Search

Epidermal growth factor receptor (EGFR) is a validated target for non-small-cell lung cancer (NSCLC). However, the treatment for EGFR-C797S mutation induced by third-generation EGFR inhibitors remains a concern. Therefore, the development of the fourth-generation EGFR inhibitors to overcome the EGFR-C797S mutation has great potential for clinical treatment. In this article, we designed and synthesized a series of diphenyl ether substituted quinazolin-4-amine derivatives that simultaneously occupy the ATP binding pocket and the allosteric site of EGFR. Among the newly synthesized compounds, 9d displayed excellent kinase activity against EGFR L858R/T790M/C797S with an IC 50 value of 0.005 μM, and exhibited anti-proliferation activity in BaF3-EGFR L858R/T790M/C797S cells with the IC 50 value of 0.865 μM. Furthermore, 9d could suppress phosphorylation of EGFR and induce cell apoptosis and cycle arrest at G2 phase in a dose-dependent manner in BaF3-EGFR L858R/T790M/C797S cells. More importantly, 9d displayed significant antitumor effects in BaF3-EGFR L858R/T790M/C797S xenograft mouse model (30 mg/kg, TGI = 71.14 %). All the results indicated compound 9d might be a novel fourth-generation EGFR inhibitor for further development in overcoming the EGFR-C797S resistance mutation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Succinate dehydrogenase (SDH), also recognized as succinate ubiquinone oxidoreductase (SQR), is considered one of the most promising targets for fungicide development, garnering significant international interest. We have focused on the development of highly effective, broad-spectrum-targeted SDH inhibitors. Using an active scaffold combining strategy, we designed and synthesized a series of novel diphenyl ether formylhydrazine derivatives, and most compounds have demonstrated broad-spectrum antifungal activity. Notably, compound M8 exhibited antifungal activity of more than 93% against four tested pathogen types at a concentration of 10 μg/mL, with an EC 50 value below 0.3 μg/mL for each pathogen, outperforming boscalid. Additionally, compound M8 exhibited a control efficacy of 83% against Sclerotinia sclerotiorum on rapeseed leaves at a concentration of 200 μg/mL and demonstrated an 87% efficacy in controlling Fusarium graminearum on wheat ears when applied at 400 μg/mL. Structure-activity relationship research suggested that para-substituted benzene rings are more effective, offering stronger and more extensive antifungal potency. Further investigation, including enzyme inhibition assays, mycelial morphology observations, and molecular docking studies, suggests that the antifungal potency of M8 is due to the inhibition of its SDH activity. Therefore, our research positions compound M8 as a highly promising lead compound with broad-spectrum antifungal properties, potentially introducing a new class of fungicide.

Lignin is anticipated to serve as a replacement for dwindling fossil fuel resources owing to its abundant sources and renewable nature. The electrochemical oxidation technique for depolymerizing lignin has garnered significant interest for its environmentally friendly and mild operating conditions. Nevertheless, the current utilization of auxiliary electrolytes, predominantly organic bases, ionic liquids, and other specialized substances, poses a constraint on the widespread adoption of this approach. Furthermore, there is a scarcity of instances where electrochemical technology has been employed to depolymerize the α-O-4 bond in lignin for the production of highly selective acetals. In this study, a sodium chloride/methanol (NaCl/MeOH) system was utilized for the direct depolymerization of the α-O-4 bond in a lignin model molecule, specifically benzyl phenyl ether (BPE). The optimal conditions resulted in a 95.2 % conversion rate of the BPE substrate and a high yield of 94.5 % for the main product, benzaldehyde dimethyl acetal(Bda). This research offers a promising approach for the electrocatalytic depolymerization of α-O-4 bonds in lignin, leading to the selective production of acetal chemicals using a common auxiliary electrolyte at room temperature in just 2 h., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Succinate dehydrogenase inhibitor (SDHI) fungicides play important roles in the control of plant fungal diseases. However, they are facing serious challenges from issues with resistance and cross-resistance, primarily attributed to their frequent application and structural similarities. There is an urgent need to design and develop SDHI fungicides with novel structures., Results: Aiming to discover novel potent SDHI fungicides, 31 innovative pyrazole β-ketonitrile derivatives with diphenyl ether moiety were rationally designed and synthesized, which were guided by a 3D-QSAR model from our previous study. The optimal target compound A23 exhibited not only outstanding in vitro inhibitory activities against Rhizoctonia solani with a half-maximal effective concentration (EC 50 ) value of 0.0398 μg mL -1 comparable to that for fluxapyroxad (EC 50  = 0.0375 μg mL -1 ), but also a moderate protective efficacy in vivo against rice sheath blight. Porcine succinate dehydrogenase (SDH) enzymatic inhibitory assay revealed that A23 is a potent inhibitor of SDH, with a half-maximal inhibitory concentration of 0.0425 μm. Docking study within R. solani SDH indicated that A23 effectively binds into the ubiquinone site mainly through hydrogen-bonds, and cation-π and π-π interactions., Conclusion: The identified β-ketonitrile compound A23 containing diphenyl ether moiety is a potent SDH inhibitor, which might be a good lead for novel fungicide research and optimization. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Given the prevalence of the malignant weed Chinese Sprangletop ( Leptochloa chinensis (L.) Nees) in rice fields, the development of novel herbicides against this weed has aroused wide interest. Here, we report a novel diphenyl ether-pyrimidine hybrid, DEP- 5 , serving as a systematic pre/postemergence herbicide candidate for broad-spectrum weed control in rice fields, specifically for L. chinensis . Notably, DEP- 5 exhibits over 80% herbicidal activity against the resistant biotypes even at 37.5 g a.i./ha under greenhouse conditions and has complete control of L. chinensis at 150 g a.i./ha in the rice fields. We uncover that DEP- 5 acts as a noncompetitive inhibitor of acetohydroxyacid synthase (AHAS) with an inhibition constant ( K i ) of 39.4 μM. We propose that DEP- 5 binds to AHAS in two hydrophobic-driven binding modes that differ from commercial AHAS inhibitors. Overall, these findings demonstrate that DEP- 5 has great potential to be developed into a herbicide for L. chinensis control and inspire fresh concepts for novel AHAS-inhibiting herbicide design.

Background: Phytopathogenic bacteria cause severe losses to crops every year. The management of crop bacterial diseases with chemical agents has been considered as the main strategy. In order to cope with the bactericide resistance made by the pathogens, new antibacterials need to be continuously developed., Results: A chemical investigation from the endophytic fungus Rhexocercosporidium sp. Dzf14 has led to the isolation of 12 diphenyl ethers including two new ones named rhexocerin E (1) and rhexocercosporin G (2), along with two new depsides named rhexocerdepsides A (3) and B (4). The structures and absolute configurations of the new compounds were determined through comprehensive analysis of spectroscopic data and quantum chemical ECD calculations. Diphenyl ethers showed obviously antibacterial activity on Gram-positive bacteria. The structure-activity relationship of diphenyl ethers revealed that prenylation was critical to the antibacterial activity. Among them, rhexocercosporin D (12) possessed the strongest activity against Clavibacter michiganensis and Bacillus subtilis, and was selected for further mechanistic studies. It was found that rhexocercosporin D displayed bactericidal activity by affecting homeostasis of cell membranes. In addition to its rapid bactericidal effects on Gram-positive bacteria, rhexocercosporin D could restore the susceptibility against Gram-negative Agrobacterium tumefaciens by synergistic action with colistin., Conclusion: Twelve diphenyl ethers and two depsides were isolated from endophytic fungus Rhexocercosporidium sp. Dzf14. Isopentenyl was critical for diphenyl ethers against Gram-positive bacteria. Rhexocercosporin D could affect homeostasis of bacterial cell membrane to exert rapid bactericidal activity. These findings highlight the antibacterial potential of the diphenyl ethers in crop bacterial disease management. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Asterric acid and its analogs belong to diphenyl ethers (DPEs) with multiple substitutions on A/B aromatic rings. This member of DPEs originates from the polyketide pathway and displays a wide range of biological effects. Though the structures of asterric acid analogs are not complex, there were only more than 50 asterric acid analogs found in nature from 1960 to 2023. In this review, the structures, bioactivities, and biosynthesis of asterric acid analogs are summarized. More importantly, the empirical rule about the shielding effect of B-ring on H-6 is suggested, and this provides a convenient and useful way to analyze the NMR spectral data of asterric acid analogs, based on which the chemical shift values of the A-ring in some asterric acid analogs are revised.

Ten diphenyl ethers (DPEs), including nine undescribed analogs named betaethrins A-I, were isolated from the desert plant endophytic fungus Phoma betae A.B. Frank (Didymellaceae). Their structures were determined mainly by NMR, HR-ESI-MS spectral and X-ray diffraction experiments. Betaethrins D-I possessed different fatty acid chains connected with the B-ring, which was the first report in all DPEs. The shielding effect of the B-ring on H-6 (A-ring) in methyl barceloneate, betaethrin A and betaethrins D-F (asterric acid analogs) was first observed and analyzed, which could differentiate the 1 H-NMR chemical shift values of H-4/H-6 without the assistance of 3-OH. An empirical rule was then suggested: the steric hindrance between the A- and B-rings in asterric acid analogs might prevent these two aromatic rings from rotating freely, which led to the 1 H-NMR chemical shift value of H-6 being in the high field zone due to the shielding effect of the B-ring on H-6. Based on the empirical rule, the chemical shift values of the A-ring in methyl barceloneate were revised. The possible biosynthesis of these isolates was postulated. Betaethrin H showed moderate cytotoxicity against MCF-7 and HepG2 cancer cell lines. Betaethrins A-F, H and I displayed strong antioxidant activities. These results further implied that endophytic fungi from unique environments, such as desert plants, with few chemical studies are an important resource of undescribed and bioactive metabolites., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Four new diphenyl ethers, named epicoccethers K-N (1-4), were purified from the fermentation medium of a fungus Epicoccum sorghinum derived from Myoporum bontioides, and identified through HR-ESI-MS and NMR spectral analysis. Except that compound 1 showed moderate antifungal activity against Penicillium italicum and Fusarium graminearum, the other three compounds showed stronger activity against them than triadimefon. All of them showed moderate or weak antibacterial activity towards Staphylococcus aureus and Escherichia coli with O6 and O78 serotypes except that 3 was inactive to E. coli O6., (Copyright © 2022 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

3-Nitropropanoic acid (3NP), a bioactive fungal natural product, was previously demonstrated to inhibit growth of Mycobacterium tuberculosis. Here we demonstrate that 3NP inhibits the 2-trans-enoyl-acyl carrier protein reductase (InhA) from Mycobacterium tuberculosis with an IC 50 value of 71 μM, and present the crystal structure of the ternary InhA-NAD + -3NP complex. The complex contains the InhA substrate-binding loop in an ordered, open conformation with Tyr158, a catalytically important residue whose orientation defines different InhA substrate/inhibitor complex conformations, in the "out" position. 3NP occupies a hydrophobic binding site adjacent to the NAD + cofactor and close to that utilized by the diphenyl ether triclosan, but binds predominantly via electrostatic and water-mediated hydrogen-bonding interactions with the protein backbone and NAD + cofactor. The identified mode of 3NP binding provides opportunities to improve inhibitory activity toward InhA., (© 2021 Wiley Periodicals LLC.)

The development of small-molecules targeting different components of SARS-CoV-2 is a key strategy to complement antibody-based treatments and vaccination campaigns in managing the COVID-19 pandemic. Here, we show that two thiol-based chemical probes that act as reducing agents, P2119 and P2165, inhibit infection by human coronaviruses, including SARS-CoV-2, and decrease the binding of spike glycoprotein to its receptor, the angiotensin-converting enzyme 2 (ACE2). Proteomics and reactive cysteine profiling link the antiviral activity to the reduction of key disulfides, specifically by disruption of the Cys379-Cys432 and Cys391-Cys525 pairs distal to the receptor binding motif in the receptor binding domain (RBD) of the spike glycoprotein. Computational analyses provide insight into conformation changes that occur when these disulfides break or form, consistent with an allosteric role, and indicate that P2119/P2165 target a conserved hydrophobic binding pocket in the RBD with the benzyl thiol-reducing moiety pointed directly toward Cys432. These collective findings establish the vulnerability of human coronaviruses to thiol-based chemical probes and lay the groundwork for developing compounds of this class, as a strategy to inhibit the SARS-CoV-2 infection by shifting the spike glycoprotein redox scaffold., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

The strategy "IEMAHC" (Induction of Endophyte Metabolism by Adding Host Components) was applied to the fermentation of the endophytic fungus Epicoccum sorghinum L28 from Myoporum bontioides by introducing guaiol, an ingredient of M. bontioides, into the cultivation medium, which resulted in the purification of nine new diphenyl ethers, epicoccethers A-I (1-9). Their structures were determined by overall spectroscopic analysis. HPLC-MS analysis revealed that compounds 5-7 were products generated by induction of guaiol. Compounds 6 and 7 are the first members containing an ester moiety formed by the natural long-chain fatty acid and the hydroxyl group in the phenylmethanol unit of the diphenyl ether class. The antifungal activities of compounds 1, 2, and 4-7 against Fusarium oxysporum were 1, 1, 2, 1, 2 and 4 times as high as those of the positive control triadimefon, respectively. Compounds 4 and 5 showed 1.6 times the antifungal activities of triadimefon towards Colletotrichum musae., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In the present study, a magnetic mimic multi-enzyme system was developed by encapsulating the aryloxyphenoxypropionate (AOPP) herbicide hydrolase QpeH and alcohol oxidase (AOx) in zeolitic imidazolate framework (ZIF-8) nanocrystals with magnetic Fe 3 O 4 nanoparticles (MNPs) to detect AOPP herbicides. The structural, protein loading capacity and loading ratio, porosity, and magnetic properties of QpeH/AOx@mZIF-8 were characterized by scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetric analysis, nitrogen sorption, and vibrating sample magnetometry. An AOPP herbicide colorimetric biosensor made with QpeH/AOx@mZIF-8 had the highest sensitivity toward quizalofop-P-ethyl (QpE) with a limit of detection of 8.2 μM. This system was suitable to detect two other AOPP herbicides, including fenoxaprop-P-ethyl (FpE) and haloxyfop-P-methyl (HpE). The practical application of the biosensor was verified through quantitative analysis of QpE residues in industrial wastewater and field soils. Furthermore, QpeH/AOx@mZIF-8 exhibited excellent long-term storage stability (at least 50 days), easy separation by magnet, and reusability (at least 10 cycles), supporting its promising role in simple and low-cost detection of AOPP herbicides in real environmental samples.

A known monoterpene, named γ-terpineol, was incorporated in mixed Langmuir monolayers composed of dipalmitoyl-phosphoethanolamine (DPPE) and peptidoglycans as a model of microbial membranes. Surface pressure and surface potential isotherms, dynamical surface rheology, Brewster angle microscopy (BAM), and infrared spectroscopy were employed to characterize the compound-membrane interactions. The compound expanded the monolayers denoting repulsive interactions. At 30 mN/m, the monolayer presented lower viscoelastic and in-plane elasticity parameters and an increased all-trans/gauche conformers ratio for the alkyl chains, confirming molecular order. The morphology of the monolayer was analyzed by BAM, which revealed a heterogeneous distribution of γ-terpineol along the mixed monolayer, which tends to segregate. In conclusion, the compound changes the thermodynamic, electric, rheological, morphological, and structural properties of the peptidoglycan-DPPE monolayer, which may be essential to understand, at the molecular level, the action of bioactives in selected membrane models., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Invasive breast cancer (BrCa) is predicted to affect 1 in 9 women in a lifetime;1 in 32 will die from this disease. The most aggressive forms of BrCa, basal-like/triple-negative phenotype (TNBC), are challenging to treat and result in higher mortality due high number of metastatic cases. There is a paucity of options for TNBC treatment, which highlights the need for additional innovative treatment approaches. NIH-III mice were injected in the abdominal mammary fat pad with luciferase-expressing derivative of the human TNBC cell line, MDA-MB-231 cells. Animals were gavage-fed with nitrofen at the doses of 1, 3 or 6 mg/kg/alternate days. However, several structural properties/components of nitrofen raise concerns, including its high lipophilicity (cLogP of nearly 5) and a potential toxophore in the form of a nitroarene group. Therefore, we developed analogues of nitrofen which lack the nitro group and/or have replaced the diaryl ether linker with a diarylamine that could allow modulation of polarity. In vitro anti-invasiveness activity of nitrofen analogues were evaluated by quantitative determination of invasion of MDA-MB-231-Luciferase cells through Matrigel using a Boyden chamber. Our in vivo data show that nitrofen efficiently blocks TNBC tumor metastasis. In vitro data suggest that this is not due to cytotoxicity, but rather is due to impairment of invasive capacity of the cells. Further, using an in vitro model of EMT, we show that nitrofen interferes with the process of EMT and promotes mesenchymal to epithelial transformation. In addition, we show that three of the nitrofen analogues significantly reduced invasive potential of TNBC cells, which may, at least partially, be attributed to the analogues' ability to promote mesenchymal to epithelial-like transformation of TNBC cells. Our study shows that nitrofen, and more importantly its analogues, are significantly effective in limiting the invasive potential of TNBC cell lines with minimal cytotoxic effect. Further, we demonstrate that nitrofen its analogues, are very effective in reversing mesenchymal phenotype to a more epithelial-like phenotype. This may be significant for the treatment of patients with mesenchymal-TNBC tumor subtype who are well known to exhibit high resistance to chemotherapy.

Programmed death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1) pathway is one of the most actively pursued targets in cancer immunotherapy. In a continuation of our research interest in this pathway, we synthesized and evaluated the pharmacological activities of a series of resorcinol biphenyl ether analogs as small molecule PD-1/PD-L1 inhibitors for cancer treatment. Among the 27 newly synthesized compounds, CH1 was found to have the highest inhibitory effect against PD-1/PDL-1 with an IC 50 value of 56.58 nM in the HTRF (homogenous time-resolved fluorescence) assay. In addition, CH1 dose-dependently promoted HepG2 cell death in a co-culture model of HepG2/hPD-L1 and Jurkat T cells. Furthermore, molecular modeling study indicated that CH1 binds with high affinity to the binding interface of PD-L1. Moreover, CH1 effectively inhibited tumor growth (TGI of 76.4% at 90 mg/kg) in an immune checkpoint humanized mouse model with no obvious toxicity. Finally, CH1 did not cause in vivo cardiotoxicity and bone marrow suppression (myelosuppression) to BALB/c mice. Taken together, these results suggest that CH1 deserves further investigation as a potent and safe PD-1/PDL-1 inhibitor for cancer treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Small-molecule mediated modulation of protein interactions of Bcl-2 (B-cell lymphoma-2) family proteins was clinically validated in 2015 when Venetoclax, a selective inhibitor of the antiapoptotic protein BCL-2, achieved breakthrough status designation by the FDA for treatment of lymphoid malignancies. Since then, substantial progress has been made in identifying inhibitors of other interactions of antiapoptosis proteins. However, targeting their pro-apoptotic counterparts, the "executioners" BAX, BAK, and BOK that both initiate and commit the cell to dying, has lagged behind. However, recent publications demonstrate that these proteins can be positively or negatively regulated using small molecule tool compounds. The results obtained with these molecules suggest that pharmaceutical regulation of apoptosis will have broad implications that extend beyond activating cell death in cancer. We review recent advances in identifying compounds and their utility in the exogenous control of life and death by regulating executioner proteins, with emphasis on the prototype BAX.

The research on bioactive secondary metabolites from Aspergillus fumigatus afforded six compounds, which were identified by mass spectrometer (MS) and nuclear magnetic resonance (NMR) spectroscopic analysis as cyclopyazonic acid (1), trypacidin A (2), asterric acid (3), methyl asterrate (4), demethylcitreoviranol (5), as well as (5-hydroxy-2-oxo-2H-pyran-4-yl) methyl acetate (6). Cyclopyazonic acid (1) was found to have potent antibacterial effects, especially against Bacillus licheniformis with minimal inhibitory concentration (MIC) value of 3.7μg/mL. Its antibacterial effects were possibly related to the olefinic acid group in the structure. Phenyl ether derivatives 3 and 4, and trypacidin A (2) also exhibited antimicrobial effects. In addition, compound 6 showed significant antioxidant effects with half maximal effective concentration (EC 50 ) value of 10.2μM in the ABTS (2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid) assay, which was better than the positive control.

Voltage-gated sodium channels (Navs) are promising targets for analgesic and antiepileptic therapies. Although specificity between Nav subtypes may be desirable to target specific neural types, such as nociceptors in pain, many broadly acting Nav inhibitors are clinically beneficial in neuropathic pain and epilepsy. Here, we present the first systematic characterization of vixotrigine, a Nav blocker. Using recombinant systems, we find that vixotrigine potency is enhanced in a voltage- and use-dependent manner, consistent with a state-dependent block of Navs. Furthermore, we find that vixotrigine potently inhibits sodium currents produced by both peripheral and central nervous system Nav subtypes, with use-dependent IC 50 values between 1.76 and 5.12 μM. Compared with carbamazepine, vixotrigine shows higher potency and more profound state-dependent inhibition but a similar broad spectrum of action distinct from Nav1.7- and Nav1.8-specific blockers. We find that vixotrigine rapidly inhibits Navs and prolongs recovery from the fast-inactivated state. In native rodent dorsal root ganglion sodium channels, we find that vixotrigine shifts steady-state inactivation curves. Based on these results, we conclude that vixotrigine is a broad-spectrum, state-dependent Nav blocker. SIGNIFICANCE STATEMENT: Vixotrigine blocks both peripheral and central voltage-gated sodium channel subtypes. Neurophysiological approaches in recombinant systems and sensory neurons suggest this block is state-dependent., Competing Interests: C. Hinckley, M. Hajos, and H. Naik are/were employees of and own stock/stock options in Biogen. Y. Kuryshev, A. Sers, A. Barre, and B. Buisson have no conflicts of interest to declare., (Copyright © 2020 by The Author(s).)

A series of programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors based on the resorcinol diphenyl ether scaffold were discovered by incorporating hydrophilic moieties into the side chain and converting into the corresponding hydrochloride salt. Among these compounds, P18 showed the highest inhibitory activity against PD-1/PD-L1 with an IC 50 value of 9.1 nM in a homogeneous time-resolved fluorescence binding assay. Besides, P18 promoted HepG2 cell death dose dependently in a HepG2/PD-L1 and Jurkat/PD-1 coculture cell model. Further, P18 demonstrated significantly higher water solubility (17.61 mg/mL) and improved pharmacokinetics ( e.g. , t 1/2 of ∼20 h and oral bioavailability of 12%) than the previous analogues. Moreover, P18 was highly effective in suppressing tumor growth in an immune checkpoint humanized mouse model without apparent toxicity. Collectively, these results suggest that compound P18 represents a promising PD-1/PD-L1 inhibitor worthy of further investigation as a potential anticancer agent.

The pyrazole-4-carboxamide scaffold containing a flexible amide chain has emerged as the molecular skeleton of highly efficient agricultural fungicides targeting succinate dehydrogenase (SDH). Based on the above vital structural features of succinate dehydrogenase inhibitors (SDHI), three types of novel pyrazole-4-formylhydrazine derivatives bearing a diphenyl ether moiety were rationally conceived under the guidance of a virtual docking comparison between bioactive molecules and SDH. Consistent with the virtual verification results of a molecular docking comparison, the in vitro antifungal bioassays indicated that the skeleton structure of title compounds should be optimized as an N '-(4-phenoxyphenyl)-1 H -pyrazole-4-carbohydrazide scaffold. Strikingly, N '-(4-phenoxyphenyl)-1 H -pyrazole-4-carbohydrazide derivatives 11o against Rhizoctonia solani , 11m against Fusarium graminearum , and 11g against Botrytis cinerea exhibited excellent antifungal effects, with corresponding EC 50 values of 0.14, 0.27, and 0.52 μg/mL, which were obviously better than carbendazim against R. solani (0.34 μg/mL) and F. graminearum (0.57 μg/mL) as well as penthiopyrad against B. cinerea (0.83 μg/mL). The relative studies on an in vivo bioassay against R. solani , bioactive evaluation against SDH, and molecular docking were further explored to ascertain the practical value of compound 11o as a potential fungicide targeting SDH. The present work provided a non-negligible complement for the structural optimization of antifungal leads targeting SDH.

In the present work, the anti-inflammatory and antiasthmatic potential of biseugenol, isolated as the main component from n -hexane extract from leaves of Nectandra leucantha and chemically prepared using oxidative coupling from eugenol, was evaluated in an experimental model of mixed-granulocytic asthma. Initially, in silico studies of biseugenol showed good predictions for drug-likeness, with adherence to Lipinski's rules of five (RO5), good Absorption, Distribution, Metabolism and Excretion (ADME) properties and no alerts for Pan-Assay Interference Compounds (PAINS), indicating adequate adherence to perform in vivo assays. Biseugenol (20 mg·kg -1 ) was thus administered intraperitoneally (four days of treatment) and resulted in a significant reduction in both eosinophils and neutrophils of bronchoalveolar lavage fluid in ovalbumin-sensitized mice with no statistical difference from dexamethasone (5 mg·kg -1 ). As for lung function parameters, biseugenol (20 mg·kg -1 ) significantly reduced airway and tissue damping in comparison to ovalbumin group, with similar efficacy to positive control dexamethasone. Airway hyperresponsiveness to intravenous methacholine was reduced with biseugenol but was inferior to dexamethasone in higher doses. In conclusion, biseugenol displayed antiasthmatic effects, as observed through the reduction of inflammation and airway hyperresponsiveness, with similar effects to dexamethasone, on mixed-granulocytic ovalbumin-sensitized mice.

R-2-(4-Hydroxyphenoxy)propionic acid (R-HPPA) is a pivotal intermediate for the synthesis of aryloxyphenoxypropionate (APP) herbicide. To rapidly screen microbial isolates with the capacity of hydroxylating R-2-phenoxypropionic acid to R-HPPA from various environmental samples, a convenient and safe 96-well microplate assay method with sodium nitrite (NaNO 2 ) as chromogenic reagent was proposed and optimized. The optimum assay conditions were as follows: the detection wavelength was 420 nm, the concentration of NaNO 2 solution was 6.0 g/L, color reaction temperature was 60 °C, the pH of the NaNO 2 solution was 2.4, and the reaction time was 40 min. With the aid of this method, screening for microorganisms with C-4-specific hydroxylation activity of R-PPA was conducted. As a result, 23 strains among 3744 single colonies isolated from various samples exhibited the hydroxylation activity. Among these strains, the highest bioconversion rate was achieved by Penicillium oxalicum A5 and Aspergillus versicolor A12, respectively. After 72-h cultivation in shake flask, their conversion rates of R-HPPA from 10 g/L R-PPA reached 21.18% and 40.24%, respectively. The established method was effective in rapid screening of microbes capable of biosynthesizing R-HPPA through hydroxylation of R-PPA, and the obtained two fungi species could be potentially used for R-HPPA production.

Human immunodeficiency virus (HIV)-1 remains as a global health issue that is primarily treated with highly active antiretroviral therapy, a combination of drugs that target the viral life cycle. One class of these drugs are non-nucleoside reverse transcriptase inhibitors (NNRTIs) that target the viral reverse transcriptase (RT). First generation NNRTIs were troubled with poor pharmacological properties and drug resistance, incentivizing the development of improved compounds. One class of developed compounds are the 2-naphthyl phenyl ethers, showing promising efficacy against the Y181C RT mutation. Further biochemical and structural work demonstrated differences in potency against the Y181C mutation and binding mode of the compounds. This work aims to understand the relationship between the binding mode and ability to overcome drug resistance using macromolecular x-ray crystallography. Comparison of 2-naphthyl phenyl ethers bound to Y181C RT reveal that compounds that interact with the invariant W229 are more capable of retaining efficacy against the resistance mutation. Additional modifications to these compounds at the 4-position, computationally designed to compensate for the Y181C mutation, do not demonstrate improved potency. Ultimately, we highlight important considerations for the development of future HIV-1 drugs that are able to combat drug resistance., (© 2020 The Protein Society.)

Novel small molecule compounds based on various scaffolds including chalcone, flavonoid, and resorcinol dibenzyl ether were designed and tested for their inhibitory activity against the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 (PD-1/PD-L1) pathway. Among them, compound NP19 inhibited the human PD-1/PD-L1 interaction with IC 50 values of 12.5 nM in homogeneous time-resolved fluorescence (HTRF) binding assays. In addition, NP19 dose-dependently elevated IFN-γ production in a coculture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. Furthermore, NP19 displayed significant in vivo antitumor efficacy in two different mouse models of cancer (a melanoma B16-F10 tumor model and an H22 hepatoma tumor model). Moreover, H&E staining and flow cytometry data suggested that NP19 activated the immune microenvironment in the tumor, which may contribute to its antitumor effects. This work shows NP19 is a promising lead compound for further development as a new generation of small molecule inhibitors targeting the PD-1/PD-L1 pathway.

Ion-exchange membranes are the core elements for an electrodialysis (ED) separation process. Phase inversion is an effective method, particularly for commercial membrane production. It introduces two different mechanisms, i.e., thermal induced phase separation (TIPS) and diffusion induced phase separation (DIPS). In this study, anion exchange membranes (AEMs) were prepared by grafting a quaternized moiety (QM,2-[dimethylaminomethyl]naphthalen-1-ol) through brominated poly (2,6-dimethyl-1,4-phenylene oxide) (BPPO) via the TIPS method. Those membranes were applied for selective bisulfite (HSO 3 - ) anion separation using ED. The membrane surface morphology was characterized by SEM, and the compositions were magnified using a high-resolution transmission electron microscope (HRTEM). Notably, the membranes showed excellent substance stability in an alkali medium and in grafting tests performed in a QM-soluble solvent. The ED experiment indicated that the as-prepared membrane exhibited better HSO 3 - separation performance than the state-of-the-art commercial Neosepta AMX (ASTOM, Japan) membrane.

Novel resorcinol diphenyl ether-based PROTACs (PROteolysis TArgeting Chimeras) were designed and evaluated for their inhibitory activity against the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway and their ability to degrade PD-L1 protein. Most of the compounds displayed excellent inhibitory activities against PD-1/PD-L1, as assessed by the homogenous time-resolved fluorescence (HTRF) binding assay, with IC50 values ranging from 25 nM to 200 nM. Among them, compound P22 is one of the best with an IC50 value of 39.2 nM. In addition to inhibiting PD-1/PD-L1 interaction, P22 also significantly restored the immunity repressed in a co-culture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. Furthermore, flow cytometry (FCM) and western-blot data demonstrated that P22 could moderately reduce the protein levels of PD-L1 in a lysosome-dependent manner, which may contribute to its immune effects. Preliminary FCM and western-blot data suggest that it is possible to build PD-L1-targeting PROTAC-like molecules based on PD-1/PD-L1 small molecule inhibitors, though these compounds showed only modest degradation efficiencies. Collectively, this work suggests that P22 may serve as a starting point for exploring the degradation of PD-L1 by PROTAC-like strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

R-2-(4-hydroxyphenoxy)propionicacid (HPOPA) is a valuable intermediate for the synthesis of enantiomerically pure aryloxyphenoxypropionic acid herbicides. In this work, to improve the HPOPA biosynthesis by Beauveria bassiana ZJB16002 from the substrate R-2-phenoxypropionic acid (POPA), the original HPOPA producer B. bassiana ZJB16002 was subjected to physical mutagenesis with 137 Cs-γ irradiation and chemical mutagen N-methyl-N'-nitro-N-nitrasoguanidine (NTG) induced mutagenesis. The effects of different treatment doses of the mutagens on the lethal rate and positive mutation rate were investigated, and the results showed that the optimal 137 Cs-γirradiation dose and NTG concentration was 850 Gy and 500 µg/mL, respectively. Under these conditions, a mutant strain CCN-7 with the highest HPOPA production capacity was obtained through two rounds of 137 Cs-γ irradiation treatment followed by one round of NTG mutagenesis. At the substrate (POPA) concentration of 50 g/L, HPOPA titer of CCN-7 reached 36.88 g/L, which was 9.73-fold higher than the parental strain. The morphology of the wild-type and mutant strain was compared and the results might provide helpful information in exploration of the correlation of morphology and biochemical features of B. bassiana., (© 2019 International Union of Biochemistry and Molecular Biology, Inc.)

Insect-borne parasite Trypanosoma brucei plagues humans and other animals, eliciting the disease Human African trypanosomiasis, also known as African sleeping sickness. This disease poses the biggest threat to the people in Sub-Saharan Africa. Given the high toxicity and difficulties with administration of currently available drugs, a novel treatment is needed. Building on known Human African trypanosomiasis structure-activity relationship (SAR), we now describe a number of functionally simple diphenyl ether analogs which give low micromolar activity (IC 50  = 0.16-0.96 μM) against T. b. rhodesiense. The best compound shows favorable selectivity against the L6 cell line (SI = 750) and even greater selectivity (SI = 1200) against four human cell lines. The data herein provides direction for the ongoing optimization of antitrypanosomal diphenyl ethers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

To seek new protoporphyrinogen oxidase (PPO) inhibitors with better biological activity, a series of novel diphenyl ether derivatives containing tetrahydrophthalimide were designed based on the principle of substructure splicing and bioisomerization. PPO inhibition experiments exhibited that 6c is the most potential compound, with the half-maximal inhibitory concentration (IC 50 ) value of 0.00667 mg/L, showing 7 times higher activity than Oxyfluorfen (IC 50 = 0.0426 mg/L) against maize PPO and similar herbicidal activities to Oxyfluorfen in weeding experiments in greenhouses and field weeding experiments. In view of the inspected bioactivities, the structure-activity relationship (SAR) of this series of compounds was also discussed. Crop selection experiments demonstrate that compound 6c is safe for soybeans, maize, rice, peanuts, and cotton at a dose of 300 g ai/ha. Accumulation analysis experiments showed that the accumulation of 6c in some crops (soybeans, peanuts, and cotton) was significantly lower than Oxyfluorfen. Current work suggests that compound 6c may be developed as a new herbicide candidate in fields.

Six new obovatol trimeric neolignans, houpulignans A-F (1-6) were isolated from the leaves of Magnolia officinalis var. biloba. Their structures were determined on the basis of the interpretation of HRESIMS, NMR data, and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 are the first examples of neolignans derived from three units of obovatol bearing a rare 1,4-benzodioxepane moiety. Compound 3 possesses a benzodihydropyran ring, meanwhile three units of obovatol in 4-6 are connected by an alkyl chain. Compounds 1-3 inhibited NO production in LPS-stimulated RAW264.7 cells with IC 50 values of 8.01, 20.21, and 4.05 µM, respectively., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

(R)-2-Phenoxy-propionic acid methyl ester (PPAM) is an important chiral precursor of aryloxy phenoxy propionate herbicides. The covalent immobilization of lipase from Aspergillus oryzae WZ007 and the catalysis of enantioselective (R, S)-PPAM resolution by the immobilized A. oryzae lipase (AOL) were investigated in this study. The primary amino resin LX-1000HA was selected as the support for the covalent immobilization of AOL. The K m and V max of the immobilized lipase were 1.97 mM and 4.84 × 10 3  μmol/mg min, respectively. The key reaction parameters (pH, temperature, rotation speed, and substrate concentration) for the lipase-catalyzed resolution of (R, S)-PPAM were optimized. An e.e. s of 99.5% and conversion rate of 50.8% were achieved under the optimal conditions of pH 7.5, 30 °C, and substrate concentration 500 mM. The immobilized lipase retained 87.3% of its initial activity after 15 cycles of the repeated experiments. The results demonstrated that the covalent immobilized AOL has potential industrial applications.

The extract of the strain Aspergillus flavipes DL-11 exerted antibacterial activities against six Gram-positive bacteria. During the following bioassay-guided separation, ten diphenyl ethers (1-10), two benzophenones (11-12), together with two xanthones (13-14) were isolated. Among them, 4'-chloroasterric acid (1) was a new chlorinated diphenyl ether. Their structures were elucidated by extensive spectroscopic data analysis, including IR, HR-ESI-MS, NMR experiments, and by comparison with the literature data. All compounds showed moderate to strong antibacterial effects on different Gram-positive bacteria with MIC values that ranged from 3.13 to 50 μg/mL, but none of the compounds exhibited activity against Gram-negative bacteria Vibrio parahaemolyticus ATCC17802 (MIC>100 μg/mL). In particular, the MICs of some compounds are at the level of positive control., (© 2019 Wiley-VHCA AG, Zurich, Switzerland.)

Background: The well-known antibacterial agent Triclosan (TCL) that targets bacterial enoylacyl protein reductase has been described to inhibit human fatty acid synthase (FASN) via the enoylacyl reductase domain. A Literature survey indicates that TCL is selectively toxic to cancer cells and furthermore might indeed reduce cancer incidence in vivo. A recent study found that TCL inhibits FASN by acting as an allosteric protein-protein interface (PPI) inhibitor. It induces dimer orientation changes that effect in a downstream reorientation of catalytic residues in the NADPH binding site proposing TCL as a viable scaffold to design a superior molecule that might have more inhibitory potential. This unveils tons of potential interaction space to take advantage of future inhibitor design., Objectives: Synthesis of TCL mimicking novel diphenyl ether derivatives, biological evaluation as potential antiproliferative agents and molecular docking and molecular dynamics simulation studies., Methods: A series of novel N-(1-(3-hydroxy-4-phenoxyphenyl)-3-oxo-3-phenylpropyl)acetamides (3a-n) and N-(3(3-hydroxy-4phenoxyphenyl)-3-oxo-1-phenylpropyl) acetamides (6a-n) were designed, synthesized, characterized and evaluated against HepG2, A-549, MCF-7 and Vero cell lines. The induction of antiproliferative activity of selected compounds (3d and 6c) was done by AO/EB (acridine orange/ethidium bromide) nuclear staining method, DNA fragmentation study, and cell cycle analysis was performed by flow cytometry. Molecular docking and dynamics simulation study was also performed., Results: Among the tested compounds, compound 3d was most active (IC50 13.76 ± 0.43 µM) against A-549 cell line. Compounds 3d and 3g were found to be moderately active with IC50 30.56 ± 1.1 µM and 25.05 ± 0.8 µM respectively against MCF-7 cell line. Morphological analysis of A-549 cells treated with 3d and 6c clearly demonstrated the reduction of cell viability and induction of apoptosis. DNA fragmentation was observed as a characteristic of apoptosis in treated cells. Further, cell cycle analysis by flow cytometry confirmed that compounds 3d and 6c significantly arrested the cell cycle at the G0/G1 phase. Molecular docking study demonstrated that these compounds exhibit high affinity for the human fatty acid synthase (hFASN) target. Molecular dynamics simulation study of the most active compound 3d was performed for calculating binding free energies using Molecular Mechanics-Generalized Born Surface Area (MM/GBSA)., Conclusion: Compound 3d (IC50 13.76 ± 0.43 µM) has been identified as a potential lead molecule for anticancer activity against A-549 cells followed by 3l, 6c, and 3g. Thus, the design of diphenyl ether derivatives with enhanced affinity to the binding site of hER may lead to the discovery of potential anticancer agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Human GPR40 receptor, also known as free fatty-acid receptor 1, is a Gprotein- coupled receptor that binds long chain free fatty acids to enhance glucose-dependent insulin secretion. In order to improve the resistance and efficacy, computational tools were applied to a series of 3-aryl-3-ethoxypropanoic acid derivatives. A relationship between the structure and biological activity of these compounds, was derived using a three-dimensional quantitative structure-activity relationship (3D-QSAR) study using CoMFA, CoMSIA and two-dimensional QSAR study using HQSAR methods., Methods: Building the 3D-QSAR models, CoMFA, CoMSIA and HQSAR were performed using Sybyl-X software. The ratio of training to test set was kept 70:30. For the generation of 3D-QSAR model three different alignments were used namely, distill, pharmacophore and docking based alignments. Molecular docking studies were carried out on designed molecules using the same software., Results: Among all the three methods used, Distill alignment was found to be reliable and predictive with good statistical results. The results obtained from CoMFA analysis q2, r2cv and r2 pred were 0.693, 0.69 and 0.992 respectively and in CoMSIA analysis q2, r2cv and r2pred were 0.668, 0.648 and 0.990. Contour maps of CoMFA (lipophilic and electrostatic), CoMSIA (lipophilic, electrostatic, hydrophobic, and donor) and HQSAR (positive & negative contribution) provided significant insights i.e. favoured and disfavoured regions or positive & negative contributing fragments with R1 and R2 substitutions, which gave hints for the modifications required to design new molecules with improved biological activity., Conclusion: 3D-QSAR techniques were applied for the first time on the series 3-aryl-3- ethoxypropanoic acids. All the models (CoMFA, CoMSIA and HQSAR) were found to be satisfactory according to the statistical parameters. Therefore such a methodology, whereby maximum structural information (from ligand and biological target) is explored, gives maximum insights into the plausible protein-ligand interactions and is more likely to provide potential lead candidates has been exemplified from this study., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Obovatol, a novel lignan isolated from the leaf and stem bark of Magnolia obovata Thunb exhibits many important biological activities. To discover natural-product-based potential fungicides with novel structural skeletons, a series of Mannich base derivatives were prepared by the C-4-aminomethylated modification of obovatol and all synthesized compounds were evaluated for antifungal activities in vitro against several phytopathogenic fungi using the spore germination method and the mycelium growth rate method. Furthermore, their structures were also characterized by 1 H NMR, 13 C NMR, and HR-MS, and compound 2k was further analyzed by single-crystal X-ray diffraction. Among all of the derivatives, compounds 2b (IC 50  = 28.68 µg/mL) and 2g (IC 50  = 16.90 µg/mL) demonstrated greater inhibition of Botrytis cinerea spore germination than two positive controls, hymexazol and difenoconazole. Compounds 2c, 2f, and 2g displayed potent mycelial growth inhibition of B. cinerea with an average inhibition rate (AIR) of >90% at a concentration of 100 µg/mL. Additionally, the structure-activity relationships (SARs) suggested that the introduction of a diethylamino, pyrrolyl, 1-methyl-piperazinyl or 1-ethyl-piperazinyl groups on the C-4 position of obovatol may be more likely to yield potential antifungal compounds than the introduction of 4-phenyl-piperazinyl or 4-phenyl-piperidinyl groups., (Copyright © 2019 Elsevier Inc. All rights reserved.)

An electrochemical sensor for the carcinogen 4,4'-oxydianiline (Oxy) is described. The method is based on the ability of MoS 2 nanosheets to preconcentrate Oxy. A glassy carbon electrode (GCE) was covered, by drop-casting, with MoS 2 nanosheets that were obtained by exfoliation. X-Ray photoemission spectroscopy indicates that Oxy accumulates on the MoS 2 nanosheets through an electropolymerization process similar to that reported for aniline. Both electrochemical impedance spectroscopy and atomic force microscopy were used to characterize the electrode surface at the different stages of device fabrication. Employing the current measured at +0.27 V vs. Ag/AgCl after Oxy adsorption, the modified GCE enables the voltammetric detection of Oxy at 80 nM levels with relative errors and relative standard deviations of <8.3 and <5.6%, respectively, at all the concentrations studied. The method was applied to the selective determination of Oxy in spiked river water samples. Very good selectivity and recoveries of around 95% in average are found. Graphical abstractSchematic representation of 4,4-oxydianiline electrochemical polymerization and preconcentration onto molybdenum disulfide nanosheets for the diamine determination in river waters.

Background: Obovatol, a biphenolic chemical originating from Magnolia obovata, has been utilized as a traditional medicine for the treatment of inflammatory diseases. Inflammasome induces maturation of inflammatory cytokines in response to intracellular danger signals, and its dysregulation induces inflammatory diseases., Purpose: The effect of obovatol on inflammasome activation has not been reported, although its anti-inflammatory properties have been studied., Study Design/methods: Obovatol was treated to macrophages with inflammasome triggers, and secretions of interleukin (IL)-1β, IL-18, and caspase-1 were measured as readouts of inflammasome activation. In addition, Asc pyroptosome formation, caspase-1 activity, and mitochondrial reactive oxygen species (ROS) production were analyzed in mechanical studies. Anti-inflammasome properties of obovatol were confirmed in an animal model., Results: Obovatol inhibited NLRP3, AIM2, and non-canonical inflammasomes through inhibition of Asc pyroptosome formation and mitochondrial ROS generation. In addition, obovatol disrupted the priming step of inflammasome activation and inhibited transcription of inflammatory cytokines. In mice, obovatol attenuated serum IL-1β elevation in response to monosodium urate crystals., Conclusion: Obovatol is suggested as an inhibitor of NLRP3, AIM2, and non-canonical inflammasomes., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

We herein present a method for the synthesis of HNbWO6, HNbMoO6, HTaWO6 solid acid nanosheet modified Pt/CNTs. By varying the weight of various solid acid nanosheets, a series of Pt/xHMNO6/CNTs with different solid acid compositions (x = 5, 20 wt%; M = Nb, Ta; N = Mo, W) have been prepared by carbon nanotube pretreatment, protonic exchange, solid acid exfoliation, aggregation and finally Pt particles impregnation. The Pt/xHMNO6/CNTs are characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy and NH3-temperature programmed desorption. The study revealed that HNbWO6 nanosheets were attached on CNTs, with some edges of the nanosheets being bent in shape. The acid strength of the supported Pt catalysts increases in the following order: Pt/CNTs < Pt/5HNbWO6/CNTs < Pt/20HNbMoO6/CNTs < Pt/20HNbWO6/CNTs < Pt/20HTaWO6/CNTs. In addition, the catalytic hydroconversion of lignin-derived model compound: diphenyl ether using the synthesized Pt/20HNbWO6 catalyst has been investigated.

A series of novel 2-amino-4-(3-hydroxy-4-phenoxyphenyl)-6-(4-substituted phenyl) nicotinonitriles were synthesized and evaluated against HepG2, A-549 and Vero cell lines. Compounds 3b (IC 50 16.74 ± 0.45 µM) and 3p (IC 50 10.57 ± 0.54 µM) were found to be the most active compounds against A-549 cell line among the evaluated compounds. Further 3b- and 3p-induced apoptosis was characterized by AO/EB (acridine orange/ethidium bromide) nuclear staining method and also by DNA fragmentation study. A decrease in cell viability and initiation of apoptosis was clearly evident through the morphological changes in the A-549 cells treated with 3b and 3p when stained with this method. Fragmentation of DNA into nucleosomes was observed which further confirmed the cell apoptosis in cells treated with compound 3b. Flow cytometry studies confirmed the cell cycle arrest at G2/M phase in A549 cells treated with compound 3b. Further in silico studies performed supported the in vitro anticancer activity of these compounds as depicted by dock score and binding energy values.

Rechargeable zinc-air batteries are deemed as the most feasible alternative to replace lithium-ion batteries in various applications. Among battery components, separators play a crucial role in the commercial realization of rechargeable zinc-air batteries, especially from the viewpoint of preventing zincate (Zn(OH) 4 2- ) ion crossover from the zinc anode to the air cathode. In this study, a new hydroxide exchange membrane for zinc-air batteries was synthesized using poly (2,6-dimethyl-1,4-phenylene oxide) (PPO) as the base polymer. PPO was quaternized using three tertiary amines, including trimethylamine (TMA), 1-methylpyrolidine (MPY), and 1-methylimidazole (MIM), and casted into separator films. The successful synthesis process was confirmed by proton nuclear magnetic resonance and Fourier-transform infrared spectroscopy, while their thermal stability was examined using thermogravimetric analysis. Besides, their water/electrolyte absorption capacity and dimensional change, induced by the electrolyte uptake, were studied. Ionic conductivity of PPO-TMA, PPO-MPY, and PPO-MIM was determined using electrochemical impedance spectroscopy to be 0.17, 0.16, and 0.003 mS/cm, respectively. Zincate crossover evaluation tests revealed very low zincate diffusion coefficient of 1.13 × 10 -8 , and 0.28 × 10 -8 cm 2 /min for PPO-TMA, and PPO-MPY, respectively. Moreover, galvanostatic discharge performance of the primary batteries assembled using PPO-TMA and PPO-MPY as initial battery tests showed a high specific discharge capacity and specific power of ~800 mAh/g Zn and 1000 mWh/g Zn , respectively. Low zincate crossover and high discharge capacity of these separator membranes makes them potential materials to be used in zinc-air batteries.

Microtubule targeting agents represent a very active arena in the development of anticancer agents. In particular, compounds binding at the colchicine site in tubulin are being deeply studied, and the structural information recently available on this binding site allows structure-directed design of new ligands. Structural comparison of our recently reported high resolution X-Ray structure of the cyclohexanedione derivative TUB075 bound to tubulin and the tubulin-DAMA-colchicine complex has revealed a conformational change in the αT5 loop. By a grid-based computational analysis of the tubulin-DAMA-colchicine binding site, we have identified a new favourable binding area in the colchicine-site that was unexplored by our lead TUB075. Thus, based on a structure-guided design, new cyclohexanedione derivatives have been synthesized and tested for tubulin binding and in cellular assays. As a result, we have identified diphenyl ether derivatives with IC 50 values around 10-40 nM against three different tumor cell lines and affinity constants for tubulin similar to that of colchicine around 10 7  M -1 . As expected, they halted the cell cycle progression at G2/M phase at concentrations as low as 0.08 μM., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A new and concise biosynthetic pathway of fungal diphenyl ethers (DPEs) has been elucidated and efficiently reconstructed in yeast. The pathway includes an unusual nonreducing polyketide synthase (NRPKS) responsible for the formation of a polyketide dimer with an ether bond linkage as well as two cofactor-independent enzymes that catalyze tandem regioselective decarboxylation reactions. Our discovery here opens a new window for utilizing fungal DPEs as a platform to design and synthesize analogues for the development of highly useful drug leads.

In this study, we obtained unprecedented AFM images of the Na,K-ATPase (NKA) pump after being reconstituted into DPPC and DPPC:DPPE liposomes. The mechanical properties observed in the phase images were associated with protrusions correlated to NKA microdomains, which are the darker areas seen in the AFM phase images. Protrusions in the DPPC-NKA proteoliposomes ranged from 38 to 115 nm, with 74 ± 21 nm diameter and 2.1 ± 1.4 nm height. DPPC:DPPE-NKA proteoliposomes showed protrusions from 21 to 78 nm, with 38 ± 16 nm diameter and 0.7 ± 0.5 nm height. We have estimated the presence of annular lipids in the microdomains considering that the areas of the protrusions should contain αβ oligomers and annular phospholipids. For DPPC-NKA proteoliposomes, we hypothesize that 40 phospholipids surround an (αβ) 2 dimer and 46 phospholipids are present for the DPPC:DPPE-NKA proteoliposomes in an αβ monomer. Catalytic activity measurements of both lipid compositions of proteoliposomes harboring NKA provide strong evidence regarding the protein orientation in the biomembrane. AFM data suggest that DPPC-NKA proteoliposomes are also rightside-out protein orientated, where the protrusions have an average height of 2.1 nm, while for DPPC:DPPE-NKA proteoliposomes, the majority of the protein reconstituted should be inside-out orientated, where the protrusions' average height is 0.5 nm. This result corroborates with the enzymatic analysis, where 61% and 91% of the enzymatic activity was recovered, respectively. Thus, a new application of AFM as a tool for the determination of topological features of protrusions in proteoliposomes has been brought to the scientific community, in addition to revealing the distinct catalytic orientation of enzymes present in the biomembranes model.

Three new diphenyl ethers (1-3), together with four known isopentylated diphenyl ethers derivatives (4-7), were isolated from the fermentation products of an endophytic fungus Phomopsis fukushii. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1-3 were evaluated for their anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity. The results revealed that compounds 1 and 2 showed strong inhibitions with inhibition zone diameters (IZD) of 20.2 ± 2.5 mm and 17.9 ± 2.2 mm, respectively. Compound 3 also showed good inhibition with IZD 15.2 ± 1.8 mm. The IZD data of compound 1 is close to that of positive control with IZD 21.9 ± 2.1 mm.

As a continuation of our project aimed at searching for new chemotherapeutic agents against American trypanosomiasis (Chagas disease), new selenocyanate derivatives were designed, synthesized and biologically evaluated against the clinically more relevant dividing form of Trypanosoma cruzi, the etiologic agent of this illness. In addition, in order to establish the role of each part of the selenocyanate moiety, different derivatives, in which the selenium atom or the cyano group were absent, were conceived, synthesized and biologically evaluated. In addition, in order to study the optimal position of the terminal phenoxy group, new regioisomers of WC-9 were synthesized and evaluated against T. cruzi. Finally, the resolution of a racemic mixture of a very potent conformationally rigid analogue of WC-9 was accomplished and further tested as growth inhibitors of T. cruzi proliferation. The results provide further insight into the role of the selenocyanate group in its antiparasitic activity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)