Search Results (118)

Introduction: Tumor necrosis factor-α (TNF-α) is a key regulator of inflammatory responses, and its biological activity is dependent on proteolytic processing by the tumor necrosis factor-α-converting enzyme (TACE), also known as ADAM17. Aberrant TACE activity has been associated with various inflammatory and immune-mediated diseases, positioning it as a compelling target for therapeutic intervention. Methods: While our previous study explored TACE inhibition via repositioned FDA-approved drugs, the present study aims to examine previously untested chemical scaffolds from the Enamine compound library, seeking first-in-class TACE inhibitors. We employed an integrated in silico workflow that combined ligand-based virtual screening using a graph convolutional network (GCN) model trained on known TACE inhibitors with structure-based methodologies, including molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. Results: Several enamine-derived compounds demonstrated strong predicted inhibitory potential, favorable docking scores, and stable interactions with the TACE active site. Among them, Z1459964184, Z2242870510, and Z1450394746 emerged as lead candidates based on their highly stable 300 ns RMSD and robust hydrogen bonding profile as compared to the reference compound BMS-561392. Conclusions: This study highlights the utilization of deep learning-driven screening combined with extended 300 ns molecular simulations to identify novel small-molecule scaffolds for TACE inhibition and supports further exploration of these hits as potential anti-inflammatory therapeutics. Full article

Our work introduces a facile and efficient metal-free [3+3] annulation approach for the synthesis of polysubstituted pyridines via the reaction between β-enaminonitriles and β,β-dichloromethyl peroxides. This strategy operates under mild conditions, demonstrating broad substrate scope and excellent functional group tolerance. Mechanistic investigations suggest that the reaction proceeds through a Kornblum–De La Mare rearrangement followed by S_NV-type C-Cl bond cleavage and intramolecular cyclization/condensation. By circumventing the need for transition metal catalysts or radical initiators, our method offers practical utility in organic synthesis and provides a new avenue for the rapid construction of complex pyridine scaffolds. Full article

This study developed a novel water-soluble Cellulose Acetoacetate (CAA)-chitosan (CS) composite hydrogel drug delivery system. In this system, CAA and CS molecules are cross-linked via dynamic enamine bonds, forming a three-dimensional network structure suitable for drug encapsulation and controlled release. The primary objective was to address the challenges associated with the short half-life and significant fluctuations in therapeutic concentration of cytokine drugs, such as interleukin-2 (IL-2). A hydrogel system with a three-dimensional spatial network structure was successfully constructed via dynamic enamine bonds cross-linking between the acetoacetate groups in CAA molecules and the amino groups in CS. This system exhibits the following characteristics: (1) Dynamic covalent bonds impart adjustable mechanical properties to the hydrogel, enabling precise control over gelation time and mechanical performance; (2) A hierarchical pore structure (average pore size of 100–200 μm) provides a three-dimensional confined space for efficient drug encapsulation, achieving an IL-2 encapsulation efficiency of 83.3 ± 3.1%; (3) In vitro release studies demonstrated that the cumulative release of IL-2 within 72 h ranged from 18.4% to 34.7%, indicating sustained-release behavior. Cell viability assays confirmed that the hydrogel maintained the survival rate of L929 cells above 85% (as determined by the CCK-8 method), and live/dead staining revealed no apparent cytotoxicity. Overall, this three-dimensional network hydrogel based on dynamic covalent bonds represents a promising strategy for low-dose, long-lasting cytokine delivery. Full article

Iodosulfonylation of an ethynyl group at the C2 position of 2′-deoxyadenosine or adenosine with TsI provides (E)-2-(β-iodovinyl)sulfones. The latter undergo nucleophilic substitution with amines via an addition–elimination to give β-sulfonylvinylamines (enamines). Acid-catalyzed hydrolysis of the β-sulfonylvinylamines provides 2-(β-keto)sulfones, mechanistically different probes that react with alkyl halides, resulting in α-alkylation. Adenine nucleosides with a β-ketosulfone group at C2, during conversion to their 5′-triphosphate form, undergo an unexpected conversion to 2-carboxylic acid nucleotides. The 5′-triphosphate of 2′-deoxyadenosine-2-carboxylic acid was incorporated by a human DNA polymerase into a one-nucleotide gap DNA substrate. Full article

Despite the great successes achieved by metallocene catalysts in high-value-added polyolefin elastomer, the challenging preparation conditions and undesirable high-temperature molecular weight capabilities have compromised the efficiency and cost of polyolefin in industrial production. Recently, non-metallocene catalysts have received considerable attention due to their high thermostability, especially when coordinated with early transition metals. This review provides an overview of these early transition metal non-metallocene catalysts, which are mainly composed of N,N′-, N,O-, and N,S-bidentate complexes and tridentate complexes. The structural characteristics, catalytic performance, advantages, and disadvantages of the relevant non-metallocene catalysts, as well as their applications, are discussed. Candidates for commercialization of non-metallocene catalysts are proposed—focusing on imine-enamine, amino-quinoline, and pyridine-imine catalysts—by comparing the successful industrialization cases of metallocene catalysts. Finally, the trend in the research on non-metallocene catalysts and the strategies to address the challenges limiting their commercialization are considered. Full article

Pyrrole-type compounds are widely known for their potential biological activity. However, methods for synthesizing 2,3,4,5-tetrasubstituted pyrroles remain limited. This study explores an intramolecular cyclocondensation of 2-amino acid-derived enamines to yield novel 1-(5-substituted-4-hydroxy-2-methyl-1H-pyrrol-3-yl)ethan-1-ones. Using ʟ-alanine, ʟ-tyrosine, ʟ-phenylalanine, and ʟ-tryptophan, the corresponding 2-amino esters were synthesized, converted into enamines, and cyclized under microwave irradiation (55–86% yield). The highest yield was obtained from methyl ʟ-phenylalaninate (R¹ = CH₂Ph, R⁴ = Me). Steric hindrance from bulkier groups reduced yields, while the electronic nature of R¹ influenced reactivity. Structural analysis (NMR, HR-ESI-MS) confirmed product identities, and a 5-exo-trig cyclization mechanism explained base-mediated deprotonation and steric effects. These findings highlight steric and electronic factors in this cyclocondensation, guiding reaction optimization for valuable heterocycles. Full article

1,2-Diphenylethylenediamine (DPEDA) is a privileged chiral scaffold being used in the construction of a broad variety of organocatalysts and ligands for enantioselective organic reactions. This molecule gave a significant contribution in the synthesis of structurally different bi/multifunctional organocatalysts. DPEDA played an essential role in the development of organocatalysts capable of yielding important information on the different reaction mechanisms, like enamine, iminium, hydrogen-bonding and anion-binding catalysis. The aim of the present review is to highlight and summarize the achievements reached in the last 20 years (2004–2024) in the chemistry of DPEDA-based organocatalysts for asymmetric synthesis. Full article

A one-carbon difluorocyclopropanation/ring-expansion has been developed for the chiral synthon Cyrene, which is obtained via cellulose pyrolysis. The ring-enlargement was achieved by converting Cyrene (dihydrolevoglucosenone) into an enamine, reacting it with an in situ-generated difluorocarbene, and then heating it to ring-open the cyclopropane. Access to the product provides access to fluorinated analogues of this valuable chiral biomass derivative. Full article

Enantiopure tetrahydroisoquinolines (THIQs), recognized as privileged skeletal structures in natural alkaloids, have attracted considerable attention from chemists due to their biological and pharmacological activities. Synthetic strategies for optically active THIQs have been rapidly and extensively developed in the past decades. In view of simplicity and atom economy, asymmetric reduction of N-heteroaromatics, imines, enamines, and iminium salts containing an isoquinoline (IQ) moiety should be the preferred approaches to obtain chiral THIQs. This review focuses on recent advances in the catalytic asymmetric synthesis of enantiopure THIQs via asymmetric reduction, including asymmetric hydrogenation, transfer hydrogenation, reductive amination, and deracemization. Highly enantioselective synthesis of THIQs was achieved via transition-metal-catalyzed asymmetric reduction and organocatalytic asymmetric reduction utilizing either catalyst activation or substrate activation strategy. Despite much progress in the enantioselective synthesis of THIQs, there still remain considerable opportunities and challenges for progress and developments in this field of research, particularly in the development of asymmetric catalytic systems for the direct reduction of IQs. Full article

Gossypol and its derivatives arouse interest due to their broad spectrum of biological activities. Despite its wide potential application, there is no reported example of gossypol derivatives bearing stable radical functional groups. The first gossypol nitroxide hybrid compound was prepared here via formation of a Schiff base. By this approach, synthesis of a gossypol nitroxide conjugate was performed by condensation of gossypol with a 4-amino-TEMPO (4-amino-2,2,6,6-tetramethylpiperidin-1-oxyl) free radical, which afforded the target product in high yield. Its structure was proven by a combination of NMR and EPR spectroscopy, infrared spectroscopy, mass spectrometry, and high-resolution mass spectrometry. In addition, the structure of the gossypol nitroxide was determined by single-crystal X-ray diffraction measurements. In crystals, the paramagnetic Schiff base exists in an enamine–enamine tautomeric form. The tautomer is strongly stabilized by the intra- and intermolecular hydrogen bonds promoted by the resonance of π-electrons in the aromatic system. NMR analyses of the gossypol derivative proved that in solutions, the enamine–enamine tautomeric form prevailed. The gossypol nitroxide at micromolar concentrations suppressed the growth of tumor cells; however, compared to gossypol, the cytotoxicity of the obtained conjugate was substantially lower. Full article

In the search for novel polymeric molecules that could be used as electroactive materials, seven novel polyenaminones were prepared in high yields by the transaminative polymerization of resorcinol-derived bis-enaminones with m- and p-phenylenediamine and with 2,5-diaminohydroquinone. The obtained polymers show very low solubility in organic solvents and absorb UV light and visible light at wavelengths below 500 nm. All the obtained polymeric products were tested for redox activity in a Li battery setup. The 2,5-diaminohydroquinone-derived compound showed the best redox activity, with a maximum capacity of 86 mAh/g and relatively good capacity retention, thus confirming the hydroquinone group as the primary redox-active group. Other potential redox-active groups, such as resorcinol and conjugated carbonyls, showed limited activity, while variations in the phenylene groups and the substitution of phenolic groups in the resorcinol residue did not impact the electrochemical activity of the polymers. Their electrochemical properties, together with their previously established chemical recyclability, make polyenaminones promising scaffolds for the development of materials for sustainable energy storage applications. Full article

2-Chloropyridine-3-carbonitrile derivative 1 was utilized as a key precursor to build a series of linear and angular annulated pyridines linked to a 6-hydroxy-4,7-dimethoxybenzofuran moiety. Reaction of substrate 1 with various hydrazines afforded pyrazolo[3,4-b]pyridines. Treatment of substrate 1 with 1,3-N,N-binucleophiles including 3-amino-1,2,4-triazole, 5-amino-1H-tetrazole, 3-amino-6-methyl-1,2,4-triazin-5(4H)-one and 2-aminobenzimidazole produced the novel angular pyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrimidine, pyrido[3,2-e][1,2,4]tetrazolo[1,5-a]pyrimidine, pyrido[3′,2′:5,6] pyrimido[2,1-c][1,2,4]triazine and benzo[4,5]imidazo[1,2-a]pyrido[3,2-e]pyrimidine, respectively. Reaction of substrate 1 with 1,3-C,N-binucleophiles including cyanoacetamides and 1H-benzimidazol-2-ylacetonitrile furnished 1,8-naphthyridines and benzoimidazonaphthyridine. Moreover, reacting substrate 1 with 5-aminopyrazoles gave pyrazolo[3,4-b][1,8]naphthyridines. Finally, reaction of compound 1 with 6-aminouracils as cyclic enamines yielded pyrimido[4,5-b][1,8]naphthyridines. Some of the synthesized products showed noteworthy antimicrobial efficiency against all types of microbial strains. Structures of the produced compounds were established using analytical and spectroscopic tools. Full article

A curious and noticeable structural feature in Schiff bases from 2-aminoaldoses is the fact that imino tautomers arranged equatorially in the most stable ring conformation exhibit a counterintuitive reverse anomeric effect (RAE) in the mutarotational equilibrium, i.e., the most stable and abundant anomer is the equatorial one (β). As shown by our very recent research, this effect arises from the total or partial inhibition of the exo-anomeric effect due to the presence of an intramolecular hydrogen bond between the anomeric hydroxyl and the iminic nitrogen in the axial anomer (α). When the Schiff base adopts either an enamine structure or the imino group is protonated, the exo-anomeric effect is restored, and the axial α-anomer becomes the most stable species. Although the intramolecular H-bonding should appropriately be interpreted as a genuine stereoelectronic effect, the magnitude of the RAE could be affected by other structural parameters. Herein and through a comprehensive analysis of benzylidene, cinnamylidene, naphthalene, phenanthrene, and anthracene aldehydes, we show the robustness of the RAE effect, which is similar in extent to simple aldehydes screened so far, irrespective of the size and/or hydrophobicity of the substituent at the nitrogen atom. Full article

The unusual reactivity of key enamine intermediates led to the formation of 3-methylamino-2-(2-nitrobenzoyl)-4H-naphthalen-1-one as an unexpected product in an attempted synthesis of the P. aeruginosa metabolite 2-benzyl-4(1H)-quinolone. Although the synthesis of the natural product has not been successful, this methodology allows for the easy preparation of novel derivatives carrying a carboxamide moiety at the C3 position. Full article

The goal of this study was directed to synthesize a novel class of annulated compounds containing difuro[3,2-c:3′,2′-g]chromene. Friedländer condensation of o-aminoacetyl derivative 3 was performed with some active methylene ketones, namely, 1,3-cyclohexanediones, pyrazolones, 1,3-thiazolidinones and barbituric acids, furnished furochromenofuroquinolines (4,5), furochromenofuropyrazolopyridines (6–8), furochromenofurothiazolopyridines (9,10) and furochromenofuropyridopyrimidines (11, 12), respectively. Also, condensation of substrate 3 with 5-amine-3-methyl-1H-pyrazole and 6-amino-1,3-dimethyluracil, as cyclic enamines, resulted in polyfused systems 13 and 14, respectively. In vitro antimicrobial efficiency of the prepared heterocycles against microbial strains exhibited variable inhibition action, where compound 3 was the most effective against all kinds of microorganisms. A significant cytotoxic activity was seen upon the annulation of the starting compound with thiazolopyridine (9 and 10) as well as pyridopyrimidine moieties (11, 12 and 14). The spectroscopic and analytical results were used to infer the structures of the novel synthesized compounds. Full article