Novel Nitro-Heteroaromatic Antimicrobial Agents for the Control and Eradication of Biofilm-Forming Bacteria

The synthesis and biological activity of several novel nitrothiazole, nitrobenzothiazole, and nitrofuran containing antimicrobial agents for the eradication of biofilm-forming Gram-negative and Gram-positive pathogens is described. Nitazoxanide (NTZ), nitrofurantoin, and furazolidone are commercial antimicrobials which were used as models to show how structural modification improved activity toward planktonic bacteria via minimum inhibitory concentration (MIC) assays and biofilms via minimum biofilm eradication concentration (MBEC) assays. Structure–activity relationship (SAR) studies illustrate the ways in which improvements have been made to the aforementioned antimicrobial agents. It is of particular interest in this regard that the introduction of a chloro substituent at the 5-position of NTZ (analog 1b) resulted in marked activity enhancement, as did the replacement of the 2-acetoxy substituent in the latter compound with a basic amine group (analog 7b). It is also of importance that analog 4a, which is a simple methacrylamide, displayed noteworthy activity against S. epidermidis biofilms. These lead compounds identified to have high activity towards biofilms provide promise as starting points in future pro-drug studies.

Tamoxifen Derivatives Alter Retromer-Dependent Endosomal Tubulation and Sorting to Block Retrograde Trafficking of Shiga Toxins

Shiga toxin 1 and 2 (STx1 and STx2) undergo retrograde trafficking to reach the cytosol of cells where they target ribosomes. As retrograde trafficking is essential for disease, inhibiting STx1/STx2 trafficking is therapeutically promising. Recently, we discovered that the chemotherapeutic drug tamoxifen potently inhibits the trafficking of STx1/STx2 at the critical early endosome-to-Golgi step. We further reported that the activity of tamoxifen against STx1/STx2 is independent of its selective estrogen receptor modulator (SERM) property and instead depends on its weakly basic chemical nature, which allows tamoxifen to increase endolysosomal pH and alter the recruitment of retromer to endosomes. The goal of the current work was to obtain a better understanding of the mechanism of action of tamoxifen against the more disease-relevant toxin STx2, and to differentiate between the roles of changes in endolysosomal pH and retromer function. Structure activity relationship (SAR) analyses revealed that a weakly basic amine group was essential for anti-STx2 activity. However, ability to deacidify endolysosomes was not obligatorily necessary because a tamoxifen derivative that did not increase endolysosomal pH exerted reduced, but measurable, activity. Additional assays demonstrated that protective derivatives inhibited the formation of retromer-dependent, Golgi-directed, endosomal tubules, which mediate endosome-to-Golgi transport, and the sorting of STx2 into these tubules. These results identify retromer-mediated endosomal tubulation and sorting to be fundamental processes impacted by tamoxifen; provide an explanation for the inhibitory effect of tamoxifen on STx2; and have important implications for the therapeutic use of tamoxifen, including its development for treating Shiga toxicosis.

Lewis Basic Amine Catalyzed Aza-Michael Reaction of Indole- and Pyrrole-3-carbaldehydes

3-Formyl substituted indoles or pyrroles can form HOMO-raised dearomative aza-dienamine-type intermediates with secondary amines, which can undergo direct aza-Michael addition to β-trifluoromethyl enones to afford N-alkylated products efficiently, albeit with low to fair enantioselectivity. In addition, similar asymmetric aza-Michael additions of these heteroarenes and crotonaldehyde are realized under dual catalysis of chiral amines, and the adducts are obtained with moderate to good enantioselectivity.

Construction of a bifunctional Zn(ii)–organic framework containing a basic amine functionality for selective capture and room temperature fixation of CO2

The construction of a novel 3D, porous, bifunctional Zn(ii)–organic framework featuring two-types of 1D channels for efficient fixation of CO2 to cyclic carbonates under solvent-free mild conditions of RT is reported.

Controlled release of hydrogen isotope compounds and tunneling effect in the heterogeneously-catalyzed formic acid dehydrogenation

The hydrogen isotope deuterium is widely used in the synthesis of isotopically-labeled compounds and in the fabrication of semiconductors and optical fibers. However, the facile production of deuterium gas (D2) and hydrogen deuteride (HD) in a controlled manner is a challenging task, and rational heterogeneously-catalyzed protocols are still lacking. Herein, we demonstrate the selective production of hydrogen isotope compounds from a combination of formic acid and D2O, through cooperative action by a PdAg nanocatalyst on a silica substrate whose surface is modified with amine groups. In this process, D2 is predominantly evolved by the assist of weakly basic amine moieties, while nanocatalyst particles in the vicinity of strongly basic amine groups promote the preferential formation of HD. Kinetic data and calculations based on semi-classically corrected transition state theory coupled with density functional theory suggest that quantum tunneling dominates the hydrogen/deuterium exchange reaction over the metallic PdAg surfaces.

Mesoporous polymeric catalysts with both sulfonic acid and basic amine groups for the one-pot deacetalization−Knoevenagel reaction

Acid–base bifunctional P(DVB–NH2–n-SO3H) catalysts with mesoporous structure have been prepared and characterized for a one-pot cascade reaction with good recycling properties.

Carbonic anhydrase mimics for enhanced CO2 absorption in an amine-based capture solvent

Carbonic anhydrase converts CO2 to HCO3− in physiological conditions, but in the highly basic amine-containing solutions used industrially for carbon capture, the enzyme does not function. Instead small molecule mimics can catalyze CO2 hydration.

Structural Studies of [(py)2CdFe(CO)4]3 and {(THF)5[CdFe(CO)4]3}

The structures of [(py)2CdFe(CO)4]3 and {(THF)5[CdFe(CO)4]3} have been determined (py = pyridine; THF = tetrahydrofuran). Each is composed of a six-membered ring having alternating cadmium and iron centers. The presence of the more strongly basic amine ligands in the former led to a greater contribution of an ionic resonance form, which resulted in overall longer Cd–Fe bonds and a greater contribution of a bicapped tetrahedral coordination geometry about iron. Thus, the Cd–Fe distances range from 2.5679(4) to 2.6501(1) Å for the THF complex versus 2.6445(8) to 2.6833(7) Å for the py complex. Similarly, the Fe–Cd–Fe and Cd–Fe–Cd angles for the THF complex fell in respective ranges of 139.03(2)–157.27(2)° and 84.41(1)–99.79(1)°, as compared to 135.31(3)–139.51(4)° and 102.52(3)–104.62(4)° for the py complex. The space group for the former compound is Pbcn, with a = 12.2678(2), b = 22.4601(5), and c = 17.0039(4) Å, while for the THF complex, the space group is P21/c, with a = 10.7297(2), b = 20.4961(2), c = 18.7464(3) Å, and β = 94.2715(6)°.