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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. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

Developing pure diastereoisomeric molecular hybrids for the selective inhibition of bacterial growth opened new avenues for combating the ever-increasing microbial resistance. Considering this, a series of diastereoisomeric pure pyrazolyl-dihydrofurans (7a-7y) were synthesized and characterized using NMR, LCMS, and X-ray crystallography. DFT based method was used to explore the configurational stability of cis over trans isomeric form. Considering 7a and 8a as representative isomeric forms with same structural framework, the difference in their bio-efficacy against bacterial and fungal strains was assessed using serial dilution method. The relatively high inhibition of bacterial growth by the cis isomeric form (7a) (MIC = 1.562 µg/mL), amoxicillin (MIC = 3.125 µg/mL) inspired us to broaden the substrate scope for synthesizing a series of pure diastereoisomeric cis forms as selective anti-bacterial agents. However, both the isomers displayed antifungal activity less than the standard drug (Fluconazole) employed in the study. All the reactions proceeded smoothly and yielded a diverse array of dihydrofuran derivatives. The developed synthetics were found to be non-cytotoxic against mouse fibroblast cells and didn't affect the seed germination of Brassica nigra seeds when treated at 1 mg/mL concentration. The experimentally determined in vitro results were further validated using in silico molecular docking and dynamics studies., 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. Published by Elsevier Ltd.)

α-Glucosidase, which is involved in the hydrolysis of carbohydrates to glucose and directly mediates blood glucose elevation, is a crucial therapeutic target for type 2 diabetes. In this work, 2,5-disubstituted furan derivatives containing 1,3-thiazole-2-amino or 1,3-thiazole-2-thiol moiety (III-01 ∼ III-30) were synthesized and screened for their inhibitory activity against α-glucosidase. α-Glucosidase inhibition assay demonstrated that all compounds had IC 50 in the range of 0.645-94.033 μM and more potent than standard inhibitor acarbose (IC 50  = 452.243 ± 54.142 µM). The most promising inhibitors of the two series were compound III-10 (IC 50  = 4.120 ± 0.764 μM) and III-24 (IC 50  = 0.645 ± 0.052 μM), respectively. Kinetic study and molecular docking simulation revealed that compound III-10 (Ki = 2.04 ± 0.72 μM) is a competitive inhibitor and III-24 (Ki = 0.44 ± 0.53 μM) is a noncompetitive inhibitor against α-glucosidase. Significantly, these two compounds showed nontoxicity towards HEK293, RAW264.7 and HepG2 cells, suggesting that compounds may be considered as a class of potential candidates for further developing novel antidiabetic drugs., 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 © 2023. Published by Elsevier Ltd.)

Structural optimization using plant secondary metabolites as templates is one of the important approach to discover pesticide molecules with novel skeletons. Xanthatin, a natural sesquiterpene lactone isolated from the Xanthium plants (Family: Compositae), exhibits important biological properties. In this work, a series of Michael-type amino derivatives were prepared from xanthatin and their structures were characterized by 1 H NMR, 13 C NMR and HR-MS, and their antifungal activities against several phytopathogenic fungi were evaluated according to the spore germination method and mycelium growth rate method in vitro. The results illustrated that compounds 2g (IC 50  = 78.91 µg/mL) and 2o (IC 50  = 64.51 µg/mL) exhibited more promising inhibition activity against spores of F. solani than precursor xanthatin, compounds 2g, 2l, and 2r exhibited remarkable antifungal effect on C. mandshurica with the average inhibition rates (AIRs) >90%, whereas the AIR of xanthatin was only 59.34%. Meanwhile, the preliminary structure-activity relationships suggested that the amino containing 2-methoxyethyl or 4-chlorophenylmethyl group appended in the C-13 position of xanthatin could yield potential compounds against fungal spores, and the exocyclic double bond of xanthatin is essential to maintain its mycelial growth inhibitory activity. Therefore, the aforementioned findings indicate that partial xanthatin amino-derivatives could be considered for further exploration as the potential lead structures toward development of the new environmentally friendly fungicidal candidates for sustainable crop protection., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A growing number of diseases are linked to the misfolding of integral membrane proteins, and many of these proteins are targeted for ubiquitin-proteasome-dependent degradation. One such substrate is a mutant form of the Cystic Fibrosis Transmembrane Conductance Regulator (F508del-CFTR). Protein folding "correctors" that repair the F508del-CFTR folding defect have entered the clinic, but they are unlikely to protect the entire protein from degradation. To increase the pool of F508del-CFTR protein that is available for correction by existing treatments, we determined a structure-activity relationship to improve the efficacy and reduce the toxicity of an inhibitor of the E1 ubiquitin activating enzyme that facilitates F508del-CFTR maturation. A resulting lead compound lacked measurable toxicity and improved the ability of an FDA-approved corrector to augment F508del-CFTR folding, transport the protein to the plasma membrane, and maintain its activity. These data support a proof-of-concept that modest inhibition of substrate ubiquitination improves the activity of small molecule correctors to treat CF and potentially other protein conformational disorders., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Analogs of diarylpyrrolinone lead compound 1 were prepared and tested for anti-proliferative activity in U-937 cancer cells. Alterations of 1 focused on modifying the two nitrogen atoms: a) the pyrrolinone nitrogen atom was substituted with a propyl group or replaced with an oxygen atom (furanone), and b) the substituents on the indole nitrogen were varied. These changes led to the discovery of a furanone analog 3b with sub-micromolar anti-cancer potency and tubulin polymerization inhibition activity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Further optimization of the VU0486321 series of highly selective and CNS-penetrant mGlu 1 PAMs identified unique 'molecular switches' on the central aromatic ring that engendered positive cooperativity with multiple mGlu subtypes across the receptor family, resulting in compounds with comparable activity at Group I (mGlu 1/5 ) and Group III (mGlu 4/6/7/8 ) mGlu receptors, receptors. These exciting data suggests this PAM chemotype appears to bind to multiple mGlu receptors, and that subtype selectivity is dictated by the degree of cooperativity, not a subtype selective, unique allosteric binding site. Moreover, there is interesting therapeutic potential for mGlu 1/4/7/8 PAMs, as well as the first report of a GPCR allosteric 'privileged structure'., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A series of 1,2-dihydronaphtho[2,1-b]furan derivatives were synthesized by cyclizing 1-(aryl/alkyl(arylthio)methyl)-naphthalen-2-ol and pyridinium bromides in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in very good yield. The synthesized compounds were evaluated for their anti-proliferative potential against human triple negative MDA-MB-468 and MCF-7 breast cancer cells and non-cancerous WI-38 cells (lung fibroblast cell) using MTT experiments. Among 21 synthesized compounds, three compounds (3a, 3b and 3 s) showed promising anti-cancer potential and compound 3b was found to have best anti-proliferative activities based on the results of several biochemical and microscopic experiments., 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 Ltd. All rights reserved.)

Herein we report the preparation of 3,4-dibenzylfurans and some oxidized derivatives with lignan backbone. The compounds were prepared using the Friedel-Crafts reaction with BF 3 etherate as catalyst, demethylation with iodocyclohexane, acetylation and oxidation reactions. The antimicrobial activity was evaluated through their capacity to inhibit the growth of Gram positive and Gram negative bacteria, and of the yeast Candida albicans. Among ten products assayed four furans displayed a good antimicrobial activity against Staphylococcus aureus, S. epidermidis and C. albicans; on the contrary, none of the compounds were active against Pseudomonas aeruginosa. One of them inhibited the growth of S. aureus, S. epidermidis (biofilm producer strain) and C. albicans at 16 μg/mL, showing a bactericidal activity already after one hour of treatment. In summary, the results suggest a possible use of these derivatives for general disinfection practices or antimicrobial agents in cosmesis skin-care., 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 Ltd. All rights reserved.)

Cycloaddition reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehydes (3a-g) and 4-chloro-2H-chromene-3-carbaldehydes (7a-h) with activated alkynes (4a-b) provided the 2-oxo-2H-chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates (5a-n) and 2H-chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates (8a-p). All the prepared compounds were screened for anti-inflammatory activity. In vitro anti-inflammatory activity data demonstrated that the compounds 5g, 5i, 5k-l and 8f are effective among the tested compounds against TNF-α (1.108 ± 0.002, 0.423 ± 0.022, 0.047 ± 0.001, 0.070 ± 0.002 and 0.142 ± 0.001 µM) in comparison with standard compound Prednisolone (0.033 ± 0.002 µM). Based on in vitro results, three compounds (5i, 5k and 8f) have been selected for in vivo experiments and these compounds are identified as better compounds with respect to anti-inflammatory activity in LPS induced mice model. Compound 5i was identified as potent and showed significant reduction in TNF-α and IL-6., 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 Ltd. All rights reserved.)

PI-103 (7) is a potent dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor, but its rapid in vivo metabolism hinders its further clinical development. To improve the bioavailability of PI-103, we designed and synthesized a PI-103 bioisostere, PI-103BE (9) in which the phenolic hydroxyl group of PI-103 was replaced by a boronate, a structural modification known to enhance bioavailability of molecules containing phenolic hydroxyl moieties. In cell culture, PI-103BE is partially converted to its corresponding boronic acid (10) and to a lesser extent the active ingredient, PI-103. This mixture contributes to the in vitro activity of 9 that shows reduced potency compared to the parent compound. When administered to mice by oral gavage, 9 displays a significantly improved pharmacokinetic profile compared to PI-103, which shows no oral bioavailability at the same dose. Drug exposure of 9 as measured by the area under curve (AUC) value is 88.2 ng/mL*h for 7 and 8879.9 ng/mL*h for 10. When given by intraperitoneal injection (IP), the prodrug afforded an AUC of 32.3 ng/mL*h for 7 and 400.9 ng/mL*h for 10, compared to 9.7 ng/mL*h from PI-103 injection. In plasma from both pharmacokinetic studies, 9 is fully converted to 10 and 7, with the boronic acid metabolite (10) displaying antiproliferative activities comparable to 9, but weaker than 7. The boronic bioisostere of PI-103 thus offers an improved bioavailability that could be translated to in vivo efficacy of PI-103., 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. Published by Elsevier Ltd.)

One of the arctigenin stereoisomers, (8R,8'R)-trans-form 1, showed stereospecific cytotoxicity against insect cells, Sf9 and NIAS-AeAl-2 cells. By the comparison with other stereoisomers, the most importance of the 8'R stereochemistry for the higher activities was clarified. On the other hand, the wider range of activity level among stereoisomers against cancer cells, HL-60, was not observed. The structure-activity relationship research using derivatives bearing (8R,8'R)-trans-form was performed to show the same level of activities of 3-iodo, 4-iodo, and 3,4-methylenedioxy derivatives 28, 29, and 36 as (8R,8'R)-trans-arctigenin 1. In the examination of thiono derivatives, 4-iodo thiono and 3,4-methylenedioxy thiono derivatives 66, 67 showed similar level of activities to that of (8R,8'R)-trans-arctigenin 1. The expression of ribosomal 28S rRNA gene of Sf9 cells was increased by (8R,8'R)-trans-arctigenin 1, whereas a degradation of DNA was not observed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

NanoLuc (NLuc)-furimazine bioluminescence system offers several advantages over established systems, including improved stability, smaller size, and >150-fold enhancement in bioluminescence. Herein, we designed and synthesized a series of bioluminescent substrates with varying at the C-6 position of furimazine for NLuc-furimazine bioluminescence system. Among all derivatives, compounds A6 and A11 provided excellent bioluminescence characteristics compared with furimazine in vitro and in vivo. We believe that these new NLuc substrates can broaden the application of NLuc bioluminescence techniques, especially in vivo bioluminescent imaging., 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 Ltd. All rights reserved.)

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. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

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. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

A series of new asymmetric bisamidine was designed, synthesized, and tested for their in-vitro antibacterial activity using a range of Gram-positive and Gram-negative pathogens. Most compounds demonstrated powerful antibacterial activity, and interestingly, some displayed better activity against several Gram-negative strains than the lead compound 1. The most potent bisamidine 8l exhibited 4-fold more potent activity against E. coli, K. pneumonia, P. aeruginosa, and C. freundii than compound 1. Especially 8l exhibited a powerful activity against K. pneumonia secreting NDM-1 enzyme with a minimum inhibitory concentration (MIC) of 2 μg/mL, while levofloxacin and vancomycin displayed resistance, with MICs > 128 μg/mL., 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 © 2019 Elsevier Ltd. All rights reserved.)

Aided by Structure Based Drug Discovery (SBDD), we rapidly designed a highly novel and selective series of mTOR inhibitors. This chemotype conveys exquisite kinase selectivity, excellent in vitro and in vivo potencies and ADME safety profiles. These compounds could serve as good tools to explore the potential of TORC inhibition in various human diseases., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Our understanding of the tetrahydrofuran (THF) degradation in complex environment is limited. The majority of THF degrading genes reported are group V soluble diiron monooxygenases and share greater than 95% homology with one another. In this study, we used sole-carbon-source incubation combined with high-throughput metagenomic sequencing to investigate this contaminant's degradation in environmental samples. We identified as-yet-uncultivated microbe from the genera Pseudonocardia and fungi Scedosporium sp. (Scedosporium sp. was successfully isolated) as THF degraders as containing THF degradation genes, while microbes from the genera Bordetella, Pandoraea and Rhodanobacter functioned as main cooperators by utilizing acidic intermediates and providing anti-acid mechanisms. Furthermore, a 9387-bp THF degradation cluster designated thmX from the as-yet-uncultivated Pseudonocardia (with 6 main ORFs and with 79-93% amino acid sequence identity with previously reported clusters) was discovered. We also found a THF-degrading related cytochrome P450 monooxygenase from the genus Scedosporium and predicted its cognate reductase for the first time. All the genes and clusters mentioned above were successfully amplified from samples and cloned into the suitable expression vectors. This study will provide novel insights for understanding of THF degradation mechanisms under acid stress conditions and mining new THF degradation genes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

HTL/KAI2, a member of the α/β-fold hydrolase superfamily, is known to be a receptor-like protein of lactone compounds and that triggers seed germination of Arabidopsis. However, the endogenous ligand and physiological roles of HTL/KAI2 have remained unclear. To understand the mechanism underlying seed germination involved in HTL/KAI2 signaling, it is necessary to identify the endogenous ligand of HTL/KAI2. To date, even a biosynthetic mutant of the ligand has not yet been isolated. Because exogenous agonistic chemicals can only be purchased in small amounts at high prices, the limited supply of those chemicals has hampered any large-scale experiments, such as mutant screening. Therefore, easily synthesized and scalable artificial agonist would remove the limitation of the chemical supply and contribute to the identification of the endogenous ligand of HTL/KAI2 and/or the biosynthetic mutants. In this study, we demonstrated that designed chemicals with a phenoxyfuranone scaffold potently stimulated seed germination via HTL/KAI2 in Arabidopsis. As a result of screening of these chemicals, we selected a representative compound with convincing selectivity. Here in, we provide a new promising synthetic agonist of HTL/KAI2., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A total diet study (TDS) was conducted between 2010 and 2016 to assess the risk associated with chemicals in food of non-breast-fed children from 1 to 36 months living in France. Food samples were collected, prepared "as consumed", and analyzed for chemicals of public health interest. Acrylamide, furan and polycyclic aromatic hydrocarbons (PAHs) were analyzed as heat-induced compounds produced mainly during thermal processing of foods. Dietary exposure was assessed for 705 representative children using food consumptions recorded through a 3-consecutive-days record. As all calculated margins of exposure (MOE) for PAHs exceeded 10 000, dietary exposure of the infant and toddler population was deemed tolerable with regard to the carcinogenic risk. Conversely, the exposure levels to acrylamide and furan were considered as of concern, requiring management measures to reduce the exposure essentially by reducing the formation of heat-induced compounds during food production or preparation processes. Efforts should mainly focus on major contributors to the exposure, i.e. sweet and savoury biscuits and bars, and potatoes and potato products for acrylamide, baby jars of vegetables, with or without meat or fish for acrylamide and furan., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Identification of new antibiotics suitable for the treatment of tuberculosis is required. In addition to selectivity, it is necessary to find new antibiotics that are effective when the tuberculous mycobacteria are resistant to the available therapies. The furo[2,3-b]pyridine core offers potential for this application. Herein, we have described the screening of our in-house library of furopyridines against Mycobacterium tuberculosis and identified a promising selective bioactive compound against different drug-resistant strains of this mycobacteria. The library of compounds was prepared by a CH amination reaction using mild and metal-free conditions, increasing the available information about the reactivity of furo[2,3-b]pyridine core through this reaction., (Copyright © 2019. Published by Elsevier Ltd.)

The synthesis and biological evaluation as potential urotensin-II receptor antagonists of a series of 5-arylfuran-2-carboxamide derivatives 1, bearing a 4-(3-chloro-4-(piperidin-4-yloxy)benzyl)piperazin-1-yl group, are described. The results of a systematic SAR investigation of furan-2-carboxamides with C-5 aryl groups possessing a variety of aryl ring substituents led to identification of the 3,4-difluorophenyl analog 1y as a highly potent UT antagonist with an IC 50 value of 6 nM. In addition, this substance was found to display high metabolic stability, and low hERG inhibition and cytotoxicity, and to have an acceptable PK profile., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The emergence of multidrug resistance (MDR) is a significant challenge in breast carcinoma chemotherapy. Kokusaginine isolated from Dictamnus dasycarpus Turcz. has been reported to show cytotoxicity in several human cancer cell lines including breast cancer cells MCF-7. In this study, kokusaginine showed the potent inhibitory effect on MCF-7 multidrug resistant subline MCF-7/ADR and MDA-MB-231 multidrug resistant subline MDA-MB-231/ADR. Kokusaginine markedly induced apoptosis in a concentration-dependent manner in MCF-7/ADR cells. Furthermore, kokusaginine reduced P-gp mRNA and protein levels, and suppressed P-gp function especially in MCF-7/ADR cells. In addition, kokusaginine showed to inhibit tubulin assembly and the binding of colchicine to tubulin by binding directly to tubulin and affects tubulin formation in vitro. Taken together, these results support the potential therapeutic value of kokusaginine as an anti-MDR agent in chemotherapy for breast carcinoma., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A series of novel furo[2,3-b]pyridine-2-carboxamide 4a-h/pyrido[3',2':4,5]furo[3,2-d] pyrimidin-4(3H)-one derivatives 5a-p were prepared from pyridin 2(1H) one 1 via selective O-alkylation with α-bromoethylester followed by cyclization, then reaction with different aliphatic primary amines to obtain 4 and further reaction with triethyl orthoacetate/triethyl orthoformate. Also prepared novel furo[2,3-b]pyridine-2-carbohydrazide Schiff's bases 7a-h and pyrido [3',2':4,5]furo[3,2-d]pyrimidin-4(3H)-one derivatives 8a-h starting from furo[2,3-b]pyridine carboxylate derivatives 3 by reaction with hydrazine hydrate to form 6 and reaction with diverse substituted aldehydes and cyclization. Products 4a-h, 5a-p, 7a-h and 8a-h were screened against four human cancer cell lines (HeLa, COLO205, Hep G2 and MCF 7) and one normal cell line (HEK 293). Compounds 4e, 4f, 4g, 5h, 7c, 7d, 7e and 7f showed significant anticancer activity against all the cell lines at micro molar concentration and found to be non-toxic to normal cell line. Studies for HeLa, COLO205 and MCF-7 using CoMFA and CoMSIA. Models from 3D-QSAR provided a strong basis for future rational design of more active and selective HeLa, COLO205 and MCF-7 cell line inhibitors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Inhibitors of the enzyme NQO2 (NRH: quinone oxidoreductase 2) are of potential use in cancer chemotherapy and malaria. We have previously reported that non-symmetrical furan amidines are potent inhibitors of NQO2 and here novel analogues are evaluated. The furan ring has been changed to other heterocycles (imidazole, N-methylimidazole, oxazole, thiophene) and the amidine group has been replaced with imidate, reversed amidine, N-arylamide and amidoxime to probe NQO2 activity, improve solubility and decrease basicity of the lead furan amidine. All compounds were fully characterised spectroscopically and the structure of the unexpected product N-hydroxy-4-(5-methyl-4-phenylfuran-2-yl)benzamidine was established by X-ray crystallography. The analogues were evaluated for inhibition of NQO2, which showed lower activity than the lead furan amidine. The observed structure-activity relationship for the furan-amidine series with NQO2 was rationalized by preliminary molecular docking and binding mode analysis. In addition, the oxazole-amidine analogue inhibited the growth of Plasmodium falciparum with an IC 50 value of 0.3 μM., (Copyright © 2018. Published by Elsevier Ltd.)

In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160-950 nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead compounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X receptor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED 50 : 39.6 mg/kg) and MIA-induced osteoarthritic pain models (ED 50 : 106 mg/kg)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Polyozellin is a p-terphenyl compound which was isolated from Polyozellus multiplex, and exhibits an inhibitory activity against prolyl oligopeptidase (POP). Its structure was assigned as 1 having a p-terphenyl skeleton including a p-substituted dibenzofuran moiety by spectroscopic analyses and chemical means. This paper describes the total syntheses of the proposed structure 1 for polyozellin and its o-isomer 2, revising the structure of polyozellin to the latter. These syntheses involved a double Suzuki-Miyaura coupling using chlorophenylboronic acid as a common key building block, and Cu mediated Ullmann cyclization as key steps. The inhibitory activities of synthetic compounds against POP and cancer cells were also evaluated., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Recent analysis of transcriptomes has revealed that RNA molecules perform a myriad of functions beyond coding for proteins. RNA molecules can fold into complex secondary and tertiary structures, which are critical for regulating their function. Selective Hydroxyl Acylation analyzed by Primer Extension, or SHAPE is a common method for probing RNA structure in and outside of cells. Recent developments in SHAPE include the design of acyl imidazole acylating electrophiles with alkyl azides to enrich the sites of SHAPE adduct formation. Enrichment is key for next-generation sequencing experiments as it dramatically improves the signal. In a recent comparison of different structures of such reagents, we realized that furoyl acylating reagents form hyper-stable ester adducts with hydroxyls. This prompted us to design, synthesize and test a novel dual-functioning SHAPE probe (FAI-N 3 ), which has the stable furoyl scaffold and the alkyl azide for enrichment. Herein we present the results that show FAI-N 3 is a suitable probe for RNA structure analysis by SHAPE and that it can be used for enrichment of SHAPE adducts. These results strongly demonstrate that FAI-N 3 is an ideal probe for structure probing in cells and will be very useful for sequencing-based analysis of SHAPE., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE 2 production in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors having <50 nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes. Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic properties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavailability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia with an ED 50 of 14.3 mg/kg in guinea pig., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The new lignano-9,9'-lactones (α,β-dibenzyl-γ-butyrolactone lignans), which showed the higher cytotoxicity than arctigenin, were synthesized. The well-known cytotoxic arctigenin showed activity against HL-60 cells (EC 50 =12μM), however, it was inactive against HeLa cells (EC 50 >100μM). The synthesized (3,4-dichloro, 2'-butoxy)-derivative 55 and (3,4-dichloro, 4'-butyl)-derivative 66 bearing the lignano-9,9'-lactone structures showed the EC 50 values of 10μM and 9.4μM against HL-60 cells, respectively. Against HeLa cells, the EC 50 value of the derivative 66 was 27μM. By comparing the activities with the corresponding 9,9'-epoxy structure (tetrahydrofuran compounds), the importance of the lactone structure of 55 and 66 for the higher activities was shown. The substituents on the aromatic ring of the lignano-9,9'-lactones affected the cytotoxicity level, observing more than 10-fold difference., (Copyright © 2017. Published by Elsevier Ltd.)

To control the parasitic disease of Dactylogyrus intermedius, a series of new arctigenin derivatives were designed, synthesized and tested in our study. The anthelmintic activity of most of the derivatives ranged from 1 to 10mg/L. Compared to traditional drug praziquantel (EC 50 =2.69mg/L), ether derivatives 2g and 2h exhibited slightly higher anti-parasitic activity, with the EC 50 values of 2.48 and 1.52mg/L, respectively. Furthermore, the arctigenin-imidazole hybrids 4a and 4b also removed D. intermedius effectively, with the EC 50 values of 2.13 and 2.07mg/L, respectively. The structure-activity relationship analysis indicated that four carbon atoms length of linker and imidazole substitute group could significantly increase the anthelmintic activity, and reduced the toxicity. Through the scanning electron microscope observation, compounds 4a and 4b caused the D. intermedius tegumental damage such as intensive wrinkles, holes and nodular structures. Overall, the structural optimization analysis of arctigenin suggested that 4a and 4b can be used for preventing and controlling Dactylogyrus infections and considered as promising lead compounds for the development of commercial drugs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A series of new of furan derivatised [1,4] benzothiazepine analogues were synthesized starting from 1-(furan-2-yl)ethanone. 1-(Furan-2-yl)ethanone was converted into chalcones by its reaction with various aromatic aldehydes, then were reacted with 2-aminobenzenethiol in acidic conditions to obtain the title compounds in good yields. The synthesized new compounds were characterized by 1 H NMR, 13 C NMR, Mass spectral studies and elemental analyses. All the new compounds were evaluated for their in vitro VRV-PL-8a and H + /K + ATPase inhibitor properties. Preliminary studies revealed that, some molecules amongst the designed series showed promising VRV-PL-8a and H + /K + ATPase inhibitor properties. Further, rigid body docking studies were performed to understand possible docking sites of the molecules on the target proteins and the mode of binding. This finding presents a promising series of lead molecules that can serve as prototypes for the treatment of inflammatory related disorder that can mitigate the ulcer inducing side effect shown by other NSAIDs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The enzyme ATP citrate lyase (ACL) catalyzes the formation of cytosolic acetyl CoA, the starting material for de novo lipid and cholesterol biosynthesis. The dysfunction and upregulation of ACL in numerous cancers makes it an attractive target for developing anticancer therapies. ACL inhibition by shRNA knockdown limits cancer cell proliferation and reduces cancer stemness. We designed and implemented a dual docking protocol to select virtual ACL inhibitors that were scored among the top 10 percentiles by both the Autodock Vina and the Glamdock algorithms. Via this in silico screens of a focused furoic acid library, we discovered four subtypes of furans and benzofurans as novel ACL inhibitors. The hit rate of our in silico protocol was 45.8% with 11 of 24 virtual hits confirmed as active in an in vitro ACL enzymatic assay. The IC 50 of the most potent ACL inhibitor A1 is 4.1μM. Our results demonstrated remarkable hit rate by the dual docking approach and provided novel chemical scaffolds for the development of ACL inhibitors for the treatment of cancer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Studies show that nanoscale zero-valent iron (nZVI) particles enhance the formation of chlorinated compounds such as polychlorinated dioxins and furans (PCDD/Fs) during thermal processes. However, it is unclear whether nZVI acts as a catalyst for the formation of these compounds or contains impurities, such as PCDD/Fs, within its structure. We analyzed the presence of PCDD/Fs in nZVI particles synthesized through various production methods to elucidate this uncertainty. None of the 2,3,7,8-substituted congeners were found in the commercially-produced nZVI, but they were present in the laboratory-synthesized nZVI produced through the borohydride method, particularly in particles synthesized from iron (III) chloride rather than from iron sulfate. Total PCDD/F WHO-TEQ concentrations of up to 35 pg/g were observed in nZVI particles, with hepta- and octa-chlorinated congeners being the most abundant. The reagents used in the borohydride method were also analyzed, and our findings suggest that FeCl 3 effectively contains PCDD/Fs at concentrations that could explain the concentrations observed in the nZVI product. Both FeCl 3 and nZVI showed a similar PCDD/F patterns with slight differences. These results suggest that PCDD/Fs might transfer from FeCl 3 to nZVI during the production method, and thus, care should be taken when employing certain nZVI for environmental remediation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

(-)-Cubebin (CUB), isolated from seeds of Piper cubeba, was used as starting material to obtain the derivatives (-)-hinokinin (HK) and (-)-O-benzyl cubebin (OBZ). Using paw edema as the experimental model and different chemical mediators (prostaglandin and dextran), it was observed that both derivatives were active in comparison with both negative (5% Tween® 80 in saline) and positive (indomethacin) controls. The highest reduction in the prostaglandin-induced edema was achieved by OBZ (66.0%), while HK caused a 59.2% reduction. Nonetheless, the dextran-induced paw edema was not significantly reduced by either of the derivatives (HK or OBZ), which inhibited edema formation by 18.3% and 3.5%, respectively, in contrast with the positive control, cyproheptadine, which reduced the edema by 56.0%. The docking analysis showed that OBZ presented the most stable ligand-receptor (COX-2 - cyclooxygenase-2) interaction in comparison with CUB and HK., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Ten novel fenfuram-diarylamine hybrids were designed and synthesized. And their antifungal activities against four phytopathogenic fungi have been evaluated in vitro and most of the compounds demonstrated a significant antifungal activities against Rhizoctonia solani and Sclerotinia sclerotiorum. Compound 5e exhibited the most potent antifungal activity against R. solani with an EC 50 value of 0.037mg/L, far superior to the commercially available fungicide boscalid (EC 50 =1.71mg/L) and lead fungicide fenfuram (EC 50 =6.18mg/L). Furthermore, scanning electron microscopy images showed that the mycelia on treated media grew abnormally with tenuous, wizened and overlapping colonies compared to the negative control. Molecular docking studies revealed that compound 5e featured a higher affinity for succinate dehydrogenase (SDH) than fenfuram. Furthermore, it was shown that the 3-chlorophenyl group in compound 5e formed a CH-π interaction with B/Trp-206 and a Cl-π interaction with D/Tyr-128, rendering compound 5e more active than fenfuram against SDH., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine 2e bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Estrogen biosynthesis is pivotal to many physiological processes of human. Aberrant estrogen level is closely related to a variety of diseases, including breast cancer and osteoporosis. Previously we found that 2-phenylbenzo[b]furan glycosides could promote estrogen biosynthesis. To find high active 2-phenylbenzo[b]furans, fifty-four 2-phenylbenzo[b]furans were prepared via four strategies according to corresponding substrate scopes. Biological evaluation in HEK293A cells showed that some compounds exhibited promotive activity on estrogen biosynthesis. 2-(4-Chlorophenyl)-7-methoxybenzo[b]furan possessed the highest activity with EC 50 value of 14.68μM. Furthermore, these compounds did not affect aromatase expression in HEK292A cells, indicating that these 2-phenylbenzo[b]furans might enhance estrogen biosynthesis via directly allosteric regulation of aromatase or indirectly via posttranslational modification., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A series of furano[3,2-d]pyrimidine Syk inhibitors were synthesized and optimized for their enzyme potency and selectivity versus other kinases. In addition, ADME properties were assessed and compounds were prepared with optimized profiles for in vivo experiments. Compound 23 was identified as having acceptable pharmacokinetic properties and demonstrated efficacy in a rat collagen induced arthritis model., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Activation of peroxisome proliferator-activated receptors (PPARs) plays a crucial role in cellular energy metabolism that directly impacts mitochondrial biogenesis. In this study, we demonstrate that syringaresinol, a pharmacological lignan extracted from Panax ginseng berry, moderately binds to and activates PPARβ with KD and EC50 values of 27.62±15.76μM and 18.11±4.77μM, respectively. Subsequently, the expression of peroxisome proliferator-activated receptor γ coactivator-1α together with PPARβ transcriptional targets, mitochondrial carnitine palmitoyltransferase 1 and uncoupling protein 2, was also enhanced in terms of both mRNA and protein levels. The activation of these proteins induced mitochondrial biogenesis by enrichment of mitochondrial replication and density within C2C12 myotubes. Importantly, knockdown of PPARβ reduced the syringaresinol-induced protein expression followed by the significant reduction of mitochondrial biogenesis. Taken together, our results indicate that syringaresinol induces mitochondrial biogenesis by activating PPARβ pathway., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A series of arctigenin-4-yl carbamate derivatives were synthesized and evaluated for potency in reducing β-amyloid (Aβ) content in HEK293-APPswe cells. Most of the arctigenin-4-yl aralkyl or aryl carbamate derivatives showed improved potency in reducing Aβ content. Among the synthesized compounds, arctigenin-4-yl (3-chlorophenyl)carbamate (20) exhibited the strongest potency with 78.7% Aβ content reduction at 20μM. Furthermore, the effect of arctigenin-4-yl (4-chlorophenyl)carbamate (19) and arctigenin-4-yl (3-chlorophenyl)carbamate (20) on lowing Aβ content was better than arctigenin under the concentrations of 1, 10 and 20μM., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Arylimidamide (AIA) compounds containing two pyridylimidamide terminal groups (bis-AIAs) possess outstanding in vitro antileishmanial activity, and the frontrunner bis-AIA DB766 (2,5-bis[2-(2-isopropoxy)-4-(2-pyridylimino)aminophenyl]furan) is active in visceral leishmaniasis models when given orally. Eighteen compounds containing a single pyridylimidamide terminal group (mono-AIAs) were synthesized and evaluated for their antileishmanial potential. Six of these compounds exhibited sub-micromolar potency against both intracellular Leishmania donovani and Leishmania amazonensis amastigotes, and three of these compounds also displayed selectivity indexes of 25 or greater for the parasites compared to a J774 macrophage cell line. When given orally at a dose of 100mg/kg/day for five days, compound 1b (N-(3-isopropoxy-4-(5-phenylfuran-2-yl)phenyl)picolinimidamide methanesulfonate) reduced liver parasitemia by 46% in L. donovani-infected mice. Mono-AIAs are thus a new class of candidate molecules for antileishmanial drug development., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There is very little information on the levels and particle size distributions of lower chlorinated dibenzo-p-dioxins and dibenzofurans (mono- to tri-CDD/Fs, ΣCl1-3DD/Fs) in the atmosphere, while a number of studies have examined tetra- to octa-chlorinated homologues (ΣCl4-8DD/Fs). In this study, we measured the concentration and particle size distribution of ΣCl1-3DD/Fs in ambient air in suburban Beijing and compared them with that of ΣCl4-8DD/Fs for the first time. The mean concentration of ΣCl1-3DD/Fs was 54.63 pg m(-3), which is about 5.4 times that of ΣCl4-8DD/Fs. The ΣCl1-3DD/Fs accounted for 85% of ΣCl1-8DD/Fs, and MoCDFs made up the largest proportion (43%) of PCDD/F homologues. The ΣCl1-3DD/Fs mainly occurred in the gas phase, while the ΣCl4-8DD/Fs mainly occurred in the particulate phase. The majority of ΣCl1-3DD/Fs (70%) occurred in dae > 1.0 μm particles, which is the reverse of the trend observed for ΣCl4-8DD/Fs, of which 78% occurred in dae < 1.0 μm particles. The observed high concentrations of ΣCl1-3DD/Fs and different distribution patterns demonstrate that it is necessary to consider the lower chlorinated homologues to improve our understanding of the environmental behavior and health risk assessments of PCDD/Fs in the atmosphere., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), focused on addressing the recurrent issue of plasma instability of the phthalimide moiety. Here, we evaluated a number of phthalimide bioisosteres, and ultimately identified isoindolinones as the ideal replacement that effectively address plasma instability, while maintaining acceptable mGlu1 PAM potency, DMPK profile, CNS penetration and mGluR selectivity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep and caveat-laden SAR plagues the series, but ultimately potent mGlu1 PAMs (EC50s ∼5 nM) have resulted with good DMPK properties (low intrinsic clearance, clean CYP profile, modest Fu) and CNS penetration (Kps 0.25-0.97), along with up to >450-fold selectivity versus mGlu4 and mGlu5., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The treatment of epidermal growth factor receptor (EGFR)-driven non-small cell lung cancers with the T790M resistance mutation remains a significant unmet medical need. We report the identification of 4-aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of EGFR, with excellent activity against the T790M resistance double mutants and initial single activating mutants. Using an optimization strategy focused on structure-based design and improving PK properties through metabolite identification, we obtained advanced leads with high oral exposure., (Copyright © 2015 Elsevier Ltd. All rights reserved.)