Diphenyl Ether Derivatives Research Articles

An immunoassay for the detection of triclosan-O-glucuronide, a primary human urinary metabolite of triclosan.

Triclosan-O-glucuronide (TCSG) is one of the primary urinary metabolites of the antibacterial compound triclosan or TCS that is found in many personal care products and consumer goods. We have developed a competitive, indirect heterologous ELISA for the detection of the target TCSG in urine. Such an ELISA for TCSG could be developed as a useful tool to measure this important biomarker of human exposure to TCS. Immunogens were prepared by conjugating TCSG to thyroglobulin, via heterobifunctional cross-linkers AEDP or 3-[(2-aminoethyl)dithio] propionic acid•hydrochloride and TFCS or N-[ε-trifluoroacetylcaproyloxy]succinimide ester. The coating antigen was prepared by the direct conjugation of TCSG to bovine serum albumin. Antibodies raised in rabbits 2619, 2621 (immunogen TCSG-AEDP-Thy), and 2623 (immunogen TCSG-TFCS-Thy), and the coating antigen were screened and characterized to determine their optimal concentrations. The optimized ELISA, developed with antibody 2621, gave an IC50 value of 2.85ng/mL, with the linear range (IC20-IC80) determined to be 2.6-24.8ng/mL. Selectivity of the assay was assessed by measuring cross-reactivity of antibody 2621 to related congeners such as the aglycone TCS, triclosan-O-sulfate, triclocarban, a polybrominated diphenyl ether derivative, and 3-phenoxybenzyl alcohol glucuronide. There was virtually no recognition by antibody 2621 to any of these cross-reactants. Graphical Abstract Urinary biomarker analysis of triclosan glucuronide.

ChemInform Abstract: Bioactive Diphenyl Ether Derivatives from a Gorgonian‐Derived Fungus Talaromyces sp.

AbstractThree new diphenyl ether derivatives, talaromycins A—C, are isolated together with six known analogues and evaluated for their cytotoxic and antifouling activities.

Diorcinol D Exerts Fungicidal Action against Candida albicans through Cytoplasm Membrane Destruction and ROS Accumulation.

Candida albicans, which is the most common human fungal pathogen, causes high mortality among immunocompromised patients. Antifungal drug resistance becomes a major challenge for the management of Candida infection. Diorcinol D (DD), a diphenyl ether derivative isolated from an endolichenic fungus, exerted fungicidal action against Candida species. In this study, we investigated the possible mechanism of its antifungal activity. The change of membrane dynamics and permeability suggested that the cell membrane was disrupted by the treatment of DD. This was further supported by the evidences of intracellular glycerol accumulation, alteration of cell ultrastructure, and down-regulation of genes involved in cell membrane synthesis. In addition, the treatment of C. albicans with DD resulted in the elevation of reactive oxygen species (ROS), which caused the dysfunction of mitochondria. These altogether suggested that DD exerted its antifungal activity through cytoplasmic membrane destruction and ROS accumulation. This finding is helpful to uncover the underlying mechanisms for the diphenyl ether derivatives and provides a potential application in fighting clinical fungal infections.

Discovery of InhA inhibitors with anti-mycobacterial activity through a matched molecular pair approach

The Mycobacterium tuberculosis (M. tuberculosis) enoyl-acyl carrier protein reductase (mtInhA) is an attractive enzyme and a thoroughly studied target for tuberculosis therapy. In this study, to identify novel structure-activity relationships (SARs) of mtInhA inhibitors, a series of diphenyl ether derivatives were designed based on the matched molecular pair (MMP) method, and the binding energies of these compounds were subsequently estimated by in silico structure-based drug screening (SBDS) to provide more useful data. Consequently, the 10 unique candidate compounds (KEM1-KEM10) were identified and assessed for the inhibition of mtInhA enzymatic activity, in vitro antibiotic effects against model mycobacteria and toxicity level on both intestinal bacteria and mammalian cells. Among the compounds tested, phenyl group (KEM4) and 2-fluorobenzyl group (KEM7) substitutions produced preferable inhibitory effects on mtInhA enzymatic activity relative to those provided by a furyl group (KES4: base compound) at the terminal of the compound, and KEM7 inhibited the growth of the mycobacteria strain with a lower IC50 value. Moreover, most of the candidate compounds exhibited neither inhibition of the growth of enterobacteria nor toxic effects on mammalian cells, though KEM10 exhibited toxicity against cultured MDCK cells. The structural and experimental information concerning these mtInhA inhibitors identified through MMP-based in silico screening will likely contribute to the lead optimisation of novel antibiotics for M. tuberculosis.

Bioactive diphenyl ether derivatives from a gorgonian-derived fungus Talaromyces sp.

Three new diphenyl ether derivatives, talaromycins A-C (1-3, resp.), together with six known analogs, 4-9, were isolated from a gorgonian-derived fungus, Talaromyces sp. The structures of the new compounds were determined by analysis of extensive NMR spectroscopic data. All of the isolated metabolites, 1-9, were evaluated for their cytotoxic and antifouling activities. Compound 4 exhibited pronounced cytotoxicity against the tested human cell lines with the IC50 values ranging from 4.3 to 9.8 μM. Compounds 3, 5, 8, and 9 showed potent antifouling activities against the larval settlement of the barnacle Balanus amphitrite with the EC50 values ranging from 2.2 to 4.8 μg/ml.

Synthesis and Evaluation of Antitubercular Activity of Novel Diphenyl Ether Derivatives

Novel derivatives of diphenyl ether scaffold were synthesized and evaluated for the antitubercular activity. All the synthesized molecules were characterized by spectral analysis. Evaluation of antitubercular activity of the molecules by Microplate Alamar Blue Assay (MABA) showed less to moderate activity in comparison with Triclosan. All the molecules exhibited an acceptable safety profile in the MTT assay against vero and HepG2 cell lines. © 2014 iGlobal Research and Publishing Foundation. All rights reserved.

ChemInform Abstract: Polyketide Anthraquinone, Diphenyl Ether, and Xanthone Derivatives from the Soil Fungus Penicillium sp. PSU‐RSPG99.

Abstract Three new polyketides including one new diphenyl ether, penicillither ( 1 ), one new anthraquinone, penicilliquinone ( 2 ), and one new xanthone, penicillixanthone ( 3 ), together with twelve known compounds were isolated from the soil fungus Penicillium sp. PSU-RSPG99. Their structures were identified by spectroscopic evidence. In addition, the position of a chlorine atom in 1 was confirmed by the plausible biosynthetic pathway from the isolated chlorobenzophenone. Known GKK1032B displayed mild antimycobacterial and moderate cytotoxic (against human oral carcinoma, KB, human breast cancer, MCF-7, and noncancerous Vero cell lines) activities.

Voltammetric Sensor for Fluoride Ions Using Diphenylether Derivatives Supported by NMR and Theoretical Studies

Compounds 3-(2,4-dinitrophenoxy)phenol (L1) and 3-(2-nitrophenoxy)phenol (L2) were synthesized with high yield and characterized by spectroscopic techniques. The complexation behavior of L1 and L2 for different anionic species (CN−, F−, Cl−, Br−, AcO−, I−, HSO4−, OH−, H2PO4−, ClO4−) in acetonitrile medium were investigated. L1 showed high degree of selectivity for fluoride over other anions. This selectivity could be easily observed by the naked eye, indicating that L1 is a potential colorimetric sensor for fluoride anion. Differential pulse voltammetry of both the ligands showed complete quenching of anodic peaks at 1.16 V for L1 and 1.34 V for L2 upon the addition of 1 equivalent fluoride ions. The proposed mechanism of anion detection is supported by theoretical calculations, UV studies and NMR titrations.

Acetylcholinesterase inhibitors from a marine fungus Talaromyces sp. strain LF458.

Two new oxaphenalenone dimers, talaromycesone A (1) and talaromycesone B (2), and a new isopentenyl xanthenone, talaroxanthenone (3), together with six known diphenyl ether derivatives, e.g., Δ(1',3'),-1'-dehydroxypenicillide (4), 1',2'-dehydropenicillide (5), vermixocin A (6), vermixocin B (7), 3'-methoxy-1'2'-dehydropenicillide (8), and AS-186c (9), were isolated from the culture broth and mycelia of a marine fungus Talaromyces sp. strain LF458. Compound 2 represents the first example of 1-nor oxaphenalenone dimer carbon skeleton. All isolated compounds were subjected to bioactivity assays. Compounds 1, 2, and 9 exhibited potent antibacterial activities with IC50 3.70, 17.36, and 1.34 μM, respectively, against human pathogenic Staphylococcus strains. Compounds 1, 3, and 9 displayed potent acetylcholinesterase inhibitory activities with IC50 7.49, 1.61, and 2.60 μM, respectively. Interestingly, phosphodiesterase PDE-4B2 was inhibited by compounds 3 (IC50 7.25 μM) and 9 (IC50 2.63 μM).

Chemical constituents from Phyllanthus emblica and the cytoprotective effects on H2O2-induced PC12 cell injuries.

Two new compounds (1-2), including a bisabolane-type sesquiterpenoid (1), one new diphenyl ether derivative (2), together with 23 known compounds (3-25), were isolated from the fruits of Phyllanthus emblica. Their structures were elucidated by detailed spectroscopic analysis. All the isolated compounds were screened for the DPPH scavenging effects and cytoprotective effects against H2O2 induced PC12 cells injury. Compounds 12-15 showed significant DPPH scavenging effects with the IC50 values in the range of 3.25-4.18μM. Among these potential antioxidants, compound 14 improved the survival of PC12 cells after H2O2 exposure without showing any cytotoxicity at the tested concentrations.

Elucidating the structural basis of diphenyl ether derivatives as highly potent enoyl-ACP reductase inhibitors through molecular dynamics simulations and 3D-QSAR study.

Diphenyl ether derivatives are good candidates for anti-tuberculosis agents that display a promising potency for inhibition of InhA, an essential enoyl-acyl carrier protein (ACP) reductase involved in fatty acid biosynthesis pathways in Mycobacterium tuberculosis. In this work, key structural features for the inhibition were identified by 3D-QSAR CoMSIA models, constructed based on available experimental binding properties of diphenyl ether inhibitors, and a set of four representative compounds was subjected to MD simulations of inhibitor-InhA complexes for the calculation of binding free energies. The results show that bulky groups are required for the R1 substituent on the phenyl A ring of the inhibitors to favor a hydrophobic pocket formed by residues Phe149, Met155, Pro156, Ala157, Tyr158, Pro193, Met199, Val203, Leu207, Ile215, and Leu218. Small substituents with a hydrophilic property are required at the R3 and R4 positions of the inhibitor phenyl B rings to form hydrogen bonds with the backbones of Gly96 and Met98, respectively. For the R2 substituent, small substituents with simultaneous hydrophilic or hydrophobic properties are required to favor the interaction with the pyrophosphate moiety of NAD(+) and the methyl side chain of Ala198, respectively. The reported data provide structural guidance for the design of new and potent diphenyl ether-based inhibitors with high inhibitory activities against M. tuberculosis InhA.

Polyketide anthraquinone, diphenyl ether, and xanthone derivatives from the soil fungus Penicillium sp. PSU-RSPG99

Three new polyketides including one new diphenyl ether, penicillither (1), one new anthraquinone, penicilliquinone (2), and one new xanthone, penicillixanthone (3), together with twelve known compounds were isolated from the soil fungus Penicillium sp. PSU-RSPG99. Their structures were identified by spectroscopic evidence. In addition, the position of a chlorine atom in 1 was confirmed by the plausible biosynthetic pathway from the isolated chlorobenzophenone. Known GKK1032B displayed mild antimycobacterial and moderate cytotoxic (against human oral carcinoma, KB, human breast cancer, MCF-7, and noncancerous Vero cell lines) activities.

Rational design of InhA inhibitors in the class of diphenyl ether derivatives as potential anti-tubercular agents using molecular dynamics simulations

A series of diphenyl ether derivatives were developed and showed promising potency for inhibiting InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, leading to the lysis of Mycobacterium tuberculosis. To understand the structural basis of diphenyl ether derivatives for designing more potent inhibitors, molecular dynamics (MD) simulations were performed. Based on the obtained results, the dynamic behaviour in terms of flexibility, binding free energy, binding energy decomposition, conformation, and the inhibitor–enzyme interaction of diphenyl ether inhibitors were elucidated. Phe149, Tyr158, Met161, Met199, Val203 and NAD+ are the key residues for binding of diphenyl ether inhibitors in the InhA binding pocket. Our results could provide the structural concept to design new diphenyl ether inhibitors with better enzyme inhibitory activity against M. tuberculosis InhA. The present work facilitates the design of new and potentially more effective anti-tuberculosis agents.

Diphenyl ether and benzophenone derivatives from the marine mangrove-derived fungus Penicillium sp. MA-37

Further investigation of the marine mangrove-derived fungal strain Penicillium sp. MA-37 led to the isolation of one new benzophenone, iso-monodictyphenone (1), two new diphenyl ether derivatives penikellides A (2) and B (3), and two known analogs monodictyphenone (4) and 6-[2-hydroxy-6-(hydroxymethyl)-4-methylphenoxy]-2-methoxy-3-(1-methoxy-3-methylbutyl)benzoic acid (5). The structures of these compounds were elucidated by spectroscopic analyses including 1D- and 2D-NMR and mass spectrometry. The brine shrimp lethality and antibacterial activity against five aquaculture pathogens were evaluated.

Diphenylether Derivative as Selective Inhibitor of Protein Tyrosine Phosphatase 1B (PTP1B) Over T-cell Protein Tyrosine Phosphatase (TCPTP) Identified through Virtual Screening

Even though protein tyrosine phosphatase has been identified as a validated therapeutic target over a decade for type II diabetes and obesity, developing a selective inhibitor to protein tyrosine phosphatase 1B (PTP1B) over other cellular PTPases has been a complicated task owing to the highly conserved and polar nature of the PTP1B catalytic site. Virtual screening study of in-house chemical depository resulted in the prioritization of few low molecular weight compounds as PTP1B inhibitors. The in-vitro pNPP assays were carried out on prioritized compounds in both PTP1B and T-cell protein tyrosine phosphatase (TCPTP). From this we identified four low molecular weight compounds as PTP1B inhibitors, of which the compound AU-2439 has shown 5 fold selectivity towards PTP1B over highly homologous TCPTP. In this short communication selectivity of AU-2439 is explained based on interaction with critical active site residues in both proteins using docking models.

Synthesis and Antibacterial Activities of Halogenated Hydroxy Diphenyl Ether Derivatives

Synthesis and Antibacterial Activities of Halogenated Hydroxy Diphenyl Ether Derivatives

Meroterpenoid and Diphenyl Ether Derivatives from Penicillium sp. MA-37, a Fungus Isolated from Marine Mangrove Rhizospheric Soil

Penicillium sp. MA-37, which was obtained from the rhizospheric soil of the mangrove plant Bruguiera gymnorrhiza, exhibited different chemical profiles in static and shaken fermentation modes. Three new meroterpenoid derivatives, 4,25-dehydrominiolutelide B (1), 4,25-dehydro-22-deoxyminiolutelide B (2), and isominiolutelide A (3), together with three known ones were characterized from its static fermentation, while three new diphenyl ether derivatives, namely, Δ(1('),3('))-1'-dehydroxypenicillide (4), 7-O-acetylsecopenicillide C (5), and hydroxytenellic acid B (6), along with five related metabolites were isolated from the shaken culture. The structures of these compounds were elucidated on the basis of spectroscopic analysis, and the structure of compound 2 was confirmed by X-ray crystallographic analysis. The absolute configurations of 1-3 and 6 were determined by ECD and modified Mosher's method, respectively. All isolated compounds were evaluated for brine shrimp lethality and antibacterial activity.

Cytotoxic Polyphenols from the Fungus Penicillium expansum 091 006 Endogenous with the Mangrove Plant Excoecaria agallocha

As part of our ongoing chemical investigation of biologically active metabolites from marine-derived fungi, four new polyphenols containing both phenolic bisabolane and diphenyl ether units, expansols C-F (1-4), and one new diphenyl ether derivative, 3-O-methyldiorcinol (5), as well as twelve known compounds (6-17), were isolated from Penicillium expansum 091006 endogenous with the mangrove plant Excoecaria agallocha (Euphorbiaceae). The structures of the new metabolites were determined on the basis of NMR and mass spectroscopy. Among them, expansols C (1) and E (3) exhibited weak cytotoxicity against the HL-60 cell lines with IC50 values of 18.2 and 20.8 µM, respectively. The results showed that diphenyl ether substituted phenolic bisabolanes with a Δ7 double bond in the side chain are slightly less cytotoxic to HL-60 cell lines than the 7-OH or 7-OCH3 derivatives.

Derivatives of phenyl tribromomethyl sulfone as novel compounds with potential pesticidal activity

A halogenmethylsulfonyl moiety is incorporated in numerous active herbicides and fungicides. The synthesis of tribromomethyl phenyl sulfone derivatives as novel potential pesticides is reported. The title sulfone was obtained by following three different synthetic routes, starting from 4-chlorothiophenol or 4-halogenphenyl methyl sulfone. Products of its subsequent nitration were subjected to the SNAr reactions with ammonia, amines, hydrazines and phenolates to give 2-nitroaniline, 2-nitrophenylhydrazine and diphenyl ether derivatives. Reduction of the nitro group of 4-tribromomethylsulfonyl-2-nitroaniline yielded the corresponding o-phenylenediamine substrate for preparation of structurally varied benzimidazoles.

Chlorinated chromone and diphenyl ether derivatives from the mangrove-derived fungus Pestalotiopsis sp. PSU-MA69

Four new diphenyl ethers, pestalotethers A–D (1–4), three new chromones, pestalochromones A–C (5–7), one new xanthone, pestaloxanthone (8), and one new butenolide, pestalolide (9), together with 11 known compounds were isolated from the mangrove-derived fungus Pestalotiopsis sp. PSU-MA69. Their structures were established by spectroscopic techniques. Compounds 1–3 and 5–7 are the rare chlorinated fungal metabolites of diphenyl ethers and chromones, respectively. Pestalolide (9) displayed weak antifungal activity against Candida albicans and Cryptococcus neoformans.