Benzo[]oxazoles from Anilides by -Deprotonation--SAr Cyclization.

A synthesis of benzo[]oxazoles by an -deprotonation--SAr cyclization sequence from anilide precursors is reported. Anilides derived from 2-fluorobenzaldehydes, activated toward SAr ring closure by C5 electron-withdrawing groups, were prepared and subjected to deprotonation-cyclization using 2 equiv. of KCO in anhydrous DMF.

A [3+3] Aldol-SAr-Dehydration Approach to 2-Naphthol and 7-Hydroxyquinoline Derivatives.

A one-pot [3+3] aldol-SAr-dehydration annulation sequence was utilized to fuse hindered phenols onto aromatic substrates. The transformation joins doubly activated 1,3-disubstituted acetone derivatives (dinucleophiles) with C5-activated 2-fluorobenzaldehyde SAr acceptors (dielectrophiles) in the presence of KCO in DMF at 65-70 °C to form polysubstituted 2-naphthols and 7-hydroxyquinolines. The reaction is regioselective in adding the most stable anionic center to the aldehyde followed by SAr closure of the less stabilized anion to the electron-deficient aromatic ring.

Recent Advances in Pyrimidine-Based Drugs.

Pyrimidines have become an increasingly important core structure in many drug molecules over the past 60 years. This article surveys recent areas in which pyrimidines have had a major impact in drug discovery therapeutics, including anti-infectives, anticancer, immunology, immuno-oncology, neurological disorders, chronic pain, and diabetes mellitus. The article presents the synthesis of the medicinal agents and highlights the role of the biological target with respect to the disease model.

Domino Aldol-SAr-Dehydration Sequence for [3+3] Annulations to Prepare Quinolin-2(1)-ones and 1,8-Naphthyridin-2(1)-ones.

A domino aldol-SAr-dehydration [3+3] annulation strategy has been utilized to fuse six-membered cyclic amides onto aromatic substrates. 2-Arylacetamides have been reacted with 2-fluorobenzaldehyde derivatives activated toward SAr reaction by an electron-withdrawing substituent (NO, CN, CF, COMe) at C5 to prepare 3,6-disubstituted quinolin-2(1)-ones. Additionally, 3-substituted 1,8-naphthyridin-2(1)-ones have been similarly derived from 2-fluoronicotinaldehyde.

Synthesis and Elimination Pathways of 1-Methanesulfonyl-1,2-dihydroquinoline Sulfonamides.

A series of new Morita-Baylis-Hillman acetates were prepared and reacted with methanesulfonamide (KCO, DMF, 23 °C) to produce tertiary dihydroquinoline sulfonamides in high yields. Subsequent efforts to eliminate the methylsulfonyl group from these derivatives (KCO, DMF, 90 °C) as a route to quinolines were met with mixed results. Although dihydroquinoline sulfonamides prepared from ethyl acrylate and acrylonitrile generally underwent elimination to give excellent yields of quinolines, those generated from 3-buten-2-one failed to undergo elimination and instead decomposed.

Domino Aza-Michael-SAr-Heteroaromatization Route to C5-Substituted 1-Alkyl-1-Indole-3-Carboxylic Esters.

A new synthesis of C5-substituted 1-alkyl-1-indole-3-carboxylic esters is reported. A series of methyl 2-arylacrylate aza-Michael acceptors were prepared with aromatic substitution to activate them towards SAr reaction. Subsequent reaction with a series of primary amines generated the title compounds.

Domino Nitro Reduction-Friedländer Heterocyclization for the Preparation of Quinolines.

The Friedländer synthesis offers efficient access to substituted quinolines from 2-aminobenzaldehydes and activated ketones in the presence of a base. The disadvantage of this procedure lies in the fact that relatively few 2-aminobenzaldehyde derivatives are readily available. To overcome this problem, we report a modification of this process involving the in situ reduction of 2-nitrobenzaldehydes with Fe/AcOH in the presence of active methylene compounds (AMCs) to produce substituted quinolines in high yields.

Video recording and vegetation classification elucidate sheep foraging ecology in species-rich grassland.

Factors influencing grazing behavior in species-rich grasslands have been little studied. Methodologies have mostly had a primary focus on grasslands with lower floristic diversity.We test the hypothesis that grazing behavior is influenced by both animal and plant factors and investigate the relative importance of these factors, using a novel combination of video technology and vegetation classification to analyze bite and step rates.

Synthesis and Characterization of -Isopropylacrylamide Microspheres as pH Sensors.

Swellable polymer microspheres that respond to pH were prepared by free radical dispersion polymerization using -isopropylacrylamide (NIPA), ,-methylenebisacrylamide (MBA), 2,2-dimethoxy-2-phenylacetylphenone, -tert-butylacrylamide (NTBA), and a pH-sensitive functional comonomer (acrylic acid, methacrylic acid, ethacrylic acid, or propacrylic acid). The diameter of the microspheres was between 0.5 and 1.

Dihydroquinolines, Dihydronaphthyridines and Quinolones by Domino Reactions of Morita-Baylis-Hillman Acetates.

An efficient synthetic route to highly substituted dihydroquinolines and dihydronaphthyridines has been developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates with primary aliphatic and aromatic amines in DMF at 50-90 °C. The MBH substrates incorporate a side chain acetate positioned adjacent to an acrylate or acrylonitrile aza-Michael acceptor as well as an aromatic ring activated toward SAr ring closure. A control experiment established that the initial reaction was an S2'-type displacement of the side chain acetate by the amine to generate the alkene product with the added nitrogen nucleophile positioned trans to the SAr aromatic ring acceptor.

Small Molecule Inhibitors of the Bacterioferritin (BfrB)-Ferredoxin (Bfd) Complex Kill Biofilm-Embedded Cells.

Bacteria depend on a well-regulated iron homeostasis to survive adverse environments. A key component of the iron homeostasis machinery is the compartmentalization of Fe in bacterioferritin and its subsequent mobilization as Fe to satisfy metabolic requirements. In Fe is compartmentalized in bacterioferritin (BfrB), and its mobilization to the cytosol requires binding of a ferredoxin (Bfd) to reduce the stored Fe and release the soluble Fe.

Naphthalenes and Quinolines by Domino Reactions of Morita-Baylis-Hillman Acetates.

An efficient synthetic route to highly functionalized naphthalenes and quinolines has been developed using domino reactions between Morita-Baylis-Hillman (MBH) acetates and active methylene compounds (AMCs) promoted by anhydrous KCO in dry ,-dimethylformamide (DMF) at 23 °C. The substrates incorporate allylic acetates positioned adjacent to a Michael acceptor as well as an aromatic ring activated toward a SAr ring closure. A control experiment indicated that the initial reaction was an S2'-type displacement of a side chain acetoxy by the AMC anion to afford the alkene product bearing the added nucleophile to the SAr aromatic ring acceptor.

Sheep in Species-Rich Temperate Grassland: Combining Behavioral Observations with Vegetation Characterization.

Foraging behavior of livestock in species-rich, less intensively managed grassland communities will require different methodologies from those appropriate in floristically simple environments. In this pilot study on sheep in species-rich grassland in northern Estonia, foraging behavior and the plant species of the immediate area grazed by the sheep were registered by continually-recording Go-Pro cameras. From three days of observation of five sheep (706 animal-minutes), foraging behavior was documented.

Inhibitor design to target a unique feature in the folate pocket of Staphylococcus aureus dihydrofolate reductase.

Staphylococcus aureus (Sa) is a serious concern due to increasing resistance to antibiotics. The bacterial dihydrofolate reductase enzyme is effectively inhibited by trimethoprim, a compound with antibacterial activity. Previously, we reported a trimethoprim derivative containing an acryloyl linker and a dihydophthalazine moiety demonstrating increased potency against S.

Swellable Copolymers of -isopropylacrylamide and Alkyl Acrylic Acids for Optical pH Sensing.

Swellable polymers that respond to pH (including a portion of the physiological pH range) have been prepared from -isopropylacrylamide (NIPA) copolymerized with acrylic acid, methacrylic acid, ethacrylic acid or propacrylic acid by dispersion polymerization. When the swellable polymer particles are dispersed in a polyvinyl alcohol (PVA) hydrogel membrane, large changes occur in the turbidity of the membrane (which is measured using an absorbance spectrometer) as the pH of the buffer solution in contact with the hydrogel membrane is varied. The swelling of the NIPA copolymer is nonionic, as the ionic strength of the buffer solution in contact with the PVA membrane was increased from 0.

Changes and drivers in Spanish landscapes at the Rural-Urban Interface between 1956 and 2018.

This paper presents unique comprehensive quantitative measures of the changes in Spanish rural landscapes, specifically in relation to the Rural-Urban Interface (RUI). Our objective was to investigate the urbanisation process in rural areas of Spain, thus the expansion of the RUI in an environmentally complex study area (it includes arid regions, continental areas or high mountains). The data were produced by the Spanish Rural Landscapes Monitoring System project (SISPARES), which has carried out five separate surveys for 1956, 1984, 1998, 2008 and 2018.

Tetrahydroquinoline units in flexible heteroarotinoids (Flex-Hets) convey anti-cancer properties in A2780 ovarian cancer cells.

SHetA2 (NSC 721689), our lead Flex-Het anti-cancer agent, consists of a thiochroman (Ring A) and a 4-nitrophenyl (Ring B) linked by a thiourea bridge. In this work, several series of new analogs having a tetrahydroquinoline (THQ, Ring A) unit connected by a urea or thiourea linker to a 4-substituted phenyl (Ring B) have been prepared and evaluated relative to SHetA2 in terms of binding affinity with mortalin and inhibition of A2780 ovarian cancer cells. Six of the derivatives equaled or exceeded the efficacy shown by SHetA2.

4-Benzo[][1,3]oxazin-4-ones and Dihydro Analogs from Substituted Anthranilic Acids and Orthoesters.

A one-pot route to 2-alkyl and 2-aryl-4-benzo[][1,3]oxazin-4-ones (also known as 4-3,1-benzoxazin-4-ones) has been developed and studied. The method involves the reaction of aryl-substituted anthranilic acids with orthoesters in ethanol catalyzed by acetic acid. Additionally, we have also investigated the reaction under microwave conditions.

The use of cattle for restoring and maintaining holarctic landscapes: Conclusions from a long-term study (1946-2017) in northern England.

Cattle can perform valuable ecological functions in the maintenance of high nature value (HNV) pastoral systems. They have also attracted attention as potentially filling the ecological niches of megaherbivores, notably the extinct aurochs , in rewilding initiatives. Native cattle breeds are recognized under the 1992 Rio Convention as components of biodiversity.

Small Molecule Inhibitors of the BfrB-Bfd Interaction Decrease Pseudomonas aeruginosa Fitness and Potentiate Fluoroquinolone Activity.

The iron storage protein bacterioferritin (BfrB) is central to bacterial iron homeostasis. The mobilization of iron from BfrB, which requires binding by a cognate ferredoxin (Bfd), is essential to the regulation of cytosolic iron levels in P. aeruginosa.

Synthesis and biological evaluation of SHetA2 (NSC-721689) analogs against the ovarian cancer cell line A2780.

A series of Flexible Heteroarotinoid (Flex-Het) analogs was synthesized and their biological activities were evaluated against the A2780 ovarian cancer cell line. The objective of this study was to establish structure-activity relationships (SARs) for new Flex-Het derivatives, which were previously inaccessible due to the limited availability of aryl isothiocyanate precursors. The current work developed a synthesis of isothiocyanate 13 and used it to prepare 14 diverse thiourea analogs of the lead compound SHetA2 (1, NSC-721689) from a range of commercial amines.

Country-scale mapping of ecosystem services provided by semi-natural grasslands.

Semi-natural grasslands harbour high biodiversity and play a key role in the supply of ecosystem services (ES). However, abandonment, changes in traditional management practices and agricultural intensification constitute a major threat to these grasslands worldwide and these practices have led to declines in species diversity. In this paper the multi-functionality of semi natural-grasslands is assessed from the ES perspective, within a range of common semi-natural grassland types throughout Estonia.

Quinazolin-4(3)-ones and 5,6-Dihydropyrimidin-4(3)-ones from β-Aminoamides and Orthoesters.

Quinazolin-4(3)-ones have been prepared in one step from 2-aminobenzamides and orthoesters in the presence of acetic acid. Simple 2-aminobenzamides were easily converted to the heterocycles by refluxing in absolute ethanol with 1.5 equivalents of the orthoester and 2 equivalents of acetic acid for 12⁻24 h.

Activity of oxygen-versus sulfur-containing analogs of the Flex-Het anticancer agent SHetA2.

Five series of chromans with urea and thiourea linkers connecting a chroman unit (ring A) and a 4-substituted benzene unit (ring B) have been prepared and evaluated relative to SHetA2 (NSC 721689) for activity against the human A2780 ovarian cancer cell line. The lead compound SHetA2 had a sulfur in place of the oxygen in ring A and a thiourea linker to ring B. The 2-Me-4-Me series (two sets of geminal dimethyl groups at C2 and at C4 on the ring A unit) permitted direct comparison with SHetA2.