Strong intramolecular charge-transfer effect strengthening naphthoquinone-based chemosensor: Experimental and theoretical evaluation.

An aminophenol-linked naphthoquinone-based fluorometric and colorimetric chemosensor 2-chloro-3-((3-hydroxyphenyl) amino) naphthalene-1,4-dione (2CAN-Dione) was synthesized for selective detection of Sn2+ ion in aqueous solution. The amine and conversion of carbonyl into carboxyl groups play a vital role in the sensing mechanism when Sn2+ is added to 2CAN-Dione. Comprehensive characterization of the sensor was carried out using standard spectral and analytical approaches. Because of the intramolecular charge transfer (ICT) effect and the turn-on sensing mode, the strong fluorometric emission towards Sn2+ was observed at about 435 nm. The chemosensor exhibited good selectivity for Sn2+ in the presence of coexisting metal ions. An improved linear connection was established with a low limit of detection (0.167 µM). FT-IR, 1H NMR, 13C NMR, and quantum chemistry methods were performed to verify the binding coordination mechanism. The chemosensing probe 2CAN-Dione was successfully employed in bioimaging investigations, demonstrating that it is a reliable fluorescent marker for Sn2+ in human cancer cells.

Synergistic and Additive Effects of Menadione in Combination with Antibiotics on Multidrug-Resistant Staphylococcus aureus: Insights from Structure-Function Analysis of Naphthoquinones.

Antimicrobial resistance (AMR) interferes with the effective treatment of infections and increases the risk of microbial spread and infection-related illness and death. The synergistic activities of combinations of antimicrobial compounds offer satisfactory approaches to some extent. Structurally diverse naphthoquinones (NQs) including menadione (-CH3 group at C2) exhibit substantial antimicrobial activities against multidrug-resistant (MDR) pathogens. We explored the combinations of menadione with antibiotic ciprofloxacin or ampicillin against Staphylococcus aureus and its biofilms. We found an additive (0.590 %) were also observed. However, preformed biofilms were not affected. Dent formation was also evident in S. aureus treated with the test compounds. The structure-function relationship (SFR) of NQs was used to determine and predict their activity pattern against pathogens. Analysis of 10 structurally distinct NQs revealed that the compounds with -Cl, -Br, -CH3 , or -OH groups displayed the lowest MICs (32-256 µg/mL). Furthermore, 1,4-NQs possessing a halogen or -CH3 moiety showed elevated ROS activity, whereas molecules with an -OH group affected cell integrity. Improved activity of antimicrobial combinations and SFR approaches are significant in antimicrobial therapies.

How Structure-Function Relationships of 1,4-Naphthoquinones Combat Antimicrobial Resistance in Multidrug-Resistant (MDR) Pathogens.

Antimicrobial resistance (AMR) is one of the top ten health-related threats worldwide. Among several antimicrobial agents, naphthoquinones (NQs) of plant/chemical origin possess enormous structural and functional diversity and are effective against multidrug-resistant (MDR) pathogens. 1,4-NQs possess alkyl, hydroxyl, halide, and metal groups as side chains on their double-ring structure, predominantly at the C-2, C-3, C-5, and C-8 positions. Among 1,4-NQs, hydroxyl groups at either C-2 or C-5 exhibit significant antibacterial activity against Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. (ESKAPE) and MDR categories. 1,4-NQs exhibit antibacterial activities like plasmids curing, reactive oxygen species generation, efflux pumps inhibition, anti-DNA gyrase activity, membrane permeabilization, and biofilm inhibition. This review emphasizes the structure-function relationships of 1,4-NQs against ESKAPE and MDR pathogens based on a literature review of studies published in the last 15 years. Overall, 1,4-NQs have great potential for counteracting the antimicrobial resistance of MDR pathogens.

Construction of a simple dual-channel fluorescence chemosensor for Cu2+ ion and GSSG detection and its mitochondria-targeting bioimaging applications.

Numerous chemosensors have been developed for next-generation detection systems because of their ease of use and promising characteristics to distinguish signals between various analytes binding. However, given their typically poor emission response and arduous preparation methods, very few chemosensing probes have been commercialized to date. In this work, a simple, naphthoquinone-based mitochondria-targeting chemosensor (CIA) has been fabricated for the simultaneous detection of Cu2+ and GSSG (glutathione oxidized) through an "on-off" mode in a buffered semi-aqueous solution. Significantly, the CIA chemosensor showed a sensitive detection response towards Cu2+ and GSSG with low detection limits (0.309 µM, and 0.226 µM, respectively). In addition, the detection mechanism of CIA was thoroughly verified and confirmed using numerous analytical techniques. Furthermore, CIA was utilized as a sequential fluorescence biomarker to detect Cu2+ in human cervical cancer cell lines. These findings indicate that the chemosensor CIA can discriminate human cancer cells from normal cells. The CIA was also confirmed to possess the ability to target mitochondria. More importantly, the present CIA chemosensor detected Cu2+ in zebrafish larvae, indicating the probe has tissue penetration ability.

Biopolymer and Synthetic Polymer-Based Nanocomposites in Wound Dressing Applications: A Review.

Biopolymers are materials obtained from a natural origin, such as plants, animals, microorganisms, or other living beings; they are flexible, elastic, or fibrous materials. Polysaccharides and proteins are some of the natural polymers that are widely used in wound dressing applications. In this review paper, we will provide an overview of biopolymers and synthetic polymer-based nanocomposites, which have promising applications in the biomedical research field, such as wound dressings, wound healing, tissue engineering, drug delivery, and medical implants. Since these polymers have intrinsic biocompatibility, low immunogenicity, non-toxicity, and biodegradable properties, they can be used for various clinical applications. The significant advancements in materials research, drug development, nanotechnology, and biotechnology have laid the foundation for changing the biopolymeric structural and functional properties. The properties of biopolymer and synthetic polymers were modified by blending them with nanoparticles, so that these materials can be used as a wound dressing application. Recent wound care issues, such as tissue repairs, scarless healing, and lost tissue integrity, can be treated with blended polymers. Currently, researchers are focusing on metal/metal oxide nanomaterials such as zinc oxide (ZnO), cerium oxide (CeO2), silver (Ag), titanium oxide (TiO2), iron oxide (Fe2O3), and other materials (graphene and carbon nanotubes (CNT)). These materials have good antimicrobial properties, as well as action as antibacterial agents. Due to the highly antimicrobial properties of the metal/metal oxide materials, they can be used for wound dressing applications.

Mitochondria-targeted acridine-based dual-channel fluorescence chemosensor for detection of Sn4+ and Cr2O72- ions in water and its application in discriminative detection of cancer cells.

The goal of the present work was to fabricate a new low-cost, easy-to-prepare, dual-channel fluorescence chemosensor comprised of acridine-diphenylacetyl moieties (NDA) to enable remarkable Sn4+ detection in water and biological medium. The resulting NDA-Sn4+ complex was utilized for the distinguished identification of Cr2O72- ions from other anions and biomolecules. These investigations involve the absorption, fluorescence, and electrochemical methods for the detection of Sn4+ and Cr2O72- ions in pure water. The mechanism for NDA-mediated Sn4+ detection was experimentally determined by FT-IR, NMR titrations, mass (ESI) analyses, and DFT calculations. The obtained results indicate that the NDA chemosensor possessed excellent performance characteristics including good water solubility and compatibility, quick response time (less than 10 s), high sensitivity (Sn4+ = 0.268 µM and Cr2O72- = 0.160 µM), and selectivity against coexisting metals, anions, amino acids, and peptides. The chemosensor NDA induced negligible toxicity in live cells and was successfully utilized as a biomarker for the tracking of Sn4+ in human normal and cancer cells. More importantly, NDA demonstrates distinguished recognition of Sn4+ in human cancer cells rather than in normal live cells. Additionally, NDA was shown to act as a mitochondria-targeted probe in FaDu cells.

A dual-channel colorimetric and ratiometric fluorescence chemosensor for detection of Hg2+ ion and its bioimaging applications.

A new colorimetric and ratiometric fluorescence chemosensor 4-((3-(octadecylthio)-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)benzenesulfonamide (4DBS) was synthesized and investigated for the selective detection of Hg2+ in DMSO-H2O (9:1, v/v) solution. The chemosensor was efficiently synthesized in two steps via Michael-like addition and nucleophilic substitution reactions. The ratiometric fluorescence turn-on response was obtained towards Hg2+, and its fluorescence emission peak was red-shifted by 140 nm with an associated color change from light maroon to pale yellow due to the intramolecular charge transfer effect. The formed coordination metal complex was further evaluated by FT-IR, 1H NMR, and quantum chemical analyses to confirm the binding mechanism. The detection process was sensitive/reversible, and the calculated limit of detection for Hg2+ was 0.451 µM. Furthermore, 4DBS was effectively utilized as a bioimaging agent for detection of Hg2+ in live cells and zebrafish larvae. Additionally, 4DBS showed distinguishing detection of Hg2+ in cancer cells in comparison with normal cells. Thus, 4DBS could be employed as an efficient bioimaging probe for discriminative identification of human cancer cells.

Mitochondria-targeted dual-channel colorimetric and fluorescence chemosensor for detection of Sn2+ ions in aqueous solution based on aggregation-induced emission and its bioimaging applications.

Several fluorescence and colorimetric chemosensory for Sn2+ detection in an aqueous media have been reported, but applications remain limited for discriminative Sn2+ detection in live human cells and zebrafish larvae. Herein, a mitochondria-targeted Sn2+ "turn-on" colorimetric and fluorescence chemosensor, 2CTA, with an aggregation-induced emission (AIE) response was developed. The sensing of Sn2+ was enabled by a reduction-enabled binding pathway, with the conversion of -CË­O groups to -C-OH groups at the naphthoquinone moiety. The color changed from light maroon to milky white in a buffered aqueous solution. The chemosensor 2CTA possessed the excellent characteristics of good water solubility, fast response (less than 10 s), and high sensitivity (79 nM) and selectivity for Sn2+ over other metal ions, amino acids, and peptides. The proposed binding mechanism was experimentally verified by means of FT-IR and NMR studies. The chemosensor 2CTA was successfully employed to recognize Sn2+ in live human cells and in zebrafish larvae. In addition, a colocalization study proved that the chemosensor had the ability to target mitochondria and overlapped almost completely with MitoTracker Red. Furthermore, a bioimaging study of live cells demonstrated the discriminative detection of Sn2+ in human cancer cells and the practical applications of 2CTA in biological systems.

Simple Colorimetric and Fluorescence Chemosensing Probe for Selective Detection of Sn2+ Ions in an Aqueous Solution: Evaluation of the Novel Sensing Mechanism and Its Bioimaging Applications.

An easily accessible colorimetric and fluorescence probe 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)benzenesulfonamide (4CBS) was successfully developed for the selective and sensitive detection of Sn2+ in an aqueous solution. The sensing mechanism involves reduction of -C═O into -C-OH groups in 4CBS upon the addition of Sn2+, which initiates the fluorescence turn-on mode. A better linear relationship was achieved between fluorescence intensity and Sn2+ concentration in the range of 0-62.5 µM, with a detection limit (LOD) of 0.115 µM. The binding mechanism of 4CBS for Sn2+ was confirmed by Fourier transform infrared analysis, NMR titrations, and mass (electrospray ionization) spectral analysis. Likewise, the proposed sensing mechanism was supported by quantum chemical calculations. Moreover, bioimaging studies demonstrated that the chemosensing probe 4CBS is an effective fluorescent marker for the detection of Sn2+ in living cells and zebrafish. Significantly, 4CBS was able to discriminate between Sn2+ in human cancer cells and Sn2+ in normal live cells.

Simple Fluorescence Turn-On Chemosensor for Selective Detection of Ba2+ Ion and Its Live Cell Imaging.

A phenoxazine-based fluorescence chemosensor 4PB [(4-(tert-butyl)-N-(4-((4-((5-oxo-5H-benzo[a]phenoxazin-6-yl)amino)phenyl)sulfonyl)phenyl)benzamide)] was designed and synthesized by a simple synthetic methods. The 4PB fluorescence chemosensor selectively detects Ba2+ in the existence of other alkaline metal ions. In addition, 4PB showed high selectivity and sensitivity for Ba2+ detection. The detection limit of 4PB was 0.282 µM and the binding constant was 1.0 × 106 M-1 in CH3CN/H2O (97.5:2.5 v/v, HEPES = 1.25 mM, pH 7.3) medium. This chemosensor functioned through the intramolecular charge transfer (ICT) mechanism, which was further confirmed by DFT studies. Live cell imaging in MCF-7 cells confirmed the cell permeability of 4PB and its capability for specific detection of Ba2+ in living cells.

Effect of In Ovo Injection of L-Arginine in Different Chicken Embryonic Development Stages on Post-Hatchability, Immune Response, and Myo-D and Myogenin Proteins.

The aim of this study was to evaluate the effect of in ovo injection with different ratios of L-arginine (L-Arg) into Ross broiler eggs at three different embryonic developmental stages (eighth day (d), 14th day, and 18th day) on the survival, hatchability, and body weight (BW) of one-day-old hatched chicks. Additionally, we have analyzed the levels of serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT), the protein expression of heat shock proteins (HSPs), and we have also determined micronuclei (MN) and nuclear abnormality (NA). In addition, the genotoxic effect was observed in peripheral blood cells such as the presence of micronuclei and nuclear abnormalities in the experimental groups. The results showed that survival and hatching rates as well as body weight were increased on the 14th day of incubation compared to the eighth and 18th day of incubation at lower concentrations of L-Arg. Moreover, the levels of SGOT and SGPT were also significantly (p < 0.05) increased on the 14th day of incubation at the same concentration (100 µg/µL/egg) of injection. In addition, immunoglobulin (IgM) levels were increased on the 14th day of incubation compared to other days. The protein expressions of HSP-47, HSP-60, and HSP-70 in the liver were significantly down-regulated, whereas the expression of myogenin and myoblast determination protein (MyoD) were significantly up-regulated on the 14th day after incubation when treated with all different doses such as 100 µg, 1000 µg, and 2500 µg/µL/egg, namely 3T1, 3T2, and 3T3, respectively. However, the treatment with low doses of L-Arg down-regulated the expression levels of those proteins on the 14th day of incubation. Histopathology of the liver by hematoxylin and eosin (H&E) staining showed that the majority of liver damage, specifically intracytoplasmic vacuoles, were observed in the 3T1, 3T2, and 3T3 groups. The minimum dose of 100 µg/mL/egg on the 14th day of incubation significantly prevented intracytoplasmic vacuole damages. These results demonstrate that in ovo administration of L-Arg at (100 µg/µL/egg) may be an effective method to increase chick BW, hatch rate, muscle growth-related proteins, and promote the immune response through increasing IgM on the 14th day of the incubation period.

4-Aminoindoles as 1,4-bisnucleophiles for diversity-oriented synthesis of tricyclic indoles bearing 3,4-fused seven-membered rings.

A straightforward access to tricyclic indoles bearing 3,4-fused seven-membered rings has been established by using 4-aminoindoles as 1,4-bisnucleophiles in three-component reactions. 1H-Azepino[4,3,2-cd]indoles, 4,6-dihydro-1H-azepino[4,3,2-cd]indoles and 1,3,4,6-tetrahydro-5H-azepino[4,3,2-cd]indol-5-ones could thus be synthesized in one pot in moderate to good yields. Beyond opening access to 3,4-fused tricyclic indoles, the use of easily accessible 4-aminoindoles as C,N-1,4-bisnucleophiles also provides a new platform to be used in a diversity-oriented synthesis strategy, fully displaying its benefits of maximizing molecular complexity and reaction diversity.

Synthesis and Antimicrobial Evaluation of 1,4-Naphthoquinone Derivatives as Potential Antibacterial Agents.

1,4-Naphthoquinones are an important class of compounds present in a number of natural products. In this study, a new series of 1,4-naphthoquinone derivatives were synthesized. All the synthesized compounds were tested for in vitro antimicrobial activity. In this present investigation, two Gram-positive and five Gram-negative bacterial strains and one pathogenic yeast strain were used to determine the antibacterial activity. Naphthoquinones tested for its antibacterial potencies, among seven of them displayed better antimicrobial activity against Staphylococcus aureus (S. aureus; 30-70 µg/mL). Some of the tested compounds showed moderate to low antimicrobial activity against Pseudomonas aeruginosa (P. aeruginosa) and Salmonella bongori (S. bongori; 70-150 µg/mL). In addition, most active compounds against S. aureus were evaluated for toxicity to human blood cells using a hemolysis assay. For better understanding, reactive oxygen species (ROS) generation, time-kill kinetic study, and apoptosis, necrosis responses were investigated for three representative compounds.

1,4-Naphthoquinone Analogues: Potent Antibacterial Agents and Mode of Action Evaluation.

1,4-Naphthoquinones have antibacterial activity and are a promising new class of compound that can be used to treat bacterial infections. The goal was to improve effective antibacterial agents; therefore, we synthesized a new class of naphthoquinone hybrids, which contain phenylamino-phenylthio moieties as significant counterparts. Compound 4 was modified as a substituted aryl amide moiety, which enhanced the antibacterial activity of earlier compounds 3 and 4. In this study, five bacterial strains Staphylococcus aureus (S. aureus), Listeria monocytogenes (L. monocytogenes), Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa) and Klebsiella pneumoniae (K. pneumoniae) were used to evaluate the antibacterial potency of synthesized naphthoquinones using the minimal inhibitory concentration (MIC) method. Most of the studied naphthoquinones demonstrated major antibacterial activity with a MIC of 15.6 µg/mL-500 µg/mL. Selected compounds (5a, 5f and 5x) were studied for the mode of action, using intracellular ROS generation, determination of apoptosis by the Annexin V-FITC/PI assay, a bactericidal kinetic study and in silico molecular modelling. Additionally, the redox potentials of the specified compounds were confirmed by cyclic voltammetry (CV).

Synthesis and Anticancer Evaluation of 1,4-Naphthoquinone Derivatives Containing a Phenylaminosulfanyl Moiety.

1,4-Naphthoquinones are exceptional building blocks in organic synthesis and have been used to synthesize several well-known pharmaceutically active agents. Herein we report the synthesis, structural characterization, and biological evaluation of new phenylaminosulfanyl-1,4-naphthoquinone derivatives. We evaluated the cytotoxic activity of the synthesized compounds against three human cancer cell lines: A549, HeLa, and MCF-7. Most of the synthesized compounds displayed potent cytotoxic activity. Specifically, compounds 5 e [3,5-dichloro-N-(4-((4-((1,4-dioxo-3-(phenylthio)-1,4-dihydronaphthalen-2-yl)amino)phenyl)sulfonyl)phenyl)benzamide], 5 f [N-(4-((4-((1,4-dioxo-3-(phenylthio)-1,4-dihydronaphthalen-2-yl)amino)phenyl)sulfonyl)phenyl)-3,5-dinitrobenzamide], and 5 p [N-(4-((4-((1,4-dioxo-3-(phenylthio)-1,4-dihydronaphthalen-2-yl)amino)phenyl)sulfonyl)phenyl)thiophene-2-carboxamide] showed remarkable cytotoxic activity. The synthesized compounds showed low toxicity in normal human kidney HEK293 cells. The cytotoxic mechanism of compounds 5 e, 5 f, and 5 p was explored in MCF-7 cells. The results confirmed that these three compounds induce apoptosis and arrest the cell cycle at the G1 phase. In addition, compounds 5 e, 5 f, and 5 p were found to induce apoptosis via upregulation of caspase-3 and caspase-7 proteins as well as by upregulation of the gene expression levels of caspases-3 and -7. Our findings demonstrate that compounds 5 e, 5 f, and 5 p could be potent agents against a number of cancer types.

Aldo-X Bifunctional Building Blocks for the Synthesis of Heterocycles.

Compounds containing oxygen, nitrogen, or sulfur atoms inside the rings are attracting much attention and interest due to their biological importance. In recent years, several methods for the synthesis of such molecules have been reported by using aldo-X bifunctional building blocks (AXB3 s) as substrates; these are a wide class of organic molecules that contain at least two reactive sites, among them, one aldehyde, acetal, or semiacetal group was involved. Because of the multiple reactivities, AXB3 s are widely used in the one-pot synthesis of biologically important heterocycles. This review summarizes the synthesis of important heterocycles by using AXB3 s as pivotal components in establishing multicomponent reactions, tandem reactions, and so forth. In many cases, the established reaction systems with AXB3 s were characterized by some green properties, such as easy access to the substrate, mild and environmentally benign conditions, and wide scope of the substrate.

Synthesis, molecular docking and biological evaluation of novel 6-(4-(4-aminophenylsulfonyl)phenylamino)-5H-benzo[a]phenothiazin-5-one derivatives.

A novel series of 6-(4-(4-aminophenylsulfonyl)phenylamino)-5H-benzo[a]phenothiazin-5-one derivatives have been synthesized and examined for their in vitro antibacterial activity against a panel of Gram-positive and Gram-negative bacteria. Among these, N-(4-(4-(5-oxo-5H-benzo[a]phenothiazin-6-ylamino)phenylsulfonyl)phenyl)-3,5-bis(trifluoromethyl)benzamide (3n) (0.4 µg/mL) and 4-ethyl-N-(4-(4-(5-oxo-5H-benzo[a]phenothiazin-6-ylamino)phenylsulfonyl)phenyl)benzamide (3l) (0.6 µg/mL) systems exhibited a potent inhibitory activity against Gram-positive organism Bacillus subtilis, when compare to the other synthesized compounds. Sparfloxacin (9.76 µg/mL), Norfloxacin (no activity) were employed as the standard drugs. An evaluation of the cytotoxicity of the title compounds (1, 2, 3a-n) revealed that they displayed low toxicity (26-115 mg/L) against cervical cancer cell line (SiHa). The results of these studies suggest that, phenothiazin-5-one derivatives are interesting binding agents for the development of new Gram-positive and Gram-negative antibacterial agents. To understand the interactions with protein receptors, docking simulation was done with crystal structures of B.subtilis (YmaH) and histone deacetylase (HDAC8) to determine the probable binding conformation.