of the last technical solutions in this area. The issues of developing first generation biosensors are considered. However, the main disadvantage of such systems was the significant influence of ascorbic and uric acids on the generated signal, which significantly reduced their selectivity and accuracy. To solve this problem, it is possible to use ion-selective membranes such as Nafion and polycarbonate. The second generation of glucose biosensors uses artificial mediators to facilitate electron transfer between the enzyme and the electrode. These mediators can be immobilized directly by the enzyme or introduced into an enzyme-modified electrode. Suitable mediators include conducting organic salts, ferrocene, quinone compounds, ferricyanide, transition metal complexes, phenothiazine and foxazine compounds. Effective interactions between enzymes and mediators are critical for efficient electron transport. Various approaches have been proposed to tailor mediators, such as the use of Os complexes, noncovalent functionalization of carbon nanotubes, and stabilization of artificial mediators. The third generation of enzyme glucose biosensors uses direct electron transfer to perform electrochemical reduction. Various approaches have been considered, including reassembling apoproteins on cofactor-modified enzymes and electrically coupling enzymes to electrode surfaces using redox polymers or nanomaterials such as gold nanoparticles. Such approaches ensure the formation of an effective enzyme-electrode bond. In addition, the thickness of the enzymatic layer can affect the performance of the biosensor. External factors such as temperature, pH and humidity can have a significant impact on the performance of such electrodes.

Molecular Revealing the High‐stable Polycyclic Azine Derivatives for Long‐Lifetime Aqueous Organic Flow Batteries

AbstractSoluble organic molecules with diverse and highly tunable structures are receiving more and more attention as redox‐active materials for aqueous organic flow batteries (AOFBs). However, the undesirable parasitic reactions of redox‐active molecules restrict their practical application. Herein, a general molecular stabilization strategy is proposed by introducing amino groups on 3,7‐positions of polycyclic azine derivatives (phenothiazine and phenoxazine compounds) to effectively enhance the redox activity and electrochemical stability of molecules. The theoretical calculation and a series of electrochemical analyses revealed that the 3,7‐substituted amino groups serving as the redox active sites can stabilize the intermediate radicals by delocalizing the electron density in the acidic solution, preventing nucleophilic/electrophilic attack. As a result, the designed 3,7‐bis‐((2‐hydroxyethyl)(methyl)amino)phenothiazin‐5‐ium bromide not only achieved the remarkable electrochemical cycling performance in the flow cell with an ultra‐low‐capacity fade rate of 0.00029% per cycle for 18000 cycles (62 days) and but also delivered a stable high capacity of 47 Ah L−1 (with capacity fade 0.0056% per cycle, 0.077% per day) under ambient condition. Such finding undoubtedly provides a guidance to design stable redox‐active molecules for AOFBs.

Experimental and Virtual Screening of Phenazine and Phenothiazine Derivatives in Aqueous Solution for Electrochemical Carbon Capture

Molecular redox-active compounds, including quinone and aza-aromatics, have emerged as tools for capturing carbon dioxide using renewable electricity. Given the vast and highly diverse chemical space of the candidate compounds, accessing their electrochemical properties in a rapid way is attractive for both experimental and virtual screening approaches.Here we present a study on the experimental screening of a series of commercial redox-active compounds. Phenazine and phenothiazine dyes have been experimentally tested for applications in electrochemical carbon capture, for which they are finding increasing applications as redox mediators due to their unique redox properties in aqueous solution. Nicotinamide has been used as a redox-inactive solubilizing agent to increase the solubilities of general phenazine and phenothiazine derivatives for rapid experimental screening of commercial compounds without time-consuming synthetic modifications. Cyclic voltammetry in aqueous solutions under nitrogen and carbon dioxide indicated reversible behavior in the pH swing of an aqueous solution. Bulk electrolysis experiments demonstrated the chemical stability of phenazine and phenothiazine derivatives. The redox properties and the chemical stability make phenazine and phenothiazine derivatives interesting candidates for future use as redox-active materials in electrochemical carbon capture.We also present progress towards a virtual screening for the optimization of electrochemical and physicochemical properties of redox-active compounds. Based on our experimental screening of commercial phenazine and phenothiazine compounds identifying neutral red as the lead compound, a virtual screening was performed for optimization of electrochemical and physicochemical properties using machine learning. The virtual screening development steps include (1) chemical library generation using neutral red as a lead compound, (2) molecular property prediction based on quantum chemical calculations, (3) aqueous solubility prediction using machine learning, (4) data processing and database creation, and (5) experimental validation of the optimized compounds for the use of electrochemical carbon capture. Figure 1

A Multifaceted Scaffold for Building Bioactive Compounds: Phenothiazine

Abstract: In the growing field of heterocyclic compounds, phenothiazine and the associated nucleus are among the most significant potential scaffolds with excellent pharmacological activities. The knowledge of chemistry, synthetic routes, and various physicochemical parameters of these compounds draws particular attention to create a chemical library. Related compounds synthesized by various routes have diverse pharmacological functions. The exhaustive search of phenothiazine literature helps the medicinal chemists who develop the molecules for designing new drugs. A broad view of the synthetic routes has been outlined in this study. This paper includes the chemistry, physiochemical properties, and various biological activities of phenothiazine and related compounds.

Type IV Pilus-Mediated Inhibition of Acinetobacter baumannii Biofilm Formation by Phenothiazine Compounds.

Infections by pathogenic Acinetobacter species represent a significant burden on the health care system, despite their relative rarity, due to the difficulty of treating infections through oral antibiotics. Multidrug resistance is commonly observed in clinical Acinetobacter infections and multiple molecular mechanisms have been identified for this resistance, including multidrug efflux pumps, carbapenemase enzymes, and the formation of bacterial biofilm in persistent infections. Phenothiazine compounds have been identified as a potential inhibitor of type IV pilus production in multiple Gram-negative bacterial species. Here, we report the ability of two phenothiazines to inhibit type IV pilus-dependent surface (twitching) motility and biofilm formation in multiple Acinetobacter species. Biofilm formation was inhibited in both static and continuous flow models at micromolar concentrations without significant cytotoxicity, suggesting that type IV pilus biogenesis was the primary molecular target for these compounds. These results suggest that phenothiazines may be useful lead compounds for the development of biofilm dispersal agents against Gram-negative bacterial infections. IMPORTANCE Acinetobacter infections are a growing burden on health care systems worldwide due to increasing antimicrobial resistance through multiple mechanisms. Biofilm formation is an established mechanism of antimicrobial resistance, and its inhibition has the potential to potentiate the use of existing drugs against pathogenic Acinetobacter. Additionally, as discussed in the manuscript, anti-biofilm activity by phenothiazines has the potential to help to explain their known activity against other bacteria, including Staphylococcus aureus and Mycobacterium tuberculosis.

Hologram quantitative structure-activity relationship guided in silicon molecular design of phenothiazine dye sensitizers for dye-sensitized solar cells

Hologram quantitative structure–activity relationship (HQSAR) method was successfully introduced into the structure-performance study on the phenothiazine dye sensitizers of dye-sensitized solar cells. A total of 79 phenothiazine derivatives were investigated to build the HQSAR model of power conversion efficiency. The fragment parameters of the established optimal HQSAR model are fragment size: “4 ∼ 7”, hologram length: “353”, and fragment distinction: “bonds, connections, chirality, donor and acceptor atoms”. The predictive performance of the HQSAR model was evaluated with external test set validation and leave-one-out cross-validation. The validation results demonstrate that the developed model possesses high prediction ability and stability. The molecular contribution map of this model was analyzed to reveal the key structures and modification positions for improving the power conversion efficiency, and was used to guide the molecular design of high performance dye sensitizers. The theoretical prediction result of several literature reported phenothiazine compounds indicates that the developed model is an effective and important guidance to the molecular design of dye sensitizers. Therefore, several new phenothiazine derivatives with theoretically improved power conversion efficiency were designed by the proposed HQSAR-based strategy.

Screening for inhibitors against SARS-CoV-2 and its variants

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, generating new variants that pose a threat to global health; therefore, it is imperative to obtain safe and broad-spectrum antivirals against SARS-CoV-2 and its variants. To this end, we screened compounds for their ability to inhibit viral entry, which is a critical step in virus infection. Twenty compounds that have been previously reported to inhibit SARS-CoV-2 replication were tested by using pseudoviruses containing the spike protein from the original strain (SARS-CoV-2-WH01). The cytotoxicity of these compounds was determined. Furthermore, we identified six compounds with strong antagonistic activity against the WH01 pseudovirus, and low cytotoxicity was identified. These compounds were then evaluated for their efficacy against pseudoviruses expressing the spike protein from B.1.617.2 (Delta) and B.1.1.529 (Omicron), the two most prevalent circulating strains. These assays demonstrated that two phenothiazine compounds, trifluoperazine 2HCl and thioridazine HCl, inhibit the infection of Delta and Omicron pseudoviruses. Finally, we discovered that these two compounds were highly effective against authentic SARS-CoV-2 viruses, including the WH01, Delta, and Omicron strains. Our study identified potential broad-spectrum SARS-CoV-2 inhibitors and provided insights into the development of novel therapeutics.

Synthesis and Biological Evaluation of Novel Phenothiazine Derivatives as Potential Antitumor Agents

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.

Phenothiazine, anthraquinone and related tricyclic derivatives as inhibitors of monoamine oxidase

Inhibitors of the monoamine oxidase (MAO) enzymes are important agents for the treatment of central nervous system disorders and have established roles in the therapy of neuropsychiatric diseases such as depression and in the neurodegenerative disorder, Parkinson’s disease. A number of good potency MAO inhibitors consist of tricyclic ring systems as exemplified by the structures of harmine and the phenothiazine compound methylene blue. In an attempt to discover novel MAO inhibitors, 30 phenothiazine, anthraquinone and related tricyclic derivatives were selected and evaluated as potential inhibitors of human MAO-A and MAO-B. The results show that, in general, the tricyclic compounds are specific inhibitors of MAO-A over the MAO-B isoform. Quinizarin (IC50 = 0.065 µM), 2-chloro-7-methoxy-10H-phenothiazine (IC50 = 0.576 µM) and xanthone (IC50 = 0.623 µM) proved to be the most potent MAO-A inhibitors, while the most potent MAO-B inhibition was recorded with 2-chloro-7-methoxy-10H-phenothiazine (IC50 = 1.34 µM), 1,2-diaminoanthraquinone (IC50 = 2.41 µM) and emodin (IC50 = 3.24 µM). These compounds may undergo further preclinical evaluation and development, and may also serve as potential lead compounds for the future design of MAO inhibitors.

Fluorinated phenothiazine derivatives: Photophysical properties, mechanochromism and thermochromism

Three fluorinated phenothiazine compounds (P-1, P-2, P-3) were synthesized and characterized. It was found that all of them displayed significant solvatochromism and aggregation-induced emission behaviors. It was worth noting that P-1 and P-2 exhibited obvious mechanochromic properties compared to P-3. Specifically, P-1 displayed two different colors upon grinding and smashing, and emission bands showed different shift direction. P-2 exhibited polymorphic emission, its powder emitted yellow fluorescence, whereas crystal emitted orange fluorescence. After grinding, these two states had red shifts of 76 nm and 35 nm, respectively. But P-3 only presented a red shift of 10 nm. In addition, P-1 and P-2 also had thermochromic properties. After heating, their maximum emission wavelengths all would red-shift, and the maximum red shift can be up to 71 nm. These results can be explained by wide-angle X-ray diffraction, the differential scanning calorimetry and single crystal diffraction analysis. This work provided a new idea for the preparation of materials with both mechanochromic and thermochromic characteristics.

Methylene Blue Inhibits the SARS-CoV-2 Spike-ACE2 Protein-Protein Interaction-a Mechanism that can Contribute to its Antiviral Activity Against COVID-19.

Due to our interest in the chemical space of organic dyes to identify potential small-molecule inhibitors (SMIs) for protein-protein interactions (PPIs), we initiated a screen of such compounds to assess their inhibitory activity against the interaction between SARS-CoV-2 spike protein and its cognate receptor ACE2, which is the first critical step initiating the viral attachment and entry of this coronavirus responsible for the ongoing COVID-19 pandemic. As part of this, we found that methylene blue, a tricyclic phenothiazine compound approved by the FDA for the treatment of methemoglobinemia and used for other medical applications (including the inactivation of viruses in blood products prior to transfusion when activated by light), inhibits this interaction. We confirmed that it does so in a concentration-dependent manner with a low micromolar half-maximal inhibitory concentration (IC50 = 3 μM) in our protein-based ELISA-type setup, while chloroquine, siramesine, and suramin showed no inhibitory activity in this assay. Erythrosine B, which we have shown before to be a promiscuous SMI of PPIs, also inhibited this interaction. Methylene blue inhibited the entry of a SARS-CoV-2 spike bearing pseudovirus into ACE2-expressing cells with similar IC50 (3.5 μM). Hence, this PPI inhibitory activity could contribute to its antiviral activity against SARS-CoV-2 even in the absence of light by blocking its attachment to ACE2-expressing cells and making this inexpensive and widely available drug potentially useful in the prevention and treatment of COVID-19 as an oral or inhaled medication.

Electrochemically Tagging Elastin-like Polymers-Modified Au Surfaces

We are exploring Elastin-like-Polymer (ELP) as a transducing enhancement element for biosensors. While previous work in our lab has investigated surface-bound ELP conformational state with electrochemical impedance spectroscopy to understand its stimuli-response, we would like to use ELP as an electrically active transducer in sensor applications. To achieve this, we must understand how much of the ELP is covalently attached to the electrode and functionalize the electrochemically-inert ELP with a faradaic tag. We present a proof-of-concept model for modifying the C-terminus of the ELP with Toluidine Blue O, an electrically active phenothiazine compound. Our system uses simple and accessible conjugation chemistry for this purpose and is conducted in aqueous solution. Further, reducing the thiol bonds will remove the covalently-bound ELP from the electrode surface to obtain an estimate of the ELP surface coverageThus far, we have successful decoupled the thiol-gold bond using the cyclic voltammetry reduction technique.. Electrochemical impedance spectroscopy confirmed that the modified electrode after thiol desorption returned to a similar state compared to a bare electrode. Additionally, we successfully measured an electrochemical signal attributed to the Toluidine Blue O tag conjugated to ELP based on its redox properties (Figure 1). We intend to further expand this work by refining the conjugation protocol, comparing various tags and conjugation chemistries, and relating surface coverage to desorption amounts of covalently bound ELP. Acknowledgements: The authors would like to acknowledge the financial support from the College of Medicine at Drexel University, NSF (CBET 1638896), the Collaborative Research Excellence Initiative Pilot Research Program at the University of New Hampshire, and the Hamel Center of Undergraduate Research at the University of New Hampshire. The authors also would like to acknowledge the assistance of Dr. Balog’s laboratory and Dr. Halpern’s laboratory.

Competition Between Phenothiazines and BH3 Peptide for the Binding Site of the Antiapoptotic BCL-2 Protein

The study of proteins and mechanisms involved in the apoptosis and new knowledge about cancer's biology are essential for planning new drugs. Tumor cells develop several strategies to gain proliferative advantages, including molecular alterations to evade from apoptosis. Failures in apoptosis could contribute to cancer pathogenesis, since these defects can cause the accumulation of dividing cells and do not remove genetic variants that have malignant potential. The apoptosis mechanism is composed by proteins that are members of BCL-2 and cysteine-protease families. BH3-only peptides are the “natural” intracellular ligands of BCL-2 family proteins. On the other hand, studies have proved that phenothiazine compounds influence the induction of cellular death. To understand the characteristics of phenothiazines and their effects on tumoral cells and organelles involved in the apoptosis, as well as evaluating their pharmacologic potential, we have carried out computational simulation with the purpose of relating the structures of the phenothiazines with their biological activity. Since the tridimensional (3D) structure of the target protein is known, we have employed the molecular docking approach to study the interactions between compounds and the protein's active site. Hereafter, the molecular dynamics technique was used to verify the temporal evolution of the BCL-2 complexes with phenothiazinic compounds and the BH3 peptide, the stability and the mobility of these molecules in the BCL-2 binding site. From these results, the calculation of binding free energy between the compounds and the biological target was carried out. Thus, it was possible to verify that thioridazine and trifluoperazine tend to increase the stability of the BCL-2 protein and can compete for the binding site with the BH3 peptide.

Synthesis and photophysical studies on a new fluorescent phenothiazine-based derivative.

A new typical phenothiazine compound functionalized with thienyl-indandione derivative (PTZTID) was synthesized and characterized using spectral analysis (ultraviolet-visible (UV-vis) light, infrared (IR), 1 H nuclear magnetic resonance (NMR) and 13 C NMR tools). The UV-vis absorption spectra of the PTZTID solution in 1,4-dioxane showed two absorption bands attributed to localized aromatic π-π* transitions of conjugated aromatic moieties and intramolecular charge transfer with the characteristics of a π-π* transition. The fluorescence spectra exhibited a maximum emission wavelength at 580 nm. The effect of concentration on photophysical properties took the form of a minor hypsochromic shift, which was attributed to some extent to the occurrence of H-type aggregation of the PTZTID derivative. Binary solvent effects on the spectroscopic behaviour of PTZTID were measured at different H2 O/1,4-dioxane ratios. Similarly, when increasing the water content, a hypsochromic shift was observed that resulted from H-type aggregation. Furthermore, geometry and electronic configurations of PTZTID were studied at density functional theory /B3LYP level and indicated that the compound had a nonplanar (butterfly structure).

Oral microbiological control by photodynamic action in orthodontic patients.

Orthodontics involves diagnosis and treatment of dental and skeletal malocclusions. Orthodontic apparatus may repair these malocclusions but may also impair oral hygiene making patients prone to develop both periodontal diseases and caries. Antimicrobial agents may be used to prevent this.To avoid increased antimicrobial resistance to available drugs, A-PDT (Antimicrobial Photodynamic Therapy) appears as a viable alternative. This work aimed to evaluate the efficacy of A-PDT on reducing the number of colony forming units (CFU) through the use of phenothiazine compound (methylene blue+ toluidine blue) as a photosensitizer, associated with red LED (λ640±5ηm) irradiation in orthodontic patients. Twenty-one patients consented to participate in the study. Three biofilm collections were performed around the brackets and gums of the inferior central incisors; first before any intervention (Control); second after 5min of pre-irradiation and the last one immediately after AmPDT. Subsequently, a microbiological routine for microorganism growth period were performed and CFU counting after a 24h done. The data showed that the AmPDT was able to reduce CFU count around 90% when compared to Control group (p=0.007) and also between the A-PDT and Photosensitizer groups (p=0.010). However, there were no differences between the Control and Photosensitizer groups. A-PDT associated with the use of phenothiazine compounds and red LED was able to significantly reduce the number of CFUs in orthodontic patients.

Effect of phenothiazine compounds on the secondary structure and fibrillogenesis of poly-l-lysine.

Phenothiazine molecules are effective and commonly used antipsychotic drugs, especially in the treatment of schizophrenia. However, they produce strong extrapyramidal side-effects manifested by drug-induced parkinsonism. Because Parkinson's disease as a neurodegenerative illness is associated with the formation of amyloid fibrils in neuronal cells, it is postulated that the development of phenothiazine-induced parkinsonism may be related to the phenothiazine-induced formation of fibrillar aggregates. The effect of phenothiazine compounds (fluphenazine (FPh), chlorpromazine (ChP) and propionylpromazine (PP)) on the fibrillogenesis of poly-l-lysine (PLL) was studied using Fourier-transform infrared (FTIR) spectroscopy supported by principal component analysis (PCA), vibrational circular dichroism (VCD), transmission electron microscopy (TEM) and Congo red binding assay. The fibrillogenesis of PLL is accompanied by fibril formation with charged or uncharged polypeptides with PPII (polyproline-like extended helix), α-helix or β-sheet conformations. All of the phenothiazine molecules investigated effectively reduced the temperature required to induce the formation of β-sheet-rich fibrils from α-helix-rich fibrils of PLL.

Synthesis, In Silico and In Vitro Studies of Potential Glucosamine‐6‐phosphate Synthase and Lanosterol‐14α‐demethylase Inhibitors

AbstractSome derivatives of phenothiazine and phenoxazine compounds were synthesized via Hiyama‐cross coupling reaction protocol. The intermediates were prepared by reacting 2‐aminothiophenol, 2‐aminopyridin‐3‐ol and 4,5‐diamino‐6‐hydroxylpyrimidin‐2‐thiol with 2,3‐dibromonaphthalene‐1,4‐dione in alkaline medium of anhydrous sodium carbonate. These intermediates were subjected to the fluoride‐free Hiyama cross‐coupling reaction with 2‐(dimethylsilyl)pyridine and dimethyl(2‐thienyl)silanol using magnetically separable Pd/Fe3O4 as the catalyst under aqueous conditions to yield the derivatives. Molecular descriptors of these compounds were evaluated for their drug‐likeness. Pharmacokinetic parameters were also evaluated. Molecular docking studies were performed. The synthesized compounds showed drug‐likeness. Pharmacokinetic evaluation reveals a strong plasma protein binding and potentials to cross blood‐brain barrier. 6‐(Thiophen‐2‐yl)‐5H‐11‐azabenzo[a]phenoxazin‐5‐one (8 b) and 11‐Amino‐9‐thio‐6‐(thiophen‐2‐yl)‐5H‐8,11‐diazabenzo[a]phenoxazin‐5‐one (9 b) showed highest binding energies of −5.74 and −7.25 kcal/mol with the protein targets glucosamine‐6‐phosphate synthase (2VF5) and lanosterol‐14α‐demethylase (3JUV) respectively.

Synthesis, luminescence and excited state absorption properties of conjugated D-π-A and D-π-D phenothiazine compounds

Four D-π-A or D-π-D phenothiazine compounds bearing different substituents on central π-bridge (R = -H (PTZ-1), -Br (PTZ-2), -CN (PTZ-3) and -OC12H25 (PTZ-4)) were synthesized and characterized. The influence of the substituents on the photophysics of these compounds is systematically investigated by spectroscopic methods and simulated by density functional theory (DFT) calculations. All compounds exhibit intense absorption bands in UV and visible region, which are influenced by the different substituents on the central π-bridge. Both electron-withdrawing and electron-donating substituents cause bathochromic shifts of the low energy 1π-π*/1ICT (intramolecular charge transfer) absorption bands. Meanwhile, all compounds are emissive in solution at room temperature (λem = 400–800 nm, Φem = 0.01–0.74). Their fluorescent quantum yields decrease when the electron-withdrawing substituents attached on the central π-bridge, but increase when electron-donating substituents were introduced. In addition, PTZ-1–PTZ-4 all exhibit strong triplet transient absorption (TA) in visible region. When the electron-donating substituents attached, the triplet excited-state molar extinction coefficient (190200 L mol−1 cm−1) and triplet excited-state lifetime (53.2 μs) of PTZ-4 were significantly enhanced. Their luminescent and excited state absorption properties could provide us a basis for elucidating the structure-property correlations of phenothiazine compounds and developing novel optical functional materials.