Search Results (105)

In this study, the design and synthesis of a novel series of cinnamic acid and 1,2,4-triazole hybrids were reported, aiming to enhance antioxidant and lipoxygenase inhibitory activities through pharmacophore combination. Cinnamic acid derivatives and 1,2,4-triazoles exhibit a broad spectrum of biological activities; therefore, by synthesizing hybrid molecules, we would like to exploit the beneficial characteristics of each scaffold. The general synthetic procedure comprises three synthetic steps, starting from the reaction of appropriate substituted cinnamic acid with hydrazine monohydrate in acetonitrile with cyclohexane and resulting in the formation of hydrazides. Consequently, the hydrazides reacted with phenylisothiocyanate under microwave irradiation conditions. Then, cyclization proceeded to the 1,2,4-triazole after the addition of NaOH solution and microwave irradiation. All the synthesized derivatives have been studied for their ability (a) to interact with the free radical DPPH, (b) inhibit lipid peroxidation induced by AAPH, and (c) inhibit soybean lipoxygenase. The synthesized derivatives have shown significant antioxidant activity and have been proved to be very good lipoxygenase inhibitors. Compounds 4b and 4g (IC₅₀ = 4.5 μM) are the most potent within the series followed by compound 6a (IC₅₀ = 5.0 μM). All the synthesized derivatives have been subjected to docking studies related to soybean lipoxygenase. Compound 4g exhibited a docking score of −9.2 kcal/mol and formed hydrophobic interactions with Val126, Tyr525, Lys526, Arg533, and Trp772, as well as a π−cation interaction with Lys526. 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

Spirocyclic architectures, which feature two rings sharing a single atom, are common in natural products and exhibit beneficial biological and material properties. Due to the significance of these architectures, biocatalytic dearomative spirocyclization has recently emerged as a powerful approach for constructing three-dimensional spirocyclic frameworks under mild, sustainable conditions and with exquisite stereocontrol. This review surveys the latest advances in biocatalyzed spirocyclization of all-carbon arenes (phenols and benzenes), aza-aromatics (indoles and pyrroles), and oxa-aromatics (furans). We highlight cytochrome P450s, flavin-dependent monooxygenases, multicopper oxidases, and novel metalloenzyme platforms that effect regio- and stereoselective oxidative coupling, epoxidation/semi-pinacol rearrangement, and radical-mediated cyclization to produce diverse spirocycles. Mechanistic insights gleaned from structural, computational, and isotope-labeling studies are discussed where necessary to help the readers further understand the reported reactions. Collectively, these examples demonstrate the transformative potential of biocatalysis to streamline access to spirocyclic scaffolds that are challenging to prepare through traditional methods, underscoring biocatalysis as a transformative tool for synthesizing pharmaceutically relevant spiroscaffolds while adhering to green chemistry paradigms to ultimately contribute to a cleaner and more sustainable future. Full article

With the rapid development of radical initiation technologies such as photocatalysis and electrocatalysis, radical reactions have become an increasingly attractive approach for constructing target molecules. However, designing efficient synthetic routes using radical reactions remains a significant challenge due to the inherent complexity and instability of radical intermediates. While computer-aided synthesis planning (CASP) has advanced retrosynthetic analysis for polar reactions, radical reactions have been largely overlooked in AI-driven approaches. In this study, we introduce RadicalRetro, the first deep learning-based retrosynthesis model specifically tailored for radical reactions. Our work is distinguished by three key contributions: (1) RadicalDB: A novel, manually curated database of 21.6 K radical reactions, focusing on high-impact literature and mechanistic clarity, addressing the critical gap in dedicated radical reaction datasets. (2) Model Innovation: By pretraining Chemformer on ZINC-15 and USPTO datasets followed by fine-tuning with RadicalDB, RadicalRetro achieves a Top-1 accuracy of 69.3% in radical retrosynthesis, surpassing the state-of-the-art models LocalRetro and Mol-Transformer by 23.0% and 25.4%, respectively. (3) Interpretability and Practical Utility: Attention weight analysis and case studies demonstrate that RadicalRetro effectively captures radical reaction patterns (e.g., cascade cyclizations and photocatalytic steps) and proposes synthetically viable routes, such as streamlined pathways for Tamoxifen precursors and glycoside derivatives. RadicalRetro’s performance highlights its potential to transform radical-based synthetic planning, offering chemists a robust tool to leverage the unique advantages of radical chemistry in drug synthesis. Full article

This study reports the synthesis, characterization, and antifungal evaluation of a series of pyridoxal and salicylaldehyde derivatives, using synthetic methodologies such as radical cyclizations and click chemistry. Compounds 6a and 6b, featuring a fused dihydrobenzoxepine-pyridine scaffold, demonstrated effective fungicidal activity with MIC values of 19 µg/mL against Cryptococcus neoformans 2807. Similarly, compound 6b exhibited notable activity with a MIC of 75 µg/mL against Candida auris PUJ-HUSI 537. Both compounds outperformed fluconazole (FLC) in these strains. In silico ADMET profiling revealed favorable pharmacokinetic properties, including blood–brain barrier penetration and drug-likeness parameters consistent with Lipinski’s rule of five. Cytotoxicity assays on human fibroblasts confirmed the low toxicity of compound 6a at the tested concentrations. These results highlight the potential of the fused dihydrobenzoxepine-pyridine scaffold as a promising antifungal candidate for further investigations. Full article

Quorum quenchers are emerging as an alternative to conventional antimicrobials, since they hinder the development of virulence or resistance mechanisms but without killing the microorganisms, thus, reducing the risk of antimicrobial resistance. Many quorum quenchers are analogs of the natural quorum-sensing signaling molecules or autoinducers. Thus, different analogs of natural N-acylhomoserine lactones (AHLs) have been reported for controlling virulence or reducing the production of biofilms in Gram-negative pathogens. Herein we report the preparation of AHL analogs with a variety of N-substituents in just two steps from readily available N-substituted hydroxyproline esters. The substrates underwent an oxidative radical scission of the pyrrolidine ring. The resulting N-substituted β-aminoaldehyde underwent reduction and in situ cyclization to give a variety of homoserine lactones, with N- and N,N-substituted amino derivatives and with high optical purity. The libraries were screened for the inhibition of violacein production in Chromobacterium violaceum, a Gram-negative pathogen. For the first time, N,N-disubstituted AHL analogs were studied. Several N-sulfonyl derivatives, one carbamoyl, and one N-alkyl-N-sulfonyl homoserine lactone displayed a promising inhibitory activity. Moreover, they did not display microbicide action against S. aureus, C. jejuni, S. enterica, P. aeruginosa, and C. albicans, confirming a pure QQ activity. The determination of structure–activity relationships and in silico ADME studies are also reported, which are valuable for the design of next generations QQ agents. Full article

The hypervalent iodine-mediated formation of steroidal 5/5-spiroiminals and 5/5-spiroaminals from steroidal amines is presented. Under the influence of excess PhI(OAc)₂ and iodine in acetonitrile at 0 °C, steroidal amines smoothly underwent cyclization to give a mixture of 5/5-spiroiminals and 5/5-spiroaminals. This reaction represents the first example of a C-H-activation-mediated formation of a spiroiminal. Presumably, the formation of 5/5-spiroiminals occurs through aminyl radical-mediated cyclization followed by amine-to-imine oxidation. Full article

The results of rheological studies and thermal analysis of polymer compositions based on polyacrylonitrile copolymers (PAN) of different molecular weights and asphalt isolated by n-pentane solvent deasphalting are presented. It was found that the asphalt content in mixtures with PAN at the level of 10–30 wt.% improves the rheological properties of the polymer composite melt. In particular, the temperatures of extrusion and molding of fibers tend to reduce, and the time during which the melt retains its rheological characteristics necessary for extrusion is notably increased, from 43 to 92 min. Thermal analysis by DSC revealed no effect of asphalt additive in an amount of up to 30 wt.% on radical PAN cyclization and the subsequent stage of fiber stabilization. Our study proved the possibility of preparing polymer composites based on PAN and asphalt suitable for extrusion and eventual molding of continuous filaments of synthetic fibers with reduced cost of production. Full article

Thieno[3,2-b]thiophenes are used as key components in optoelectronic materials, porous hydrogen-storage hosts, organic solar cells, and polymer semiconductors. A step-efficient synthetic protocol was proposed herein for obtaining multisubstituted thieno[3,2-b]thiophene and selenopheno[3,2-b]selenophenes in moderate to good yields via the bisulfur/biselenium cyclization of alkynyl diols with I₂/Na₂S₂O₃ or selenium. Using this strategy, substitution patterns were obtained for backbone modification in functional materials. Full article

Coumarin and its annulated heterocycles are mainly found in natural products, many of which show significant biological activities and are used extensively for the preparation of pharmaceutical products. Investigation revealed that many heterocyclic compounds fused with coumarin moiety exhibited antihelmentic, hypnotic, insecticidal, antifungal, and anti-coagulant properties. In industry, coumarin scaffolds are widely used for the preparation of drugs, agrochemicals, pesticides, and dyes. In recent studies, several coumarin derivatives have been used in materials science for the preparation of organic cell imaging materials, fluorescent biological probes, etc. Due to their immense application potential in biological science and material chemistry, much attention has been paid by researchers towards the synthesis of a new class of coumarin annulated heterocycles. In this paper, the synthesis of coumarin-annulated polycyclic heterocycles via sequential Claisen rearrangement and tin-hydride mediated radical cyclization is reported. The requisite starting materials 3-((4-chlorobut-2-yn-1-yl)oxy)-2H-chromen-2-one (1) was prepared from 3-hydroxycoumarin and 1,4-dichlorobut-2-yne. The Claisen rearrangement of 1 in refluxing chlorobenzene afforded 1-(chloromethyl)pyrano[2,3-c]chromen-5(3H)-one (2). Finally, radical cyclization reactions were carried out smoothly using ⁿBu₃SnH and AIBN in toluene at 110 °C, leading to the coumarin-annulated polycyclic heterocycles in high yields. The process is operationally simple and easy to work-up, making it convenient for the preparation of coumarin annulated heterocycles. Full article

An efficient method involving copper-catalyzed trifluoromethylthiolation and radical cyclization of N-phenylpent-4-enamides using readily available and stable AgSCF₃ as the trifluoromethylthiolating reagent is described. The method enables the synthesis of a series of potential medicinally valuable trifluoromethylthio-substituted γ-lactams and relative 2-oxazolidinone derivatives with broad functional group compatibility. Mechanistic investigations indicated that this reaction involved amidyl radical-initiated cascade 5-exo-trig cyclization followed by trifluoromethylthiolation, resulting in the formation of new C-N and C-S bonds. Full article

Binary and ternary copolymers of acrylonitrile (AN), tert-butyl acrylate (TBA), and n-butyl acrylate (BA) are synthesized through conventional radical polymerization in DMSO in the presence of 2-mercaptoethanol. The thermal behavior of binary and ternary copolymers is studied under argon atmosphere and in air. It is demonstrated that the copolymers of AN contain 1–10 mol.% of TBA split isobutylene upon heating above 160 °C, resulting in the formation of the units of acrylic acid in the chain. The carboxylic groups formed in situ are responsible for the ionic mechanism of cyclization, which starts at lower temperatures compared with pure polyacrylonitrile (PAN) or AN copolymer with BA. The activation energy of cyclization through ionic and radical mechanisms depends on copolymer composition. For the ionic mechanism, the activation energy lies in the range ca. 100–130 kJ/mole, while for the radical mechanism, it lies in the range ca. 150–190 kJ/mole. The increase in the TBA molar part in the copolymer is followed by faster consumption of nitrile groups and the evolution of a ladder structure in both binary and ternary copolymers. Thus, the incorporation of a certain amount of TBA in PAN or its copolymer with BA allows tuning the temperature range of cyclization. This feature seems attractive for applications in the production of melt-spun PAN by choosing the appropriate copolymer composition and heating mode. Full article

Synthetic radicals have intrinsic power for cascading and multifunctional reactions to construct diverse molecular scaffolds. In the previous review series, we covered 1,2-difunctionalizations, remote 1,3-, 1,4-, 1,5-, 1,6-, and 1,7-difunctionalizations, addition followed by cyclization reactions, and cycloaddition-initiated difunctionalizations. Presented in this paper are radical addition-initiated trifunctionalization reactions of alkenes, alkynes, and their derivatives. After the initial radical addition, there are different pathways, such as group or hydrogen atom transfer, cyclization, and radical coupling, to complete the second and third functionalizations. Full article

Radical reactions are powerful in the synthesis of diverse molecular scaffolds bearing functional groups. In previous review articles, we have presented 1,2-difunctionalizations, remote 1,3-, 1,4-, 1,5-, 1,6- and 1,7-difunctionalizations, and addition followed by cyclization reactions. Presented in this paper is radical cyclization followed by the second functionalization reaction. The second functionalization could be realized by atom transfer reactions, radical or transition metal-assisted coupling reactions, and reactions with neutral molecules, cationic and anionic species. Full article