Molecules

17 pages, 3836 KB

Open AccessEditor’s ChoiceArticle

Anticancer Quinolinol Small Molecules Target Multiple Pathways to Promote Cell Death and Eliminate Melanoma Cells Resistant to BRAF Inhibitors

by Xinjiang Wang, Rati Lama, Alexis D. Kelleher, Erika C. Rizzo, Samuel L. Galster, Chao Xue, Yali Zhang, Jianmin Wang, Jun Qu and Sherry R. Chemler

Molecules 2025, 30(13), 2696; https://doi.org/10.3390/molecules30132696 - 22 Jun 2025

Viewed by 980

Abstract

Small molecule inhibitors that target the E3 ligase activity of MDM2-MDM4 have been explored to inhibit the oncogenic activity of MDM2-MDM4 complex. MMRi62 is a small molecule that was identified using an MDM2-MDM4 E3 ligase-based high throughput screen and a cell-death-based secondary screen. [...] Read more.

Small molecule inhibitors that target the E3 ligase activity of MDM2-MDM4 have been explored to inhibit the oncogenic activity of MDM2-MDM4 complex. MMRi62 is a small molecule that was identified using an MDM2-MDM4 E3 ligase-based high throughput screen and a cell-death-based secondary screen. Our previous studies showed that MMRi62 promotes MDM4 degradation in cells and induces p53-independent apoptosis in cancer cells. However, MMRi62 activity in solid tumor cells such as melanoma cells, especially in BRAF inhibitor resistant melanoma cells, have not been explored. Although its promotion of MDM4 degradation is clear, the direct MMRi62 targets in cells are unknown. In this report, we show that MMRi62 is a much more potent p53-independent apoptosis inducer than conventional MDM2 inhibitors in melanoma cells. A brief structure-activity study led to development of SC-62-1 with improved activity. SC-62-1 potently inhibits and eliminates clonogenic growth of melanoma cells that acquired resistance to BRAF inhibitors. We developed a pair of active and inactive SC-62-1 probes and profiled the cellular targets of SC-62-1 using a chemical biology approach coupled with IonStar/nano-LC/MS analysis. We found that SC-62-1 covalently binds to more than 15 hundred proteins in cells. Pathways analysis showed that SC-62-1 significantly altered several pathways including carbon metabolism, RNA metabolism, amino acid metabolism, translation and cellular response to stress. This study provides mechanistic insights into the mechanisms of action for MMRi62-like quinolinols. This study also suggests multi-targeting compounds like SC-62-1 might be useful for overcoming resistance to BRAF inhibitors for improved melanoma treatment. Full article

(This article belongs to the Special Issue Small-Molecule Modulators Targeting Emerging Therapeutic Pathways: Design, Synthesis and Biological Evaluation)

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18 pages, 4031 KB

Open AccessEditor’s ChoiceArticle

On the Question of the Course of the Hetero Diels–Alder Reactions Between N-(2,2,2-Trichloroethylidene)Carboxamides and Dicyclohexylcarbodiimide: A New Case of the Stepwise Zwitterionic Cycloaddition Process

by Przemysław Woliński, Karolina Zawadzińska-Wrochniak, Ewa Dresler and Radomir Jasiński

Molecules 2025, 30(13), 2692; https://doi.org/10.3390/molecules30132692 - 21 Jun 2025

Cited by 3 | Viewed by 1100

Abstract

The regioselectivity and the molecular mechanism of the Diels–Alder reactions between N-(2,2,2-trichloroethylidene)carboxamides and dicyclohexylcarbodiimide were explored based on the ωB97xd/6-311G(d) (PCM) calculations. It was found that the reaction course is determined by polar local interactions. It is interesting that the most favored [...] Read more.

The regioselectivity and the molecular mechanism of the Diels–Alder reactions between N-(2,2,2-trichloroethylidene)carboxamides and dicyclohexylcarbodiimide were explored based on the ωB97xd/6-311G(d) (PCM) calculations. It was found that the reaction course is determined by polar local interactions. It is interesting that the most favored reaction channel is realized not via classical single-step Diels–Alder mechanism, but according to the stepwise scheme with the intervention of the zwitterionic intermediate. The details of the electron density redistribution along the reaction coordinate were explained using the ELF technique. Full article

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17 pages, 3516 KB

Open AccessEditor’s ChoiceArticle

Is the Greener Approach Better? Application of Electrochemistry in the Synthesis of Perylenediimides

by Patrycja Filipek, Agata Szlapa-Kula, Stanisław Krompiec, Krzysztof Zemlak, Bartłomiej Kula, Karol Erfurt and Michał Filapek

Molecules 2025, 30(13), 2683; https://doi.org/10.3390/molecules30132683 - 21 Jun 2025

Viewed by 511

Abstract

Perylenediimides are an interesting group of compounds that are finding more and more applications. However, the synthetic route of obtaining and modifying them is usually very complicated, costly, and time-consuming. Therefore, the conducted research aimed to develop new, greener, electrochemical methods of obtaining [...] Read more.

Perylenediimides are an interesting group of compounds that are finding more and more applications. However, the synthetic route of obtaining and modifying them is usually very complicated, costly, and time-consuming. Therefore, the conducted research aimed to develop new, greener, electrochemical methods of obtaining unknown perylenediimides (containing 2-ethylhexyl at the nitrogen atom). For the products obtained in this way, optical and electrochemical studies were conducted and compared with DFT results (i.e., energy gaps and HOMO and LUMO levels). Asa result of optical studies, different emission wavelengths of two isomers originating from the same excitation wavelength were observed. Electrochemical studies also confirmed significant differences in properties between the obtained isomers. Spectroelectrochemical measurements were also performed; they revealed the electrochromic properties of the obtained isomers in the visible and near-infrared range. Considering all the properties (optical and (spectro)electrochemical), the obtained compounds have a high potential for use in optoelectronic devices. Moreover, unprecedented pi-expansion of cis-DBPDI via 1,2-bis(p-bromophenyl)acetylene Diels–Alder cycloaddition into the bay region was also realized successfully. Summing up, electrosynthesis and further pi-expansion via cycloaddition offer a sea of opportunities for obtaining nanographenes. Full article

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21 pages, 4310 KB

Open AccessEditor’s ChoiceArticle

Evaluating Triazole-Substituted Pyrrolopyrimidines as CSF1R Inhibitors

by Srinivasulu Cherukupalli, Jan Eickhoff, Carsten Degenhart, Peter Habenberger, Anke Unger, Bård Helge Hoff and Eirik Sundby

Molecules 2025, 30(12), 2641; https://doi.org/10.3390/molecules30122641 - 18 Jun 2025

Viewed by 1076

Abstract

6-Aryl-7H-pyrrolo[2,3-d]pyrimidin-4-amines have promising properties as colony-stimulating factor 1 receptor (CSF1R) inhibitors. Inspired by these antagonists, two series of 1,2,3-triazole analogues (28 compounds) were synthesized and evaluated as CSF1R inhibitors. Enzymatic IC₅₀ profiling showed that 27 of the 28 [...] Read more.

6-Aryl-7H-pyrrolo[2,3-d]pyrimidin-4-amines have promising properties as colony-stimulating factor 1 receptor (CSF1R) inhibitors. Inspired by these antagonists, two series of 1,2,3-triazole analogues (28 compounds) were synthesized and evaluated as CSF1R inhibitors. Enzymatic IC₅₀ profiling showed that 27 of the 28 derivatives had lower IC₅₀ than the reference drug PLX-3397. Three derivatives displayed CSF1R Ba/F3 cellular IC₅₀ well below 1 µM. Profiling of the most promising triazole analogue (compound 27a) toward a panel of kinases reveals a high selectivity for CSF1R with respect to its family kinases, but 27a also inhibits ABL, SRC, and YES kinases. Molecular docking of 27a toward two CSF1R X-ray structures identified two different ligand-inverted binding poses, which triggers interest for further investigations. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation, 3rd Edition)

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25 pages, 6878 KB

Open AccessEditor’s ChoiceArticle

Multifunctional Evaluation of Graphene Oxide–Sulfonamide Nanoconjugates: Antimicrobial, Antibiofilm, Cytocompatibility and Xenobiotic Metabolism Gene Expression Insight

by Irina Zarafu, Irina Mușat, Carmen Limban, Diana C. Nuță, Ioana Daniela Dulama, Cristiana Radulescu, Raluca Maria Stirbescu, Arnaud Tatibouet, Carmen M. Chifiriuc, Luminita Marutescu, Marcela Popa, Laura D. Dragu, Elena Radu, Ioana Nicolau, Coralia Bleotu and Petre Ionita

Molecules 2025, 30(12), 2585; https://doi.org/10.3390/molecules30122585 - 13 Jun 2025

Cited by 2 | Viewed by 868

Abstract

The clinical utility of sulfonamide antibiotics is increasingly challenged by antimicrobial resistance and pharmacokinetic limitations. In this study, we synthesized five graphene oxide–sulfonamide nanoconjugates (GO–S1 to GO–S5) via covalent functionalization, comprehensively characterized them by IR, Raman, SEM, EDS, etc., and evaluated their antimicrobial, [...] Read more.

The clinical utility of sulfonamide antibiotics is increasingly challenged by antimicrobial resistance and pharmacokinetic limitations. In this study, we synthesized five graphene oxide–sulfonamide nanoconjugates (GO–S1 to GO–S5) via covalent functionalization, comprehensively characterized them by IR, Raman, SEM, EDS, etc., and evaluated their antimicrobial, antibiofilm, cytotoxic, apoptotic, hemolytic and gene expression-modulating effects. While the free sulfonamides (S1–S5) exhibited superior antimicrobial activity in planktonic cultures (MICs as low as 19 μg/mL), their GO-functionalized counterparts demonstrated enhanced antibiofilm efficacy, particularly against Pseudomonas aeruginosa (MBIC: 78–312 μg/mL). Cytotoxicity studies using CellTiter assays and Incucyte live-cell imaging revealed low toxicity for all compounds below 250 μg/mL. Morphological and gene expression analyses indicated mild pro-apoptotic effects, predominantly via caspase-9 and caspase-7 activation, with minimal caspase-3 involvement. Hemolysis assays confirmed the improved blood compatibility of GO–Sx conjugates compared to GO alone. Furthermore, qRT-PCR analysis showed that GO–Sx modulated the expression of key xenobiotic metabolism genes (CYPs and NATs), highlighting potential pharmacokinetic implications. Among all tested formulations, GOS3, GOS4 and GOS5 emerged as the most promising candidates, balancing low cytotoxicity, high hemocompatibility and strong antibiofilm activity. These findings support the use of graphene oxide nanocarriers to enhance the therapeutic potential of sulfonamides, particularly in the context of biofilm-associated infections. Full article

(This article belongs to the Section Nanochemistry)

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29 pages, 15607 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Visible-Light-Driven Co₃O₄/Nb₂O₅ Heterojunction Nanocomposites for Efficient Photocatalytic and Antimicrobial Performance in Wastewater Treatment

by Anil Pandey, Santu Shrestha, Rupesh Kandel, Narayan Gyawali, Subas Acharya, Pujan Nepal, Binod Gaire, Vince Fualo and Jae Ryang Hahn

Molecules 2025, 30(12), 2561; https://doi.org/10.3390/molecules30122561 - 12 Jun 2025

Cited by 2 | Viewed by 1804

Abstract

The development of high-performance photocatalysts is vital for combating water pollution and microbial contamination. In this study, visible-light-active Z-scheme heterojunction nanocomposites composed of Co₃O₄ and Nb₂O₅ (CNNC) were synthesized via co-crystallization and subsequent high-pressure annealing to enhance [...] Read more.

The development of high-performance photocatalysts is vital for combating water pollution and microbial contamination. In this study, visible-light-active Z-scheme heterojunction nanocomposites composed of Co₃O₄ and Nb₂O₅ (CNNC) were synthesized via co-crystallization and subsequent high-pressure annealing to enhance photocatalytic and antimicrobial performance. Structural and optical analyses via XRD, FESEM, TEM, XPS, and PL confirmed the heterojunction formation between porous Co₃O₄ nanoparticles (CONP) and columnar orthorhombic Nb₂O₅ nanoparticles (NONP). The CNNC exhibited significantly improved photocatalytic activity, achieving degradation efficiencies of 95.1% for methylene blue, 72.6% for tetracycline, and 90.0% for Congo red within 150 min. Kinetic studies showed that CNNC’s rate constants were 367% and 466% of those of CONP and NONP, respectively. Moreover, CNNC demonstrated a strong antibacterial effect on Staphylococcus aureus and Escherichia coli with ZOI values of 9.3 mm and 6.8 mm, respectively. Mechanistic analysis revealed that the Z-scheme charge-transfer pathway improved charge separation and reduced electron–hole recombination, contributing to the promoted photocatalytic efficiency. The nanocomposite also showed robust stability and recyclability over five times. These results highlight the promise of CNNC as a bifunctional, visible-light-driven photocatalyst for pollutant decomposition and microbial control. Full article

(This article belongs to the Special Issue Wastewater Treatment: Functional Materials and Advanced Technology, 2nd Edition)

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24 pages, 1714 KB

Open AccessEditor’s ChoiceReview

Engineering and Exploiting Immobilized Peptide Organocatalysts for Modern Synthesis

by Marco Francescato, Hang Liao and Luca Gentilucci

Molecules 2025, 30(12), 2517; https://doi.org/10.3390/molecules30122517 - 9 Jun 2025

Viewed by 1238

Abstract

Short- and medium-sized peptides have long been used as effective and versatile organocatalysts. In the early 80s, Inoue used diketopiperazines in the Strecker reaction, while Juliá and Colonna reported the epoxidation of chalcone catalyzed by poly-L-Ala. Since then, a variety of peptide-catalyzed reactions [...] Read more.

Short- and medium-sized peptides have long been used as effective and versatile organocatalysts. In the early 80s, Inoue used diketopiperazines in the Strecker reaction, while Juliá and Colonna reported the epoxidation of chalcone catalyzed by poly-L-Ala. Since then, a variety of peptide-catalyzed reactions have been described. However, peptide synthesis typically implicates the use of toxic reagents and generates wastes; therefore, peptide recycling is expected to significantly improve the overall sustainability of the process. Easy recovery and recycling of peptide catalysts can be expediently attained by covalent binding, inclusion, or adsorption. In addition, immobilization can significantly accelerate the screening of new peptide catalysts. For these reasons, diverse supports have been tested, including natural or synthetic polymers, porous polymeric networks, inorganic porous materials, organic-inorganic hybrid materials, and finally metal–organic frame-works. Full article

(This article belongs to the Special Issue Organocatalysis: Past, Present, and Future Perspectives)

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15 pages, 1936 KB

Open AccessEditor’s ChoiceArticle

Studying the Formation of Fullerenes During Catagenesis

by Jens Dreschmann and Wolfgang Schrader

Molecules 2025, 30(12), 2516; https://doi.org/10.3390/molecules30122516 - 9 Jun 2025

Viewed by 682

Abstract

The formation of polycyclic aromatic hydrocarbons (PAHs) during catagenesis does not exclusively lead to planar structures. The inclusion of five-ring elements increases the curvature of PAHs and yields bent molecules. These bowl-like configurations may end in the formation of spherical carbon allotropes as [...] Read more.

The formation of polycyclic aromatic hydrocarbons (PAHs) during catagenesis does not exclusively lead to planar structures. The inclusion of five-ring elements increases the curvature of PAHs and yields bent molecules. These bowl-like configurations may end in the formation of spherical carbon allotropes as fullerenes or nanotubes, as recently shown. The presence of fullerenes in crude oil raises the question of why the reaction is feasible under catagenic conditions although the laboratory synthesis of fullerenes commonly requires high-energy environments. This study focuses on the feasibility of the simulation of catagenesis under laboratory conditions and the question of which building blocks may lead to spherical structures. Possible educts, reaction mechanisms, and conditions such as temperature are discussed and related to experimental outcomes. For the simulation under laboratory conditions, a light gas condensate was fractionated by distillation in order to reduce the number of compounds per fraction and make them distinguishable. The characterization of the resulting fractions was performed through GC-MS and GC-FID measurements before heat application in a closed reactor. High-resolution mass spectrometry (HRMS) measurements of the products indicated PAH growth and, more importantly, the formation of fullerenes. Interestingly, the characterized fullerenes mostly comprised the range of non-IPR (isolated pentagon rule) fullerenes. Full article

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67 pages, 16344 KB

Open AccessEditor’s ChoiceReview

Enantiomerically Pure ansa-η⁵-Complexes of Transition Metals as an Effective Tool for Chirality Transfer

by Pavel V. Kovyazin, Leonard M. Khalilov and Lyudmila V. Parfenova

Molecules 2025, 30(12), 2511; https://doi.org/10.3390/molecules30122511 - 8 Jun 2025

Cited by 2 | Viewed by 1015

Abstract

Chiral ansa-η⁵-complexes of transition metals have shown remarkable efficacy in organometallic synthesis and catalysis. Additionally, enantiomerically pure ansa-complexes hold promise for the development of novel chiral materials and pharmaceuticals. The discovery and synthesis of a diverse range of [...] Read more.

Chiral ansa-η⁵-complexes of transition metals have shown remarkable efficacy in organometallic synthesis and catalysis. Additionally, enantiomerically pure ansa-complexes hold promise for the development of novel chiral materials and pharmaceuticals. The discovery and synthesis of a diverse range of group IVB and IIIB metal complexes represents a significant milestone in the advancement of stereoselective catalytic methods for constructing metal-C, C-C, C-H, and C-heteroatom bonds. The synthesis of enantiomerically pure metallocenes can be accomplished through several strategies: utilizing optically active precursors of η⁵-ligands, separation of diastereomers of complexes with enantiomerically pure agents, and synthesis via the stereocontrolled reactions of enantiomerically pure σ-complexes with prochiral anions of η⁵-ligands. This review focuses on the analysis of various nuances of the synthesis of enantiomerically pure ansa-η⁵-complexes of titanium and lanthanum families. Their applicability as effective catalysts in asymmetric carbomagnesiation, carbo- and cycloalumination, oligo- and polymerization, Diels–Alder cycloaddition, reactions of zirconaaziridines, cyclization, hydrosilylation, hydrogenation, hydroamination, and other processes are highlighted as well. Full article

(This article belongs to the Special Issue Advances in Metallocene Chemistry)

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11 pages, 465 KB

Open AccessEditor’s ChoiceArticle

Rapid Enantiomeric Ratio Determination of Multiple Amino Acids Using Ion Mobility-Mass Spectrometry

by Wenqing Xu, Estelle Rathahao-Paris and Sandra Alves

Molecules 2025, 30(12), 2497; https://doi.org/10.3390/molecules30122497 - 6 Jun 2025

Viewed by 722

Abstract

Chiral analysis is becoming increasingly important across various scientific fields, including chemistry, pharmaceuticals, biosciences, and more recently, metabolomics. In this context, a high-resolution and high-throughput method was developed for the simultaneous determination of the enantiomeric ratio (er) of seven pairs of [...] Read more.

Chiral analysis is becoming increasingly important across various scientific fields, including chemistry, pharmaceuticals, biosciences, and more recently, metabolomics. In this context, a high-resolution and high-throughput method was developed for the simultaneous determination of the enantiomeric ratio (er) of seven pairs of amino acid (AA) enantiomers (Arg, Gln, His, Met, Pro, Tyr, and Trp) using flow injection analysis coupled with ion mobility-mass spectrometry (FIA-IM-MS) technology. Specifically, the Single Ion Mobility Monitoring (SIM²) mode on a TIMS-Tof^TM instrument enabled the rapid relative quantification of chiral compound mixtures. A linear model accurately described the relationship between enantiomeric ratio and IM-MS response for Arg, Gln, and Pro enantiomers, as evidenced by high R² values and unbiased residuals. In contrast, non-linear trends were observed for His, Tyr, and Trp, where a quadratic model significantly improved the fit. However, the linear model was retained for Met, despite an R² of about 0.98, due to its comparable performance and simplicity. Measurement accuracy was confirmed with very good recovery rates for er values of 0.95 and 0.99 across all AAs. Finally, the potential of the FIA-SIM²-MS approach in chiral analysis was demonstrated, particularly its ability to provide a reliable and efficient high-throughput tool for accurate er determination. Full article

(This article belongs to the Special Issue Enantioselective Synthesis, Enantiomeric Separations and Chiral Recognition: 3rd Edition)

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16 pages, 1650 KB

Open AccessEditor’s ChoiceArticle

Application of VUV/Sulfite Defluorination System for the Simple Detection of Perfluoroalkyl Substances

by Shiyong Tao, Yilin Chen, Xiao Mei, Luyao Jin, Feng Wu and Jing Xu

Molecules 2025, 30(11), 2475; https://doi.org/10.3390/molecules30112475 - 5 Jun 2025

Cited by 1 | Viewed by 1246

Abstract

This study investigated the defluorination of PFOA and PFOS using a vacuum ultraviolet (VUV)/sulfite system, and evaluated its potential application in quantifying individual perfluoroalkyl substances (PFAS). Results showed that 81.9% and 87.5% defluorination of PFOA and PFOS were achieved after 120 min of [...] Read more.

This study investigated the defluorination of PFOA and PFOS using a vacuum ultraviolet (VUV)/sulfite system, and evaluated its potential application in quantifying individual perfluoroalkyl substances (PFAS). Results showed that 81.9% and 87.5% defluorination of PFOA and PFOS were achieved after 120 min of photoreaction under conditions of pH 12 and 20 mM of sulfite. Higher pH and sulfite dosage facilitated the reaction, while competing ions could suppress the defluorination efficiency. Based on the optimized defluorination conditions for individual PFAS, the potential of fluoride release amount, as an indirect quantification indicator, was further assessed. A strong linearity between the fluoride release and initial PFAS concentration (R² > 0.999) was observed in the PFAS concentration range of 2–100 μM, and such linearity was also shown in the presence of sediment leachates. This correlation enabled the estimation of individual PFAS concentrations by measuring fluoride release after defluorination treatment. The approach was further demonstrated in an adsorption experiment, where calculated distribution coefficients (K_oc) for PFAS–sediment interactions were consistent with previously reported values, supporting the analytical validity of the method under controlled conditions. Overall, this work presents a simple and cost-effective indirect analytical strategy of applying a VUV/sulfite defluorination system for individual PFAS quantitative detection in complex environmental matrices. Full article

(This article belongs to the Section Green Chemistry)

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19 pages, 1937 KB

Open AccessEditor’s ChoiceReview

Current Approaches to Microplastics Detection and Plastic Biodegradation

by Paula Przygoda-Kuś, Katarzyna E. Kosiorowska, Aneta K. Urbanek and Aleksandra M. Mirończuk

Molecules 2025, 30(11), 2462; https://doi.org/10.3390/molecules30112462 - 4 Jun 2025

Cited by 3 | Viewed by 3722

Abstract

Environmental concerns about the widespread use of non-biodegradable plastic have generated interest in developing quick and effective methods to degrade synthetic polymers. With millions of tons of plastic waste generated annually, biodegradation by microorganisms presents a promising and eco-friendly solution. However, a bottleneck [...] Read more.

Environmental concerns about the widespread use of non-biodegradable plastic have generated interest in developing quick and effective methods to degrade synthetic polymers. With millions of tons of plastic waste generated annually, biodegradation by microorganisms presents a promising and eco-friendly solution. However, a bottleneck has arisen due to the lack of standardized methods for verification of the biodegradation process. Based on this literature review, he techniques most commonly employed for this purpose currently include measuring mass loss, examining the surface of plastic fragments by scanning electron microscopy (SEM) and atomic force microscopy (AFM), and using analytical methods such as Fourier transform infrared spectroscopy (FTIR), pyrolysis–gas chromatography–mass spectrometry (Pyr-GC/MS) or high-performance liquid chromatography (HPLC). Each of these methods has its advantages and disadvantages. Nevertheless, currently, there is no universal approach to accurately assess the ability of individual microorganisms to degrade plastics. In this review, we summarize the latest advances in techniques for detecting biodegradation of synthetic polymers and future directions in the development of sustainable strategies for mitigating plastic pollution. Full article

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14 pages, 1353 KB

Open AccessEditor’s ChoiceArticle

One-Pot Syntheses and Characterization of Group VI Carbonyl NHC Coordination Compounds

by Zala Stopar, Evelin Gruden, Melita Tramšek and Gašper Tavčar

Molecules 2025, 30(11), 2433; https://doi.org/10.3390/molecules30112433 - 2 Jun 2025

Viewed by 785

Abstract

The reactions of N-heterocyclic carbenes (IMesNHC and IPrNHC) with transition metal carbonyls of group VI (Cr(CO)₆, Mo(CO)₆, and W(CO)₆) were carried out in acetonitrile in simple one-pot syntheses and led to the formation of the coordination [...] Read more.

The reactions of N-heterocyclic carbenes (IMesNHC and IPrNHC) with transition metal carbonyls of group VI (Cr(CO)₆, Mo(CO)₆, and W(CO)₆) were carried out in acetonitrile in simple one-pot syntheses and led to the formation of the coordination compounds IMesNHC–Cr(CO)₅ (1a), IMesNHC–Mo(CO)₅ (2a), IMesNHC–W(CO)₅ (3a), IPrNHC–Cr(CO)₅ (1b), IPrNHC–Mo(CO)₅ (2b), and IPrNHC–W(CO)₅ (3b). With the exception of 1b, the coordination compounds were formed selectively and in high yields. The method represents an effective and easy-to-perform alternative to the previously described methods for NHC–M(CO)₅ (M = Cr, Mo, W). All prepared compounds were characterized by NMR and Raman spectroscopy. Compounds 1a, 2a, 3a, and 2b were also crystallized and structurally characterized by X-ray structure analysis. Finally, the structural features of all compounds were compared with DFT calculations of structurally optimized coordination compounds. Full article

(This article belongs to the Special Issue Featured Papers in Organometallic Chemistry—2nd Edition)

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18 pages, 2229 KB

Open AccessEditor’s ChoiceArticle

The Puzzle of the New Type of Intermediate in the Course of [2 + 2] Cycloaddition with the Participation of Conjugated Nitroalkenes: MEDT Computational Study

by Radomir Jasiński and Agnieszka Kącka-Zych

Molecules 2025, 30(11), 2410; https://doi.org/10.3390/molecules30112410 - 30 May 2025

Cited by 1 | Viewed by 1399

Abstract

The phenomena of regio- and stereoselectivity and the molecular mechanism of the [2 + 2] cycloaddition reaction between (E)-2-arylnitroethenes and the ynamine molecular system were analyzed using wb97xd/6-311 + G(d) (PCM) quantumchemical calculations. It was found that, independently of the stepwise nature of [...] Read more.

The phenomena of regio- and stereoselectivity and the molecular mechanism of the [2 + 2] cycloaddition reaction between (E)-2-arylnitroethenes and the ynamine molecular system were analyzed using wb97xd/6-311 + G(d) (PCM) quantumchemical calculations. It was found that, independently of the stepwise nature of the cycloaddition, the full retention of the stereoconfiguration of the nitroalkene can be interpreted and explained. Next, the analysis of the electronic properties of the localized reaction intermediate suggests its possible zwitterionic nature. Additionally, the solvent and the substituent effect on the reaction course were also evaluated. In consequence, the proposed mechanism can be treated as general for some groups of [2 + 2] cycloaddition processes. Lastly, for the model process, the full Bonding Evolution Theory (BET) analysis along the reaction coordinate was performed. It was found that the [2 + 2] cycloaddition reaction between (E)-2-phenylonitroethene and ynamine begins with the formation of two pseudoradical centers at the C2 and C3 atoms. First, a C2-C3 single bond is formed in phase V by combining two pseudoradical centers, while the formation of a second C4-C1 single bond begins at the last, eleventh phase of the reaction path. A BET analysis of intermediate (I) allows it to be classified as a compound with a pseudoradical structure. Next to zwitterions and biradicals, it is evidently new type of intermediate on the path of the [2 + 2] cycloaddition reaction. Full article

(This article belongs to the Section Organic Chemistry)

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33 pages, 4695 KB

Open AccessEditor’s ChoiceReview

CO₂-Responsive Vinyl Polymers: From Synthesis to Application

by Mahshab Sheraz and Rui Wang

Molecules 2025, 30(11), 2350; https://doi.org/10.3390/molecules30112350 - 28 May 2025

Cited by 1 | Viewed by 1355

Abstract

CO₂-responsive polymers have emerged as a significant class of smart materials, distinguished by their ability to reversibly alter their properties upon exposure to CO₂. Due to CO₂’s abundant availability, low cost, non-toxicity, energy efficiency, and excellent biocompatibility, [...] Read more.

CO₂-responsive polymers have emerged as a significant class of smart materials, distinguished by their ability to reversibly alter their properties upon exposure to CO₂. Due to CO₂’s abundant availability, low cost, non-toxicity, energy efficiency, and excellent biocompatibility, these polymers offer remarkable environmental and practical advantages. This review succinctly explores recent advancements in the synthesis, mechanisms, and applications of CO₂-responsive polymers, emphasizing the pivotal roles of specific acidic and basic functional groups such as carboxylic acids, phenolic groups, amines, amidines, guanidines, and imidazoles. Advanced polymerization techniques including free radical polymerization (FRP), atom transfer radical polymerization (ATRP), reversible addition-fragmentation chain transfer (RAFT), and nitroxide-mediated polymerization (NMP) are critically evaluated for their precision and flexibility in polymer design. Significant applications in smart separation, carbon capture, drug delivery, desalination, emulsions, tissue engineering, and sensing technologies are discussed comprehensively. Although substantial progress has been made, ongoing challenges include enhancing response speed, durability, sustainability, and economic viability. Future research is recommended to focus on innovative polymer structures, computational modeling, hybrid materials, and greener synthesis methods. This review aims to inspire continued exploration and practical utilization of CO₂-responsive polymers to address pressing environmental and technological needs. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules: Recent Advances and the Next in Macromolecular Chemistry)

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15 pages, 2709 KB

Open AccessEditor’s ChoiceArticle

Design, Synthesis, and Biological Evaluations of a Novel Resveratrol-Type Analogue Against VEGF

by Shengying Lin, Maggie Suisui Guo, Roy Wai-Lun Tang, Yutong Ye, Jiahui Wu, Yuen Man Ho, Ran Duan, Ka Wing Leung, Tina Ting-Xia Dong and Karl Wah-Keung Tsim

Molecules 2025, 30(11), 2345; https://doi.org/10.3390/molecules30112345 - 27 May 2025

Viewed by 2965

Abstract

Vascular endothelial growth factor (VEGF), also known as VEGF-A, has been reported to mediate various diseases, including cancer and wet age-related macular degeneration (wAMD). Despite the fact that VEGF inhibitors are commercially available and appear to be effective in clinical applications, adverse effects [...] Read more.

Vascular endothelial growth factor (VEGF), also known as VEGF-A, has been reported to mediate various diseases, including cancer and wet age-related macular degeneration (wAMD). Despite the fact that VEGF inhibitors are commercially available and appear to be effective in clinical applications, adverse effects have been caused by these treatments. There is an unmet need for developing novel VEGF-targeted treatments against these diseases. Resveratrol, a phytochemical derived from fruits and vegetables, has shown promising potency in suppressing VEGF-mediated bioactivities through a series of in vitro and in vivo testing models. Herein, we report that RE-1, a synthetic resveratrol-type analog, displays robust inhibitory activities against VEGF and its downstream signaling pathways, surpassing its parental molecule, resveratrol. In addition, the drug capabilities of RE-1 were evaluated. As a newly synthesized chemical, RE-1 could be considered for subsequent pharmacological development targeting VEGF-related diseases. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Evaluation of Medicinal Potential Compounds)

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25 pages, 4306 KB

Open AccessEditor’s ChoiceArticle

Design and Evaluation of a Crosslinked Chitosan-Based Scaffold Containing Hyaluronic Acid for Articular Cartilage Reconstruction

by Salim Hamidi, Mickael Maton, Feng Hildebrand, Valérie Gaucher, Cédric Bossard, Frédéric Cazaux, Jean Noel Staelens, Nicolas Blanchemain and Bernard Martel

Molecules 2025, 30(10), 2202; https://doi.org/10.3390/molecules30102202 - 17 May 2025

Cited by 1 | Viewed by 1484

Abstract

Polymeric scaffolds are promising in tissue engineering due to their structural similarity to extracellular matrix components. This study aimed to design freeze-dried hydrogels based on chitosan (CHT) and hyaluronic acid (HA). Chitosan-based gels were crosslinked with oxidized maltodextrin (MDo) before the freeze-drying step, [...] Read more.

Polymeric scaffolds are promising in tissue engineering due to their structural similarity to extracellular matrix components. This study aimed to design freeze-dried hydrogels based on chitosan (CHT) and hyaluronic acid (HA). Chitosan-based gels were crosslinked with oxidized maltodextrin (MDo) before the freeze-drying step, resulting in spongy porous scaffolds. Based on the state-of-the-art, our hypothesis was that crosslinking would increase scaffold stiffness and delay the degradation of the CHT:HA resorbable scaffolds swelled in a hydrated physiological environment. The physicochemical and mechanical properties of crosslinked CHT- and CHT:HA-based scaffolds were analyzed. Hygroscopic and swelling behavior were assessed using dynamic vapor sorption analysis and batch studies. Degradation was evaluated under different conditions, including in phosphate-buffered saline (PBS), PBS with lysozyme, and lactic acid solutions, to investigate scaffold resistance against enzymatic and acidic degradation. The porosity of the spongy materials was characterized using scanning electron microscopy, while dynamic mechanical analysis provided information on the mechanical properties. Crosslinked scaffolds showed reduced swelling, slower degradation rates, and increased stiffness, confirming MDo as an effective crosslinking agent. Scaffolds loaded with ciprofloxacin (CFX) demonstrated their ability to deliver therapeutic agents, as the CFX loading capacity was promoted by CHT–CFX interactions. Microbiologic investigation confirmed the results. Finally, cytotoxicity tests displayed no toxicity. In conclusion, MDo-crosslinked CHT and CHT:HA scaffolds exhibit enhanced stability, functionality, and mechanical performance, making them promising for cartilage tissue engineering. Full article

(This article belongs to the Special Issue Chitosan, Chitosan Derivatives, Polysaccharides and Their Applications—2nd Edition)

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14 pages, 3464 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Dual-Engineering Tailored Co₃O₄ Hollow Microspheres Assembled by Nanosheets for Boosting Oxygen Evolution Reaction

by Yinghan Cui, Shiduo Yang, Jianqiang Zhu, Zaidong Wang, Sen Chen, Jian Qi and Huan Wang

Molecules 2025, 30(10), 2181; https://doi.org/10.3390/molecules30102181 - 16 May 2025

Cited by 2 | Viewed by 709

Abstract

The development of efficient, low-cost electrocatalysts for the oxygen evolution reaction (OER) is crucial for advancing sustainable hydrogen production through water splitting. This study presents a dual-engineering strategy to enhance the OER performance of Co₃O₄ by synthesizing hollow microspheres assembled [...] Read more.

The development of efficient, low-cost electrocatalysts for the oxygen evolution reaction (OER) is crucial for advancing sustainable hydrogen production through water splitting. This study presents a dual-engineering strategy to enhance the OER performance of Co₃O₄ by synthesizing hollow microspheres assembled from nanosheets (HMNs) with abundant oxygen vacancies and highly active crystal facet exposure. Through a modified one-step hydrothermal process, Co₃O₄ HMNs with exposed (111) and (100) crystal facets were successfully fabricated, demonstrating superior OER activity compared to Co₃O₄ nanocubes (NCs) with only (100) facet exposure. The optimized Co₃O₄-5% HMNs exhibited a low overpotential of 330 mV at 10 mA cm⁻² and a Tafel slope of 69 mV dec⁻¹. The enhanced performance was attributed to the synergistic effects of crystal facet engineering and defect engineering, which optimized the Co-O bond energy, increased the number of active sites, and improved conductivity. The unique hollow structure further facilitated mass transport and prevented nanosheet stacking, exposing more edge sites for catalytic reactions. This work highlights the potential of geometric and electronic structure modulation in designing high-performance OER catalysts for sustainable energy applications. Full article

(This article belongs to the Special Issue Synthesis and Applications of Novel Low-Dimensional Nanomaterials in Catalysis)

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25 pages, 3752 KB

Open AccessEditor’s ChoiceArticle

Synthesis of 3-Carboxy-6-sulfamoylquinolones and Mefloquine-Based Compounds as Panx1 Blockers: Molecular Docking, Electrophysiological and Cell Culture Studies

by Letizia Crocetti, Maria Paola Giovannoni, Tengis S. Pavlov, Veniamin Ivanov, Fabrizio Melani and Gabriella Guerrini

Molecules 2025, 30(10), 2171; https://doi.org/10.3390/molecules30102171 - 15 May 2025

Cited by 1 | Viewed by 1104

Abstract

The membrane channel protein Panx1 is a promising therapeutic target since its involvement was demonstrated in a variety of pathologies such as neuropathic pain, ischemic stroke and cancer. As a continuation of our previous work in this field, we report here the synthesis [...] Read more.

The membrane channel protein Panx1 is a promising therapeutic target since its involvement was demonstrated in a variety of pathologies such as neuropathic pain, ischemic stroke and cancer. As a continuation of our previous work in this field, we report here the synthesis and biological evaluation of two classes of compounds as Panx1 blockers: 3-carboxy-6-sulphonamidoquinolone derivatives and new Mefloquine analogs. The series of 3-carboxy-6-sulphonamidoquinolones gave interesting results, affording powerful Panx1 channel blockers with 73.2 < I% < 100 at 50 µM. In particular, 12f was a more potent Panx1 blocker than the reference compound CBX (IC₅₀ = 2.7 µM versus IC₅₀ = 7.1 µM), and its profile was further investigated in a cell culture model of polycystic kidney disease. Finally, interesting results have been highlighted by new molecular modeling studies. Full article

(This article belongs to the Special Issue The Design, Synthesis, and Biological Activity of New Drug Candidates, 2nd Edition)

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21 pages, 1526 KB

Open AccessEditor’s ChoiceArticle

Strawberry Tree Fruit Residue as Carbon Source Towards Sustainable Fuel Biodesulfurization by Gordonia alkanivorans Strain 1B

by Susana M. Paixão, Tiago P. Silva, Francisco Salgado and Luís Alves

Molecules 2025, 30(10), 2137; https://doi.org/10.3390/molecules30102137 - 13 May 2025

Viewed by 654

Abstract

Biodesulfurization (BDS) is a clean technology that uses microorganisms to efficiently remove sulfur from recalcitrant organosulfur compounds present in fuels (fossil fuels or new-generation fuels resulting from pyrolysis and hydrothermal liquefaction). One of the limitations of this technology is the low desulfurization rates. [...] Read more.

Biodesulfurization (BDS) is a clean technology that uses microorganisms to efficiently remove sulfur from recalcitrant organosulfur compounds present in fuels (fossil fuels or new-generation fuels resulting from pyrolysis and hydrothermal liquefaction). One of the limitations of this technology is the low desulfurization rates. These result in the need for greater amounts of biocatalyst and lead to increased production costs. To mitigate this issue, several approaches have been pursued, such as the use of alternative carbon sources (C-sources) from agro-industrial waste streams or the co-production of high-added-value products by microorganisms. The main goal of this work is to assess the potential of strawberry tree fruit residue (STFr) as an alternative C-source for a BDS biorefinery using Gordonia alkanivorans strain 1B, a well-known desulfurizing bacterium with high biotechnological potential. Hence, the first step was to produce sugar-rich liquor from the STFr and employ it in shake-flask assays to evaluate the influence of different pretreatments (treatments with 1–4% activated charcoal for prior phenolics removal) on metabolic parameters and BDS rates. Afterwards, the liquor was used as the C-source in chemostat assays, compared to commercial sugars, to develop and optimize the use of STFr-liquor as a viable C-source towards cost-effective biocatalyst production. Moreover, the high-market-value bioproducts simultaneously produced during microbial growth were also evaluated. In this context, the best results, considering both the production of biocatalysts with BDS activity and simultaneous bioproduct production (carotenoids and gordofactin biosurfactant/bioemulsifier) were achieved when strain 1B was cultivated in a chemostat with untreated STFr-liquor (5.4 g/L fructose + glucose, 6:4 ratio) as the C-source and in a sulfur-free mineral-minimized culture medium at a dilution rate of 0.04 h⁻¹. Cells from this steady-state culture (STFr L1) achieved the highest desulfurization with 250 mM of dibenzothiophene as a reference organosulfur compound, producing a maximum of ≈213 mM of 2-hydroxibyphenil (2-HBP) with a corresponding specific rate (q_2-HBP) of 6.50 µmol/g(_DCW)/h (where DCW = dry cell weight). This demonstrates the potential of STFr as a sustainable alternative C-source for the production of cost-effective biocatalysts without compromising BDS ability. Additionally, cells grown in STFr L1 also presented the highest production of added-value products (338 ± 15 µg/g_(DCW) of carotenoids and 8 U/mL of gordofactin). These results open prospects for a future G. alkanivorans strain 1B biorefinery that integrates BDS, waste valorization, and the production of added-value products, contributing to the global economic viability of a BDS process and making BDS scale-up a reality in the near future. Full article

(This article belongs to the Special Issue Advances in Biomass Chemicals: Transformation and Valorization)

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19 pages, 6348 KB

Open AccessEditor’s ChoiceArticle

Synthesis, Characterisation, Biological Evaluation and In Silico Studies of Quinoline–1,2,3-Triazole–Anilines as Potential Antitubercular and Anti-HIV Agents

by Snethemba S. Magwaza, Darian Naidu, Oluwatoba E. Oyeneyin, Sibusiso Senzani, Nompumelelo P. Mkhwanazi and Matshawandile Tukulula

Molecules 2025, 30(10), 2119; https://doi.org/10.3390/molecules30102119 - 10 May 2025

Cited by 2 | Viewed by 1742

Abstract

HIV/AIDS and Mycobacterial tuberculosis (Mtb) are the leading cause of deaths worldwide. Thus, better medicaments are required to manage these diseases. Quinolines have shown great potential due to their broad spectrum of biological activity. Thus, quinoline–1,2,3-triazole–aniline hybrids were synthesised in moderate [...] Read more.

HIV/AIDS and Mycobacterial tuberculosis (Mtb) are the leading cause of deaths worldwide. Thus, better medicaments are required to manage these diseases. Quinolines have shown great potential due to their broad spectrum of biological activity. Thus, quinoline–1,2,3-triazole–aniline hybrids were synthesised in moderate to good yields. Compounds 11g (IC₅₀ = 0.388 µM), 11h (IC₅₀ = 0.01032 µM) and 11i (IC₅₀ = 0.167 µM) exhibited the most promising in vitro activities against the wild-type HIV-1 subtype B, with 11h being 9-fold more active than AZT (IC₅₀ = 0.0909 µM), the reference drug. Furthermore, compound 11h displayed moderate activity, with a MIC₉₀ of 88μM against Mtb’s H37Rv strain. Cytotoxicity studies on TZM-bl cell lines revealed that most of the tested compounds were generally non-cytotoxic; the selectivity index (SI) for 11h, the front runner, is >2472. Molecular docking studies revealed that 11h interacted with Phe112, Tyr108, Glu283 and Trp86 amino acid residues in the active site of HIV-1. DFT studies revealed that 11h has the ability to donate and accept electrons to and from available orbitals. The predicted ADMET studies showed that these compounds possess drug-likeness, and 11h has the potential for further optimisation as an anti-HIV-1 agent. Full article

(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis and Medicinal Chemistry Applications)

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12 pages, 1656 KB

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Organophotoredox-Catalyzed Stereoselective Synthesis of Bicyclo[3.2.0]heptanes via [2+2] Photocycloaddition

by Tommaso Benettin, Simonetta Resta, Alessandra Forni, Laura Raimondi, Alessandra Puglisi and Sergio Rossi

Molecules 2025, 30(10), 2090; https://doi.org/10.3390/molecules30102090 - 8 May 2025

Viewed by 1258

Abstract

The stereoselective synthesis of bicyclo[3.2.0]heptanes via an anion radical [2+2] photocycloaddition of aryl bis-enone derivatives was investigated. By employing chiral oxazolidinone auxiliaries bound to aryl bis-enone substrates, enantioenriched, highly substituted bicyclo[3.2.0]heptanes have been synthesized. The reaction, mediated by Eosin Y and promoted by [...] Read more.

The stereoselective synthesis of bicyclo[3.2.0]heptanes via an anion radical [2+2] photocycloaddition of aryl bis-enone derivatives was investigated. By employing chiral oxazolidinone auxiliaries bound to aryl bis-enone substrates, enantioenriched, highly substituted bicyclo[3.2.0]heptanes have been synthesized. The reaction, mediated by Eosin Y and promoted by LiBr under visible light irradiation, has been studied both experimentally and computationally to elucidate the mechanism and stereoselective outcomes. The process proceeds via a syn-closure pathway, leading to the formation of the corresponding cis-anti diastereoisomers as major products isolated and characterized by X-ray analysis; DFT calculations provided useful insights and computational support which allow a plausible reaction mechanism to be proposed that agrees with the collected experimental data. Full article

(This article belongs to the Special Issue Cyclization Reactions in Organic Synthesis: Recent Developments)

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25 pages, 8081 KB

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Discovery, Biological Evaluation and Binding Mode Investigation of Novel Butyrylcholinesterase Inhibitors Through Hybrid Virtual Screening

by Lizi Li, Puchen Zhao, Can Yang, Qin Yin, Na Wang, Yan Liu and Yanfang Li

Molecules 2025, 30(10), 2093; https://doi.org/10.3390/molecules30102093 - 8 May 2025

Cited by 2 | Viewed by 1223

Abstract

Butyrylcholinesterase (BChE), plays a critical role in alleviating the symptoms of Alzheimer’s disease (AD) by regulating acetylcholine levels, emerging as an attractive target for AD treatment. This study employed a quantitative structure–activity relationship (QSAR) model based on ECFP4 molecular fingerprints with several machine [...] Read more.

Butyrylcholinesterase (BChE), plays a critical role in alleviating the symptoms of Alzheimer’s disease (AD) by regulating acetylcholine levels, emerging as an attractive target for AD treatment. This study employed a quantitative structure–activity relationship (QSAR) model based on ECFP4 molecular fingerprints with several machine learning algorithms (XGBoost, RF, SVM, KNN), among which the XGBoost model showed the best performance (AUC = 0.9740). A hybrid strategy integrating ligand- and structure-based virtual screening identified 12 hits from the Topscience core database, three of which were identified for the first time. Among them, piboserod and Rotigotine demonstrated the best BChE inhibitory potency (IC₅₀ = 15.33 μM and 12.76 μM, respectively) and exhibited favorable safety profiles as well as neuroprotective effects in vitro. Notably, Rotigotine, a marketed drug, was newly recognized for its anti-AD potential, with further enzyme kinetic analyses revealing that it acts as a mixed-type inhibitor in a non-competitive mode. Fluorescence spectroscopy, molecular docking, and molecular dynamics simulations further clarified their binding modes and stability. This study provides an innovative screening strategy for the discovery of BChE inhibitors, which not only identifies promising drug candidates for the treatment of AD but also demonstrates the potential of machine learning in drug discovery. Full article

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18 pages, 2382 KB

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Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates

by Andrea Bagán, Alba López-Ruiz, Sònia Abás, Elies Molins, Belén Pérez, Itziar Muneta-Arrate, Luis F. Callado and Carmen Escolano

Molecules 2025, 30(9), 2078; https://doi.org/10.3390/molecules30092078 - 7 May 2025

Viewed by 1512

Abstract

Imidazoline I₂ receptors (I₂-IR) are untapped therapeutic targets lacking a structural description. Although the levels of I₂-IR are dysregulated in a plethora of illnesses, the arsenal of ligands that can modulate I₂-IR is limited. In this [...] Read more.

Imidazoline I₂ receptors (I₂-IR) are untapped therapeutic targets lacking a structural description. Although the levels of I₂-IR are dysregulated in a plethora of illnesses, the arsenal of ligands that can modulate I₂-IR is limited. In this framework, we have reported several new structural families embodying the iminophosphonate functional group that have an excellent affinity and selectivity for I₂-IR, and selected members have demonstrated relevant pharmacological properties in murine models of neurodegeneration and Alzheimer’s disease. Starting with these iminophosphonates, we continued to exploit their high degree of functionalization through a short and efficient synthesis to access unprecedented 2,3-di, 2,2,3-tri, 2,3,4-tri, and 2,2,3,4-tetrasubstituted diethyl (pyrrolidine-2-yl) phosphonates. The stereochemistry of the new compounds was unequivocally characterized by X-ray crystallographic analyses. Two selected compounds with structural features shared with the starting products were pharmacologically evaluated, allowing us to deduce the required key structural motifs for biologically active aminophosphonate derivatives. Full article

(This article belongs to the Special Issue Heterocycles: Design, Synthesis and Biological Evaluation, 3rd Edition)

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15 pages, 1754 KB

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Capillary Electrophoresis Electrospray Ionization Mass Spectrometry Reveals Metabolic Perturbations During Nematode Infection in Drosophila melanogaster

by Yayra T. Tuani, Navid J. Ayon, Rosemary M. Onjiko, Sam B. Choi, Shruti Yadav, Ioannis Eleftherianos and Peter Nemes

Molecules 2025, 30(9), 2023; https://doi.org/10.3390/molecules30092023 - 1 May 2025

Viewed by 949

Abstract

Drosophila melanogaster is broadly used to model host–pathogen interactions. Entomopathogenic nematodes are excellent research tools for dissecting the molecular and functional basis of parasitism and the host’s anti-parasitic response. In this work, we used discovery metabolomics to explore the differences in the metabolome [...] Read more.

Drosophila melanogaster is broadly used to model host–pathogen interactions. Entomopathogenic nematodes are excellent research tools for dissecting the molecular and functional basis of parasitism and the host’s anti-parasitic response. In this work, we used discovery metabolomics to explore the differences in the metabolome composition of wild type D. melanogaster larvae that were infected with symbiotic nematodes (Steinernema carpocapsae carrying Xenorhabdus nematophila mutualistic bacteria) or axenic nematodes (S. carpocapsae lacking their bacterial partners). Benefiting from their high separation power, sensitivity, and compatibility with low amounts of the starting metabolome, we leveraged microanalytical capillary electrophoresis electrospray ionization mass spectrometry (CE-ESI-MS) to profile the small (<500 Da) polar portion of the metabolome among these experimental treatments. We detected and quantified 122 different small molecules, of which 50 were identified with high confidence. Supervised multivariate analysis revealed that the infection was paralleled with changes in amino acid biosynthesis (arginine, phenylalanine, tryptophan, and tyrosine), metabolism (alanine, arginine, aspartate, glutamate, glycine, proline, serine, and threonine), and classical signalling (aspartate, γ-aminobutyrate, glutamate, and pyridoxine). This study demonstrates the ability of high-sensitivity CE-ESI-MS to uncover metabolic perturbations during infection. The results from the metadata may facilitate the design of targeted studies to explore small biomolecules and their functions during host–pathogen interaction. Full article

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14 pages, 1555 KB

Open AccessEditor’s ChoiceArticle

Synthesis of 1,4-Benzodiazepines via Intramolecular C–N Bond Coupling and Ring Opening of Azetidines

by Xin-Ming Xu, Sen Chen, Shao-Lei Duan, Xiang-Min Wang, Qian Liu and Kai Sun

Molecules 2025, 30(9), 2014; https://doi.org/10.3390/molecules30092014 - 30 Apr 2025

Viewed by 2592

Abstract

A facile and efficient synthesis of functionalized 1,4-benzodiazepine derivatives under mild conditions was developed. The CuI/N,N-dimethylglycine-catalyzed intramolecular cross-coupling reaction of 1-(2-bromobenzyl)azetidine-2-carboxamides proceeded smoothly under mild conditions to provide 1,4,9,10a-tetrahydroazeto[1,2-a]benzo[e][1,4]diazepin-10(2H)-ones. The resulting azetidine-fused 1,4-benzodiazepine compounds underwent [...] Read more.

A facile and efficient synthesis of functionalized 1,4-benzodiazepine derivatives under mild conditions was developed. The CuI/N,N-dimethylglycine-catalyzed intramolecular cross-coupling reaction of 1-(2-bromobenzyl)azetidine-2-carboxamides proceeded smoothly under mild conditions to provide 1,4,9,10a-tetrahydroazeto[1,2-a]benzo[e][1,4]diazepin-10(2H)-ones. The resulting azetidine-fused 1,4-benzodiazepine compounds underwent consecutive N-methylation with methyl triflate and the opening of the four-membered heterocyclic ring by NaN₃, KCN and PhSNa to produce diverse 1,4-benzodiazepine derivatives in good to excellent yields. Upon treatment with methyl chloroformate, on the other hand, the 1,4,9,10a-tetrahydroazeto[1,2-a]benzo[e][1,4]diazepin-10(2H)-ones were straightforwardly converted into 2-chloroethyl-substituted 1,4-benzodiazepine derivatives. Full article

(This article belongs to the Special Issue Synthesis, Modification and Application of Heterocyclic Compounds)

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18 pages, 7203 KB

Open AccessEditor’s ChoiceArticle

Study on the Catalytic Performance of Nickel(II) Complexes with Distinct Triazine Support Structures in Ethylene Oligomerization via Different Experiment Designs

by Xiaobing Wei, Jiahui Li, Dan Li, Lijun Guo, Yanling Xiao and Cuiqin Li

Molecules 2025, 30(9), 1977; https://doi.org/10.3390/molecules30091977 - 29 Apr 2025

Cited by 2 | Viewed by 727

Abstract

Covalent organic frameworks hold great promise for heterogeneous catalysis because of their porous structure for gas adsorption and tunable functionality. Two triazine support materials (MAmPA-COF and MAoPA-COF) were prepared by using melamine as the linked monomer and meta-phthalaldehyde (MPA) [...] Read more.

Covalent organic frameworks hold great promise for heterogeneous catalysis because of their porous structure for gas adsorption and tunable functionality. Two triazine support materials (MAmPA-COF and MAoPA-COF) were prepared by using melamine as the linked monomer and meta-phthalaldehyde (MPA) or ortho-phthalaldehyde (OPA) as the sub-construction monomer. Two nickel(II) complexes (Ni@MAmPA-COF and Ni@MAoPA-COF) based on the synthesized COFs were prepared to use for ethylene oligomerization. The nickel(II) complexes had good catalytic activities in ethylene oligomerization. Moreover, the substituent position of the aldehyde group in the sub-construction monomer had a certain influence on the specific surface area, morphology and catalytic activity. The morphology of Ni@MAmPA-COF was spherical, while Ni@MAoPA-COF exhibited layered stacking shapes and had a large specific surface area. Ni@MAoPA-COF has a higher catalytic activity and higher selectivity for low-carbon olefins in ethylene oligomerization due to its larger specific surface area and smaller pore width. Ni@MAoPA-COF has good recyclability and still had excellent catalytic activity after three cycles. Based on the gray correlation analysis and single factor experiment, the reaction pressure was the most important factor affecting the activity of Ni@MAoPA-COF in ethylene oligomerization, and the molar ratio of Al/Ni was the main important factor affecting the selectivity. Full article

(This article belongs to the Special Issue Exclusive Feature Papers in Macromolecular Chemistry)

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24 pages, 16546 KB

Open AccessEditor’s ChoiceArticle

Multi-Modal Design, Synthesis, and Biological Evaluation of Novel Fusidic Acid Derivatives

by Luqi Wang, Zhiyuan Geng, Yuhang Liu, Linhui Cao, Yao Liu, Hourui Zhang, Yi Bi and Jing Lu

Molecules 2025, 30(9), 1983; https://doi.org/10.3390/molecules30091983 - 29 Apr 2025

Viewed by 771

Abstract

Fusidic acid (FA), a tetracyclic triterpenoid, has been approved to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. However, there are few reports about FA derivatives with high efficacy superior to FA, manifesting the difficulty of discovering the derivatives based on experience-based drug design. In [...] Read more.

Fusidic acid (FA), a tetracyclic triterpenoid, has been approved to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. However, there are few reports about FA derivatives with high efficacy superior to FA, manifesting the difficulty of discovering the derivatives based on experience-based drug design. In this study, we employed a stepwise method to discover novel FA derivatives. First, molecular dynamics (MD) simulations were performed to identify the molecular mechanism of FA against elongation factor G (EF-G) and drug resistance. Then, we utilized a scaffold decorator to design novel FA derivatives at the 3- and 21-positions of FA. The ligand-based and structure-based screening models, including Chemprop and RTMScore, were employed to identify promising hits from the generated set. Ten generated FA derivatives with high efficacy in the Chemprop and RTMScore models were synthesized for in vitro testing. Compounds 4 and 10 demonstrated a 2-fold increase in potency against MRSA strains compared to FA. This study highlights the significant impact of AI-based methods on the design of novel FA derivatives with drug efficacy, which provides a new approach for drug discovery. Full article

(This article belongs to the Special Issue Advances in Antibacterial Molecules)

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19 pages, 3964 KB

Open AccessEditor’s ChoiceArticle

Tuning 2,3-Bis(arylimino)butane-nickel Precatalysts for High-Molecular-Weight Polyethylene Elastomers

by Dongzhi Zhu, Dedong Jia, Qiuyue Zhang, Yanping Ma, Qaiser Mahmood and Wen-Hua Sun

Molecules 2025, 30(8), 1847; https://doi.org/10.3390/molecules30081847 - 20 Apr 2025

Cited by 3 | Viewed by 718

Abstract

The catalytic performance of α-diiminonickel complexes is highly sensitive to structural modifications in their ligand frameworks. In this study, a series of unsymmetrical 2,3-bis(arylimino)butane-nickel complexes featuring ortho-2,6-dibenzhydryl groups as sterically demanding motifs and para-methyl groups as electron-donating enhancers were proposed and [...] Read more.

The catalytic performance of α-diiminonickel complexes is highly sensitive to structural modifications in their ligand frameworks. In this study, a series of unsymmetrical 2,3-bis(arylimino)butane-nickel complexes featuring ortho-2,6-dibenzhydryl groups as sterically demanding motifs and para-methyl groups as electron-donating enhancers were proposed and synthesized. These nickel complexes were thoroughly characterized using FTIR, elemental analysis, and single-crystal X-ray diffraction (for Ni4 and Ni5), revealing deviations from ideal tetrahedral geometry. Upon activation with Et₂AlCl, these complexes demonstrated exceptional ethylene polymerization activity, achieving a remarkable value of 13.67 × 10⁶ g PE mol⁻¹ (Ni) h⁻¹ at 20 °C. Notably, even at 80 °C, the nickel complexes maintained a high activity of 1.97 × 10⁶ g PE mol⁻¹ (Ni) h⁻¹, showcasing superiority compared to previously reported unsymmetrical 2,3-bis(arylimino)butane-nickel complexes. The resulting polyethylenes exhibited ultra-high molecular weights (M_w: 3.33–19.47 × 10⁵ g mol⁻¹) and tunable branching densities (84–217/1000C), which were effectively controlled by polymerization temperature. Moreover, the mechanical properties of the polyethylenes, including tensile strength (σ_b = 0.74–16.83 MPa), elongation at break (ε_b = 271–475%), and elastic recovery (SR = 42–74%), were finely tailored by optimizing molecular weight, crystallinity, and branching degree. The prepared polyethylenes displayed outstanding elastic recovery, a hallmark of high-performance thermoplastic elastomers, making them promising candidates for advanced material applications. Full article

(This article belongs to the Special Issue Featured Papers in Organometallic Chemistry—2nd Edition)

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14 pages, 1851 KB

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Mechanochemical Sequential Deoxygenative Cross-Coupling Reactions of Phenols Under Ruthenium-Nickel Catalysis

by Satenik Mkrtchyan, Vishal B. Purohit, Michał Jakubczyk, Vaibhav D. Prajapati, Ronak V. Prajapati, Michael G. Garcia, Eugene Karpun, Vitaliy Yepishev, Manoj K. Saini, Sehrish Sarfaraz, Khurshid Ayub, Gabriela Addová, Juraj Filo and Viktor O. Iaroshenko

Molecules 2025, 30(8), 1835; https://doi.org/10.3390/molecules30081835 - 19 Apr 2025

Cited by 3 | Viewed by 2816

Abstract

Herein, we report the first mechanochemical strategy for the Ru-catalyzed deoxygenative borylation of free phenols via C–O bond cleavage. This Ru-catalyzed phenolic borylation approach has been successfully extended to the Suzuki–Miyaura-type cross-coupling of phenols with aryl bromides. The protocol accepts a wide scope [...] Read more.

Herein, we report the first mechanochemical strategy for the Ru-catalyzed deoxygenative borylation of free phenols via C–O bond cleavage. This Ru-catalyzed phenolic borylation approach has been successfully extended to the Suzuki–Miyaura-type cross-coupling of phenols with aryl bromides. The protocol accepts a wide scope of phenolic substrates, allowing the synthesis of aryl pinacolboranes and biphenyl structures in excellent yields and serving as a better alternative to classical cross-coupling reactions in the context of pot, atom, and step economy synthesis. Full article

(This article belongs to the Special Issue Cross-Coupling and Related Reactions: Past and New Reactions for the Future)

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18 pages, 3197 KB

Open AccessEditor’s ChoiceArticle

Bimodal Poly(lactic-co-glycolic acid) Nanocarrier with Zinc Oxide and Iron Oxide for Fluorescence and Magnetic Resonance Imaging

by Thúlio Wliandon Lemos Barbosa, Laurent Lemaire, Isabelle Verdu, Larissa Santos, Natália Galvão de Freitas, Mariana Picchi Salto and Leila Aparecida Chiavacci

Molecules 2025, 30(8), 1818; https://doi.org/10.3390/molecules30081818 - 18 Apr 2025

Cited by 1 | Viewed by 841

Abstract

Zinc oxide (ZnO) and iron oxide (IO) nanoparticles have been identified as promising candidates for biomedical applications, based on their unique physicochemical properties. The association of these nanoparticles in a single system creates a bimodal entity, allowing the excellent luminescent properties of ZnO [...] Read more.

Zinc oxide (ZnO) and iron oxide (IO) nanoparticles have been identified as promising candidates for biomedical applications, based on their unique physicochemical properties. The association of these nanoparticles in a single system creates a bimodal entity, allowing the excellent luminescent properties of ZnO quantum dots to be combined with the contrast agent of IO for magnetic resonance imaging (MRI). The present study focuses on the luminescent and MRI properties of a new poly(lactic-co-glycolic acid) (PLGA) nanocarrier system formulation containing ZnO NPs and IO NPs in different nominal ratios. Microscopic analysis (TEM and SEM) reveals a circular morphology with IO and ZnO NPs. The average diameter of the particles was determined to be 220 nm, as measured by DLS. The luminescence results indicate that the PLGA system shows strong emission in the visible range, and the MRI analysis shows a high r2 relaxivity of 171 mM⁻¹ s⁻¹ at 7T. The optimized formulation, exhibiting a molar ratio of Fe:Zn ranging from 1:10 to 1:13 (mol:mol), demonstrates superior fluorescence and MRI performance, underscoring the significance of nanoparticle composition in bimodal imaging applications. The systems evaluated demonstrate no toxicity in the THP-1 cells for doses of up to 128 µg mL⁻¹, with efficient labeling after 4 h of incubation, yielding images of strong luminescence and T2 contrast. The PLGA:ZnO:IO system demonstrates considerable potential as a bimodal platform for diagnostic imaging. Full article

(This article belongs to the Special Issue Nanostructured Materials: Synthesis, Functionalization and Applications in Biomedicine—2nd Edition)

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13 pages, 6388 KB

Open AccessEditor’s ChoiceArticle

Identification of Novel Compounds That Bind to the HGF β-Chain In Silico, Verification by Molecular Mechanics and Quantum Mechanics, and Validation of Their HGF Inhibitory Activity In Vitro

by Ko Suzuki, Keitaro Inoue, Ryota Namiguchi, Seiya Morita, Suzuho Hayakawa, Mikuri Yokota, Katsuya Sakai, Kunio Matsumoto and Shunsuke Aoki

Molecules 2025, 30(8), 1801; https://doi.org/10.3390/molecules30081801 - 17 Apr 2025

Cited by 1 | Viewed by 851

Abstract

The development of small-molecule drugs targeting growth factors for cancer therapy remains a significant challenge, with only limited successful cases. We attempted to identify hepatocyte growth factor (HGF) inhibitors as novel anti-cancer small-molecule drugs. To identify compounds that bind to the β-chain of [...] Read more.

The development of small-molecule drugs targeting growth factors for cancer therapy remains a significant challenge, with only limited successful cases. We attempted to identify hepatocyte growth factor (HGF) inhibitors as novel anti-cancer small-molecule drugs. To identify compounds that bind to the β-chain of HGF and inhibit signaling through HGF and its receptor Met interaction, we performed a hierarchical in silico drug screen using a three-dimensional compound structure library (Chembridge, 154,118 compounds). We experimentally tested whether 10 compounds selected as candidates for novel anticancer agents exhibit inhibition of HGF activity. Compounds 6 and 7 potently inhibited Met phosphorylation in the human EHEMES-1 cell line, with IC₅₀ values of 20.4 and 11.9 μM, respectively. Molecular dynamics simulations of the Compound 6/7–HGF β-chain complex structures suggest that Compounds 6 and 7 stably bind to the interface pocket of the HGF β-chain. MM-PBSA, MM-GBSA, and FMO analyses identified crucial amino acid residues for inhibition against the HGF β-chain. By interfering with the HGF/Met interaction, these compounds may attenuate downstream signaling pathways involved in cancer cell proliferation and metastasis. Further optimization and comprehensive evaluations are necessary to advance these compounds toward clinical application in cancer therapy. Full article

(This article belongs to the Special Issue Novel Inhibitors: Design, Synthesis, Biological Activities and Modelling Studies)

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19 pages, 2004 KB

Open AccessEditor’s ChoiceArticle

6-Chlorocoumarin Conjugates with Nucleobases and Nucleosides as Potent Anti-Hepatitis C Virus Agents

by Shu-Yu Lin, Wen-Chieh Huang, Shwu-Chen Tsay, Johan Neyts, Pieter Leyssen, Chun-Cheng Lin, Kuo Chu Hwang, Jia-Cherng Horng and Jih Ru Hwu

Molecules 2025, 30(8), 1776; https://doi.org/10.3390/molecules30081776 - 15 Apr 2025

Viewed by 671

Abstract

On the basis of a “chemo-combination strategy”, (6-chloro)coumarin was incorporated to purines and pyrimidines, as well as their corresponding nucleosides, with a –SCH₂– linker at different positions under alkaline conditions. These conjugates were found to exert an antiviral effect on the [...] Read more.

On the basis of a “chemo-combination strategy”, (6-chloro)coumarin was incorporated to purines and pyrimidines, as well as their corresponding nucleosides, with a –SCH₂– linker at different positions under alkaline conditions. These conjugates were found to exert an antiviral effect on the 1b subgenomic replicon replication of the hepatitis C virus (HCV) in Huh 5-2 and Huh 9-13 cells. In this compound library containing 14 new compounds, 6-[(6′-chlorocoumarin-3′-yl)methylthio]purine, 6-(6′-chlorocoumarin-3′-yl)methylthio-9-(β-D-ribofuranos-1″-yl)purine, and 2-[(6′-chlorocoumarin-3′-yl)methylthio]uracil showed great inhibitory abilities, with EC₅₀ values between 6.6 and 9.4 μM and selectivity indexes >16–41. Moreover, the structure–activity relationship between purines and pyrimidines is elucidated, which reveals the critical factor of the attachment of the coumarin moiety at different positions in purines and pyrimidines. Full article

(This article belongs to the Special Issue Nucleoside and Nucleotide Analogues: Chemical Synthesis and Applications)

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26 pages, 4882 KB

Open AccessEditor’s ChoiceArticle

Lead-Structure-Based Rigidization Approach to Optimize SirReal-Type Sirt2 Inhibitors

by Matthias Frei, Thomas Wein and Franz Bracher

Molecules 2025, 30(8), 1728; https://doi.org/10.3390/molecules30081728 - 11 Apr 2025

Cited by 2 | Viewed by 1064

Abstract

Sirtuins are involved in cellular processes in multiple ways. Therefore, the development of potent and selective Sirt2 inhibitors provides an important contribution to understanding physiological and pathophysiological mechanisms, particularly for the research and treatment of cancer and neurodegenerative diseases. Based on established SirReal-type [...] Read more.

Sirtuins are involved in cellular processes in multiple ways. Therefore, the development of potent and selective Sirt2 inhibitors provides an important contribution to understanding physiological and pathophysiological mechanisms, particularly for the research and treatment of cancer and neurodegenerative diseases. Based on established SirReal-type lead inhibitors, further selective Sirt2 inhibitors were synthesized in a docking-guided rigidization approach, and the knowledge regarding requirements and properties of the Sirt2-binding pocket was expanded by means of a comprehensive SAR study. Naphthalene derivative FM69 emerged from the screening as the most potent rigidized inhibitor, which, with an IC₅₀ value of 0.15 µM against Sirt2, represents a promising foundation for the further development of novel potent and selective Sirt2 inhibitors based on the presented rigidization strategy. Full article

(This article belongs to the Special Issue Organic Synthesis and Medicinal Chemistry, Two Inseparable Partners: Recent Advances in Heterocyclic Chemistry)

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15 pages, 1951 KB

Open AccessEditor’s ChoiceArticle

Liposomes for Magnetic Resonance Image-Guided Drug Delivery; Lipid Chain Length Affects Drug Release and MRI Relaxivity

by Paul Cressey, Jacob C. Wilson, Maral Amrahli and Maya Thanou

Molecules 2025, 30(8), 1729; https://doi.org/10.3390/molecules30081729 - 11 Apr 2025

Viewed by 928

Abstract

Image-guided drug delivery is a method for tracking drug carriers for activation in specific lesions in the body. Image guidance uses the labelling of the drug or carrier and a clinically approved imaging modality. MRI (magnetic resonance image)-guided drug delivery has been considered [...] Read more.

Image-guided drug delivery is a method for tracking drug carriers for activation in specific lesions in the body. Image guidance uses the labelling of the drug or carrier and a clinically approved imaging modality. MRI (magnetic resonance image)-guided drug delivery has been considered for focused ultrasound tumour-targeted drug release. Liposomes are labelled for MRI tracking and the confirmation of drug delivery. In this study, we prepared two lipids conjugated to Gd-DOTA that confer MR imaging properties. Two lipid conjugates to DOTA, a C₁₈ (LCA-1) and a C₁₆ (LCA-2), were synthesised. The lipids were combined at different ratios within the lipid mix, and we investigated their effects on the liposome’s T_m using DSC (differential scanning calorimetry) and on relaxivity using NMR. The results show that when different combinations of LCA-1 and LCA-2 were introduced into the liposomes, their ratio affected both thermal drug release and relaxivity. As these lipids are part of the liposomal membrane, they confer tracking ability, and their effect on relaxivity due to thermal release could enable the confirmation of liposomal drug release using MRI at clinically relevant magnetic field strengths. Full article

(This article belongs to the Special Issue Molecular Approaches to Drug Discovery and Development)

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18 pages, 5022 KB

Open AccessEditor’s ChoiceReview

Searching for New Gold(I)-Based Complexes as Anticancer and/or Antiviral Agents

by Paola Checconi, Annaluisa Mariconda, Alessia Catalano, Jessica Ceramella, Michele Pellegrino, Stefano Aquaro, Maria Stefania Sinicropi and Pasquale Longo

Molecules 2025, 30(8), 1726; https://doi.org/10.3390/molecules30081726 - 11 Apr 2025

Cited by 4 | Viewed by 1382

Abstract

Approaches capable of simultaneously treating cancer and protecting susceptible patients from lethal infections are highly desirable, although they prove challenging. Taking inspiration from the well-known anticancer platinum complexes, successive studies about the complexation of organic compounds with other late transition metals, such as [...] Read more.

Approaches capable of simultaneously treating cancer and protecting susceptible patients from lethal infections are highly desirable, although they prove challenging. Taking inspiration from the well-known anticancer platinum complexes, successive studies about the complexation of organic compounds with other late transition metals, such as silver, gold, palladium, rhodium, ruthenium, iridium, and osmium, have led to remarkable anticancer activities. Among the numerous chemical moieties studied, N-heterocyclic carbenes (NHCs) have revealed very attractive activities due to their favorable chemical properties. Specifically, gold–NHC complexes emerged as some of the most active complexes acting as antitumor agents. On the other hand, some recent studies have highlighted the involvement of these complexes in antiviral research as well. The well-known gold-based, orally available complex auranofin approved by the Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis has been suggested as a repositioned drug for both cancer and viral infections. In the era of the COVID-19 pandemic, the most interesting goal could be the discovery of gold–NHC complexes as dual antiviral and anticancer agents. In this review, the most recent studies regarding the anticancer and antiviral activities of gold(I)–NHC complexes will be analyzed and discussed, offering an interesting insight into the research in this field. Full article

(This article belongs to the Special Issue Exclusive Feature Papers in Inorganic Chemistry, 3rd Edition)

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64 pages, 42508 KB

Open AccessEditor’s ChoiceReview

Transition Metal Catalysis for the Asymmetric Synthesis of 2-Arylethylamines: A Review of the New Millennium

by Alejandro Manchado, Ángel García-González, Carlos T. Nieto, Nieves G. Ledesma, David Díez and Narciso M. Garrido

Molecules 2025, 30(8), 1721; https://doi.org/10.3390/molecules30081721 - 11 Apr 2025

Viewed by 2652

Abstract

The 2-arylethylamine motif is very well-known in medicinal chemistry because of its interesting properties when it comes to interacting with the Central Neural System thanks to its ability to pass the blood–brain barrier. This nitrogen-containing family of compounds is of great interest in [...] Read more.

The 2-arylethylamine motif is very well-known in medicinal chemistry because of its interesting properties when it comes to interacting with the Central Neural System thanks to its ability to pass the blood–brain barrier. This nitrogen-containing family of compounds is of great interest in synthetic organic chemistry and, when it comes to its asymmetric synthesis, great challenges can be faced in order to obtain the chiral purity required in the drug industry. Thus, we provide a concise transition metal review presenting the recent advances in the synthesis of chiral 2-arylethylamines using transition metals as the main catalysts in the introduction of chirality. Both conventional and photocatalysis methods will be covered, considering the main transition metal used in the studies. Full article

(This article belongs to the Special Issue Current Development of Asymmetric Catalysis and Synthesis)

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14 pages, 5415 KB

Open AccessEditor’s ChoiceArticle

Amphiphilic Styrene-Based Pyrene Derivatives: Tunable Aggregation Luminescence and Their Photo-Induced Dimerization Behavior

by Junying Zhang, Xingwei Luo and Juan Qiu

Molecules 2025, 30(8), 1719; https://doi.org/10.3390/molecules30081719 - 11 Apr 2025

Viewed by 764

Abstract

Since the discovery of the aggregation-induced emission (AIE) phenomenon, various stimuli-responsive materials have been rapidly developed. However, how to achieve the transition between aggregation-caused quenching (ACQ) and AIE through molecular design is an urgent problem to be solved. In this work, we synthesized [...] Read more.

Since the discovery of the aggregation-induced emission (AIE) phenomenon, various stimuli-responsive materials have been rapidly developed. However, how to achieve the transition between aggregation-caused quenching (ACQ) and AIE through molecular design is an urgent problem to be solved. In this work, we synthesized and studied the aggregation luminescence behavior and photochromism of two different substituted pyrene ethylene derivatives, 1-H and 1-CN. Due to the different substituents attached to the ethylene unit, 1-H exhibits ACQ luminescence behavior. When the substituent is a cyanide group, it exhibits AIE behavior. In addition, the ordered nanoparticles formed by self-assembly in aqueous solution exhibit interesting photo-induced cyclization behavior, which leads to fluorescence quenching under ultraviolet light irradiation (λ = 365 nm). Therefore, due to their amphiphilicity and photo-responsiveness, these compounds can be used as anticounterfeiting inks in information encryption. This work contributes new members to the family of amphiphilic photo-responsive materials and demonstrates their potential applications in optical information storage and multi-color luminescence. Full article

(This article belongs to the Special Issue Advances in Functional Organic Dye Chemistry)

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21 pages, 2433 KB

Open AccessEditor’s ChoiceReview

Harnessing Microalgae as Sustainable Cell Factories for Polyamine-Based Nanosilica for Biomedical Applications

by Sik Yoon, Boon Huat Bay and Ken Matsumoto

Molecules 2025, 30(8), 1666; https://doi.org/10.3390/molecules30081666 - 8 Apr 2025

Cited by 3 | Viewed by 1412

Abstract

Microalgae are microscopic unicellular organisms that inhabit marine, freshwater, and moist terrestrial ecosystems. The vast number and diversity of microalgal species provide a significant reservoir of biologically active compounds, highly promising for biomedical applications. Diatoms are unicellular eukaryotic algae belonging to the class [...] Read more.

Microalgae are microscopic unicellular organisms that inhabit marine, freshwater, and moist terrestrial ecosystems. The vast number and diversity of microalgal species provide a significant reservoir of biologically active compounds, highly promising for biomedical applications. Diatoms are unicellular eukaryotic algae belonging to the class Bacillariophyceae. They possess intricately structured silica-based cell walls, which contain long-chain polyamines that play important roles in the formation of silica. Long-chain polyamines are uncommon polyamines found only in organisms that produce biosilica. Diatomite, which is a marine sediment of the remains of the silica skeleton of diatoms, could be an abundant source of biogenic silica that can easily be converted to silica particles. This concise review focuses on the biofabrication of polyamine-based nanosilica from diatoms and highlights the possibility of utilizing diatom biosilica as a nanocarrier for drug and siRNA delivery, bioimaging, and bone tissue engineering. The challenges that may affect diatom production, including environmental stresses and climate change, are discussed together with the prospect of increasing diatom-based biosilica production with the desired nanostructures via genetic manipulation. Full article

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17 pages, 3268 KB

Open AccessEditor’s ChoiceArticle

Gold(III) Complexes with 2-(1-Ethylbenzyl)pyridine as Promising Antimicrobial and Antitumor Agents

by Antonio Zucca, Bruna Canu, Maria I. Pilo, Sergio Stoccoro, Giacomo Senzacqua, Sara Fais, Giuseppina Pichiri and Alessandra Scano

Molecules 2025, 30(7), 1611; https://doi.org/10.3390/molecules30071611 - 4 Apr 2025

Viewed by 1195

Abstract

Antimicrobial resistance (AMR) is one of the most urgent public health problems worldwide; multidrug resistance (MDR) is also of concern. In an effort to find new classes of antibiotics, recent studies have found that coordination compounds of noble metals show promising biological effects [...] Read more.

Antimicrobial resistance (AMR) is one of the most urgent public health problems worldwide; multidrug resistance (MDR) is also of concern. In an effort to find new classes of antibiotics, recent studies have found that coordination compounds of noble metals show promising biological effects both in vitro and in vivo, deserving attention as a new class of possible antimicrobial agents. Metal ions in biological systems can essentially have two roles: structural or functional. In the former, the metal ion serves to stabilize structures, especially proteins, while in the latter, the metal is involved in bio-site reactivity (essentially in metallo-enzymes). Two new complexes with 2-(1-ethyl-benzyl)pyridine (py^eb), one monodentate adduct and one cyclometalated ([Au(py^eb)Cl₃] and [Au(py^eb-H)Cl₂], respectively), have been synthesized, characterized, and tested against Gram-positive and Gram-negative bacteria, as well as yeasts, revealing promising antibacterial and antibiofilm properties. The two complexes have been thoroughly characterized by means of 1D and 2D NMR spectroscopy, as well as by cyclic voltammetry, conductivity measurements, FT-IR, and elemental analysis. The study showed that the two derivatives are structurally and chemically different, with the cyclometalated complex being chemically and electrochemically more stable. Antimicrobial assays demonstrated that solutions of the monodentate adduct and of the cyclometalated complex have inhibitory and antibiofilm effects against the pathogenic bacteria E. coli, K. pneumoniae, S. aureus, and S. pyogenes but were unable to reveal a fungicidal effect on C. albicans. A preliminary study was conducted to assess the anti-cancer activity of the compounds, and treatments with the gold compounds also resulted in a significant reduction in the metabolic activity of HT29 colon cancer cells. Full article

(This article belongs to the Special Issue Featured Papers in Organometallic Chemistry—2nd Edition)

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18 pages, 2503 KB

Open AccessEditor’s ChoiceArticle

Towards Metabolic Organic Radical Contrast Agents (mORCAs) for Magnetic Resonance Imaging

by Shuyang Zhang, Sabina Dhakal, Evan Curtis, Hunter Miller, Joseph T. Paletta, Connor Gee, Suchada Rajca, Forrest Kievit and Andrzej Rajca

Molecules 2025, 30(7), 1581; https://doi.org/10.3390/molecules30071581 - 2 Apr 2025

Viewed by 3370

Abstract

We report two conjugates of gem-diethyl pyrroline nitroxide radicals with D-mannosamine as potential metabolic organic radical contrast agents, mORCAs, circumventing the need for biorthogonal reactions. In-cell EPR spectroscopy, using Jurkat cells and analogous conjugate, based on a pyrrolidine nitroxide radical, shows an [...] Read more.

We report two conjugates of gem-diethyl pyrroline nitroxide radicals with D-mannosamine as potential metabolic organic radical contrast agents, mORCAs, circumventing the need for biorthogonal reactions. In-cell EPR spectroscopy, using Jurkat cells and analogous conjugate, based on a pyrrolidine nitroxide radical, shows an efficient incorporation of highly immobilized nitroxides, with a correlation time of τ_cor = 20 ns. In vivo MRI experiments in mice show that the paramagnetic nitroxide radical shortens the T₁ and T₂ relaxation times of protons in water located in the kidney and brain by only up to ~10% after 3 d. Ex vivo EPR spectroscopic analyses indicate that the contrast agents in mouse tissues are primarily localized in the kidney, lung, liver, heart, and blood, which primarily contain immobilized nitroxide radicals with τ_cor = 4–9 ns. The spin concentrations in tissues remain low (1–3 nmol g⁻¹) at 24 h after the third mORCA injection, approximately one to two orders of magnitude lower than those of ORCAFluor and BASP-ORCA (measured at ~24 h post-injection). These low spin concentrations explain the small proton T₁ and T₂ relaxation changes observed in in vivo MRI. Full article

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23 pages, 15163 KB

Open AccessEditor’s ChoiceReview

The Role of Flow Chemistry on the Synthesis of Pyrazoles, Pyrazolines and Pyrazole-Fused Scaffolds

by Catarina M. Correia, Artur M. S. Silva and Vera L. M. Silva

Molecules 2025, 30(7), 1582; https://doi.org/10.3390/molecules30071582 - 2 Apr 2025

Cited by 3 | Viewed by 4873

Abstract

Nitrogen-containing heterocycles are fundamental scaffolds in organic chemistry, particularly due to their prevalence in pharmaceuticals, agrochemicals and materials science. Among them, five-membered rings, containing two nitrogen atoms in adjacent positions—such as pyrazoles, pyrazolines and indazoles—are especially significant due to their versatile biological activities [...] Read more.

Nitrogen-containing heterocycles are fundamental scaffolds in organic chemistry, particularly due to their prevalence in pharmaceuticals, agrochemicals and materials science. Among them, five-membered rings, containing two nitrogen atoms in adjacent positions—such as pyrazoles, pyrazolines and indazoles—are especially significant due to their versatile biological activities and structural properties, which led to the search for greener, faster and more efficient methods for their synthesis. Conventional batch synthesis methods, while effective, often face challenges related to reaction efficiency, scalability and safety. Flow chemistry has emerged as a powerful alternative, offering enhanced control over reaction parameters, improved safety profiles and opportunities for scaling up synthesis processes efficiently. This review explores the impact of flow chemistry on the synthesis of these pivotal heterocycles, highlighting its advantages over the conventional batch methods. Although indazoles have a five-membered ring fused with a benzene ring, they will also be considered in this review due to their biological relevance. Full article

(This article belongs to the Special Issue Recent Advances in the Synthesis, Functionalization and Applications of Pyrazole-Type Compounds III)

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11 pages, 3856 KB

Open AccessEditor’s ChoiceArticle

Supramolecular Double-Helical Polymers: Supramolecular Chiral Induction and Asymmetric Catalysis

by Xiaojun Guo, Xinyu Jia, Qin He, Wengui Duan, Yanjun Zhang, Yan Huang and Luzhi Liu

Molecules 2025, 30(7), 1517; https://doi.org/10.3390/molecules30071517 - 28 Mar 2025

Cited by 3 | Viewed by 1362

Abstract

Seeking a supramolecular chiral system induced by trace chiral molecules instead of traditional complex and expensive chiral ligands to achieve high yield or ee value conversion of the products is of great significance in asymmetric synthesis but still remains a challenge. Herein, two [...] Read more.

Seeking a supramolecular chiral system induced by trace chiral molecules instead of traditional complex and expensive chiral ligands to achieve high yield or ee value conversion of the products is of great significance in asymmetric synthesis but still remains a challenge. Herein, two types of double helical supramolecular chiral systems, (M)-Helix and (P)-Helix, with opposite chiral optics were constructed in situ using tyrosine-functionalized pillar[5]arene as inducers. These systems exhibit chiroptical stability and enable remarkable chirality amplification from 7 mol% chiral seeds. When applied to intermolecular olefin cyano-trifluoromethylation, (M)-Helix exhibits remarkable catalytic efficiency (yield up to 89%), whereas (P)-Helix achieves higher enantioselectivity (ee up to 84%). This research will provide new ideas for supramolecular chiral catalysts in organic asymmetric catalysis applications. Full article

(This article belongs to the Special Issue Recent Advances in Supramolecular Chemistry)

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15 pages, 8158 KB

Open AccessEditor’s ChoiceArticle

Effect of Functional Group-Modified UiO-66 on the Dehydrogenation of Ammonia Borane

by Senliang Xi, Dawei Xu, Renzeng Chen, Wenhao Yao, Wenying Wu, Teng Zhang and Liang Yu

Molecules 2025, 30(7), 1487; https://doi.org/10.3390/molecules30071487 - 27 Mar 2025

Viewed by 969

Abstract

Ammonia borane (AB) has attracted much attention in the field of solid-state hydrogen storage due to its high hydrogen storage capacity. Nanoconfinement in UiO-66 can reduce the hydrogen release temperature. In particular, terephthalic acid was used as a linker to further improve the [...] Read more.

Ammonia borane (AB) has attracted much attention in the field of solid-state hydrogen storage due to its high hydrogen storage capacity. Nanoconfinement in UiO-66 can reduce the hydrogen release temperature. In particular, terephthalic acid was used as a linker to further improve the dehydrogenation properties through the modification of -NH₂, -OH, -NO₂, -Br, and -F groups. The hydrogen release content of 0.5AB/UiO-66 was 1.98 wt.%, whereas the hydrogen release content of UiO-66-2OH modified by -OH groups increased to 3.85 wt.%. The non-covalent interaction results show that -NH₂ and -OH preferred adsorption with -BH₃, and the H in -NH₂ and -OH were able to interact directly with the H in AB to modify the dehydrogenation process of AB, whereas -NO₂, -Br, and -F indirectly affected the charge density of hydrogen atoms in AB to alter the dehydrogenation property of AB. The modification of functional groups provides a theoretical basis for the design of high-performance MOF nanoconfinement AB composite hydrogen storage materials. Full article

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13 pages, 1908 KB

Open AccessEditor’s ChoiceArticle

Aggregation-Induced Luminescent 3-Phenylpyrano[4,3-b]quinolizine Derivatives as Photosensitizers with Anti-Cancer Properties

by Masayori Hagimori, Tatsusada Yoshida, Takuma Tsutsumi, Fumiko Hara, Shinya Takada, Yukiko Ogawa and Keitaro Tanaka

Molecules 2025, 30(7), 1422; https://doi.org/10.3390/molecules30071422 - 23 Mar 2025

Viewed by 808

Abstract

Photodynamic therapy (PDT) has garnered significant attention as an effective and safe method for cancer therapy, with ongoing efforts to develop new photosensitizers to enhance its efficacy. This study aimed to develop novel photosensitizers with aggregation-induced emission enhancement (AIEE) properties. A series of [...] Read more.

Photodynamic therapy (PDT) has garnered significant attention as an effective and safe method for cancer therapy, with ongoing efforts to develop new photosensitizers to enhance its efficacy. This study aimed to develop novel photosensitizers with aggregation-induced emission enhancement (AIEE) properties. A series of 3-phenyl pyrano[4,3-b]quinolizine compounds (3–10) were synthesized by reacting pyrones (1a–e) with 2-pyridylacetate (2a) or 2-pyridylacetonitrile (2b) and then evaluated for their potential as photosensitizers. Spectroscopic analyses revealed that all compounds emitted blue to green fluorescence in ethanol, with emission wavelengths ranging from 446 nm to 515 nm. Compounds 5 and 6, lacking a substituent at position 5 of pyrano[4,3-b]quinolizine, exhibited AIEE behavior in aqueous solution. Furthermore, all compounds produced reactive oxygen species upon exposure to LED light. Notably, compounds 5 and 6 demonstrate high singlet oxygen (¹O₂) generation efficiency in water-rich solvents, where they tend to aggregate, contributing to their potential to destroy cancer cells. In vitro studies using human colon cancer cells (Colo205) demonstrated that 5 and 6 exhibited potent anti-tumor activity upon exposure to LED light. These findings suggest that compounds 5 and 6, based on 3-phenyl pyrano[4,3-b]quinolizine, possessing AIEE properties, are potential new photosensitizers for PDT. Full article

(This article belongs to the Special Issue Design, Synthesis and Evaluation of Novel Anticancer Agents, 2nd Edition)

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19 pages, 1820 KB

Open AccessEditor’s ChoiceArticle

Synthesis of Functionalized 1H-Imidazoles via Denitrogenative Transformation of 5-Amino-1,2,3-Triazoles

by Pavel S. Gribanov, Anna N. Philippova, Alexander F. Smol’yakov, Diana N. Tukhvatullina, Viktoria A. Vlasova, Maxim A. Topchiy, Andrey F. Asachenko and Sergey N. Osipov

Molecules 2025, 30(7), 1401; https://doi.org/10.3390/molecules30071401 - 21 Mar 2025

Viewed by 3268

Abstract

An efficient access to novel 2-substituted 1H-imidazole derivatives was developed based on acid-mediated denitrogenative transformation of 5-amino-1,2,3-triazole derivatives available through dipolar azide−nitrile cycloaddition (DCR). The proposed approach includes intramolecular cyclization of 5-amino-4-aryl-1-(2,2-diethoxyethyl) 1,2,3-triazoles followed by triazole ring opening and insertion of [...] Read more.

An efficient access to novel 2-substituted 1H-imidazole derivatives was developed based on acid-mediated denitrogenative transformation of 5-amino-1,2,3-triazole derivatives available through dipolar azide−nitrile cycloaddition (DCR). The proposed approach includes intramolecular cyclization of 5-amino-4-aryl-1-(2,2-diethoxyethyl) 1,2,3-triazoles followed by triazole ring opening and insertion of in situ formed carbene intermediate into the O-H bond of different alcohols under acidic conditions. Full article

(This article belongs to the Special Issue Synthesis and Functionalization of Nitrogen Heterocycles)

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21 pages, 5487 KB

Open AccessEditor’s ChoiceReview

Targeting the CXCR4/CXCL12 Axis in Cancer Therapy: Analysis of Recent Advances in the Development of Potential Anticancer Agents

by Gerardina Smaldone, Francesca Di Matteo, Roberta Castelluccio, Valeria Napolitano, Maria Rosaria Miranda, Michele Manfra, Pietro Campiglia and Vincenzo Vestuto

Molecules 2025, 30(6), 1380; https://doi.org/10.3390/molecules30061380 - 20 Mar 2025

Cited by 5 | Viewed by 4047

Abstract

Cancer, a leading cause of premature death, arises from genetic and epigenetic mutations that transform normal cells into tumor cells, enabling them to proliferate, evade cell death, and stimulate angiogenesis. Recent evidence indicates that chemokines are essential in tumor development, activating receptors that [...] Read more.

Cancer, a leading cause of premature death, arises from genetic and epigenetic mutations that transform normal cells into tumor cells, enabling them to proliferate, evade cell death, and stimulate angiogenesis. Recent evidence indicates that chemokines are essential in tumor development, activating receptors that promote proliferation, invasion, and metastasis. The CXCR4/CXCL12 signaling pathway is gaining attention as a promising target for cancer therapy. CXCR4, a chemokine receptor, is often overexpressed in various types of cancer, including kidney, lung, brain, prostate, breast, pancreas, ovarian, and melanomas. When it binds to its endogenous ligand, CXCL12, it promotes cell survival, proliferation, and migration, crucial mechanisms for the retention of hematopoietic stem cells in the bone marrow and the movement of lymphocytes. The extensive expression of CXCR4 in cancer, coupled with the constant presence of CXCL12 in various organs, drives the activation of this axis, which in turn facilitates angiogenesis, tumor progression, and metastasis. Given the detrimental role of the CXCR4/CXCL12 axis, the search for drugs acting selectively against this protein represents an open challenge. This review aims to summarize the recent advancements in the design and development of CXCR4 antagonists as potential anticancer agents. Full article

(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Novel Antitumor Drugs)

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11 pages, 5854 KB

Open AccessEditor’s ChoiceArticle

Novel Fe(II)-Based Supramolecular Film Prepared by Interfacial Self-Assembly of an Asymmetric Polypyridine Ligand and Its Electrochromic Performance

by Xiya Chen, Xiaomeng Sun, Tingting Dai, Hongwei Wang, Qian Zhao, Chunxia Yang, Xianchao Du, Xiaojing Xing, Xinfeng Cheng and Dongfang Qiu

Molecules 2025, 30(6), 1376; https://doi.org/10.3390/molecules30061376 - 19 Mar 2025

Cited by 2 | Viewed by 773

Abstract

An asymmetric two-arm polypyridine ligand 4′-{4-[4-(2,2′-dipyridyl)phenyl]}-2,2′:6′,2′-terpyridine (TPY-Ph-BPY) with double coordination units was synthesized using the one-step Suzuki reaction. The metallic supramolecular film was subsequently obtained by the Fe²⁺-induced self-assembly method at the CHCl₃-H₂O interface, which [...] Read more.

An asymmetric two-arm polypyridine ligand 4′-{4-[4-(2,2′-dipyridyl)phenyl]}-2,2′:6′,2′-terpyridine (TPY-Ph-BPY) with double coordination units was synthesized using the one-step Suzuki reaction. The metallic supramolecular film was subsequently obtained by the Fe²⁺-induced self-assembly method at the CHCl₃-H₂O interface, which displayed a distinct flat and continuous morphology. The supramolecular film-coated ITO electrode demonstrated a reversible electrochemical redox behavior with pronounced color changes between purple and light green. Its solid-state electrochromic device had an optical contrast (ΔT%) of 26.2% at λ_max = 573 nm with balanced coloring (t_c = 2.4 s) and bleaching (t_b = 2.6 s) times and a high current efficiency of 507.8 cm²/C. Moreover, good cycling stability with a long-term reversible color change was observed beyond 900 cycles. These results suggested the promising potential of the TPY-Ph-BPY-Fe(II) supramolecular film for electrochromic applications. Full article

(This article belongs to the Special Issue Metal Complexes: Synthesis, Characterization and Applications)

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17 pages, 2057 KB

Open AccessEditor’s ChoiceArticle

Synthesis of Adenine Nucleosides with a Reactive (β-Iodovinyl)sulfone or (β-Keto)sulfone Group at the C2 Position and Their Polymerase-Catalyzed Incorporation into DNA

by A. Hasan Howlader, Richard Fernandez, Pawlos S. Tsegay, Yuan Liu and Stanislaw F. Wnuk

Molecules 2025, 30(6), 1358; https://doi.org/10.3390/molecules30061358 - 18 Mar 2025

Cited by 1 | Viewed by 973

Abstract

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 [...] Read more.

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

(This article belongs to the Special Issue Exclusive Feature Papers in Synthetic Medicinal Chemistry)

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44 pages, 115423 KB

Open AccessEditor’s ChoiceReview

Research Progress in Epoxidation of Light Small-Molecule Olefins

by Guanghui Zhao, Tianfu Yang, Jincheng Liu, Xianming Xu, Yulong Wang, Yongjun Zhang, Meng Gao, Chao Xiong and Hongbing Ji

Molecules 2025, 30(6), 1340; https://doi.org/10.3390/molecules30061340 - 17 Mar 2025

Cited by 3 | Viewed by 2014

Abstract

Light olefins, as important bulk raw materials in the petrochemical industry, play an irreplaceable role in the development of the manufacturing industry and the economy. The epoxides of light olefins are important intermediates for the synthesis of polymers, drugs, and fine chemicals, and [...] Read more.

Light olefins, as important bulk raw materials in the petrochemical industry, play an irreplaceable role in the development of the manufacturing industry and the economy. The epoxides of light olefins are important intermediates for the synthesis of polymers, drugs, and fine chemicals, and their green, efficient, and safe synthesis has attracted much attention. This review focuses on the research progress of light olefin epoxidation and elucidates traditional epoxidation methods, such as the chlorohydrin method. Although these processes have mature processes, they have drawbacks, including equipment corrosion, environmental pollution, poor safety, and high waste emissions. Special emphasis is placed on catalytic epoxidation systems using oxygen or organic peroxides as oxygen sources. For homogeneous catalytic systems, certain metal complexes exhibit high activity and selectivity yet are difficult to separate and recycle. Moreover, heterogeneous catalytic systems have become a research hotspot due to their advantages of easy separation and reusability, with supported metal catalysts being a prime example. Meanwhile, the effects of reaction temperature, pressure, solvent, etc., on epoxidation are explored. The specific reaction mechanisms are also studied and analyzed. Current research challenges, including enhancing catalyst stability and reducing costs, are summarized. In the future, developing highly efficient, green, and economically viable epoxidation technologies for large-scale industrial applications represents an important research direction in this field. Full article

(This article belongs to the Special Issue Metal-Catalyzed Organic Transformations: Expanding Horizons in Synthetic Methodology)

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