Search Results (830)

DNA direct reactive impurities (DDRIs) can react with nucleophilic sites of DNA, leading to mutations. The control strategies outlined in International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7 are based on the known compound structure of DDRIs. Non-target screening of DDRIs in drugs is still challenging due to the diversity of the species and the poor stability. In this study, a derivatization reagent including a reactive group and report group was designed to screen DDRIs. Based on the electrophilic theory of chemical carcinogenesis, an amine reagent was used as a reactive group to interact with DDRIs. Two derivatization reagents, p-methoxyaniline and p-methoxybenzoyl-β-alaninamide, were employed, each containing different chromatographic modification groups to mitigate matrix effects. The derivatization products were analyzed by ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UPLC-HRMS). Non-target screening for DDRIs was achieved by product ions filtering of the report group. Full article

Highly Hazardous Pesticides (HHPs) pose severe risks to human health and the environment, making it essential to understand their molecular stability and degradation pathways. In this study, the Quantum Theory of Atoms in Molecules (QTAIM) was applied to four representative organophosphate pesticides, allowing the identification of electronically weak bonds as intrinsic sites of lability. These findings are consistent with reported hydrolytic, oxidative, enzymatic, and microbial degradation routes. Importantly, QTAIM descriptors proved largely insensitive to solvation, confirming their intrinsic character within the molecular electronic structure. To complement QTAIM, conceptual DFT (Density Functional Theory) reactivity indices were analyzed, revealing that solvent effects induce more noticeable variations in global and local descriptors than in topological parameters. In addition, a Topological Analysis of the Fukui Function (TAFF) was performed, which mapped nucleophilic, electrophilic, and radical susceptibilities directly onto QTAIM basins. The TAFF analysis confirmed that bonds identified as weak by QTAIM (notably P–O, P–S, and P–N linkages) also coincide with the most reactive sites, thereby reinforcing their mechanistic role in degradation pathways. This integrated framework highlights the robustness of QTAIM, the sensitivity of global and local reactivity descriptors to solvation revealed by conceptual DFT, and the complementary insights provided by TAFF, contributing to risk assessment, remediation strategies, and the rational design of safer pesticides. Full article

Treatment of N,N-dimethylhydrazinoalkenes with diethylzinc followed by exposure of the resulting ethylzinc amides to high vacuum drives a Schlenck redistribution metalloamination/cyclization to generate the corresponding bis(organozinc) intermediates in excellent conversions. Direct treatment of these with appropriate aryl or vinyl electrophiles in the presence of catalytic PdCl₂ (DPEphos) provides the corresponding arylated or alkenylated pyrrolidines and piperidines with high efficiency. Full article

Background/Objectives: SARS-CoV-2 pandemic led to the identification of peptide-based main protease (M^pro) inhibitors. The overwhelming majority of them carry an electrophilic warhead and a γ-lactam at the P1 position. During the selectivity assessment of an in-house Michael acceptors targeting SARS-CoV-2 M^pro, we unexpectedly observed a significant inhibition of human cathepsin S (hCatS). Methods: The biological investigation of three compounds (i.e., SPR38, SPR39, and SPR41) against hCatS was performed. The binding mode of SPRs was investigated by docking and molecular dynamics simulations. Results: Biological investigation has corroborated that hCatS is sensitive to peptide-based analogues harbouring γ-lactam at the P1 position and a vinyl methyl ketone warhead. In silico studies revealed that despite being solvent exposed, the γ-lactam at P1 might be involved in water-mediated H-bonds that could be optimized to gain inhibition potency and selectivity. Conclusions: The molecules repurposing of peptide-based SARS-CoV-2 M^pro inhibitors carrying the γ-lactam at the P1 site could pave the way for the identification of novel potent and selective hCatS ligands. Full article

Chrysin (5,7-dihydroxyflavone) is a flavonoid widely distributed in propolis, honey, and various plant sources. It exhibits a wide range of pharmacological activities, including anti-inflammatory, antioxidant, anticancer, antimicrobial, and anti-diabetic effects. However, its clinical translation is hampered by poor aqueous solubility, low bioavailability, and rapid metabolic clearance. To address these limitations and expand the chemical space of this natural scaffold, extensive synthetic efforts have focused on generating structurally diverse chrysin derivatives that possess improved drug-like properties. This review systematically categorizes synthetic methodologies—such as etherification, esterification, transition-metal-mediated couplings, sigmatropic rearrangements, and electrophilic substitutions—and integrates them with corresponding biological outcomes. Particular emphasis is placed on recent (2020–present) advances that directly link structural modifications with pharmacological enhancements, thereby offering comparative structure–activity relationship (SAR) insights. In addition, transition-metal-catalyzed C–C bond-forming reactions are highlighted in a dedicated section, underscoring their growing role in accessing bioactive chrysin analogs previously unattainable by conventional chemistry. Unlike prior reviews that mainly summarized biological activities or broadly covered flavonoid scaffolds, this article bridges synthetic diversification with pharmacological evaluation. It provides both critical synthesis and mechanistic interpretation. Overall, this work consolidates current knowledge and suggests future directions that integrate synthetic innovation with pharmacological validation and address pharmacokinetic challenges in chrysin derivatives. Full article

A focused library of 1,2,4-thiadiazolidin-3,5-diones (THIA-1–10), previously characterized as hydrogen sulfide (H₂S) donors, was evaluated for inhibitory activity against cysteine proteases. We included two key cysteine proteases aiming at antiviral drug development—SARS-CoV-2 3CLpro (Mpro) and PLpro—alongside reference enzymes Papain and Cathepsin L. The compounds exhibited distinct selectivity profiles and inhibition mechanisms. The ability to act as covalent inhibitors of 3CLpro in the nanomolar range is of particular interest, with compounds THIA-6, -7, and -10 proving to be the most potent inhibitors of the series, and compounds THIA-1, -2, and -8 proving to be the most selective with respect to the other proteases. We explored the molecular bases of the observed activity profile of THIA-1–10 through computational studies, which supported and complemented the experimental findings, paving the way for future structure optimization. The results highlight that inhibitory potency depends not only on electrophilicity but also on the ability to access the catalytic cysteine within the active site. The dual functionality of THIA-1–10 as H₂S donors and selective cysteine protease inhibitors underscores its potential as a promising lead for therapeutic development. Full article

Animal slaughtering causes the cessation of oxygen delivery and that of nutrients such as cystine, glucose and others to muscle cells. In muscle cells, the changes in oxygen level and pH cause mitochondria, the endoplasmic reticulum, xanthine oxidase and uncoupled NOS to increase the level of O₂^•−, affecting the generation of H₂O₂ and the release of iron ions from ferritin. The activation of enzymes that remove and dislocate fatty acids from the membrane affects the sensitivity of muscle cells to peroxidation and ferroptosis. Increasing PUFAs in membrane phospholipids, by feeding animals a diet high in w-3 fatty acids, is a driving factor that increases lipid peroxidation and possible muscle ferroptosis. The activation of lipoxygenases by ROS to Fe³⁺-lipoxygenase increases hydroperoxide levels in cells. The labile iron pool generated by a “redox cycle” catalyzes phospholipid hydroperoxides to generate lipid electrophiles, proximate executioners of ferroptosis. Ferroptosis in food muscle cells is protected by high concentrations of vitamin E and selenium. In fresh muscle cells, glutathione peroxidase (GSH-PX) and other endogenous antioxidant enzymes are active and prevent lipid peroxidation; however, muscle heating eliminates enzymatic activities, making cells prone to high non-enzymatic lipid peroxidation. In muscle cells, coupled myoglobin and vitamin E act as a hydroperoxidase, preventing the generation of lipid electrophiles. Free iron ion chelators or effectors such as deferoxamine, EDTA, or ceruloplasmin are strong inhibitors of muscle cell lipid peroxidation, proving that muscle ferroptosis is mostly dependent on and catalyzed by the labile iron redox cycle. Full article

Acyl chloride alcoholysis is a fundamental and typically high-yielding method for ester synthesis. However, competitive side reactions can occur when the acyl chloride possesses multiple electrophilic sites and the alcohol is a strong nucleophile. We report an example of this phenomenon: the reaction of pentafluorobenzoyl chloride with 1,1,1,3,3,3-hexafluoropropan-2-ol yields not only the expected ester but also a significant quantity of the 1,1,1,3,3,3-hexafluoropropan-2-yl 2,3,5,6-tetrafluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)benzoate. The formation of the latter results from an effective nucleophilic aromatic substitution (S_NAr) at the para-fluorine position of the pentafluorophenyl ring by the hexafluoroisopropoxide anion. Full article

In this article, the 1,3-dipolar cycloaddition (1,3-DC) reactions between 4-acyl-1H-pyrrole-2,3-diones fused at the [e]-side with a heterocyclic moiety (FPDs) and diphenylnitrone are studied using Molecular Electron Density Theory (MEDT) at different computational levels. An analysis of the global reactivity descriptors has determined the role of the reagents. FPDs will act as electrophiles, while diphenylnitrone will be a nucleophile. It was found that the reactions proceed according to a one-step but asynchronous mechanism. Additionally, based on the Bonding Evolution Theory (BET) analysis of the model 1,3-DC reaction between FPDs 1b and diphenylnitrone 2, we can distinguish eight different phases. The formation of the first C1-O5 single bond takes place in phase VII through the disappearance of the V(C1) monosynaptic basin and the depopulation of the V″(O5) monosynaptic basin, while the formation of the second C2-C3 single bond begins at the last phase of the reaction through the connection of two V(C2) and V(C3) monosynaptic basins. Based on this, we can classify this reaction as a “one-step two-stage” process. Furthermore, molecular dynamics (MD) simulation analysis up to 100 ns demonstrated the stability of both the 2P3B–Ligand1 and 2P3B–Zidovudine complexes. An enhancer of shape compression was generated for ligand1, whereas Zidovudine generated a more packed and stable hydrogen bond network that would allow a better occupancy of the active site. Full article

The mechanism of the electrophilic addition between phenylacetylene and N-heterocyclic carbene borane (NHC–borane), initiated by di-tert-butyl peroxide (DTBP), was elucidated at the M06-2X-D3/ma-def2-TZVP level to yield the Z-configured product. The computational results show that DTBP undergoes homolysis to generate two t-BuO· radicals; subsequently, it undergoes an H-shift reaction with N-heterocyclic carbene borane to form the N-heterocyclic carbene boron radical. Then, it is added to phenylacetylene to obtain the product radical intermediate. Finally, the product is yielded via an H-shift reaction. Meanwhile, this paper also explores the formation pathways of relevant byproducts. Structural analysis of the reaction reveals that weak interactions have a significant impact on the selectivity of the Z-configuration of the product. In addition, electron spin density contour maps are used to explain the electron distribution and reaction sites during the reaction process. This paper will provide relevant theoretical support for this type of addition reaction. Full article

Identifying the most reactive conformation of a molecule is a central challenge in computational chemistry, particularly when reactivity depends on subtle conformational effects. While most conformation search tools aim to find the lowest-energy structure, they often overlook the electronic descriptors that govern chemical reactivity. In this work, we present GAELLE, a cheminformatics tool that combines conformer generation with quantum reactivity descriptors to identify the most reactive structure of a molecule in solution. GAELLE integrates an evolutionary algorithm with fast semiempirical quantum chemical calculations (xTB), enabling the automated ranking of conformers based on HOMO–LUMO gap minimization (Pearson’s principle of maximum hardness) and electrophilicity index (Parr’s electrophilicity scale). Solvent effects are accounted for via implicit solvation models (GBSA/ALPB) to ensure realistic evaluation of reactivity in solution. The method is fully SMILES-driven, open-source, and scalable to medium-sized drug-like molecules. Applications to reactive intermediates, bioactive conformations, and pre-reactive complexes demonstrate the method’s relevance for mechanism elucidation, molecular design, and in silico screening. GAELLE is publicly available and offers a reactivity-focused alternative to traditional energy-minimization tools in conformational analysis. Full article

Graphitic carbon nitride is recognized as a very promising support structure to anchor single atoms and small, sub-nanometric metal clusters, with vast applications in catalysis. In the current manuscript, we aim to study the geometry and electronic structures of the small, sub-nanometric monometallic (copper or nickel) and bimetallic (copper–nickel) clusters anchored to the graphitic carbon nitride. Our Density Functional Theory (DFT) study reveals that Cu and Ni, when in the form of isolated single atoms, lie in the plane of the support. Once the atoms agglomerate and form small clusters, they tend to bind above the carbon nitride (C₃N₄) plane. The nickel atoms form shorter bonds with the support than the copper atoms do, which is reflected by the binding energies. Atoms directly bound to the support become oxidized, forming electrophilic sites at the surface. The computed negative metal–support binding energies mean that the investigated Cu/Ni-C₃N₄ composites are stable, and the metal species will not easily leach from the support. Full article

Sulfur Fluoride Exchange (SuFEx) chemistry represents an emerging class of click reactions that has found broad applications in drug discovery and materials science. Traditionally, SuFEx reactivity has been regarded as the exclusive privilege of sulfur and fluorine. Accordingly, the scaffolds exhibiting SuFEx-like reactivity without sulfur or fluorine have remained underdeveloped. Indeed, SuFEx reactions may represent a more generalizable mode of chemical reactivity. By enhancing the electrophilicity of the carbonyl group and increasing the steric hindrance around the carbon center, we identified disubstituted Meldrum’s acid as a novel carbon-based scaffold with SuFEx-like reactivity. Various O-, S-, and N-nucleophiles are viable exchange partners in the presence of Barton’s base or DBU. In addition to the original method, a catalytic protocol was developed and successfully applied to drug derivatization, including the gram-scale modification of acetaminophen. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) serves as a master transcriptional regulator of cellular antioxidant responses through orchestration of cytoprotective gene expression, establishing its significance as a therapeutic target in cerebral pathophysiology. Classical electrophilic NRF2 activators, despite potent activation potential, exhibit paradoxically reduced therapeutic efficacy relative to single antioxidants, attributable to concurrent oxidative stress generation, glutathione depletion, mitochondrial impairment, and systemic toxicity. Although emerging non-electrophilic pharmacological activators offer therapeutic potential, their utility remains limited by bioavailability and suboptimal potency, underscoring the imperative for innovative therapeutic strategies to harness this cytoprotective pathway. Non-pharmacological interventions, including neuromodulation, physical exercise, and lifestyle modifications, activate NRF2 through non-canonical, non-electrophilic pathways involving protein–protein interaction inhibition, KEAP1 degradation, post-translational and transcriptional modulation, and protein stabilization, though mechanistic characterization remains incomplete. Such interventions utilize multi-mechanistic approaches that synergistically integrate multiple non-electrophilic NRF2 pathways or judiciously combine electrophilic and non-electrophilic mechanisms while mitigating electrophile-induced toxicity. This strategy confers neuroprotective effects without the contraindications characteristic of classical electrophilic activators. This review comprehensively examines the mechanistic underpinnings of non-pharmacological NRF2 modulation, highlighting non-electrophilic activation pathways that bypass the limitations inherent to electrophilic activators. The evidence presented herein positions non-pharmacological interventions as viable therapeutic approaches for achieving non-electrophilic NRF2 activation in the treatment of cerebrovascular and neurodegenerative pathologies. Full article

A new Schiff base, (E)-2-(((1,10-phenanthrolin-5-yl)imino)methyl)-4,6-di-tert-butylphenol (Fen-IHB), was designed to incorporate an intramolecular hydrogen bond (IHB) between the phenolic OH and the azomethine nitrogen with the goal of modulating its physicochemical and biological properties. Fen-IHB was synthesized by condensation of 5-amino-1,10-phenanthroline with 3,5-di-tert-butyl-2-hydroxybenzaldehyde and exhaustively characterized by HR-ESI-MS, FTIR, 1D/2D NMR (¹H, ¹³C, DEPT-45, HH-COSY, CH-COSY, D₂O exchange), and UV–Vis spectroscopy. Cyclic voltammetry in anhydrous CH₃CN revealed a single irreversible cathodic peak at −1.43 V (vs. Ag/Ag⁺), which is consistent with the intramolecular reductive coupling of the azomethine moiety. Density functional theory (DFT) calculations, including MEP mapping, Fukui functions, dual descriptor analysis, and Fukui potentials with dual descriptor potential, identified the exocyclic azomethine carbon as the principal nucleophilic site and the phenolic ring (hydroxyl oxygen and adjacent carbons) as the main electrophilic region. Noncovalent interaction (NCI) analysis further confirmed the strength and geometry of the intramolecular hydrogen bond (IHB). In vitro antimicrobial assays indicated that Fen-IHB was inactive against Gram-negative facultative anaerobes (Salmonella enterica serovar Typhimurium and Typhi, Escherichia coli) and strictly anaerobic Gram-positive species (Clostridioides difficile, Roseburia inulinivorans, Blautia coccoides), as any growth inhibition was indistinguishable from the DMSO control. Conversely, Fen-IHB displayed measurable activity against Gram-positive aerobes and aerotolerant anaerobes, including Bacillus subtilis, Streptococcus pyogenes, Enterococcus faecalis, Staphylococcus aureus, and Staphylococcus haemolyticus. Overall, these comprehensive characterization results confirm the distinctive chemical and electronic properties of Fen-IHB, underlining the crucial role of the intramolecular hydrogen bond and electronic descriptors in defining its reactivity profile and selective biological activity. Full article