Search Results (218)

This review summarizes the methods for the synthesis of α-phosphonocinnamates and their heterocyclic analogs, which have found important applications in materials chemistry, as convenient building blocks in organic synthesis and in other areas of science and technology. Five complementary disconnections are critically compared: (i) Knoevenagel condensation of phosphonoacetates or phosphonoacetic acid with (hetero)aromatic aldehydes and N-tosylimines under amine, amine/carboxylic acid, or amine/Lewis acid catalysis; (ii) arsine-mediated condensation of 2-bromophosphonoacetates with aldehydes; (iii) Mn(III)- or Ag(I)-mediated radical C–P bond formation on cinnamic esters; (iv) phosphine-catalyzed hydrophosphonylation of arylpropiolates; and (v) Heck coupling of aryldiazonium salts with α-phosphonoacrylates. The factors that govern (E)/(Z) selectivity, the substrate scope (electron-rich versus electron-deficient (hetero)arenes), and the chemoselectivity issues encountered with salicylaldehydes—where acyclic phosphonocinnamates, 3-phosphonocoumarins, and [1,2]benzoxaphosphinines (2-phosphacoumarins) compete—are analyzed in detail. A dedicated section covers the synthesis of coumarin-3-phosphonates, including Knoevenagel-type cyclization, Mn(III), Ag(I), Cu or Pd-catalyzed and electrochemical phosphorylation of preformed coumarins, decarboxylative phosphorylation, and intramolecular cyclization strategies. Conflicting literature reports are reconciled where possible, and the practical strengths and limitations of each protocol are highlighted to guide method selection. Full article

Heterocyclic unnatural amino acids and their biheterocyclic derivatives represent invaluable structural scaffolds in modern medicinal chemistry and peptidomimetics due to their ability to induce conformational constraints and modulate pharmacokinetic profiles. While saturated nitrogen heterocycles and monocycle heteroaromatic systems are well-established pharmacophores, research on linear biheterocyclic amino acid frameworks remains significantly underrepresented in the literature. Addressing this structural gap, this study aims to synthesize and characterize a novel series of functionalized pyrimidine (hetero)cyclic molecular hybrids acting as chiral heterocyclic amino acid derivatives. The target pyrimidine-5-carboxylates and pyrimidine-4-carboxylic acid derivatives were prepared from β-dicarbonyl compounds and their corresponding enamine analogues via cyclocondensation approaches. Particular attention was paid to reaction optimization, substrate scope exploration, and stereochemical integrity preservation, utilizing chiral HPLC analysis to evaluate enantiomeric retention. Pyrimidine-5-carboxylates prepared from β-enamino keto esters retained high enantiomeric excess (90.2–100% ee), whereas cyclization of β-diketones under strongly basic conditions at elevated temperature resulted in complete racemization (ee < 1%). Modification of the synthetic route and application of milder cyclization conditions partially suppressed racemization, affording pyrimidine derivatives with 61.8–65.5% ee. These findings suggest that substrate structure influences stereochemical integrity during pyrimidine synthesis. Full article

Pyrazole derivatives have attracted considerable interest in medicinal chemistry as adaptable frameworks for developing cholinesterase inhibitors, owing to their advantageous physicochemical properties and structural flexibility. The heteroaromatic characteristics of the pyrazole core allow for various substitution patterns, promoting selective interactions with both the catalytically active site (CAS) and the peripheral anionic site (PAS) of cholinesterase enzymes. These attributes enable pyrazole-based drugs to be viable candidates for the therapy of cognitive disorders, especially Alzheimer’s disease. This study aims to systematically describe medicinal chemistry studies on pyrazole-based cholinesterase inhibitors conducted from 2020 to 2025. The focus is on structural alterations of the pyrazole core and their impact on the inhibitory action against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using structure–activity relationship (SAR) analysis. Recent advancements in in vitro enzymatic inhibition studies, molecular docking, kinetic analysis, ADME predictions, and multi-target-directed ligand (MTDL) techniques are rigorously evaluated to elucidate trends in potency, selectivity, and drug-like characteristics based on information retrieved from three search engines: Scopus, PubMed, and Google Scholar. This review addresses significant challenges in pharmacokinetics, blood–brain barrier permeability, and safety while delineating prospects for integrating rational design, computational modeling, and biological validation to expedite the development of clinically relevant pyrazole-based cholinesterase inhibitors for Alzheimer’s disease. Full article

Six novel pyrazole-based carbohydrazone derivatives (3a–3f) bearing structurally diverse heteroaromatic substituents were synthesized and characterized by ATR-FTIR, ¹H NMR, APT-¹³C NMR, and HRMS analyses. Their multifunctional bioactivity was evaluated using antioxidant, photoprotective, CT-DNA-associated spectroscopic response, cytotoxicity, and scratch wound closure assays. Antioxidant activity was assessed by DPPH radical scavenging, Fe²⁺ chelation, and ferric thiocyanate (FTC) assays against appropriate reference standards, while photoprotective potential was determined by spectrophotometric SPF analysis using carrot seed oil as a reference. The benzothiazole-containing derivative (3f) showed the strongest DPPH scavenging activity, FTC antioxidant capacity, and photoprotective activity, while also producing one of the most pronounced CT-DNA-associated spectroscopic responses under the experimental conditions employed. In contrast, the benzimidazole derivative (3e) displayed the highest Fe²⁺ chelating activity among the synthesized compounds. In cell-based assays, the imidazole- and thiazole-containing derivatives (3b and 3c) showed the most favorable balance between growth-inhibitory potency and selectivity toward A431 epidermoid carcinoma cells relative to HaCaT keratinocytes. Scratch assay results did not support direct anti-migratory activity under the tested conditions but indicated compound-dependent modulation of wound-closure-associated cellular responses. Overall, these findings demonstrate that heteroaromatic substitution strongly modulates redox behavior, CT-DNA-associated spectroscopic behavior, photophysical properties, and cytotoxic selectivity in pyrazole-based carbohydrazones, identifying this scaffold as a structurally tunable platform for further bioactivity optimization. Full article

Considering the expanded interest in reducing organic solvents in synthesis, surfactants and surfactant-based catalysis have been used to carry out various organic transformations in water. In recent years, the integration of Lewis and Brønsted acid catalysis with micellar systems has gained considerable attention as a powerful approach to enhance reaction efficiency while minimizing the environmental impact of synthetic processes. In this article, we depict the most recent advances in the water-interceded synthesis of different organic systems by utilizing different surfactant-type catalysts, which are important structural motifs in pharmaceuticals, agrochemicals and functional materials. Further, these methods incorporate green reaction media, mild reaction conditions, and a great yield of product with high purity in a shorter interval of time. Understanding the scope and impact of this area, authors have made efforts to collect and compile the data that indicates many named reactions, such as Friedlander annulation, aldol condensation, the Biginelli reaction, the Mannich reaction, Suzuki–Miyaura cross-coupling, etc., now take place using surfactant-based catalysts. Full article

A new type of bio-based adsorbents thiamine-functionalized maleated chitosan (CSMA@TA) was prepared and tested to help the effective removal of methylene blue (MB) in water systems. Successful functionalization was confirmed using structural and surface analysis by FTIR, SEM, XRD, TGA, BET and XPS that revealed a mesoporous structure with a surface area of 50.61 m²/g, pore volume of 0.062 cm³/g and an average pore diameter of 2.65 nm, as well as incorporation of active sites containing nitrogen and sulfur. The best fit of the Langmuir model (R² ≈ 0.986; RMSE less than 1.0) demonstrated that the adsorption capacity of CSMA@TA was highly dependent on operation parameters, with an optimum adsorption capacity of about 230 mg/g and a removal efficiency of more than 93.4% under an initial MB concentration of 25 mg/L. Kinetic studies followed the pseudo-second-order model (R² ≈ 0.986), indicating that the uptake was dominated by chemisorption. Analysis of intraparticle diffusion indicated that the adsorption process involved three stages: diffusion in the boundary layer (k1d = 17.95 mg/g·min^−1/2), which controlled the first stage; gradual diffusion in the pore diffusion; and stabilization of the equilibrium. The thermodynamic parameters indicated the presence of strong adsorbate-adsorbent interactions and interfacial structuring. ∆G° values ranged between −24.85 and −23.56 kJ/mol, ∆H° = −44.08 kJ/mol, and ∆S° = −64.65 J/molK indicated strong adsorbate-adsorbent interactions and interfacial structuring. The adsorbent also exhibited good reusability, retaining more than 90% of its initial efficiency after five cycles, making it stable. The enhanced performance of CSMA@TA is due to the synergistic effect of carboxyl groups and heteroaromatic thiamine moieties, which enable electrostatic attraction, hydrogen bonding, and π–π interactions. These findings support the claim that CSMA@TA is a high-efficiency, sustainable, and reusable adsorbent with strong potential for practical wastewater treatment applications. Full article

This study demonstrates the high efficiency and selectivity of p-toluenesulfonic acid-based deep eutectic solvents (DESs) for simultaneous extractive denitrogenation (EDN) and desulfurization (EDS) of model fuel. Three DESs—TBPB:PTSA, TBAB:PTSA, and ChCl:PTSA (1:1 molar ratio)—were synthesized and evaluated for their effectiveness against representative heteroaromatic pollutants: thiophene, dibenzothiophene, pyridine, and carbazole. The phosphonium-based TBPB:PTSA exhibited the highest extraction performance, achieving over 96% removal of nitrogen species and up to 85% removal of sulfur species at 40 °C. Increasing the temperature enhanced desulfurization by reducing viscosity, thereby improving mass transfer kinetics. Additionally, a 3:1 ratio of DES to fuel provided an optimal balance between solvent economy and operational efficiency. Denitrogenation was driven by strong acid–base protonation facilitated by PTSA, while desulfurization was governed by π–π and dispersion interactions, modulated by the hydrophobicity of the cations. The DES achieved nearly quantitative nitrogen removal and satisfactory sulfur extraction after three reuse cycles, while multistage operation enabled complete purification within four extraction steps. ¹H NMR analysis confirmed that no DES components were found in the raffinate phase, verifying the immiscibility and stability of the solvent. These results indicate that TBPB:PTSA is a robust, regenerable, and environmentally benign solvent, effectively enabling simultaneous EDN–EDS of hydrocarbon fuels and positioning it as a promising green alternative to traditional hydrogen-based refining methods. Full article

Phenothiazine is a heteroaromatic molecule capable of various noncovalent interactions, including halogen bonding and π-stacked association. Despite its broad use in functional materials and pharmaceutical ingredients, a systematic comparison of these interaction modes has been lacking. Here, we report a combined experimental and computational study of intermolecular interactions of phenothiazine with a prototypical halogen-bond (HaB) donor (tetrabromomethane), planar π-electron acceptors (tetracyanopyrazine and tetrafluoro-p-benzoquinone), and multifunctional species capable of both interaction types (iodo- and bromo-3,5-dinitrobenzenes). X-ray structural analysis revealed that CBr₄ forms exclusively C–Br···π halogen bonds with the aromatic rings of phenothiazine, whereas all π-acceptors yield alternating donor–acceptor stacks characterized by multiple short contacts indicative of multicenter interactions. Notably, co-crystals of iodo- and bromodinitrobenzenes with phenothiazine display only π-stacked architectures. Density-functional calculations showed that isolated HaB complexes involving N, S, or π sites of phenothiazine possess comparable binding energies (≈−3 kcal mol⁻¹), whereas π-stacked complexes are substantially stronger (≈−9–12 kcal mol⁻¹). QTAIM, NCI, NBO, and energy-decomposition analyses indicated that while amounts of charge transfer in halogen-bonded and π-stacked complexes are comparable, the enhanced stability of the latter originates primarily from a large dispersion contribution. These results rationalize the solid-state preference for π-stacking over halogen bonding in systems where both motifs are accessible and clarify the hierarchy and physical origin of noncovalent interactions involving phenothiazine, providing guidance for the design of supramolecular assemblies and functional materials based on this versatile electron donor. Full article

In the present work, we describe the synthesis of a new heterocyclic derivative, 2-(naphthalen-1-yl)-2,3,5,6-tetrahydro-1H-isoquinolino[8,1,2-hij]quinazoline 1, using the reaction between the aminal 1,3,6,8-tetraazatricyclo[4.4.1.1^3,8]dodecane 2 (TATD) and 1-naphthylamine 3 as the first scaffold of a four-step linear synthetic route. In the first step, a condensation catalyzed by acetic acid in 96% ethanol was carried out, leading to the formation of the intermediate 3-(naphthalen-1-yl)-1,2,3,4-tetrahydrobenzo[h]quinazoline 4. Subsequently, this intermediate was acylated with 2-chloroacetyl chloride in the presence of triethylamine and under an inert atmosphere, obtaining the compound 2-chloro-1-(3-(naphthalen-1-yl)-3,4-dihydrobenzo[h]quinazolin-1(2H)-yl)ethan-1-one 5. In the third step, an intramolecular Friedel–Crafts cyclization was carried out using aluminum trichloride as a catalyst, yielding 2-(naphthalen-1-yl)-1,2,3,6-tetrahydro-5H-isoquinolino[8,1,2-hij]quinazolin-5-one 6. Finally, the reduction of this lactam with phosphorus pentachloride and sodium borohydride under anhydrous conditions led to the further closure of the polycyclic system, yielding the final product 1. The proposed route demonstrates the feasibility of using TATD 2 as a versatile precursor for constructing condensed heterocyclic systems of structural interest and potential relevance in advanced organic synthesis. Full article

Background: Dipeptidyl peptidase-4 (DPP4) is a key metabolic enzyme involved in postprandial glucose regulation through incretin hormone modulation, making it an important target in nutrition and metabolic health research. Although dietary and plant-derived bioactive compounds have been reported to influence DPP4, exploration of the food-associated chemical space remains limited by its size and diversity. Methods: Here, we present an integrated computational framework combining machine learning, molecular docking, and molecular dynamics simulations to prioritize dietary and supplemental compounds with potential interaction capacity toward DPP4. Supervised classification models were trained on a curated DPP4 bioactivity dataset and evaluated using scaffold-based partitioning to ensure chemically realistic generalization. Results: The top-performing random forest model achieved robust performance across independent splits (mean AUC 0.889 ± 0.017; average precision 0.959 ± 0.010) and was applied to screen 69,574 food-derived compounds. Model interpretation identified recurring heteroaromatic and polar substructural features associated with predicted interaction propensity. Structure-based screening further prioritized seven food-derived compounds, including lipid-associated coenzyme A derivatives, which occupied the canonical DPP4 binding site with favorable docking scores (−13.12 to −12.06 kcal/mol). Extended molecular dynamics simulations (500 ns) demonstrated stable binding geometries, compact hydrogen-bond networks, and consistent engagement of key DPP4 residues, including Glu205, Glu206, Arg125, and Tyr631. Conclusions: Overall, our study provides a scalable computational strategy for identifying bioactive dietary and supplemental compounds with potential relevance to metabolic regulation. The framework supports nutraceutical research and functional food development by enabling targeted experimental investigation of diet–enzyme interactions. Full article

This study explores the multifaceted anticancer mechanisms of flavanone analogues and spiropyrazoline condensed with flavanone ring against colorectal cancer (CRC) cell lines. Five-membered heteroaromatic scaffolds, in particular, have gained prominence in medicinal chemistry as they offer enhanced metabolic stability, solubility and bioavailability, crucial factors in developing effective drugs. Building upon previous findings, we investigated three lead derivatives (1, 3, and 5) with potent antiproliferative activity (IC₅₀ < 35 μM). The compounds induced pronounced oxidative stress, evidenced by increased lipid peroxidation and reduced membrane fluidity, primarily within the hydrophobic layers of cell membranes. Preincubation with the antioxidant N-acetylcysteine (NAC) significantly attenuated these effects, confirming the pivotal role of reactive oxygen species (ROS) in their cytotoxicity. Mechanistic studies revealed that the derivatives triggered intrinsic apoptosis, characterized by the cleavage of PARP and the activation of caspase-9 and caspase-3. Furthermore, the compounds modulated key signaling pathways involved in cell survival and proliferation. Specifically, they inhibited the pro-oncogenic ERK1/2 MAPK pathway while inducing cell line-dependent alterations in p38 and JNK activity. Concurrently, all derivatives reduced the level of the transcription factor Nrf2, a master regulator of antioxidant defense and a mediator of chemoresistance in CRC. Collectively, these findings indicate that flavanone/chromanone derivatives exert their anticancer activity through a synergistic mechanism involving ROS generation, disruption of redox homeostasis, inhibition of Nrf2 signaling, and modulation of MAPK-dependent apoptotic pathways. These results highlight the therapeutic potential of flavanone-based compounds and their spiropyrazoline analogues as multifunctional anticancer agents targeting oxidative stress and survival signaling in colorectal cancer. Full article

The discovery of a mechanism by which bile acids (BAs) regulate fat synthesis by modulating the activation of the farnesoid X receptor (FXR) in the liver and intestines has highlighted the central role of BAs in triglyceride synthesis in the liver. FXR has been reported as a promising drug target for primary biliary cholangitis, metabolic-dysfunction-associated steatohepatitis, and metabolic-dysfunction-associated steatotic liver disease. A large number of FXR modulators with various chemotypes have been developed by many research groups. Although several FXR modulators are advancing into clinical trials, ongoing efforts aim to develop new FXR modulators that minimize the adverse effects associated with long-term administration. To develop drug candidates targeting FXR, various heterocyclic and/or fused heteroaromatic rings have been employed as the core and/or parts of the structures, out of which benzimidazole has been recognized as a valuable structural motif due to its synthetic accessibility and its versatility in constructing structurally diverse target molecules. Herein, we report on the development of FXR modulators incorporating benzimidazole as a fused heteroaromatic ring. Full article

Benzodichalcogenophenes represent a valuable class of organic π-conjugated systems that have been investigated in a plethora of cutting-edge applications in the field of materials chemistry. Isomeric benzodifuran (BDF), benzodithiophene (BDT) and benzodiselenophene (BDS) analogs of phenanthrene, in which the two heteroaromatic rings are ortho-fused onto a benzene ring, represent convenient frameworks as functional materials in organic electronics. The orientation of the two condensed heteroaromatic rings with respect to the central benzene ring provides diverse structural isomers, which significantly differ in degrees of curvature, electronic and electrochemical properties. Furthermore, tailored modification and functionalization strategies enable fine-tuning of their intrinsic properties, leading to unique systems. This review offers a comprehensive overview of synthetic methodologies for constructing isomeric BDF, BDT and BDS skeletons, alongside an analysis of their electrochemical properties as influenced by the nature of heteroatoms. Finally, the most relevant applications of these systems, ranging from optoelectronics, supramolecular chemistry, and emerging biological studies, are discussed, providing valuable insights for future research direction. Full article

Fused-bicyclic heteroaromatic cores are a common framework in drugs and other biologically active compounds. Those containing azine rings are widely used in drug discovery campaigns. Although these cores are very common, C–H functionalization of their azine moieties remains challenging, especially in annulation reactions. Therefore, this review highlights the progress made over the years in C–H annulation reactions that have produced these essential 6,5-fused bicyclic heteroaromatic cores for drug discovery. For that, the review was divided according to the five-membered rings moiety (pyrrole, pyrazole, imidazole, furan, thiophen, and thiazole) fused to different azines (pyridine, pyrazine, pyridazine, pyrimidine, and triazine). Although some important advances have been made over the years, there remains a need for research in synthetic methodology to expand the use of these heteroaromatic cores in biologically active compounds. Full article

Background: Heteroaromatic iodine-containing compounds have been previously recognized for their broad-spectrum antimicrobial activity. This study aims to systematically investigate their potential repurposing as anticancer agents, with a particular focus on understanding the structural determinants that influence their cytotoxicity and selectivity toward malignant cells. Methods: A series of heteroaromatic iodine-containing derivatives were synthesized and evaluated for anticancer activity. Their cytotoxic effects were measured and compared between cancerous and normal cell lines to determine selectivity. Structural features, including heteroaromatic moieties and substituents, were analyzed to identify correlations with biological activity. Results: Among the tested compounds, derivatives 3e, 3g, and 3l demonstrated significant cytotoxic effects while exhibiting favorable selectivity indices. These findings indicate that these compounds preferentially target malignant cells over normal cells, thereby mitigating the issue of systemic toxicity often associated with traditional chemotherapeutics. The enhanced anticancer activity appears to be influenced by specific structural elements within the heteroaromatic framework. Conclusions: The study highlights the potential of heteroaromatic iodine-containing compounds as promising anticancer candidates. Rational structural modifications within these heterocyclic systems can effectively modulate bioactivity and improve therapeutic selectivity. These results support further development of this compound class for anticancer applications. Full article