Search Results (887)

Six 1,4-disubstituted pyrazoles linked to a benzenesulfonamide and a benzodioxane unit have been synthesized through a copper(I)-catalyzed formal [3+2] cycloaddition (32CA) reaction of alkynes with 3-arylsydnones. The Cu-catalyzed sydnone–alkyne cycloaddition (CuSAC) procedure has been optimized to promote the formation of the pyrazole ring and to deliver in three steps the six target compounds 5a–f, fully characterized by ¹H/¹³C-NMR and mass spectrometry (EIMS). Ten solvent conditions were evaluated. The reaction proceeded most efficiently in the presence of copper(II) sulfate pentahydrate in aqueous t-butanol in the presence sodium acetate, to reach a yield of 96%. The mechanism of the Cu(I)-catalyzed reaction has been studied within the Molecular Electron Density Theory (MEDT). This rection is a domino process that consists in a Cu(I)-catalyzed formal [3+2] cycloaddition followed of an extrusion of CO₂ yielding the final pyrazole. The capacity of heterocyclic compounds 5a–f to interact with human cyclophilin A (Cyp A), which is a host cofactor for hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1), and with the HIV-1 protein gp120-CD4 was evaluated using molecular docking. Compounds 5a,b,d,f showed a satisfactory protein binding capacity. The physicochemical and metabolic properties of the compounds were also evaluated in silico. These predictions provide important information to guide future design in this series of potential antiviral agents. Full article

Gold(I) complexes are particularly useful as catalysts in a variety of reactions including, in particular, the electrophilic activation of alkyne substrates, yet they generally require the addition of a silver salt to activate the gold complex by removing an anionic ligand. This results into higher costs and possible problems related to the non-innocence of the silver additive. In this contribution, we highlight the possibility to proficiently use a dinuclear monocationic gold(I) complex developed in our laboratory as a silver-free catalyst. The complex, featuring a bridging N-phosphanyl-N-heterocyclic carbene (NHCP) ligand, indeed exhibits notable activity and selectivity in standard alkyne hydroamination and hydroalkoxylation reactions, particularly in the case of internal alkynes and secondary aromatic amines as substrates. Full article

Donor human milk (DHM) provided by human milk banks is considered the optimal feeding alternative to mother’s own milk for premature or medically compromised infants. Before distribution, DHM is subjected to Holder pasteurization (HoP) by milk banks to eliminate potential pathogens. In this study, FT-IR, GC and GC-MS were applied to characterize changes in the volatile organic compounds (VOCs) and lipid components of human milk (HM) samples that were treated by HoP. FT-IR analysis revealed changes in specific band regions, indicating modifications to triglycerides and fatty acid (FA) organization and possible disruption of the milk fat globule membrane. There was also an increase in ester groups, suggesting that HoP increases lipid oxidation. GC analysis showed a reduction in long-chain FAs, including certain omega-3 and omega-6 polyunsaturated FAs (PUFAs). GC-MS analysis showed that HoP-treated samples contained higher levels of alkanes, aldehydes, aromatics and ketones than raw HM. Conversely, other compounds, including furans, and alkynes, were found exclusively in pasteurized HM. These results show that HoP affects the lipid and VOC components of HM, highlighting the need for research into alternative pathogen elimination strategies in human milk bank practices. Full article

Alkenylidenecyclopropanes (ACPs) have emerged as versatile and highly reactive building blocks in transition-metal-catalyzed transformations. Their strained cyclopropane framework, combined with an exocyclic alkene, enables diverse bond-activation pathways and promotes efficient cycloaddition reactions. In recent years, ACPs have been widely developed as three-carbon synthons in a variety of higher-order cycloadditions. This review provides a systematic overview of transition-metal-catalyzed ACP transformations, focusing on their applications in [3+2], [3+2+2], [3+2+1], [4+3], and [4+3+2] cycloaddition reactions with reaction partners such as alkenes, alkynes, carbonyl compounds, imines, dienes, and carbon monoxide. Particular attention is given to mechanistic aspects, including cyclopropane ring-opening processes and the formation of key metal–carbene and π-allyl intermediates that govern reactivity and selectivity. Factors influencing regioselectivity, stereoselectivity, and catalyst design are also discussed. The synthetic potential of ACP chemistry is illustrated through representative applications in the total synthesis of complex natural products, such as pyrovellerolactone and (+)-zizaene. Overall, this review highlights recent advances in ACP-based cycloaddition strategies and emphasizes their growing significance in modern synthetic chemistry. Full article

We report a straightforward and versatile synthetic route to pyridinium-fused 1,3-selenazoles via the electrophilic cyclization of 2-pyridylselenyl chloride with alkynes. The reaction proceeds efficiently under mild conditions with representative terminal and internal alkynes. While the cyclization exhibits high regioselectivity favoring the 3-substituted isomer for most substrates, reactions with 2-pyridyl- and 2-quinolylacetylenes yield regioisomeric mixtures. DFT calculations rationalize this divergence, revealing a competition between kinetic and thermodynamic control; the 3-isomer is kinetically favored, while the 2-isomer is thermodynamically stabilized by an ancillary chalcogen bond between the selenium atom and the pyridine nitrogen of the alkyne substituent. Molecular structures were confirmed by single-crystal X-ray diffraction, and the non-covalent interactions governing supramolecular assembly in the solid state were rigorously analyzed using MEP surfaces, the QTAIM, and NBO analysis. Antifungal evaluation identified several compounds with notable activity against phytopathogenic fungi, highlighting the potential of this novel heterocyclic scaffold in agrochemical applications. Full article

Monoacylglycerol lipase (MAGL) is a key regulator of lipid signaling networks implicated in tumor progression and represents an attractive anticancer target. To combine MAGL inhibition with potentially enhanced uptake by highly glycolytic cancer cells, we designed glycoconjugated analogs of a N-benzoylpiperidine MAGL inhibitor scaffold bearing a glucopyranose unit. An alkyne-functionalized benzoylpiperidine intermediate was prepared and coupled to azido sugars through a CuAAC “click” reaction to afford two triazole-linked glycoconjugates. In a colorimetric assay on human MAGL, the new compounds 17 and 18 inhibited the enzyme with IC₅₀ values of 43.3 and 68.8 μM, respectively, confirming compatibility with MAGL inhibition albeit with reduced potency versus reference triazole-substituted benzoylpiperidine 13 (IC₅₀ = 4.1 μM). In PANC-1 pancreatic cancer cells, both glycoconjugates were inactive in high-glucose medium, but displayed antiproliferative activity under low-glucose conditions (GI₅₀ 17 = 129 μM; GI₅₀ 18 = 12 μM), consistent with glucose-dependent uptake/competition. Overall, these first-in-class MAGL-targeting glycoconjugates provide a starting point for optimizing dual MAGL inhibition and metabolically driven cellular selectivity. Full article

1,4-Disubstituted 1,2,3-triazoles are readily obtained by copper(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC)—the most widespread illustration of click chemistry to date. 1,2,3-Triazoles form a vast and easily accessible library of precursors for synthesizing 1,2,3-triazolium ionic liquids (TILs). A series of four 1,3,4-trisubstituted TILs with N-1-n-octyl, N-3-methyl and different C-4 substituents (i.e., aromatic, aliphatic, PEGylated and perfluorinated groups) is synthesized in two steps involving: (i) CuAAC to generate 1,2,3-triazole precursors and (ii) N-alkylation of the 1,2,3-triazole groups with methyl iodide to afford the corresponding 1,2,3-triazolium salts with iodide counter-anions. A thorough investigation of the correlations between structure and properties is carried out using NMR spectroscopy, high-resolution mass spectrometry, differential scanning calorimetry, thermogravimetric analysis and broadband dielectric spectroscopy. The PEGylated TIL has also undergone ion metathesis to produce the TIL analogue with a bis(trifluoromethylsulfonyl)imide counter-anion. Of all the synthesized TILs, this derivative exhibits the lowest glass transition temperature (T_g = −76 °C), the highest thermal stability (T_d10 = 345 °C) and the greatest ionic conductivity (σ_DC = 6.5 × 10⁻⁴ S cm⁻¹ at 30 °C under anhydrous conditions). Full article

Antimicrobial resistance (AMR) threatens global health, particularly through the rise of multidrug-resistant tuberculosis (MDR-TB) and other critical bacterial infections such as methicillin-resistant Staphylococcus aureus (MRSA). Rifamycins remain frontline antibiotics but are increasingly undermined by resistance. Here, we introduce a click-enabled platform for the synthesis of C8-functionalized rifamycins, which can be converted in a single additional step into efficacious 3′-hydroxy-5′-aminobenzoxazinorifamycins (bxRifs) and enzymatically into 25-deacetylated rifamycins (deAcRifs), providing access to novel antibacterial scaffolds that expand beyond the scope of traditional C8 modifications. Accordingly, we establish a modular strategy for late-stage analog development of the complex natural product rifamycin S, wherein azido and alkyne functionalities are installed via tailored core chemistry and converted into 1,2,3-triazoles through copper(I)-catalyzed click chemistry. Another key feature of this work is the development of systematic HPLC purification methods, enabling the isolation of analytically pure compounds despite structural complexity. The resulting analogs exhibit distinct antibacterial profiles, notably against Gram-positive bacteria including MRSA and Streptococcus mutans, informing structure–activity relationships and offering a foundation for further optimization. This approach supports the rapid diversification of rifamycin scaffolds to combat the escalating threat of AMR, while also establishing a foundation for future discovery through bioorthogonal applications. Full article

Amphiphilic copolymers based on polystyrene and polyglycidol combine the chemical inertness of polystyrene with the biocompatibility of polyglycidol, making them attractive materials for polymeric micelles. While comb-like architectures have been explored to control micellization behavior and biological response, a direct comparison between comb-like and coil-comb topologies in polystyrene–polyglycidol copolymers at identical polyglycidol content remains insufficiently investigated. In this work, amphiphilic comb-like and coil-comb polystyrene–polyglycidol copolymers were synthesized via copper-catalyzed azide–alkyne click chemistry by grafting a monoalkyne-terminated polyglycidol precursor onto azide-functionalized random and block styrene copolymers. The copolymers were characterized by size exclusion chromatography and nuclear magnetic resonance. Polymeric micelles were prepared by nanoprecipitation, and their self-assembly in aqueous solution was investigated by critical micelle concentration determination, dynamic and electrophoretic light scattering, and atomic force microscopy. Both copolymers formed stable aqueous dispersions and exhibited comparable critical micelle concentrations. At identical polyglycidol content, the random copolymer formed a uniform, monomodal micellar population, whereas the block-based coil-comb architecture led to bimodal size distributions, indicating the coexistence of two distinct micellar populations. The investigated systems showed low cytotoxicity and did not induce significant oxidative stress within the studied concentration range. On isolated rat brain sub-cellular fractions (synaptosomes, mitochondria and microsomes), administered alone, the comb-like and coil-comb polystyrene-polyglycidol copolymers did not reveal statistically significant neurotoxic effects. The results demonstrate that macromolecular architecture plays a key role in governing micellar organization and in vitro biological response in polystyrene–polyglycidol copolymers, highlighting their potential as architecture-controlled polymer-based nanocarriers. Full article

The cycloaddition reaction is one of the most common reactions in organic chemistry. It has been applied in various fields. Herein, we focus on the application of cycloaddition reactions in investigating biological molecules and materials using magnetic resonance techniques. To facilitate magnetic resonance studies such as electron paramagnetic resonance (EPR) spectroscopy and paramagnetic nuclear magnetic resonance (NMR) spectroscopy, there is often a requirement to attach spin labels and paramagnetic tags to the system of interest. The cycloaddition reaction is one of the ways to tether these spin labels and paramagnetic tags. In this review, we highlight the applications of various cycloaddition reactions such as the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction, the strain-promoted azide–alkyne cycloaddition (SPAAC) reaction and the Diels–Alder reaction in the interdisciplinary field of magnetic resonance studies of biomolecules, including proteins, nucleic acids, carbohydrates, lipids and glycans, as well as materials. Full article

Click chemistry is highly valued in the design of polymeric biomaterials due to its ability to generate complex structures and localized surface modifications. However, prominent mechanisms in click chemistry, such as copper-catalyzed azide-alkyne cycloaddition (CuAAC), are inefficient for the synthesis and/or modification of biomaterials because they present significant limitations for in vivo applications. The presence of residual copper in the material is toxic and requires extensive purification, increasing production costs and hindering scalability and availability for in vivo applications. To overcome these limitations and ensure the safety and biocompatibility of materials, biorthogonal reactions such as strain-promoted azide-alkyne cycloaddition (SPAAC) have been developed. Thiol-ene/thiol-yne and Diels–Alder mechanisms are also relevant for the formation of robust polymer networks with specific characteristics and attractive advantages for generating biocompatible materials. These reactions not only improve cell integration and reduce fibrosis in in vivo applications but also enable the creation of functional structures for tissue regeneration. This review provides a comprehensive analysis of advances in the synthesis of biomaterials for tissue regeneration using hydrogels designed via click chemistry, as well as the various mechanisms and structural considerations. Full article

This work reports the synthesis and characterization of a new molecular hybrid 4, created by combining 1,4-naphthoquinone with the drug zidovudine (AZT) through an azide-alkyne cycloaddition reaction catalyzed by Cu¹⁺. In vitro studies assessed the anti-trypanosomatid activity of hybrid 4, along with its precursors and synthetic intermediates (1, 2, and 3), against Trypanosoma cruzi (T. cruzi Tulahuen C2C4 LacZ), Trypanosoma brucei (T. b. brucei 427), and Leishmania infantum, as well as cytotoxicity in RAW 264.7 macrophages and LLC-MK2 cells. The biological results confirm the molecular design, showing that the new hybrid is effective against both epimastigotes and amastigotes of T. cruzi (IC₅₀ = 22.26 ± 5.78 μM and 143.10 ± 5.79 μM, respectively), with approximately 4.5-fold better capacity than AZT to inhibit the epimastigote form. Additionally, the hybrid was also active against bloodstream T. b. brucei (IC₅₀ = 54.47 ± 6.70 μM), with approximately 2.2-fold better capacity than AZT to inhibit this parasite. It also shows low toxicity in RAW 264.7 macrophages (CC₅₀ > 200 μM) and LLC-MK2 cells (CC₅₀ > 200 μM). For example, hybrid 4 exhibited approximately a 6.6-fold higher SI than 1,4-naphthoquinone 1 against T. cruzi amastigotes. In this context, the work contributes to the broader knowledge base guiding the design of hybrid molecules for antiparasitic chemotherapy. It provides a rational foundation for preparing subsequent, more potent analogues. Full article

Apart from in hydrosilylation, platinum has traditionally played a limited role in homogeneous catalysis due to its high thermodynamic stability and lower intrinsic reactivity compared to other group 10 metals. However, the emergence of N-heterocyclic carbene (NHC) ligands has substantially broadened the catalytic profile of transition metals by enabling access to new mechanistic pathways and enhancing robustness under demanding conditions. This review summarizes advances in Pt–NHC catalysis reported between 2010 and 2025. These transformations encompass hydrosilylation of amides and CO₂, hydroboration and diboration, hydroamination, alkyne hydration, hydrogenation, selective alkyne dimerization, Suzuki–Miyaura coupling, arene C–H borylation, and cycloisomerization reactions, in which NHC ligands enhance bond activation, control regio- and stereoselectivity, and stabilize reactive Pt intermediates, including chiral architectures, enabling high enantioselectivity. Full article

We report the first synthesis of IspH-directed prodrugs targeting the terminal enzyme of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, (E)-4-hydroxy-3-methylbut-2-enyl diphosphate reductase (IspH or LytB). A series of alkyne and pyridine monophosphate cycloSaligenyl (cycloSal) prodrugs were prepared to enhance membrane permeability by masking the phosphate group. The effects of electron-withdrawing (Cl, CF₃) and electron-donating (OCH₃, NH₂) substituents were examined, together with amino acid-functionalized and mutual prodrug analogs. Among the synthesized compounds, chlorine-substituted derivatives 5c and 6c displayed the strongest antimycobacterial activity against Mycobacterium smegmatis, surpassing isoniazid in agar diffusion assays. These results indicate that electron-withdrawing substituents accelerate prodrug hydrolysis and facilitate intracellular release of the active inhibitor. This work provides the first experimental evidence of an IspH-targeted prodrug approach, highlighting the cycloSal strategy as a valuable tool for delivering phosphorylated inhibitors and developing novel antimycobacterial agents acting through the MEP pathway. Full article

A synthetically accessible library of N-acyl sulfonamides was constructed using a combination of copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) and N-acylation of primary sulfonamides. The proposed two-step reaction sequence had a high experimentally confirmed synthetic success rate (up to 85%) and gave reasonable product yields (up to 61%). As a result of the validation process, a 262-member compound library (out of >70K accessible combinations) was prepared. Biological profiling of the synthesized library by differential scanning fluorimetry and enzymatic assays identified several low micromolar inhibitors of human carbonic anhydrase. The interaction of the discovered hits with the biological target was studied by docking and molecular dynamics. Full article