Phenazine Derivatives Research Articles

Recent Advances in Phenazine Natural Products: Chemical Structures and Biological Activities.

Phenazine natural products are a class of colored nitrogen-containing heterocycles produced by various microorganisms mainly originating from marine and terrestrial sources. The tricyclic ring molecules show various chemical structures and the decorating groups dedicate extensive pharmacological activities, including antimicrobial, anticancer, antiparasitic, anti-inflammatory, and insecticidal. These secondary metabolites provide natural materials for screening and developing medicinal compounds in the field of medicine and agriculture due to biological activities. The review presents a systematic summary of the literature on natural phenazines in the past decade, including over 150 compounds, such as hydroxylated, O-methylated, N-methylated, N-oxide, terpenoid, halogenated, glycosylated phenazines, saphenic acid derivatives, and other phenazine derivatives, along with their characterized antimicrobial and anticancer activities. This review may provide guidance for the investigation of phenazines in the future.

Recent Advances in Phenazine Natural Products: Biosynthesis and Metabolic Engineering.

Phenazine natural products are a class of nitrogen-containing heterocyclic compounds produced by microorganisms. The tricyclic ring molecules show various chemical structures and extensive pharmacological activities, such as antimicrobial, anticancer, antiparasitic, anti-inflammatory, and insecticidal activities, with low toxicity to the environment. Since phenazine-1-carboxylic acid has been developed as a registered biopesticide, the application of phenazine natural products will be promising in the field of agriculture pathogenic fungi control based on broad-spectrum antifungal activity, minimal toxicity to the environment, and improvement of crop production. Currently, there are still plenty of intriguing hidden biosynthetic pathways of phenazine natural products to be discovered, and the titer of naturally occurring phenazine natural products is insufficient for agricultural applications. In this review, we spotlight the progress regarding biosynthesis and metabolic engineering research of phenazine natural products in the past decade. The review provides useful insights concerning phenazine natural products production and more clues on new phenazine derivatives biosynthesis.

Profiling Metabolites with Antifungal Activities from Endophytic Plant-Beneficial Strains of Pseudomonas chlororaphis Isolated from Chamaecytisus albus (Hack.) Rothm.

Fungal phytopathogens represent a large and economically significant challenge to food production worldwide. Thus, the application of biocontrol agents can be an alternative. In the present study, we carried out biological, metabolomic, and genetic analyses of three endophytic isolates from nodules of Chamaecytisus albus, classified as Pseudomonas chlororaphis acting as antifungal agents. The efficiency of production of their diffusible and volatile antifungal compounds (VOCs) was verified in antagonistic assays with the use of soil-borne phytopathogens: B. cinerea, F. oxysporum, and S. sclerotiorum. Diffusible metabolites were identified using chromatographic and spectrometric analyses (HPTLC, GC-MS, and LC-MS/MS). The phzF, phzO, and prnC genes in the genomes of bacterial strains were confirmed by PCR. In turn, the plant growth promotion (PGP) properties (production of HCN, auxins, siderophores, and hydrolytic enzymes, phosphate solubilization) of pseudomonads were bioassayed. The data analysis showed that all tested strains have broad-range antifungal activity with varying degrees of antagonism. The most abundant bioactive compounds were phenazine derivatives: phenazine-1-carboxylic acid (PCA), 2-hydroxy-phenazine, and diketopiperazine derivatives as well as ortho-dialkyl-aromatic acids, pyrrolnitrin, siderophores, and HCN. The results indicate that the tested P. chlororaphis isolates exhibit characteristics of biocontrol organisms; therefore, they have potential to be used in sustainable agriculture and as commercial postharvest fungicides to be used in fruits and vegetables.

Characterization of Lomofungin Gene Cluster Enables the Biosynthesis of Related Phenazine Derivatives.

Phenazine-based small molecules are nitrogen-containing heterocyclic compounds with diverse bioactivities and electron transfer properties that exhibit promising applications in pharmaceutical and electrochemical industries. However, the biosynthetic mechanism of highly substituted natural phenazines remains poorly understood. In this study, we report the direct cloning and heterologous expression of the lomofungin biosynthetic gene cluster (BGC) from Streptomyces lomondensis S015. Reconstruction and overexpression of the BGCs in Streptomyces coelicolor M1152 resulted in eight phenazine derivatives including two novel hybrid phenazine metabolites, and the biosynthetic pathway of lomofungin was proposed. Furthermore, gene deletion suggested that NAD(P)H-dependent oxidoreductase gene lomo14 is a nonessential gene in the biosynthesis of lomofungin. Cytotoxicity evaluation of the isolated phenazines and lomofungin was performed. Specifically, lomofungin shows substantial inhibition against two human cancer cells, HCT116 and 5637. These results provide insights into the biosynthetic mechanism of lomofungin, which will be useful for the directed biosynthesis of natural phenazine derivatives.

Modern approaches to the synthesis of phenazine derivatives (microreview)

Modern approaches to the synthesis of phenazine derivatives (microreview)

Evaluation of Phenazine Derivatives from the Lichen-Associated Streptomyces flavidovirens as Potent Antineuroinflammatory Agents In Vitro and In Vivo.

Eighteen nitrogen-containing compounds (1-18) were isolated from cultures of the lichen-associated Streptomyces flavidovirens collected from the Qinghai-Tibet Plateau, including seven phenazine derivatives with three new ones, named subphenazines A-C (2-4), two new furan pyrrolidones (8-9), and nine known alkaloids. The structures were elucidated by spectroscopic data analysis, and absolute configurations were determined by single-crystal X-ray diffraction and ECD calculations. The phenazine-type derivatives, in particular compound 3, exhibited significantly better antineuroinflammatory activity than other isolated compounds (8-18). Compound 3 inhibited the release of proinflammatory cytokines including IL-6, TNF-α, and PGE2, and the nuclear translocation of NF-κB; it also reduced the oxidative stress and activated the Nrf2 signaling pathway in LPS-induced BV2 microglia cells. In vivo anti-inflammatory activity in zebrafish indicated that 3 inhibited LPS-stimulated ROS generation. These findings suggested that compound 3 might be a potent antineuroinflammatory agent through the regulation of the NF-κB/Nrf2 signaling pathways.

Stepwise synthesis of magnetic mesoporous silica nanoparticles decorated with SnO2 quantum dots as an efficient, recyclable, and green nanocatalyst for the synthesis of benzo[a]pyrano[3,2‐c]phenazine derivatives

In this research, magnetic mesoporous silica nanoparticles decorated with SnO2 quantum dots (M‐MSNs/SnO2[QDs]) were successfully synthesized and characterized using several advanced techniques including FT‐IR, XRD, FE‐SEM, EDS, elemental mapping, VSM, and BET. This study demonstrates the synthesis of benzo[a]pyrano[3,2‐c]phenazine derivatives via a four‐component reaction between 2‐hydroxy‐1,4‐naphthoquinone, ortho‐phenylenediamine, malononitrile, and benzaldehyde derivatives in the presence of M‐MSNs/SnO2(QDs) in ethanol as a green solvent. The proposed catalyst efficiently catalyzed the synthesis of these compounds with yields of 87–96% in 70–100 minutes. The presented method offers a cost‐effective and environmentally friendly approach with numerous advantages, including high product yields, simple operation, short reaction times, low‐cost purification, and facile catalyst recovery.

Investigating the effect of nitrogen and chlorine Co–doped carbon quantum dots in phenazine and quinoxaline sensitized solar cells

We investigated five dyes for dye-sensitized solar cells (DSSCs) relying upon derivatives of phenazine and quinoxaline and also studied their optical characteristics and the influence of functional groups such as (-CH3, -NO2, -C = O, -CN, and -OH) on these characteristics. When the prepared dyes are directly used at DSSCs, 9-Nitrobenzo[a]phenazin-5-ol (3b) dye device showed an improved Jsc (0.288 mA cm−2), Voc (0.437 V), FF (0.446), and η (0.056 %) than the sensitized solar cells by other dyes. In the following, nitrogen-doped carbon quantum dot and nitrogen, chlorine co-doped carbon quantum dot are used to improve the performance of DSSCs. The results showed that the device sensitized using the sensitizer (5-hydroxybenzo[α]phenazin-9-yl)(phenyl) methanone (3c)/NCQD has the highest photovoltaic efficiency with Jsc (0.979 mA cm−2), Voc (0.465 V), FF (0.370), and η (0.168 %). The N and Cl co-doped carbon dots were synthesized with a green approach to improve the performance of solar cells by the co-sensitization method. This approach is improving the efficiency of DCSSs with a simple, eco-friendly, and low-cost technique. Among the prepared sensitizers, (5-hydroxybenzo[α]phenazin-9-yl)(phenyl) methanone (3c)/N, Cl-CQD demonstrates the highest photovoltaic efficiency with Jsc (1.31 mA cm−2), Voc (0.495 V), FF (0.466), and η (0.303 %). FT-IR, XRD, 13C NMR, 1H NMR, TEM, EDS-Map, AFM, DLS, and PL studies were used to confirm the structure of the synthesized dyes and quantum dots.

Oxygen-vacancy-enriched MgO/carbon composite as a highly efficient electrocatalyst for phenazine/dihydrophenazine redox reaction of aqueous phenazine redox flow battery

Phenazine derivatives are attractive anolyte redox-active species in aqueous redox flow batteries (ARFBs). Unfortunately, they typically suffer from sluggish reaction kinetics, resulting in poor rate capability and inferior energy efficiency, especially under high current densities. Herein, we report a composite of MgO and Ketjen black carbon (MgO/KB) that can serve as a low-cost ARFB electrocatalyst to significantly improve the redox reaction kinetics of phenazine derivatives. The MgO/KB composite catalyst exhibits excellent catalytic performance, with an area-specific resistance (ASR) of 1.54 and 1.11 Ω/cm2 for the charge and discharge processes, respectively, as well as improved energy efficiency, capacity utilization, and durability in practical ARFB applications. Detailed research confirms that the oxygen vacancies within the MgO promote electron transfer and enhance catalytic activity for the electrochemical reaction of phenazine derivatives. Using density functional theory (DFT) calculations, we unveil that the underlying catalytic enhancement mechanism stems from a low free energy barrier of the rate-determining step (RDS) on oxygen-vacancy-enriched MgO for the oxidation reaction of dihydro-phenazine derivative. These findings will guide the design of highly active electrocatalysts for organic ARFBs.

A Computational Approach for the Discovery of Novel DNA Methyltransferase Inhibitors.

Nowadays, the explosion of knowledge in the field of epigenetics has revealed new pathways toward the treatment of multifactorial diseases, rendering the key players of the epigenetic machinery the focus of today's pharmaceutical landscape. Among epigenetic enzymes, DNA methyltransferases (DNMTs) are first studied as inhibition targets for cancer treatment. The increasing clinical interest in DNMTs has led to advanced experimental and computational strategies in the search for novel DNMT inhibitors. Considering the importance of epigenetic targets as a novel and promising pharmaceutical trend, the present study attempted to discover novel inhibitors of natural origin against DNMTs using a combination of structure and ligand-based computational approaches. Particularly, a pharmacophore-based virtual screening was performed, followed by molecular docking and molecular dynamics simulations in order to establish an accurate and robust selection methodology. Our screening protocol prioritized five natural-derived compounds, derivatives of coumarins, flavones, chalcones, benzoic acids, and phenazine, bearing completely diverse chemical scaffolds from FDA-approved "Epi-drugs". Their total DNMT inhibitory activity was evaluated, revealing promising results for the derived hits with an inhibitory activity ranging within 30-45% at 100 µM of the tested compounds.

Synthesis of benzo[a]furo[2, 3-c]phenazine derivatives via microwave irradiation by catalyzed Fe3O4@MCM-48@IL/Pd for high-performance removal of rhodamine B and determination of losartan using modified glassy carbon electrode

Synthesis of benzo[a]furo[2, 3-c]phenazine derivatives via microwave irradiation by catalyzed Fe3O4@MCM-48@IL/Pd for high-performance removal of rhodamine B and determination of losartan using modified glassy carbon electrode

Carbazole/triphenylamine-functionalized phenanthro[4,5-abc]phenazines: Synthesis and luminescence properties

Two phenanthro[4,5-abc]phenazine derivatives, 11-(3,6-di‑tert‑butyl‑9H-carbazol-9-yl)phenanthro[4,5-abc]phenazine (PyQ-Cz) and 4-(phenanthro[4,5-abc]phenazin-11-yl)-N,N-diphenylaniline (PyQ-TPA), were synthesized by grafting the an electron-donating carbazole and triphenylamine segments onto the pyrene-fused quinoxaline (PyQ) core, respectively and characterized by NMR (1H and 13C) and high resolution mass spectrometry. Their thermal, photophysical and electrochemical properties were systematically investigated. These compounds exhibited excellent thermal stability and intense yellow emission and orange emission in dichloromethane solution, whereas they exhibited green emission in solid films. Based on their high photoluminescence quantum yields and the frontier orbital energies, the doped devices with a structure of ITO/PEDOT:PSS (30 nm)/CBP:PyQ derivatives (x wt%) (25 nm)/TPBi (35 nm)/Liq (2 nm)/Al (150 nm) were fabricated by solution-processed the emitting layers to investigate their electroluminescence (EL) performances, in which the doped devices of PyQ-Cz exhibited the maximum external quantum efficiency (EQEmax) of 1.86 %, while the PyQ-TPA doped devices showed an EQEmax of 0.82 %.

Modelling energy-harvesting processes in primitive cells: Proton transport across bilayers driven by the oxidation of sulfite

A frequently debated topic related to the origin of life centers around the question of how complex forms of life on today's Earth may have evolved over time from simpler predecessors. For example, the question of how proton concentration gradients across cellular membranes developed in ancestral protocells remains unanswered. This process, which is indispensable for the generation of chemical energy in modern organisms, is driven by energy derived from redox processes in the respiratory chain. Since it is highly unlikely that the complex machinery of the respiratory chain was available on early Earth, we provide an example of how proton gradients can be established in less complex systems. Utilizing liposomes as models of primitive cells, we were able to generate proton gradients of about two pH units across the liposome bilayers using redox reactions as the driving force. Electrons were transferred from sodium sulfite present on the outside of the liposomes to ferricyanide, which was trapped on the inside. A lipid-soluble phenazine derivative served as a shuttle that transferred both electrons and protons across the lipid bilayer. Because sulfite would have been an abundant reduced solute available to the earliest cells, we propose that it may have been a primary source of redox energy for primitive chemiosmotic energy transduction.

Bacillus sp. G2112 Detoxifies Phenazine-1-carboxylic Acid by N5 Glucosylation.

Microbial symbionts of plants constitute promising sources of biocontrol organisms to fight plant pathogens. Bacillus sp. G2112 and Pseudomonas sp. G124 isolated from cucumber (Cucumis sativus) leaves inhibited the plant pathogens Erwinia and Fusarium. When Bacillus sp. G2112 and Pseudomonas sp. G124 were co-cultivated, a red halo appeared around Bacillus sp. G2112 colonies. Metabolite profiling using liquid chromatography coupled to UV and mass spectrometry revealed that the antibiotic phenazine-1-carboxylic acid (PCA) released by Pseudomonas sp. G124 was transformed by Bacillus sp. G2112 to red pigments. In the presence of PCA (>40 µg/mL), Bacillus sp. G2112 could not grow. However, already-grown Bacillus sp. G2112 (OD600 > 1.0) survived PCA treatment, converting it to red pigments. These pigments were purified by reverse-phase chromatography, and identified by high-resolution mass spectrometry, NMR, and chemical degradation as unprecedented 5N-glucosylated phenazine derivatives: 7-imino-5N-(1'β-D-glucopyranosyl)-5,7-dihydrophenazine-1-carboxylic acid and 3-imino-5N-(1'β-D-glucopyranosyl)-3,5-dihydrophenazine-1-carboxylic acid. 3-imino-5N-(1'β-D-glucopyranosyl)-3,5-dihydrophenazine-1-carboxylic acid did not inhibit Bacillus sp. G2112, proving that the observed modification constitutes a resistance mechanism. The coexistence of microorganisms-especially under natural/field conditions-calls for such adaptations, such as PCA inactivation, but these can weaken the potential of the producing organism against pathogens and should be considered during the development of biocontrol strategies.

Solvation controlled excited-state dynamics in a donor-acceptor phenazine-imidazole derivative.

In the past few decades, significant efforts have been devoted to developing phenazine derivatives in various fields such as medicine, pesticides, dyes, and conductive materials owing to their highly Stokes-shifted fluorescence and distinctive photophysical properties. The modulation of the surrounding environment can effectively influence the luminescent behavior of phenazine derivatives, prompting us to investigate the solvent effect on the excited state dynamics. Herein, we present the solvent controlled excited state dynamics of a novel triphenylamine-based phenazine-imidazole molecule (TPAIP) through steady-state spectra and femtosecond transient absorption spectra. The fluorescence emission spectrum exhibited a redshift with increasing solvent polarity, indicating the existence of a charge transfer state. Furthermore, by tracking the femtosecond transient absorption spectra of TPAIP, we found that the nature of the relaxed S1 state was strongly influenced by the solvent polarity: intersystem crossing character appears in apolar solvent, whereas intramolecular charge transfer character occurs in polar solvent because of solvation. These findings provide significant theoretical insights into the impact of solvents on the excited state dynamics within phenazine derivatives. This understanding supports diverse applications ranging from advanced biological probe design to photocatalysis and pharmaceutical research.

Self-revealing kinetically captured self-assembly of a N,N′-diphenyl-dihydrodibenzo[a,c]phenazine derivative

We have developed a vibration-induced emission-active fluorogen capable of kinetically-captured self-assembly and visualizing its own self-assembly process in real time and in situ. CPL with a glum of 7.1 × 10−2 is achieved.

Synthesis and biological activity of imidazole phenazine derivatives as potential inhibitors for NS2B-NS3 dengue protease

A series of new imidazole-phenazine derivatives were synthesized via a two-step process. The condensation of 2,3-diaminophenazine and benzaldehyde derivatives proceeds with intermediate formation of an aniline Schiff base, which undergoes subsequent cyclodehydrogenation in situ. The structures of the synthesized compounds were characterized by 1D and 2D NMR, FTIR and HRMS. A total of thirteen imidazole phenazine derivatives were synthesized and validated for their inhibitory activity as anti-dengue agents by an in vitro DENV2 NS2B-NS3 protease assay using a fluorogenic Boc-Gly-Arg-Arg-AMC substrate. Two para-substituted imidazole phenazines, 3e and 3k, were found to be promising lead molecules for novel NS2B-NS3 protease inhibitors with IC50 of 54.8 μM and 71.9 μM, respectively, compared to quercetin as a control (IC50 104.8 μM). The in silico study was performed using AutoDock Vina to identify the binding energy and conformation of 3e and 3k with the active site of the DENV2 NS2B-NS3 protease Wichapong model. The results indicate better binding properties of 3e and 3k with calculated binding energies of −8.5 and −8.4 kcal mol−1, respectively, compared to the binding energy of quercetin of −7.2 kcal mol−1, which corroborates well with the experimental observations.

Tailoring hydroxyl groups of organic phenazine anodes for high-performance and stable alkaline batteries

With the aid of a hydroxyl group as an electron-donating group, the redox potential of phenazine derivatives is reduced, and the rate performance increases due to the hydrogen bonds between hydroxyl molecules.

Enabling Long-Life Aqueous Organic Redox Flow Batteries with a Highly Stable, Low Redox Potential Phenazine Anolyte.

Aqueous organic redox flow batteries (AORFBs) are considered a promising energy storage technology due to the sustainability and designability of organic active molecules. Despite this, most of AORFBs suffer from limited stability and low voltage because of the chemical instability and high redox potential of organic molecules in anolyte. Herein, we propose a new phenazine derivative, 4,4'-(phenazine-2,3-diylbis(oxy))dibutyric acid (2,3-O-DBAP), as a water-soluble and chemically stable anodic active molecules. By combining calculations and experiments, we demonstrate that 2,3-O-DBAP exhibits a higher solubility, a lower redox potential (-0.699 V vs SHE), and greater chemical stability than other O-DBAP isomers. Then, we demonstrate a long-lasting flow cell with an average discharge voltage of 1.12 V, a low fade rate of 0.0127%, and a lifespan of 62 days at pH 14 using 2,3-O-DBAP paired with ferri/ferrocyanide. The negligible self-discharge behavior also verifies the high stability of 2,3-O-DBAP. These results highlight the importance of molecular engineering for AORFBs.

A High-Performance Phenazine-Based Cathode for Aqueous Organic Zinc-Ion Battery

Aqueous Zinc-ion batteries are very appealing for massive energy storage applications due to their inherent safety, low cost, and longevity. Nevertheless, the lack of positive electrode material (cathode) caused by the slow diffusion of Zn2+ inside solid inorganic frameworks is impeding their advancement. Organic electrode materials have recently been endorsed as a less-toxic and environment-benign substitute for traditional inorganic electrode materials. Even though, its performance is hampered by the poor rate capability and limited cycle life caused by cathode material deterioration during Zn2+ insertion/de-insertion. An efficient charge-discharge in aqueous zinc ion batteries, even at high current densities with good capacity retention, is made possible by the stability of aromatic organic heterocyclic cathode materials with the necessary intermolecular spacing. Herein, we describe a strategy to utilize a commercially available redox-active organic molecule (ROM), Phenazine (PNZ) derivative, which can offer efficient and reversible Zn2+ storage due to its high molecular symmetry with low molecular weight. The use of a cation exchange membrane and optimization of volume of the electrolyte and conductive carbon enabled the PNZ electrode to provide a better specific capacity value of 247 mAh g-1 (90% of the theoretical capacity of PNZ) at 1 A g-1 with a good capacity retention of 75 % over 300 cycles. These results indicated that exceptional water insolubility in small organic molecules like PNZ would make them a desirable electrode material for AZIBs. In contrast to conventional design ideas for organic electrode materials such as having a larger molecular weight or adding certain polar functional groups to the organic molecular bulk, our research offered fresh and insightful recommendations for the creation of simpler organic electrodes. Fig. 1. Cyclic performance with charge-discharge plots of PNZ/Katjen black carbon Zinc coin cells with Nafion 212 membrane a) capacity vs. voltage plot b) cycle number vs. capacity plot. Figure 1