The structural similarity between an MmpL3 inhibitor BM212, and a cannabinoid receptor modulator rimonabant, prompted us to investigate the anti-tubercular activity of rimonabant and its analogues. ...Further optimization, particularly through incorporation of silicon into the scaffold, resulted in new compounds with significant improvement in anti-tubercular activity against Mycobacterium tuberculosis (H37Rv). The sila analogue 18a was found to be the most potent antimycobacterial compound (MIC, 31 ng/mL) from this series with an excellent selectivity index.
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•The antitubercular activity of diaryl pyrazoles (rimonabant analogues) was investigated as part of drug scaffold repurposing.•From SAR analysis, silicon incorporation increased the anti-TB potential of the series.•The sila analogue 18a was the most potent compound (MIC 31 ng/mL, H37Rv).•Compound 18e (MIC 390 ng/mL) was the best in terms of in vitro pharmacokinetics.
Loperamide (1a), an opioid receptor agonist, is in clinical use as an antidiarrheal agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1a (R3 COH→R3 SiOH) ...leads to sila-loperamide (1b). Sila-loperamide was synthesized in a multistep procedure, starting from triethoxyvinylsilane and taking advantage of the 4-methoxyphenyl (MOP) unit as a protecting group for silicon. The in vitro and in vivo pharmacokinetic (PK) and pharmacodynamic (PD) properties of the C/Si analogues 1a and 1b were determined and compared. Despite significant differences in the in vitro PK properties of loperamide and sila-loperamide regarding clearance, permeability, and efflux, both compounds exhibited nearly identical in vivo PK profiles. The increase in metabolic stability of the silicon compound 1b observed in vitro seems to be counterbalanced by an increase in efflux and diminished permeability compared to the parent carbon compound 1a. Overall, sila-loperamide exhibits high unbound clearance (CLu ), leading to a significant decrease in unbound concentration (Cu ) and unbound area under the curve (AUCu ) after oral exposure, compared to loperamide. In vitro and in vivo metabolic studies showed an altered profile of biotransformation for the silicon compound 1b, leading to the formation of a more polar and quickly cleared metabolite and preventing the formation of the silicon analogue of the neurotoxic metabolite observed for the parent carbon compound 1a. These differences can be correlated with the different chemical properties of the C/Si analogues 1a and 1b. This study provides some of the most detailed insights into the effects of a carbon/silicon switch and how this carbon/silicon exchange affects overall drug properties.
A series of silicon‐containing derivatives of the polycyclic musk odorant galaxolide (4 a) was synthesized, that is, disila‐galaxolide ((4RS,7SR)‐4 b/(4RS,7RS)‐4 b), its methylene derivative rac‐9, ...and its nor analogue rac‐10. The tricyclic title compounds with their 7,8‐dihydro‐6,8‐disila‐6 H‐cyclopentagisochromane skeleton were prepared in multistep syntheses by using a cobalt‐catalyzed 2+2+2 cycloaddition of the mono‐ yne H2CCHCH2OCH2CCB(pin) (B(pin)=4,4,5,5‐tetramethyl‐1,3,2‐di‐ oxaborolan‐2‐yl) with the diynes H2CCSi(CH3)2CCH2 or H2C‐ Si(CH3)2CCH2 as the key step. Employing Cr(CO)3(MeCN)3 as an auxiliary, the disila‐galaxolide diastereomers (4RS,7SR)‐4 b and (4RS,7RS)‐4 b could be chromatographically separated through their tricarbonylchromium(0) complexes, followed by oxidative decomplexation. The identity of the title compounds and their precursors was established by elemental analyses and multinuclear NMR spectroscopic studies and in some cases additionally by crystal structure analyses. Compounds (4RS,7SR)‐4 b, (4RS,7RS)‐4 b, rac‐9, and rac‐10 were characterized for their olfactory properties, including GC‐olfactory studies of the racemic compounds on a chiral stationary phase. As for the parent galaxolide stereoisomers 4 a, only one enantiomer of the silicon compounds (4RS,7SR)‐4 b, (4RS,7RS)‐4 b, rac‐9, and rac‐10, smelt upon enantioselective GC‐olfactometry, which according to the elution sequence is assumed to be also (4S)‐configured as in the case of the galaxolide stereoisomers. The disila‐analogues (4S,7R)‐4 b and (4S,7S)‐4 b were, however, about one order of magnitude less intense in terms of their odor threshold than their parent carbon compounds (4S,7R)‐4 a and (4S,7S)‐4 a. The introduction of a 7‐methylene group in disila‐galaxolide (4 b→rac‐9) improved the odor threshold by a factor of two. With the novel silicon‐containing galaxolide derivatives, the presumed hydrophobic bulk binding pocket of the corresponding musk receptor(s) could be characterized in more detail, which could be useful for the design of novel musk odorants with an improved environmental profile.
Fragrant sila‐musks: Silicon‐containing derivatives of the polycyclic musk odorant galaxolide (see scheme) were synthesized and characterized for their olfactory properties. The disila‐galaxolide diastereomers (4RS,7SR) and (4RS,7RS) were obtained by chromatographic separation of their corresponding chromium complexes, followed by oxidative decomplexation. The relatively rigid structures of these polycycles, in combination with the carbon/silicon switch strategy, makes the single stereoisomers of these C/Si analogues ideal candidates for structure–odor correlations in the musk domain.
Therapeutic options for brain infections caused by pathogens with a reduced sensitivity to drugs are limited. Recent reports on the potential use of linezolid in treating brain infections prompted us ...to design novel compounds around this scaffold. Herein, we describe the design and synthesis of various oxazolidinone antibiotics with the incorporation of silicon. Our findings in preclinical species suggest that silicon incorporation is highly useful in improving brain exposures. Interestingly, three compounds from this series demonstrated up to a 30-fold higher brain/plasma ratio when compared to linezolid thereby indicating their therapeutic potential in brain associated disorders.
Fluoroquinolones (FQs) are the most commonly used antimicrobial drugs and regardless of their advantages in the healthcare sector, the pollution of these antimicrobial drugs in the environment has ...big concerns about human and environmental health. The presence of these antibiotic drugs even at the lowest concentrations in the environment has resulted in the emergence and spread of antibiotic resistance. Hence, it is necessary to remediate these pollutants from the environment. Previously alkaline laccase (SilA) from Streptomyces ipomoeae has been demonstrated to show degrading potentials against two of the FQs, Ciprofloxacin (CIP) and Norfloxacin (NOR); however, the molecular mechanism was not elucidated in detail. In this study, we have analyzed the possible molecular catalytic mechanism of FQ degrading SilA-laccase for the degradation of the FQs, CIP, NOR and Ofloxacin (OFL) using three-dimensional protein structure modeling, molecular docking and molecular dynamic (MD) studies. The comparative protein sequence analysis revealed the presence of tetrapeptide conserved catalytic motif, His
102
-X-His
104
-Gly
105
. After evaluating the active site of the enzyme in depth using CDD, COACH and S-site tools, we have identified the catalytic triad composed of three conserved amino acid residues, His
102
, Val
103
and Tyr
108
with which ligands interacted during the catalysis process. By analyzing the MD trajectories, it is revealed that the highest degradation potential of SilA is for CIP followed by NOR and OFL. Ultimately, this study provides the possible comparative catalytic mechanism for the degradation of CIP, NOR and OFL by the SilA enzyme.
Communicated by Ramaswamy H. Sarma
Ovaj članak se bavi eksperimentalnim istraživanjem faktora trenja kod kliznih ležaja bez ponovnog podmazivanja. Istraživanje uključuje određivanje iznosa faktora trenja i usporedbu ovisno o ...opterećenju i broju okretaja mjerenih na kliznom paru bez ponovnog podmazivanja koji se sastoji od kliznih ležaja i vratila. Rezultat ovog pokusa je pokazatelj izmjerenih vrijednosti kliznog para u radnim uvjetima. Sve slike mjerenja i uvjeta opterećenja za svaki ležaj predstavljene su pomoću dijagrama.
•Role of laccase from Streptomyces ipomoeae on wheat straw lignin was investigated.•Analytical pyrolysis discerned ligninolytic activity from wild and mutant strains.•Laccase is found a key enzyme in ...S. ipomoeae (SilA) for lignin solubilisation in solid state fermentation.
Streptomycetes are actually considered one of the main groups of ligninolytic microoganisms producing a lignin-carbohydate complex named APPL (acid precipitable polymeric lignin) when growing on lignocellulosic materials. Although in these conditions the production of hemicellulolytic and oxidative extracellular enzymes were reported the specific role of laccases in lignin degradation is poorly understood. SilA, a thermostable salt-resistant and pH-versatile laccase produced by Streptomyces ipomoeae CECT 3341 was recently discovered and their particular characteristics make attractive to deep in its knowledge for biotechnological and environmental purposes. Pyrolysis/GC–MS was used to analyse the behaviour of the laccase-producing strain (SilA strain) and a laccase-negative mutant (SilA− strain) when growing on wheat straw in solid-state fermentation (SSF). Quantitative yields of APPL and the relative abundance of lignin-derived compounds were much higher for SilA strain than for SilA− showing a higher solubilizing activity of S. ipomoeae wild-type on lignocellulosic residues. Nonetheless the patterns of lignin derived compounds found in the APPL pyrograms were similar for both strains and distinct from the control showing a shortening of lignin propyl side-chains. Our results demonstrate that SilA laccase is a key enzyme in the lignin solubilization by S. ipomoeae and also points to the involvement of other oxidative enzymatic activities distinct to laccase in this process.
Generating a conversation between nineteenth-century poet Walt Whitman and contemporary composer John Luther Adams, this article offers a sonic-elemental account of American geography and community. ...It argues that Adams and Whitman treat America as a constellation of elemental relations between bodies and materialities, and that sound helps to discern and describe those relations. In doing so, the article outlines initial parameters of an elemental politics that relates political actions to their surrounding soundscapes, thus emphasizing communality while rebuffing nationalism and spanning across multiple times and places while remaining rooted in specific present situations. To make this argument, the article draws upon scholarship in elemental media studies, new materialism, and soundscape theory. It treats both poetry and music as types of elemental sound art, appreciating that sonic vibrations affect bodies below the level of consciousness even when finding expression in perceivable language or music.
The construction industry of all countries in the world is facing the issue of sustainable development. How to make effective and accurate decision-making on the three pillars (Environment; Economy; ...Social influence) is the key factor. This manuscript is based on an accurate evaluation framework and theoretical modelling. Through a comprehensive evaluation of six cable-stayed highway bridges in the entire life cycle of five provinces in China (from cradle to grave), the research shows that life cycle impact assessment (LCIA), life cycle cost assessment (LCCA), and social impact life assessment (SILA) are under the influence of multi-factor change decisions. The manuscript focused on the analysis of the natural environment over 100 years, material replacement, waste recycling, traffic density, casualty costs, community benefits and other key factors. Based on the analysis data, the close connection between high pollution levels and high cost in the maintenance stage was deeply promoted, an innovative comprehensive evaluation discrete mathematical decision-making model was established, and a reasonable interval between gross domestic product (GDP) and sustainable development was determined.
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Allylsilanes underwent sila-ene reaction with sulfur dioxide in the presence of Lewis acid catalysts. The obtained Vogel’s silyl sulfinates were found to act as sulfinyl transfer ...agents in reactions with aryl, heteroaryl, alkyl, and allyl Grignard reagents proceeding with the expulsion of the trialkylsilyloxy group to give allyl sulfoxides in up to 83% yield. The nucleophilic attack of Grignard reagents was accelerated in toluene and in the presence of LiCl or ZnCl2 as Lewis acidic additives. The developed method allows the transformation of allylsilanes into allyl sulfoxides.
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