- NADP-dependent glutamate dehydrogenases in a dimorphic zygomycete Benjaminiella poitrasii: Purification, characterization and their evaluation as an antifungal drug target
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Background: It has been reported that the genes coding for NADP-dependent glutamate dehydrogenases (NADP-GDHs) showed a cause-effect relationship with Yeast-Hypha (Y[sbnd]H) reversible transition in a zygomycete Benjaminiella poitrasii. As Y[sbnd]H transition is significant in human pathogenic fungi for their survival and proliferation in the host, the NADP-GDHs can be explored as antifungal drug targets. Methods: The yeast-form specific BpNADPGDH I and hyphal-form specific BpNADPGDH II of B. poitrasii were purified by heterologous expression in E. coli BL-21 cells and characterized. The structural analogs of L-glutamate, dimethyl esters of isophthalic acid (DMIP) and its derivatives were designed, synthesized and screened for inhibition of NADP-GDH activity as well as Y[sbnd]H transition in B. poitrasii, and also in human pathogenic Candida albicans strains. Results: The BpNADPGDH I and BpNADPGDH II were found to be homo-hexameric proteins with native molecular mass of 282 kDa and 298 kDa, respectively and subunit molecular weights of 47 kDa and 49 kDa, respectively. Besides the distinct kinetic properties, BpNADPGDH I and BpNADPGDH II were found to be regulated by cAMP-dependent- and Calmodulin (CaM) dependent- protein kinases, respectively. The DMIP compounds showed a more pronounced effect on H-form specific BpNADPGDH II and inhibited Y[sbnd]H transition as well as growth in B. poitrasii and C. albicans strains. Conclusion: The present study will be useful to design and develop antifungal drugs against dimorphic human pathogens using glutamate dehydrogenase as a target. Significance: Glutamate dehydrogenases can be explored as a target against human pathogenic fungi.
- Deshpande, Mukund V.,Kulkarni, Anand M.,Pathan, Ejaj K.,Prasanna, Nallaballe V. L.,Ramana, Chepuri V.
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- Knotaxanes - Rotaxanes with knots as stoppers
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Get knotted: Molecular knots have been used as stoppers in the assembly of "knotaxanes", a new family of topologically chiral rotaxanes (see picture). Two knotaxanes were separated into enantiomers using HPLC with a chiral stationary phase and characteriz
- Lukin, Oleg,Kubota, Takateru,Okamoto, Yoshio,Schelhase, Frauke,Yoneva, Albena,Mueller, Walter M.,Mueller, Ute,Voegtle, Fritz
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- Enhanced Carboxylate Binding Using Urea Amide-Based Receptors with Internal Lewis Acid Coordination: A Cooperative Polarization Effect
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A structural design strategy is described that greatly improves the acetate binding ability of neutral urea and amide-based receptors. The enhanced binding is due to a cooperative polarization effect which is induced by intramolecular coordination of the
- Hughes, Martin Patrick,Smith, Bradley D.
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- Synthesis of polyaramids in γ-valerolactone-based organic electrolyte solutions
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The current synthetic procedures for polyaramids mainly involve the use of amide solvents such asN-methylpyrrolidone andN,N-dimethylacetamide. However, these solvents are suspected to be teratogenic and are considered ‘Substances of Very High Concern’ by the European Commission. Here we propose a benign alternative solvent system: an Organic Electrolyte Solution (OES) consisting of γ-valerolactone (GVL) and a small amount of the ionic liquid 1-methyl-3-octylimidazolium chloride, [C8MIm][Cl]. Three commercially relevant polyaramids were synthesized: poly-p-phenylene terephthalamide (PPTA), poly-m-phenylene isophthalamide (PMIA) and copoly(p-phenylene/3,4′-diphenylether terephthalamide) (ODA/PPTA). PMIA was successfully synthesized in the OES containing [C8MIm][Cl] in a molar fraction ofxIL= 0.043, achieving an inherent viscosity ofηinh= 1.94 ± 0.064 dL g?1, which is on par with the current industrial standard and the benchmark lab scale synthesis. The reaction mixture could also be directly used for the wet spinning of polyaramid fibers, and all components of the solvent could be recycled in good yields by a series of evaporation and distillation steps. ODA/PPTA could be synthesized, but only rather low inherent viscosities were achieved. The reaction mixture was too viscoelastic to be spun by our small-scale spinning setup. PPTA always instantly precipitated and could not be synthesized from a [C8MIm][Cl]/GVL OES. α-Picoline, the organic base which was added to capture the released HCl during the reaction, was found to play a pivotal role in the polymerization reaction. By undergoing an acid-base reaction with HCl, it forms a protic ionic liquidin situwhich increases the solubility of the polymer.
- Winters, Jonas,Bolia, Raheed,Dehaen, Wim,Binnemans, Koen
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supporting information
p. 1228 - 1239
(2021/02/26)
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- General method for quickly synthesizing bridge-linked bisamide, triamide and tetraamide derivatives through ultrasonic radiation method and application
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The invention belongs to the technical field of organic synthesis, specifically discloses bridge-linked bisamide, triamide and tetraamide derivatives and a general method for ultrasonic radiation quick synthesis thereof, and also relates to the applicatio
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Paragraph 0057-0059
(2017/07/14)
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- Identification and SAR Evaluation of Hemozoin-Inhibiting Benzamides Active against Plasmodium falciparum
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Quinoline antimalarials target hemozoin formation causing a cytotoxic accumulation of ferriprotoporphyrin IX (Fe(III)PPIX). Well-developed SAR models exist for β-hematin inhibition, parasite activity, and cellular mechanisms for this compound class, but no comparably detailed investigations exist for other hemozoin inhibiting chemotypes. Here, benzamide analogues based on previous HTS hits have been purchased or synthesized. Only derivatives containing an electron deficient aromatic ring and capable of adopting flat conformations, optimal for π-π interactions with Fe(III)PPIX, inhibited β-hematin formation. The two most potent analogues showed nanomolar parasite activity, with little CQ cross-resistance, low cytotoxicity, and high in vitro microsomal stability. Selected analogues inhibited hemozoin formation in Plasmodium falciparum causing high levels of free heme. In contrast to quinolines, introduction of amine side chains did not lead to benzamide accumulation in the parasite. These data reveal complex relationships between heme binding, free heme levels, cellular accumulation, and in vitro activity of potential novel antimalarials.
- Wicht, Kathryn J.,Combrinck, Jill M.,Smith, Peter J.,Hunter, Roger,Egan, Timothy J.
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p. 6512 - 6530
(2016/07/23)
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- Aromatic isophthalamides aggregate in lipid bilayers: Evidence for a cooperative transport mechanism
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The synthesis and anion transport properties of a series of transmembrane anion transporters based on an isophthalamide scaffold with phenyl, naphthyl or anthracenyl central rings are reported. Anion transport studies using POPC vesicles, showed that the
- Berry, Stuart N.,Busschaert, Nathalie,Frankling, Charlotte L.,Salter, Dale,Gale, Philip A.
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supporting information
p. 3136 - 3143
(2015/04/27)
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- Anion complexation and transport by isophthalamide and dipicolinamide derivatives: DNA plasmid transformation in E. coli
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Tris-arenes based on either isophthalic acid or 2,6-dipicolinic acid have been known for more than a decade to bind anions. Recent studies have also demonstrated their ability to transport various ions through membranes. In this report, we demonstrate two
- Atkins, Jason L.,Patel, Mohit B.,Daschbach, Megan M.,Meisel, Joseph W.,Gokel, George W.
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body text
p. 13546 - 13549
(2012/10/08)
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- Dianilides of dipicolinic acid function as synthetic chloride channels
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We report that N2,N6-bis(4-nitrophenyl)pyridine-2,6- dicarboxamide, which is related to known isophthalic acid dianilides, transports Cl- ions through phospholipid bilayer membranes and shows clear evidence of channel acti
- Yamnitz, Carl R.,Negin, Saeedeh,Carasel, I. Alexandru,Winter, Rudolph K.,Gokel, George W.
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supporting information; experimental part
p. 2838 - 2840
(2010/09/04)
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- Structures and excited states of extended and folded mono-, di-, and tri-N-arylbenzamides
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The relationship between molecular structure and electronic properties of 18 N-arylbenzamides has been investigated. The secondary amides adopt extended trans-amide conformations, whereas the tertiary amides adopt folded cis-amide conformations in which the N-aryl group is approximately perpendicular to the benzoyl group. The N-aryl groups of the tertiary di- and triamides occupy the same face of the benzoyl group and display edge-to-face aryl-aryl interactions. The long-wavelength absorption maxima of the secondary amides are red-shifted as the number of N-aryl groups increases, whereas the tertiary amides display are blue-shifted. ZINDO calculations aid in the assignment of the absorption and luminescence spectra. In all cases the lowest energy singlet state is assigned to a forbidden n,B* (carbonyl lone-pair to benzoyl) transition. The structureless fluorescence of the secondary and tertiary amides is assigned to planar and twisted n.B* singlets, respectively. The allowed absorption bands are assigned to A,B* (arene-to-benzoyl) or A,A* (arene-to-arene) transitions which are localized on a single arene, and the structured phosphorescence is assigned to A,A* triplet states.
- Lewis, Frederick D.,Long, Timothy M.,Stern, Charlotte L.,Liu, Weizhong
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p. 3254 - 3262
(2007/10/03)
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