Search Results (209)

Herein, starting from (R)-(+)-α-methylbenzylamine, we report an efficient synthesis and full characterization of a new (R)-3-(1-hydroxyethylidene)-1-(1-phenylethyl)piperidine-2,4-dione, a new tetramic acid analog. The key steps involved a non-classical Corey–Chaykovsky intramolecular cyclization reaction to access the corresponding zwitterion, followed by a sequential desulfurization/reduction and condensation procedure. The titled product was obtained in five steps, and the desired product 7 with an overall 58% yield. Full article

The Pschorr reaction is a radical-mediated intramolecular cyclization involving diazonium salts, affording five-, six- and seven-membered fused polycyclic and heterocyclic rings, discovered by R. Pschorr in the late nineteenth century. Over the years, this classic reaction has played an important role in ring-forming reactions. In 2009 we reviewed the progress in the field. The intervening years have witnessed major advances in the application of Pschorr reaction that are mediated by various metals, by photocatalysis, and by ionic liquids, leading to the development of new and improved methods for the synthesis of diverse bioactive heterocycles. The notable progress in the field since our 2009 review provided the impetus to summarize, discuss, and put these advances in perspective. Full article

Antimicrobial peptides (AMPs) have re-emerged as promising anti-infective agents, particularly against multidrug-resistant bacteria; however, their therapeutic development remains constrained by proteolytic degradation, host cell toxicity, and rapid systemic clearance. Rather than focusing solely on sequence discovery, recent efforts have shifted toward structural and supramolecular modification strategies aimed at improving stability, selectivity, and pharmacological performance. This review critically analyzes intramolecular modifications—including phosphorylation, glycosylation, acetylation, methylation, and backbone cyclization—that modulate peptide conformation and resistance to enzymatic degradation. In parallel, extramolecular approaches such as PEGylation, lipidation, and conjugation to antibiotics, siderophores, or antibodies are examined in the context of enhanced targeting and prolonged bioavailability. Particular emphasis is placed on localized delivery systems, including hydrogels, polymeric films, and nanofibrous scaffolds, which enable spatially controlled administration and mitigate systemic exposure. By integrating evidence from ex vivo and in vivo infection models, this work delineates the translational potential and remaining bottlenecks of chemically engineered AMP platforms for skin and soft tissue infections. Full article

Better understanding the controlling factors of shale oil quality including density and viscosity plays a key role in exploring these unconventional pay zones efficiently and profitably. The shale oil extracted from the middle Permian Lucaogou Formation (P₂l) of Santanghu Basin becomes denser and more viscous from the Tiaohu Sag to Malang Sag. It has been proven that oil quality is negatively correlated with saturated hydrocarbon content and positively correlated with aromatic/resin content. However, the underlying controls at the molecular levels are not yet clear. In order to reveal the fundamental controls, shale oil samples with varying density and viscosity were collected from these two sags, and molecular compositions of these samples were analyzed by using gas chromatography–mass spectrometry (GC–MS) for the saturated and aromatic hydrocarbons and electrospray ionization (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FT–ICR MS) for heteroatom hydrocarbons in resin fraction. Thereafter, correlation analysis was performed between oil density and viscosity and geochemical parameters associated with saturated, aromatic and NSO-containing compounds. The experimental results indicate that the oil thermal maturity levels play a major role, since both density and viscosity present significant negative correlations (correlation coefficient > 0.5) with the maturity parameters of n-alkanes, terpanes, steranes and triaromatic steranes. Organic facies also play a partial role as indicated by the significant positive correlations between density and viscosity and the parameters of tricyclic terpanes, dibenzothiophene/phenanthrene, and methylated phenanthrenes. In resin fraction, density presents better correlations with acid compounds, including O_x (x = 5–9), N₁O_x (x = 0–2) and N₂O₃ species, and viscosity shows better correlations with basic N-containing compounds (N₁O₁, N₁O₃, and N₂O₁ species) and S-containing compounds (N₁S₁ and O₁S₁ species). This indicates that the cross-linking by acid oxygen-containing compounds and the intramolecular and intermolecular forces induced by basic N-containing compounds and sulfur-containing compounds play an important role in directing the P₂l shale oil quality. Moreover, the ratios of specific species with low-to-high double bond equivalents (DBEs) and the homologues with low molecular weight to high molecular weight both present significant negative correlations with density and saturated and aromatic maturity parameters. This highlights the effects of bond cleavage, cyclization and aromatization reactions with elevated thermal maturity in enhancing oil quality in the targeted pay zones. Most P₂l shale oil sources were deposited under the reducing lacustrine setting, containing mainly Type I/II kerogens. Shale oils from Tiaohu Sag are more matured than those from Malang Sag, which is supposed to be responsible for the better oil quality in Tiaohu Sag. This study provides the supporting evidence for regulating shale oil quality in the Santanghu Basin at the molecular levels, and should be helpful in identifying the sweet spots of shale oil plays in this area. Full article

Quinoline-2,4-dione derivatives represent an essential class of heterocycle scaffolds that have demonstrated wide applications in modern drug discovery. However, the efficient construction of 3,3-difluoro-quinoline-2,4-diones with broad substrate generality remains a significant challenge and has not yet been reported. Herein, we developed the nickel-catalyzed intramolecular radical cyclization of 2-bromo-2,2-difluoro-N-(2-cyanoaryl)acetamides to achieve various 3,3-difluoro-quinoline-2,4-diones in good yields. The scalability and practical applicability of this method were demonstrated through large-scale reactions. Full article

In the present work, we describe the synthesis of a new heterocyclic derivative, 2-(naphthalen-1-yl)-2,3,5,6-tetrahydro-1H-isoquinolino[8,1,2-hij]quinazoline 1, using the reaction between the aminal 1,3,6,8-tetraazatricyclo[4.4.1.1^3,8]dodecane 2 (TATD) and 1-naphthylamine 3 as the first scaffold of a four-step linear synthetic route. In the first step, a condensation catalyzed by acetic acid in 96% ethanol was carried out, leading to the formation of the intermediate 3-(naphthalen-1-yl)-1,2,3,4-tetrahydrobenzo[h]quinazoline 4. Subsequently, this intermediate was acylated with 2-chloroacetyl chloride in the presence of triethylamine and under an inert atmosphere, obtaining the compound 2-chloro-1-(3-(naphthalen-1-yl)-3,4-dihydrobenzo[h]quinazolin-1(2H)-yl)ethan-1-one 5. In the third step, an intramolecular Friedel–Crafts cyclization was carried out using aluminum trichloride as a catalyst, yielding 2-(naphthalen-1-yl)-1,2,3,6-tetrahydro-5H-isoquinolino[8,1,2-hij]quinazolin-5-one 6. Finally, the reduction of this lactam with phosphorus pentachloride and sodium borohydride under anhydrous conditions led to the further closure of the polycyclic system, yielding the final product 1. The proposed route demonstrates the feasibility of using TATD 2 as a versatile precursor for constructing condensed heterocyclic systems of structural interest and potential relevance in advanced organic synthesis. Full article

A green and efficient method was developed for the synthesis of 1,8-dioxo-octahydroxanthene derivatives using linear alkylbenzene sulfonic acid (LABSA) as an eco-friendly Brønsted acid catalyst under aqueous reflux conditions. This system combines micellar catalysis and acid activation to afford tricyclic products in high yields and with excellent purity. The transformation proceeds via a Knoevenagel–Michael sequence between dimedone and aromatic aldehydes, followed by intramolecular cyclization. The method exhibits broad substrate tolerance, affording yields between 80 and 92. The simplicity, scalability, and environmental compatibility of this process establish LABSA as a promising alternative to conventional acids for the green synthesis of pharmacologically relevant xanthene derivatives. Full article

Density functional theory (DFT) calculations elucidate the mechanism of diastereoselective cyclization of 2-picoline with 1,5-hexadiene catalyzed by a cationic half-sandwich scandium complex. The catalytic cycle proceeds through four key stages: formation of active species, initial alkene insertion, cis-selective cyclization, and protonation. Central to the mechanism is the dual role of 2-picoline, which initially coordinates as a supporting ligand to facilitate C–H activation and regioselective 1,2-insertion but must dissociate to enable stereocontrol. The mono(2-picoline)-coordinated complex C3 is identified as the thermodynamically favored active species. C–H activation reactivity follows the trend: ortho-C(sp²)–H (2-picoline-free) > ortho-C(sp²)–H (2-picoline-coordinated) > benzylic C(sp³)–H (2-picoline-free) > benzylic C(sp³)–H (2-picoline-coordinated), a preference governed by a wider C_α–Sc–C_α′ angle and shorter Sc···X (X = C_α, C_α′, H) distances that enhance scandium–substrate interaction. Subsequent 1,5-hexadiene insertion proceeds with high 1,2-regioselectivity through a picoline-assisted pathway. The stereoselectivity-determining step reveals a mechanistic dichotomy: while picoline coordination is essential for initial activation, its dissociation is required for intramolecular cyclization. This ligand displacement avoids prohibitive steric repulsion in the transition state, directing the reaction exclusively toward the cis-cyclized product. The cycle concludes with a sterically accessible mono-coordinated protonation. This work establishes a “ligand-enabled then ligand-displaced” mechanism, highlighting dynamic substrate coordination as a critical design principle for achieving high selectivity in rare-earth-catalyzed C–H functionalization. Full article

Nucleophilic ring-opening of bis(oxiranes), containing several reactive centers, can be used to elaborate straightforward atom-economy and stereoselective approaches to polyfunctionalized compounds. In the present work, ring-opening of cis- and trans-diastereomers of a spirocyclic bis(oxirane), containing a cyclooctane core (namely, 1,8-dioxadispiro[2.3.2.3]dodecane), upon treatment with various amines, was studied. Trans-isomer afforded aminoalcohols with 9-oxabicyclo[3.3.1]nonane moiety, formed via domino-process, including opening of an oxirane ring followed by intramolecular cyclization. Ring-opening of cis-isomer gave aminosubstituted cis-cyclooctane-1,5-diols, derived from independent reaction of two oxirane moieties. Activation of oxirane rings by the addition of LiClO₄, acting as a Lewis acid, allowed the involvement of a number of primary and secondary aliphatic amines as well as aniline derivatives in the reaction. Scope and limitations of the reaction were studied and a series of aminoalcohols with a 9-oxabicyclo[3.3.1]nonane core and symmetric diaminodiols with a cyclooctane core were obtained. Full article

Heterologous expression of silent biosynthetic gene clusters represents a key strategy for the discovery of structurally novel natural products. In this study, we obtained ten new tetronate natural products, designated as talactones A–J (1–10), through heterologous expression of a polyketide synthase–nonribosomal peptide synthetase (PKS-NRPS) gene cluster (tho) from the fungus Aspergillus flavipes LY1-5 in A. nidulans A1145. Their structures were elucidated by comprehensive HR-ESI-MS and NMR analyses. Notably, talactone A (1) contains a rare 1,4-thiazepane scaffold, whereas talactones B (2) and C (3) feature a novel 2,3-dihydrofuro [3,4-b]pyridine-4,5(1H,7H)-dione skeleton. Biosynthetic investigations indicate that the 1,4-thiazepane ring in 1 arises from a non-enzymatic reaction between a tetronate acid and cysteine, while 2 and 3 are derived from 5 and 6, respectively, via spontaneous intramolecular cyclization under acidic conditions. Antibacterial activity assays revealed that compounds 1–3, 9, and 10 exhibit moderate antibacterial effects. Full article

Perimidine derivatives are versatile heterocycles with growing significance in medicinal chemistry and materials sciences. However, their structural variety remains limited. This study focused on the synthesis and crystal structure characterization of a new perimidine-based molecule. A bicyclic perimidine lactone, (1S,4R)-4,7,7-trimethyl-1-(1H-perimidin-2-yl)-2-oxabicyclo[2.2.1]heptan-3-one (1), was synthesized through an intramolecular dehydration of a monoamide intermediate formed from 1,8-diaminonaphthalene and (1S)-(–)-camphanic chloride under basic conditions. The product was purified and crystallized from acetone, giving single crystals suitable for X-ray diffraction. Structural analysis revealed two stereogenic centers and crystallization in the chiral tetragonal P4₃2₁2 space group, with stabilization through N—H···O and C—H···N hydrogen bonds as well as C—H···π interactions. Full article

Cysteine (Cys) is an essential thiol in food and biological systems, yet its selective quantification remains challenging due to interference from structurally related analytes such as homocysteine (Hcy) and glutathione (GSH). Here, we report a hemicyanine-based, turn-off fluorescent probe (PRH) that undergoes Cys-triggered cyclization to release PRH-OH, resulting in fluorescence quenching. PRH exhibits near-infrared emission at 630 nm, enabling low self-absorption and reduced background. The probe affords a broad linear range (0–100 μM) with a detection limit of 0.344 μM, along with high selectivity over Hcy, GSH, and 18 other amino acids. In food matrices (garlic, onion, and dried red pepper), PRH achieved recoveries of 98.8–101.3% with RSD < 2% (n = 3), demonstrating analytical robustness. Live-cell imaging in HeLa cells further verified practical responsiveness: N-ethylmaleimide-mediated thiol depletion increased PRH fluorescence, whereas Cys replenishment decreased it, consistent with the probe’s turn-off behavior. DFT calculations support an intramolecular charge-transfer change upon Cys reaction, correlating with the observed spectral shift. Overall, PRH provides a simple and selective platform for reliable Cys quantification in food samples and for visualizing Cys dynamics in cells. Full article

For a family of 24-atom triazine macrocycles, a single intramolecular hydrogen bond (IMHB) network leads to a conserved, hinge-like motif in solution. Modifications to the backbone of these macrocycles preserve this motif. Modifications to peripheral sites lead to conformational isomers due to hindered bond rotation while conserving the hinge motif. Here, a competitive IMHB network is introduced by the addition of a hydrogen bond donor on the periphery. Cyclization remains quantitative, but multiple conformers result. Three conformers are derived from the hinge motif. Three others are attributed to a new motif that utilizes the new IMHB network. Crystallographic analysis confirms this hypothesis and establishes that this new motif differs significantly from the original with respect to overall shape and disposition of groups. Variable temperature ¹H NMR spectroscopy is used to partially assign the spectra because conformers adopting the hinge motif undergo dynamic motion on the NMR timescale, while the new motif appears static. QTAIM analysis corroborates the hydrogen bond designations in the new conformer and categorizes these interactions as moderate and strong. Full article

2-Oxazolines are five-membered heterocyclic compounds with significant biological properties. They also play an important role in organic synthesis, acting as chiral ligands and protecting groups for hydroxyamino acids and amino alcohols. Poly(2-oxazolines) are known coating materials, for example, in biomedicine. Classic synthetic methods of 2-oxazolines involve a dehydrative cyclisation reaction between amino alcohols and carboxylic acids, acid chlorides, nitriles, imidates, and aldehydes. However, the electrophilic intramolecular cyclization of unsaturated amides is becoming an increasingly important synthetic method for the preparation of 2-oxazolines. This brief review summarizes procedures for synthesizing oxazolines using the electrophilic intramolecular oxidative cyclisation of N-allyl and N-propargyl amides, as published between 2014 and 2024. It covers the synthesis of 5-halomethyl-, 5-trifluoromethyl-, 5-sulfonylmethyl-, 5-sulfenylmethyl-, 5-selenylmethyl-, 5-acetoxymethyl-, 5-hydroxymethyl-, 5-aminomethyl-, 5-alkilo-, and 5-alkylideneoxazolines. Full article

The therapeutic use of non-steroidal anti-inflammatory drugs (NSAIDs) is limited by gastrointestinal and renal adverse effects caused by non-selective COX-1 and COX-2 inhibition. To address this issue, a new series of naproxen–azetidinone hybrids was rationally designed and synthesized to enhance COX-2 selectivity and reduce off-target toxicity. The synthesis involved esterification, hydrazide formation, Schiff base condensation, and intramolecular cyclization with chloroacetyl chloride. Structural characterization was achieved through FT-IR, ¹H NMR, and ¹³C NMR analyses. In silico ADMET profiling confirmed compliance with Lipinski’s rule and predicted favorable gastrointestinal absorption. Molecular docking revealed high COX-2 binding affinities (−11.93 to −9.72 kcal/mol), while MM/GBSA analysis identified compound N4_c (ΔG = −62.27 kcal/mol) as the most stable complex, surpassing meloxicam and naproxen. DFT (B3LYP/6-31G(d,p)) frontier molecular orbital analysis indicated a narrow HOMO–LUMO gap (ΔE = 2.97 eV) for N4_c, suggesting high electronic reactivity and strong enzyme interaction. Molecular dynamics simulations confirmed complex stability. In vivo anti-inflammatory testing using an egg-white-induced rat paw edema model showed that N4_d, N4_e, and N4_f achieved higher inhibition (19.22%, 16.98%, and 16.98%) than naproxen (4.3%). These results highlight 2-azetidinone–naproxen hybrids as promising selective COX-2 inhibitors with enhanced pharmacokinetic and electronic properties. Full article