Coenzyme A (CoA) facilitates fatty acid synthesis, energy production, gene regulation, and antioxidant function. While CoA biosynthesis is well-characterized, the mechanisms governing CoA degradation remain poorly understood. Here, we identify the Metazoan Homolog of SpoT, MESH1, as a CoA phosphatase that dephosphorylates CoA at the 3' position of the ribose ring to form dephospho-CoA (dp-CoA). Recent studies have shown that CoA, similar to glutathione (GSH), is a cysteine-derived metabolite that protects cells against ferroptosis. Ferroptosis induced by blocking cystine import depletes CoA biosynthesis, while CoA restoration rescues cells from ferroptosis. We found that MESH1 knockdown preserved CoA levels by preventing its degradation, contributing to ferroptosis protection, indicating the bifunctional role of MESH1 in regulating CoA and previously reported NADPH. Mechanistically, MESH1 knockdown elevates CoA levels, maintaining functional mitochondrial thioredoxin system, thereby preventing mitochondrial lipid peroxidation. In Drosophila, we found that dMesh1 overexpression leads to ferroptosis-mediated muscle atrophy, which can be rescued by increasing CoA and NADPH levels. Taken together, these findings establish MESH1 as a key phosphatase that governs ferroptosis sensitivity by coordinating CoA and NADPH homeostasis, unveiling a novel link between CoA degradation, mitochondrial integrity, and muscle health.

We report the first collective biomimetic synthesis of xanchryones A (1), B (2), and I-N (3-8, respectively), all featuring a benzoxazole scaffold, by employing a synthetic strategy based on biogenetic building blocks (BBBs). These compounds were efficiently assembled in six steps from commercially available 3,4,5-trimethoxyphenol. Notably, the benzoxazole ring was constructed for the first time using rationally designed p-quinones and amino acids as substrates, enabling precise control of the nitrogen and oxygen positions in the benzoxazole ring. This BBB-based biomimetic strategy provides a concise route to structurally diverse natural benzoxazoles and offers insight into their biogenetic origin.

The chemistry of vitamin C adducts was revisited to investigate their pH sensitivity, photophysical properties, optical behavior, and assess their potential as eco-friendly pH indicators. In this study, a series of ascorbic acid adducts were synthesized through a straightforward, high-yield method. Their acid-base responsiveness is driven by a reversible protonation-deprotonation process between the hydrazineyl and azo groups, causing observable color changes. Analysis of substituent effects demonstrated that strong electron-withdrawing groups like nitro (-NO₂) significantly impact the electronic structure, particularly when located at the ortho or para positions of the aromatic ring. Solvatochromic studies revealed that the ortho-nitro adduct 3(b) and para-nitro adduct 3(d) exhibited positive solvatochromism, with their absorption wavelengths increasing in more polar solvents. Notably, 3(b) displayed a consistent yellow color with λmax around 396 nm across solvents, indicating its structural stability and solvent-independent optical behavior, making it a robust and versatile pH indicator. Halochromic studies in aqueous media revealed pronounced bathochromic shifts for both 3(b) and 3(d) under alkaline conditions. The 3(b) exhibited a color change from yellow to dark purple (λmax = 534 nm), while the 3(d) transitioned from colorless (λmax = 361 nm) to dark rosewood (λmax = 472 nm). Spectrographic analysis determined that 3(b) had a pKa of 8.99 and 3(d) a pKa of 10.68. The band gap analyses conducted under both alkaline and acidic conditions provide detailed insights into the optical properties and electronic transitions of the most promising adducts, 3(b) and 3(d). The optical band gap energies obtained from UV-Vis spectroscopy, Eg(optical) and Eg(Tauc), showed strong agreement with the electrochemically measured band gap, Eg(electronic). These findings were further corroborated by computational results from DFT (B3LYP/6-311 + G(d,p)), where the theoretically calculated band gaps, Eg(DFT), validated the experimentally derived values and provided additional information through frontier molecular orbital (FMO) analysis, indicating the presence of an efficient push-pull electronic system throughout the adduct structures. Correlation of DFT outputs with Tauc-plot analyses clarified the nature of the electronic transitions, including π → π*, n → π*, and intramolecular charge-transfer (ICT) processes, and determined whether these transitions were direct or indirect, and whether they were symmetry-allowed or forbidden. Biochemical assays further supported the proposed neutral proton-transfer mechanisms operating under both acidic and basic conditions for the promising adducts. Thermal analysis divulged thermal stability up to 210 °C. Acid-based titration tests showed that 3(b) and 3(d) produced sharp and accurate endpoints comparable to the standard methyl red indicator, while 3(c) did not exhibit a reliable color transition. Given their green origin, tunable structures, and visual responsiveness, these ascorbic pH indicators hold promising candidates for sustainable applications in food coloration, cosmetics, and medical diagnostics.

Tailoring dansyl probes: H vs CHO substitution for selective sub-nanomolar detection of picric acid.

Recent studies have reported a correlation between SRC and EGFR as key factors contributing to tumor aggressiveness in cancers, such as glioblastoma, colon, breast, and lung cancers. Resistance to therapy remains a major obstacle in cancer treatment. Therefore, the discovery of novel compounds with inhibitory potential is crucial. In this study, urea- and pyrimidine-containing compounds structurally similar to osimertinib were designed as potential inhibitors of both SRC and EGFR kinases, with the aim of identifying compounds that may also overcome resistance conferred by mutations. The compounds were synthesized through the development of new synthetic routes. Their structure-activity relationships (SAR) were evaluated using in vitro enzyme inhibition assays, cell culture experiments, molecular docking, and molecular dynamics studies. Compounds 19, 20, and 21, which bear substitutions at the third position of the indole ring, inhibited SRC kinase with 77.75-89.22% activity. These compounds also demonstrated notable cytotoxicity against the PC3 cell line, with IC50 values of 7.89, 6.92, and 9.85 μM, respectively, comparable to reference compounds cisplatin (IC50 = 5.16 μM) and dasatinib (IC50 = 0.9 μM). Notably, compound 20 was active against both EGFR and SRC kinases, with IC50 values of 3.91 μM and 0.00058 μM, respectively. Compound 20 also exhibited the strongest cytotoxic effect on prostate cancer cells (IC50 = 6.92 μM). Further analyses indicated that compound 20 induced apoptosis in cancer cells by increasing the levels of caspase-3, caspase-8, and Bax, while reducing Bcl-2 expression. Molecular docking and dynamics studies revealed strong interactions of compound 20 with the target receptors. Docking and biological activity studies indicated that compound 20 (1-(2- Fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidine-2-yl)amino)phenyl)-3- phenylurea) is a promising dual inhibitor of both EGFR and SRC kinases. In silico analyses further support the potential therapeutic efficacy of compound 20. Overall, compound 20 emerged as the most promising candidate from this study, warranting further investigation for its therapeutic potential.

Design, synthesis and biological evaluation of (±)-kusunokinin derivatives as potent anticancer agents.

ABSTRACT 1,3‐Dimethylbenzimidazoline (BIH) is an organic hydride with a strong hydride‐donating capacity. Photochemical regeneration of BIH derivatives from their oxidized form, 1,3‐benzimidazolium, using inexpensive reductants is crucial for their practical application as catalysts. We observed that 2‐aryl‐BIH compounds, bearing a heteroatom–hydrogen bond at the ortho‐position of the phenyl substituent attached to the C2 position of the benzimidazoline ring, underwent rapid regeneration by ascorbate under visible‐light irradiation. Computational analyses revealed that the heteroatom–hydrogen bond facilitated BIH regeneration by forming a hydrogen bond with ascorbate and/or by mediating inter‐ and intramolecular transfer of a proton and an electron. This paper presents an environmentally sustainable strategy for utilizing BIH‐based systems as reductive catalysts.

Structure-Activity relationship and optimization of drug-like properties of antituberculosis 3-(4,4-dimethyl-1,4-azasilinane)methylpyrazole MmpL3 inhibitors.

Understanding roles of different radicals (·OH, SO4·-and ClO·) in the thiacloprid degradation.

Highly substituted imidazoles are privileged scaffolds in medicinal and synthetic chemistry; however, general and modular access to densely substituted variants remains limited. Although Ugi-derived imidazole formation has been reported in isolated cases, its broader applicability has not been systematically explored. Herein, we present a comprehensive expansion and optimization of an Ugi-based one-pot synthesis enabling the preparation of tetrasubstituted imidazoles from readily accessible glyoxal derivatives. In contrast to earlier studies largely restricted to aryl glyoxals, this protocol demonstrates broad compatibility with aliphatic and aromatic glyoxals, as well as diverse amines, carboxylic acids, and isocyanides, providing full substitution control over all four positions of the imidazole ring. Key parameters governing chemoselectivity and ammonium-induced cyclization were identified, affording the target imidazoles in moderate to excellent yields. This study establishes the Ugi-imidazole transformation as a robust and diversity-oriented synthetic platform suitable for the rapid generation of medicinally relevant imidazole scaffolds.

This computational study describes the mechanisms behind some interesting features of an acyclic nitrone obtained from the oxidation of 5-methylaminomethyl uridine (mnm5U), a pyrimidine ribonucleoside found at the wobble anticodon position of tRNA. The ground state geometry of this nitrone is characterized by an H-bond (1.9 Å) between the N-O and the H-O (at the 5' position of the ribofuranose ring) bonds. The S0-S2 and S0-S3 transitions at this geometry are strongly allowed. These vertical excitations are followed by relaxation passages through consecutive conical intersection (CI) channels (CIS3/S2 → CIS2/S1 → CIS0/S1). The CNO moiety becomes upside or downside twisted along these pathways with a continuous decrease in the C-O bond distance, eventually leading to their respective oxaziridines. The reverse thermal pathway of oxaziridine → nitrone conversion requires overcoming a barrier of 27 kcal/mol, while the oxaziridine → amide conversion through a [1,2]-H shift requires more energy (40-47 kcal/mol). Investigations on the spin-trapping ability of this ribonucleoside-derived nitrone have indicated its possible efficiency in this field. The ΔGrxn,aq values of the spin-adduct formations of this nitrone with biologically important free radicals are in line with those of the best known spin-traps. These results open up a so far unexplored possibility of a new class of spin-trapping nitrones formed on tRNA oxidation.

Seizures are a common reason for drugs to fail during development, but they are difficult to predict preclinically. Enoxacin, a fluoroquinolone, rarely causes convulsions as a monotherapy, but convulsions have been seen after combination therapy with fenbufen, a non-steroidal anti-inflammatory drug. The interaction between the drugs is thought to result from inhibition of GABAA receptors, which are not their primary targets. Here we show that, among 15 marketed fluoroquinolones and one active metabolite, six, including enoxacin, inhibited GABA-evoked depolarization in cells expressing human GABAA receptors when administered with felbinac, the active metabolite of fenbufen. Within these six except for a prodrug possessed a piperazinyl group at the seventh position of the quinolone ring. We also administered enoxacin or norfloxacin plus felbinac to rats and determined the cerebrospinal fluid concentrations of each drug when convulsions occurred. As we previously reported, an increase in network burst frequency recorded from primary cultured rat cortical neurons on microelectrode arrays is a risk marker for seizures, so we tested whether this assay could predict seizures induced by drug interactions between fluoroquinolones and felbinac. When co-administered with felbinac, only those fluoroquinolones that inhibited GABA currents in patch-clamp tests increased network burst frequency. Principal component analysis using 17 microelectrode array parameters supported that the mechanism of action was due to GABA antagonism in rodent neurons. Thus, the microelectrode array assay predicted seizure risks from the combination of enoxacin and the active metabolite of fenbufen and identified other fluoroquinolones with seizure risk potential.

Pyrrolidine, a five-membered nitrogen-containing heterocycle, has emerged as an important structural motif in medicinal chemistry owing to its pronounced pharmacological versatility, conformational flexibility, and favorable physicochemical properties. In recent years, pyrrolidine-based compounds have attracted considerable attention for their therapeutic potential in the management of diabetes and cancer, two major global health challenges. This review compiles and critically analyzes recent advances in the design, synthesis, and biological evaluation of pyrrolidine derivatives exhibiting antidiabetic and anticancer activities. Particular emphasis is placed on structure-activity relationship (SAR) studies, highlighting how subtle modifications in substitution patterns, electronic properties, and steric factors markedly influence biological performance. Numerous studies demonstrate that strategic functionalization at key positions of the pyrrolidine ring leads to enhanced selectivity, improved inhibition of carbohydrate-metabolizing enzymes (including α-glucosidase, α-amylase, and DPP-IV), and pronounced antiproliferative effects against a range of cancer cell lines. By integrating important findings reported over the past decade (2013-2025), this review underscores the potential of pyrrolidine derivatives as dual-action therapeutic agents and provides a coherent framework to guide the rational design of future drug candidates.

Protecting hierarchical data via multi-level encryption and authenticating high-contrast touch traces represents an emerging frontier demanding technological innovation in molecular materials. Herein, via precise molecular interventions, three D-A-A' (donor-acceptor-acceptor) type aggregation induced emission (AIE)-active positional isomers (p-TPy, m-TPy, and o-TPy) are designed by varying the pyridine ring position in the acceptor. Their systematic investigation reveals key photophysical and structure-property insights, revealing their potential in advanced security and encryption. Positional modulation regulates electron-accepting strength and molecular packing, leading to red-shifted solid-state emission and influencing PLQY, transient PL, solvatochromism, and thermal stability as supported by crystal analysis and theoretical calculations. These stimuli-adaptive isomers address two critical challenges in advanced security systems. First, thermochromic luminescent materials (TLMs) exhibiting multiple temperature-dependent luminescent states are formulated as security inks by doping the para-isomer into phase-change matrices, enabling a multi-level security system. Second, a red-emissive, water-soluble amphiphilic fluorescent probe is obtained by functionalizing the para-isomer into a pyridinium emitter (p-TPyMe), capable of detecting latent fingerprints on diverse substrates and revealing level-3 ridge details with an exceptional contrast value of 5.39. These results demonstrate how molecular design in single chromophores translates into strategic AIE-active stimuli-adaptive positional isomers with intricate structure-property relationships, highlighting their potential for next-generation anti-counterfeiting, data encryption, and forensic technologies.

ABSTRACT This paper reports the utility of Pd(II)‐catalyzed bidentate directing group picolinamide‐aided ( ortho ) γ ‐ or δ ‐C‐H oxygenation and trideuteromethoxylation of aromatic rings, as a route for constructing new entities of trideuteromethyl‐aryl ethers. Accordingly, the introduction of the O ‐CD 3 unit in the ortho position of aromatic rings in α ‐alkylbenzylamines, amino alcohols, and amino acids with CD 3 OD or CD 3 CD 2 OD was accomplished. Apart from the picolinamide directing group, other directing groups, such as 5‐methylisoxazole‐3‐carboxamide (MICA), quinoline‐2‐carboxamide, and benzamide directing groups, were used for conducting the trideuteromethoxylation of aromatic rings of the target compound, and the picolinamide DG was found to be efficient in all reactions. We have described the synthetic utility of the trideuteromethoxylated aryl ethers obtained in this work by synthesizing aromatic motif‐based peptides using deuteromethoxylated compounds and trideuteromethoxylated α ‐methylbenzylamine‐derived sulfamoylcarbamate motifs. Various deuterium‐containing compounds, particularly aromatic rings containing N ‐CD 3 or O ‐CD 3 units, are known as potential drug candidates in the literature. Accordingly, this work contributes to enriching the library of O ‐CD 3 or O ‐CD 2 CD 3 unit‐containing aromatic motifs and a method for their preparation through directing group‐aided trideuteromethoxylation or pentadeuteroethoxylation of ortho C(sp 2 )─H bonds of aromatic rings.

4-aniloquinazolines are found in several anticancer drugs approved by the United States Food and Drug Administration (US FDA), and act primarily as receptor tyrosine kinase inhibitors (RTKs). Structure-activity relationship studies of 4-anilinoquinazolines targeting the epidermal growth factor receptor (EGFR) have demonstrated that the groups at the C6 and C7 positions play a fundamental role in solubility and activity of these compounds, since they are projected toward the solvent region. On the other hand, groups at the C3’ and C4’ positions are related to enhanced inhibitory activity and modulation within the allosteric pocket, respectively. Although 4-anilinoquinazolines act primarily as EGFR inhibitors, significant inhibitory activity against other receptors such as vascular endothelial growth factor receptor 2 (VEGFR2), human epidermal growth factor receptor-type 2 (HER2), several human carbonic anhydrase isoforms (hCA), and histone deacetylase 6 (HDAC6) has been reported. Herein, we present recent advances (2020-2025) in the design and synthesis of novel 4-anilinoquinazolines with anticancer activity, focusing especially on functionalization methodologies applied to this scaffold and how these modifications influence its inhibitory and antiproliferative activity against different receptors and cell lines, respectively. • 4-Anilinoquinazoline scaffolds play an important role as tyrosine kinase inhibitors. • Solubility and activity are affected by groups at the C6 and C7 positions of the quinazoline ring. • Groups at the C3’ and C4’ positions of the aniline moiety may increase inhibitory activity and modulate the allosteric pocket. • In order to synthesize more anticancer candidates, new functionalization methodologies are required.

Sterically hindered aryl C-glycosides are biologically important, yet their stereoselective synthesis remains challenging due to severe anomeric congestion. Here we report a next-generation, ligand-enabled, stereospecific Pd-catalyzed glycosyl cross-coupling that efficiently delivers sterically hindered aryl C-glycosides with exclusive anomeric control. Two underexplored biarylmonophosphine ligands, featuring P-bound 3,5-bis(trifluoromethyl)phenyl groups and methoxy or isopropoxy substituents at the 2'- and 6'-positions of the lower aryl ring, are uniquely effective for this challenging C-glycosylation. The scope and practicality of this next-generation Stille glycosylation are demonstrated in over 65 examples, including (un)protected sugars, deoxy sugars, and oligosaccharides. Crystallography reveals that bromide-bridged dimeric Pd(II) complexes as intrinsic features of diarylbiaryl monophosphine ligands, while natural bond orbital (NBO) analysis shows that subtle ligand electronics control the selectivity between β-methoxy elimination and C-C reductive elimination. This predictable, highly chemo- and stereoselective protocol expands the glycosylation toolbox, enables glycomimetic drug discovery, and informs rational ligand design.

The conjunctival placodes of the avian eye form in an intriguing and conserved sequence in a circular annulus around the cornea. These 13-16 placodes develop into papillae that are essential for inducing underlying intramembranous flat bones, known as scleral ossicles, which form an important part of the ocular skeleton. The numbers of papillae present are used in almost all bird staging tables as an important anatomical feature for accurate staging. Despite this, we are lacking knowledge on how these papillae are induced and how the regular spacing between these placodes/papillae is patterned, both within chicken embryos and in other bird species. In this study, we conduct a comparative assessment of the spacing of conjunctival placodes during ontogeny in chicken embryos and compare this to the spacing in quail and ducks, which develop at different rates and have different body sizes. Our results indicate that the average spacing between papillae changes over development in chicken embryos, but that no change in spacing occurs in the first set of induced placodes (group 1). We further show that placode spacing differs even in birds with similar eye diameters and placode/papillae number (quail vs. duck). The position of the placode ring with respect to the cornea also varies in these species. Interestingly, despite different incubation durations, all three species develop placodes at 28%-33% of their incubation period. Overall, our data indicate that mathematical models describing the patterning of these regularly spaced placodes should consider both eye growth and papillae ring position.

Bulky N-heterocyclic carbenes (NHCs) are powerful tools for controlling the coordination environment and reactivity at inorganic elements. Herein, we report an exceptionally bulky NHC, BnITr (BnITr = [(C6H4){NCPh3}2C:]), which features a percent buried volume (%Vbur) that exceeds 60%. The steric and electronic properties of BnITr were elucidated through a combined experimental and computational study focused on selected silver, gold, and rhodium complexes. The structural impact of the benzylated backbone in BnITr leads to the positioning of phenyl rings within the flanking N-trityl (CPh3, Tr) groups in close proximity to the carbene donor center, enabling the isolation/stabilization of hitherto elusive examples of (quasi)-monocoordinated lithium and gallium(i) cations. Attempts to generate the one-coordinate Pd(0) complex, [BnITr–Pd], led to an unusual redox-triggered ligand activation/–CPh3 group migration to palladium.

Here, we present the first method of synthesis of cyano- (F-CNCbl) and aqua (F-H2OCbl) cobalamins, fluorinated at the C10 (meso) position of the corrin ring, and characterization of their redox properties. The reductive decyanation of F-CNCbl by glutathione and the reduction of F-H2OCbl to Co(II)-form (F-Cbl(II)) by glutathione or reduced nicotinamide adenine dinucleotide proceed more efficiently than the reactions involving unmodified complexes, which may facilitate their intracellular processing, especially in the case of patients with impaired metabolism of CblC-protein. The stability of the C-F bond in fluorinated Cbls displays remarkable stability upon F-Cbl(II) reduction to the Co(I) form is a remarkable finding, in stark contrast to the elimination of the Br atom in meso-brominated cobalamin is eliminated during this process.