Search Results (1,657)

We report the synthesis of a modified benzothiazole sulfide. This compound contains a heterocyclic core, a Boc-protected hydroxylamine, and an appended alkyne. This benzothiazole was accessed through three total steps, including an amidation reaction and two nucleophilic aromatic substitutions. The identity of the title compound was confirmed through ¹H, ¹³C, ¹H–¹H COSY, HSQC, and HMBC NMR, in addition to IR, MALDI-MS, HRMS, and HPLC. Full article

Spontaneous deamidation and isomerization of asparagine (Asn) residues is a major pathway of nonenzymatic protein aging, where Asn-Gly-containing peptides (NG motifs) represent the most reactive sequence. In this context, the first step of isomerization is succinimide formation, which is initiated by a concerted proton-transfer and nucleophilic activation step. Although the overall mechanism is established, the detailed nature of the rate-determining succinimide formation step and the possible role of nuclear quantum effects remain unclear. Here, we combine density functional theory (DFT), intrinsic reaction coordinate (IRC) analysis, and quantitative NMR kinetics to investigate hydrogen/deuterium (H/D) substitution effects on NG isomerization in different model peptides, which represent both conformationally flexible and restricted systems. Deuteration preserves the reaction pathway and structural evolution, indicating an invariant classical reaction coordinate. However, kinetic isotope effects in the flexible peptide system reveal a mixed classical–tunneling mechanism in the rate-determining step with observable deviations from classical over-the-barrier behavior. In contrast, the conformationally restricted peptide shows suppressed tunneling contributions. These findings demonstrate that conformational accessibility modulates proton tunneling in spontaneous peptide rearrangements and extends nuclear quantum effects beyond enzymatic systems to nonenzymatic processes associated with protein aging. Full article

A series of fluorine-substituent-containing sulfonated poly(arylene ether) membranes was synthesized and evaluated as proton exchange membranes for fuel cell applications. Fluorinated difluoro monomers were first reacted with three different diol monomers through nucleophilic polycondensation to obtain 4FP4-series polymers, followed by controlled sulfonation to produce six S4FP4-series membranes with different ion exchange capacities and microphase-separated morphologies. FT-IR, ¹H-NMR, and ¹⁹F NMR spectroscopy confirmed the chemical structures of monomers, polymers, and sulfonated polymers. The resulting polymers exhibited good film-forming ability and high thermal stability. The sulfonated membranes showed ion exchange capacities of 1.74–2.80 mmol/g, water uptake of 24.7–116.3%, and favorable dimensional stability under elevated temperature. Most S4FP4 membranes exhibited proton conductivities higher than that of Nafion 211. In particular, S4FP4a (IEC of 1.74) achieved a proton conductivity of 262 mS cm⁻¹ at 80 °C and 95% RH and a maximum fuel cell power density of 1.07 W cm⁻², outperforming Nafion 211. TEM analysis revealed that fluorine substitution promoted effective microphase separation and continuous mesoscale aggregated domain. These results demonstrate that fluorinated sulfonated poly(arylene ether)s are promising candidates for high-performance proton exchange membranes. Full article

The Pd(0)-catalysed aryloxylation of 6-O-tert-butyldimethylsilyl-3,4-di-O-isobutyloxycarbonyl-d-glucal (3) with a series of phenolic nucleophiles was investigated as an efficient approach to the synthesis of unsaturated aryl O-glycosides. Under the optimized reaction conditions, the corresponding 2,3- and 3,4-unsaturated O-glycosides were obtained in good to excellent yields and with high β-selectivity. In most cases, the reactions proceeded with a marked preference for the formation of 2,3-unsaturated β-glycosides, whereas chlorophenols exhibited distinct reactivity patterns, resulting in diminished regioselectivity and the additional formation of α-anomeric 2,3-unsaturated glycosides. Comparison with the previously reported reactions of 6-O-tert-butyldiphenylsilyl-3,4-di-O-isobutyloxycarbonyl-d-glucal demonstrated a pronounced influence of the silyl protecting group on the product yields and regioselectivity, with the TBDMS-protected donor generally affording higher yields and enhanced selectivity toward 2,3-unsaturated products. Furthermore, the developed methodology was successfully extended to carbohydrate nucleophiles, enabling the synthesis of model trisaccharides and demonstrating its applicability to oligosaccharide synthesis. Full article

Background: Glioblastoma (GBM) is the most aggressive subtype of malignant glioma. Current therapeutic options remain limited, highlighting the need for the development of novel compounds capable of improving the efficacy of standard treatments. This study aimed to evaluate the biological activity of a series of pyrazolone-based hydrazone compounds (TPPs) in vitro GBM cell lines. Methods: The eight TPPs were synthesized by a nucleophilic addition reaction of different substituted hydrazines with 1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-phenylethan-1-one and tested on two human GBM cell lines, T98 and U87. The cytotoxic effects were evaluated via MTT assay. The most active compound was further investigated at IC₅₀ and IC₂₅ concentrations to evaluate mechanisms of cellular damage, including reactive oxygen species (ROS) production and mitochondrial membrane potential (ΔΨ_m) changes. Additional assays included colony formation, cell cycle analysis, and evaluation of DNA damage and apoptosis markers. Results: TPP25 exhibited the highest activity with IC₅₀ values of 11.01 μM (95% CI: 10.42 to 11.64) and 13.12 μM (95% CI: 10.23 to 16.87) on T98 and U87 lines, respectively. Treatment induced early ROS production and mitochondrial depolarization, along with a significant reduction in colony formation. Cell cycle analysis revealed accumulation in the sub-G0 phase, consistent with increased cell death, supported by propidium iodide uptake. Furthermore, the results suggest the involvement of an apoptotic-like mechanism as supported by Annexin V positivity, γ-H2AX upregulation and transient caspase-3 activation. Conclusions: TPP25 demonstrates significant in vitro cytotoxicity, likely driven by a pro-apoptotic mechanism. This profile positions it as a potential lead compound for further preclinical evaluation, supporting its future transition into in vivo GBM models. Full article

One-pot protocols leading to target products in two or more sequential reactions, without the separation and isolation of intermediate products, are powerful synthetic tools. In fact, they surpass usual procedures based on single-step reactions in terms of efficiency, cost, and green aspects. The appeal of such methodologies is further increased with the use of catalysts, which makes the process easier and more efficient, minimizing unwanted byproducts. In this context, this paper describes three new one-pot protocols, based on an oxo-Re(V)-catalyzed Meyer–Schuster rearrangement of different secondary propargylic alcohols to the corresponding α,β-unsaturated ketones. These products, without isolation, subsequently, can undergo the 1,4-conjugate addition of a soft Gilman copper nucleophile or the intramolecular cyclocondensation with hydrazine hydrochloride to pyrazoles. Moreover, the ketone formed by the addition of a Gilman reagent can further be reduced in situ with LiAlH₄ to the corresponding secondary alcohol. The remarkable aspects of these novel procedures involving two and three one-pot consecutive steps are the high overall yields, the readily available reaction conditions, and the compatible presence of two transition metallic species in the same reaction medium. Full article

Monoanionic [N,N] donor ligands, typified by the delocalized β-1,3-diketiminates, are important ligands for stabilizing metal complexes from across the periodic table. In contrast, non-delocalized iminoenamides maintain asymmetric donor atoms. We report the synthesis and structures of alkali metal salts of three iminoenamines: 2-(arylamido)-5-methylcyclopent-2-en-1-arylimine (aryl = 2,6-diisopropylphenyl, Dipp) and 2-(arylamido)-cyclohex-2-en-1-arylimine (aryl = mesityl, Mes, or Dipp). The successful deprotonation of all proligands was achieved when non-nucleophilic benzyl or tetramethylpiperidide bases were used. The mesityl-substituted proligand reacted with nBuLi or PhLi via deprotonation to give the desired lithium iminoenamide salt, whereas the Dipp-substituted proligands underwent nucleophilic addition. X-ray diffraction revealed dimeric structures through [N,N] coordination and through η⁶-arene interactions to a neighboring aryl group. However, a coordination polymer was formed for the potassium salt of the iminoenamide featuring N-Dipp substituents and a cyclohexene backbone because, unlike the methylcyclopentene backbone ligand, it does not feature a methyl group blocking this side of the enamide N-Dipp ring. The potassium salt of the N-mesityl ligand revealed coordination through only the N-atoms. DOSY NMR revealed a mixture of aggregation states in benzene solution, including monomers, benzene-coordinated monomers, and the presence of monomer/dimer equilibria. Sterically bulkier Dipp groups were more likely to lead to monomeric structures in solution. Full article

Quinoline is a bicyclic aromatic heterocycle composed of a fused benzene and pyridine ring, and it has held an important place in medicinal chemistry for nearly two centuries. F. Runge first isolated it from coal tar in 1834, and it was later found to form the structural core of well-known natural products such as quinine, camptothecin, and γ-fagarine. Its asymmetric electron distribution, amphoteric character, and ability to undergo both electrophilic and nucleophilic substitution confer considerable pharmacophoric versatility on the quinoline scaffold. This review covers the chemistry and therapeutic relevance of quinoline derivatives, with an emphasis on their pharmacological significance rather than on their synthesis alone. It begins with a brief account of the scaffold’s structural features and main synthetic routes, then examines the biological activities reported for quinoline-based compounds, including antibacterial, anticancer, anti-inflammatory, antimalarial, antiparasitic, antitubercular, antioxidant, and antiviral activities, together with structure–activity relationships discussed at the level of specific ligand–target interactions where data allow. The last section covers more recent directions in quinoline-based drug discovery, including PROTAC degraders, kinase inhibitors, and multitarget-directed ligands, an area not extensively addressed in earlier reviews of this scaffold. The literature surveyed here shows that quinoline derivatives continue to serve as a versatile scaffold for generating new leads, linking established synthetic chemistry with current mechanistic and computational approaches. The continued diversification of quinoline-based chemotypes and their biological mechanisms reinforces the importance of this scaffold as a versatile platform for medicinal chemistry and drug discovery. Full article

In this study, we developed two complementary synthetic routes to novel piperidine- and azetidine-containing 2,3-disubstituted propanoic acid derivatives as heterocyclic amino acid building blocks. The strategy employs ketone- and carboxylic acid-derived Meldrum’s acid intermediates, which are converted into common α,β-unsaturated methyl esters through methanolysis; they are subsequently diversified via DBU-promoted aza-Michael addition with saturated cyclic amines and aromatic NH-heterocycles. The ketone-derived approach provided piperidine-containing derivatives in 35–89% yield and the corresponding azetidine analogues in 61–92% yield, whereas the complementary acid-derived route afforded regioisomeric products in 59–85% and 61–89% yield, respectively. Both synthetic sequences tolerated a broad range of nitrogen nucleophiles, and no alternative regioisomeric aza-Michael products were detected for heterocycles containing multiple nitrogen atoms. The structures of the synthesized compounds were established via ¹H, ¹³C, ¹⁵N, and ¹⁹F NMR spectroscopy together with HRMS, including detailed multidimensional NMR analysis of representative products. The developed methodology provides efficient access to structurally diverse heterocyclic propanoic acid derivatives and expands the repertoire of amino acid building blocks available for peptide chemistry, medicinal chemistry, and DNA-encoded library synthesis. Full article

The electrochemical sensing of similar catecholamines remains challenging due to their overlapping redox behavior and similar reactivity, which often results in poorly selective reaction pathways. Herein, we report a bioinspired tyrosinase electro-catalytic system that enables the modulation of the catecholamine reactivity through the integration of enzymatic oxidation with electrochemical transformation. The biocatalytic platform consisted of electroactive lignin nanoparticles (LNPs) supporting tyrosinase drop cast on the graphene-based screen-printed electrode. The overall reaction included the oxidation of catecholamines to ortho-quinones, followed by nucleophile addition of cysteine under control of the redox environment. Overall, coupling enzymatic catalysis with electrochemical regulation enabled selectivity in the oxidative functionalization of catecholamines, providing a sustainable strategy for tuning reactivity in advanced bioinspired catalytic systems. Full article

3,4-dihydrocoumarins and spiro compounds constitute an important class of privileged frameworks present in a wide variety of natural and synthetic molecules with diverse applications. In this study, we developed an organocatalytic methodology for the construction of complex and diverse chiral spiro-bridged 3,4-dihydrocoumarins through a Diels–Alder/Nucleophilic ring-closing cascade via trienamine activation. The reaction proceeds efficiently with different trienamine precursors and a range of coumarin-3-carboxamides, which act as both dienophile and intramolecular nucleophile species. This process affords the desired products in good yields and with a high degree of stereocontrol. Furthermore, several transformations on the newly formed spiro-piperidone ring demonstrate the synthetic utility of the obtained compounds. Full article

An efficient and stereoselective method for the synthesis of chiral biheterocyclic N-Boc-protected pyrrolidine derivatives bearing indole, pyrazole, and indazole moieties is presented. In this approach, nucleophilic substitution of heterocyclic carboxylates with enantiomerically pure N-Boc-3-methanesulfonyloxypyrrolidines is used to afford N-(pyrrolidin-3-yl) derivatives in high yields with an inverted configuration. The methodology accommodates a range of substrates, enabling structural diversity. Reactions with pyrazole- and indazolecarboxylates generate regioisomeric products. Representative peptide-coupling reactions further demonstrated the synthetic utility of the synthesized chiral biheterocyclic pyrrolidine derivatives containing protected amino and carboxyl functionalities as building blocks for peptide synthesis. Halogenated indole and pyrazole derivatives underwent further functionalization via palladium-catalyzed cross-coupling to introduce aryl, heteroaryl, and alkynyl substituents. All of the N-Boc-substituted biheterocycle–pyrrolidine carboxylates displayed NMR spectra with two sets of signals, notable signal broadening, or both. These effects are due to the dynamic equilibrium between two conformers in a deuterated solvent and were studied in depth. The structures and stereochemistry of the synthesized compounds were confirmed by means of chiral HPLC, single-crystal X-ray diffraction, and advanced NMR analyses. This synthetic strategy provides access to chiral heterocyclic amino acid-like building blocks for peptide synthesis and medicinal chemistry. Full article

The reaction of 2,5-dimethylfuran (DMF) with two equivalents of α-nitrosostyrene (NS) leading to a tricyclic 1,2-oxazine nitrone (TON) has been examined theoretically at the ωB97X-D/6-311G(d,p) computational level. In this case, the domino process should be considered: (i) a [4+2] cycloaddition (42CA) between DMF and NS yielding a bicyclic 1,2-oxazine (BO); and (ii) a second formal [3+2] cycloaddition (32CA) reaction between BO and NS yielding the final TON. Analysis of the reactivity indices shows that DMF and BO generated along the first 42CA reaction are strong nucleophiles, while NS is a strong electrophile. The first 42CA reaction takes place according to a one-step mechanism. In turn, the second 32CA proceeds according to a two-step mechanism through the zwitterionic intermediate ZW. It is worth noting that the activation enthalpy of the significant point (TS-1mn) of the 42CA is very low, 2.17 kcal·mol⁻¹, the reaction being strongly exothermic by −37.71 kcal·mol⁻¹. This cycloaddition reaction is completely meta regioselective and endo stereoselective. The first step of the formal 32CA reaction has an activation enthalpy of 8.48 kcal·mol⁻¹ (TS-21), the overall domino process being strongly exothermic by −40.34 kcal·mol⁻¹. Both TS-1mn and TS-21 are associated with highly asynchronous single bond processes. The high global electron density transfer (GEDT) found at both TSs, higher than 0.32e, points out the high polar character of these cycloaddition reactions, classified as reverse electron density flux (REDF). Electron Localization Function (ELF) analysis of TS-1mn and TS-21 shows that the C2-C3 and C3-N5 bonds are not formed at the same time, while in the intermediate ZW we observed the creation of one of them. Full article

Utilization of tetra-n-butylammonium fluoride (TBAF) as a new, hitherto unknown devulcanization aid in the chemical devulcanization of sulfur crosslinked diene rubber has been demonstrated. The influences of crosslink structure (the ratio of mono-, di-, and polysulfidic bonds) and carbon black (CB) loading on the efficiency of acrylonitrile-butadiene-rubber (NBR) devulcanization have been studied. The rubber vulcanizates were treated with TBAF solutions under varying conditions (solution concentration, solvent type, temperature, and reaction time). Changes in crosslink density and other relevant network properties of the rubber vulcanizates were measured. Results showed a significant reduction in crosslink density—up to 50% after chemical treatment. The fluoride-based approach, in which fluoride salt is a source of nucleophilic fluoride anions (F⁻), can cleave the sulfidic crosslinks, demonstrating significant potential for efficient recycling of used rubber vulcanizates by their devulcanization. Full article

The positional arrangement of BN and CC units in B₆C₆N₆ cyclic nanorings profoundly influences their stability, electronic structure, optical response, and reactivity. Here, we comparatively investigate eight positional isomers (C1–C8) using DFT and TD-DFT calculations. Among C1–C8, C1 is the most stable, and C8 is the most unstable in the range of 200–1000 K. Their relative stability is governed by B-N charge separation, homonuclear B-B and N-N defects (charge repulsion), and bond-angle distortion (ring tension). The HOMO–LUMO gaps range from 4.40 eV (C3) to 8.45 eV (C2), indicating distinct kinetic stability. Aromaticity analysis reveals that all isomers are nonaromatic. In the gas phase, the lowest-energy absorption bands of C1 and C3 are located at about 429 nm and 606 nm, respectively. Due to different transition mechanisms, namely locally excited (LE) for the former and charge-transfer (CT) for the latter, solvent polarity has dramatically different influence on these two absorption bands. Compared to their positions in the gas phase, these absorption bands are blue-shifted about 20 nm and 220 nm in water, respectively. Reactivity analysis identifies the B-B bond in C7 as the strongest electrophilic site (LEAE = −2.93 eV), with the surrounding framework serving as nucleophilic domains, endowing C7 with the strongest bifunctional reactivity. This work establishes a comprehensive structure–property map for B₆C₆N₆ isomers, providing guidance for designing BCN-based nanorings for catalysis, molecular recognition, and optoelectronics. Full article