Search Results (289)

Azolium-derived metallates are well-established intermediates in metal–N-heterocyclic carbene chemistry; however, their potential as standalone therapeutic agents remains largely unexplored. Herein, we report the first systematic biological investigation of a diverse family of Au(I), Cu(I), Pt(II), Pd(II), and Ru(II) metallates paired with functionalized azolium cations. The complexes were synthesized quantitatively through a simple, atom-economical, and purification-free protocol under aerobic conditions in technical-grade green solvents. Structural characterization by multinuclear NMR spectroscopy and single-crystal X-ray diffraction confirmed metallate formation and enabled the first isolation and crystallographic characterization of unprecedented azolium-derived ruthenates. The antiproliferative activity of the complexes was evaluated against cisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer cell lines, alongside non-cancerous MRC-5 fibroblasts. Backbone-functionalized derivatives emerged as the most potent compounds, displaying activities comparable or superior to cisplatin in A2780 cells and up to 1000-fold higher potency in the resistant A2780cis model. Notably, unlike cisplatin, the metallates retained nearly unchanged IC₅₀ values across both ovarian cancer lines, strongly suggesting resistance-evasive mechanisms of action. While benzylazido- and methyl guanosine-derived complexes generally exhibited lower overall potency, several members retained significant activity in resistant cells while showing markedly reduced toxicity toward normal fibroblasts, highlighting promising selectivity profiles. Ethoxide-functionalized derivatives and platinum-based metallates combined pronounced anticancer activity with favourable therapeutic windows. Overall, this work establishes azolium-derived metallates as a previously overlooked class of metal-based anticancer agents combining exceptional synthetic accessibility, broad structural tunability, and remarkable activity against platinum-resistant ovarian cancer. Full article

N⁶-methyladenine and N⁶,N⁶-dimethyladenine are the heterocyclic bases present in the RNA of eukaryotic and bacterial cells and play important regulatory roles. How the degradation of such modified nucleic acids, and the subsequent demethylation of modified heterocyclic bases, occurs in the bacterium Escherichia coli is not established. Here, we investigated the growth of adenine auxotroph strains in a minimal M9 medium supplemented with either N⁶-methyladenine or N⁶,N⁶-dimethyladenine. We found that N⁶-methyladenine supported the growth of ∆purH::Km but not that of the ∆purA::Km strain, whereas N⁶,N⁶-dimethyladenine did not support the growth of either adenine auxotroph. Similar experiments performed using structurally related 2-amino-N⁶-methylpurine and 2-amino-N⁶,N⁶-dimethylpurine bases—using ∆guaA::Km, ∆guaB::Km, and ∆purH::Km guanine auxotrophs—demonstrated that growth of only the ∆guaB::Km mutant was supported by 2-amino-N⁶-methylpurine but not by its dimethylated counterpart. We expressed and purified C-teminus 6xHis tagged E. coli adenine/adenosine deaminases AdeC and Add and tested their substrate specificity. We demonstrated that AdeC protein does not catalyse deamination of either N⁶-methyl- or N⁶,N⁶-dimethyladenine, whereas Add catalyses deamination of N⁶-methyl- but not that of N⁶,N⁶-dimethyladenosine. Based on our findings, biochemical pathways leading to the demodification and return into metabolism of N⁶-methyladenine and 2-amino-N⁶-methylpurine in E. coli are proposed. Full article

The fusion of heterocycles onto an anthraquinone scaffold represents a promising strategy to optimize anticancer activity. This study has the aim to synthesize and characterize novel anthra[1,2-b]furan compounds based on the natural product aloe-emodin. Six novel anthra[1,2-b]furans bearing phenyl, n-hexane, and methoxy carbonyl substituents were synthesized starting from aloe-emodin. The synthetic route employed involved acetyl protection of aloe-emodin, electrophilic aromatic halogenation, subsequent Castro–Stephens coupling, spontaneous intramolecular cyclization, and deprotection of hydroxyl groups. These newly synthesized compounds were evaluated for their cytotoxic activity against various cancer cell lines, including lung adenocarcinoma (A5492), colorectal carcinoma (HCT116), hepatocellular carcinoma (HepG2), ovarian cancer (Skov3), and breast cancer (MCF-7), using the CCK8 assay. The anthra[1,2-b]furan derivative 10c, which contains a methoxy carbonyl group, demonstrated excellent potency against lung (A549) and breast (MCF-7) cancer cell lines, with IC₅₀ values of 0.49 and 2.91 µM, respectively. This preliminary cytotoxic finding shows compound 10c as a promising hit for further investigations towards a promising lead compound. Full article

The review summarizes the literature data on the C−H functionalization of six-membered polyaza heterocycles, specifically diazine and triazine skeletons, which are important in medicine and pharmacology, as examples. The analysis covers the works published mainly over the last 20 years. The review focuses on strategies involving the use of transition metal-based catalysts or organic oxidants, where the nature of the N-heterocycles and the substrate molecules can be exploited to control regioselectivity. Each of these strategies has certain advantages as well as serious disadvantages and limitations. In addition to the experimental procedures, mechanistic schemes are discussed to provide a deeper understanding of the reactions described. The material presented allows us to draw the unambiguous conclusion that C−H bond functionalization processes are of crucial importance in the synthesis of molecules that exhibit a wide range of biological activity. Full article

Background/Objectives: Cancer remains one of the most significant challenges in modern medicine, requiring the continuous development of novel molecular scaffolds with anticancer potential that act through multiple pathways. Heterocyclic compounds incorporating indole, triazole, oxadiazole, and thiadiazine motifs have attracted considerable attention due to their diverse pharmacological activities. This study aimed to design, synthesize, and evaluate new hybrid heterocyclic systems, including 1,2,4-triazole, 1,3,4-oxadiazole, and thiadiazine motifs, targeting liver and breast cancer. Methods: A series of indolyl-based heterocyclic compounds was synthesized using efficient and environmentally friendly protocols. Indolyl-triazol-thiadiazin-6-ol 5 was prepared via solvent-free fusion of esters 2 and 3 or the corresponding acid 4. Oxadiazole derivatives were produced by reacting hydrazide intermediates with carbon disulfide. Triazole derivatives were synthesized via cylization of thiosemicarbazide 9 in aqueous KOH (4.0 N). Structural characterization was performed using Fourier Transform InfraRed (FTIR), ¹H and ¹³C NMR spectroscopy, and electron impact mass spectrometry (EIMS). Cytotoxic activity was evaluated against liver and breast cancer cell lines, and VEGFR-2 kinase inhibition was assessed for selected derivatives. Results: The synthesized compounds demonstrated notable cytotoxicity activity, with compounds 4, 5, and 9 exhibiting IC₅₀ values in the low micromolar range. Enzymatic assays revealed that compounds 4 and 9 showed strong VEGFR-2 inhibition (97.9% and 96.4%, respectively), indicating apoptosis-inducing effects. Conclusions: The synthesized indolyl-based hybrid heterocycles represent a promising chemotype with in vitro cytotoxic activity and VEGFR-2 inhibitory effects, supporting further investigation, optimization, and mechanistic studies to evaluate their potential lead for anticancer drug development. Full article

Background: Heterocycle compounds with acridine, quinoline, indole, and pyridine nuclei are potentially active for anticancer activity since they can promote inhibition of vital enzymes, decreasing cell survival after binding to biomolecules. However, unspecific biological interactions can result in unwanted effects, which should be defined during the synthesis and proposition of new molecules. Thus, the objective of this study was to investigate the biological and teratogenic effects of four nitrogen heterocycles proposed for anticancer therapy. Methods: Four 2-cyano-N-phenylacrylamine type derivatives containing acridine (3a), quinoline (3b), indole (3c), and pyridine (3d) nuclei were synthesized and characterized. They were evaluated for their ability to interact with DNA, physicochemical and pharmacokinetic predictions, in vitro and in silico methodologies, besides in vitro inhibition of the Topoisomerase IIα enzyme, antiproliferative activity in tumor and non-tumor cells, hemolytic activity with human erythrocytes, and in vivo toxicological studies with zebrafish embryos. Results: UV–vis absorption studies with ssDNA revealed different spectroscopic effects, with binding constants (Kb) ranging from 1.41 × 10⁵ to 6.46 × 10⁴ M⁻¹. The fluorescence quenching constant (Ksv) with ethidium bromide (EB) varied between 0.53 and 0.67 × 10³ M⁻¹. The compounds intercalated into DNA base pairs, a mechanism confirmed by molecular docking, with 3b (quinoline) showing the most substantial interaction. All derivatives exhibited antitopoisomerase IIα activity at 100 μM and were cytotoxic against MCF-7 and T47-D breast tumor cells, particularly against the more aggressive T47-D lineage. No hemolytic activity was observed in human erythrocytes. In vivo assays in zebrafish embryos showed no toxicological or cardiotoxic effects. However, all compounds altered superoxide dismutase (SOD) and catalase (CAT) enzymatic activity, requiring further studies on reactive oxygen species (ROS) generation to assess potential adverse effects. Furthermore, significant results were observed in the physicochemical and pharmacokinetic parameters of the synthesized compounds. Conclusions: The findings highlight the quinoline derivative (3b) as the most promising nitrogen heterocycle due to its antiproliferative activity and biomolecular interactions without adverse effects in zebrafish embryos, distinguishing it from clinically available agents. Full article

For those who did not follow the invention and development of enantioselective catalysis, this review introduces pertinent historical aspects of the field and presents the scientific concepts of asymmetric bio- and organocatalysis. They are powerful technologies applied in organic laboratories and industry. They realize chiral amplification by converting inexpensive achiral substrates and reagents into enantiomerically enriched products using readily recoverable solvents, if any are used. Racemic substrates can also be deracemized catalytically. More sustainable fabrications are now available that require neither toxic metallic species nor costly reaction conditions in terms of energy, atmosphere control, product purification, and safety. Nature has been the source of the first asymmetric catalysts (microorganisms, enzymes, alkaloids, amino acids, peptides, terpenoids, sugars, and their derivatives). They act as temporary chiral auxiliaries and lower the activation free energy of the reaction by altering the reaction mechanism. Reductions, oxidations, carbon-carbon and carbon-heteroatom bond-forming reactions are part of the process panoply. Asymmetric catalyzed multicomponent and domino reactions are becoming common. Typical modes of activation are proton transfers, hydrogen bonded complex formation, charged or uncharged acid/base pairing (e.g., σ-hole catalysts), formation of equilibria between achiral aldehydes and ketones with their chiral iminium salt or/and enamine intermediates, umpolung of aldehydes and ketones by reaction with N-heterocyclic carbenes (NHCs), phase transfer catalysis (PTC), etc. Often, the best enantioselectivities are observed with polyfunctional catalysts derived from natural compounds, but not always. They may combine to form chiral structures containing nitrogen, phosphorus, sulfur, selenium, and iodine functional moieties. Today, man-made enantiomerically enriched catalysts, if not enantiomerically pure, are available in both enantiomeric forms. Being robust, they are recovered and reused readily. Full article

Copper(II) coordination complexes with coumarin-derived heterocyclic ligands are promising in inorganic therapeutics for anticancer and antimicrobial applications. To establish quantitative structure–activity relationships for lead design, we studied six copper(II) complexes (Cu1–Cu6)with four- and five-coordinate geometries using Density Functional Theory, Conceptual Density Functional Theory, and visualization analyses. Geometry optimization at M06/6-31G(d)+DZVP revealed distorted coordination environments from $d^9$ Jahn–Teller effects. Tridentate $N_{2}O$-chelatedcomplexes (Cu4–Cu6) showed greater aqueous stability ($\Delta G_{solv}=-43$ to $-50$ kcal·mol⁻¹) than four-coordinate analogs ($-29$ to $-31$ kcal·mol⁻¹). CDFT global descriptors contrasted reactivity: four-coordinate Cu1–Cu2 had higher electron affinity (>4.2 eV) and electrophilicity (>5.7 eV), suggesting propensity for redox cycling and for undergoing nucleophilic attack by DNA bases, whereas Cu4–Cu6 displayed increased chemical hardness (3.43–3.54 eV) and lower electrophilicity (≈3.8 eV), implying enhanced kinetic stability and bioavailability. Frontier orbital analysis indicated ligand-to-metal charge transfer via a LUMO delocalized over the $\pi$-conjugated coumarin, facilitating intercalation by $\pi$-$\pi$ stacking. The visualization showed strong covalent bonds (blue isosurfaces) stabilizing the metal and dispersive $\pi$ interactions (green surfaces) on the ligand, enabling solvent interactions and biomolecular recognition. Tridentate $N_{2}O$ coordination thus balances electronic stability and biological reactivity, making Cu4–Cu6 promising for further study. Full article

Background: 8-Hydroxyquinoline and phthalimide are two significant heterocyclic scaffolds in medicinal chemistry due to their pharmacological profiles. Hybridizing these pharmacophores and further modifying them via modified Mannich reactions provides a strategy to improve their physicochemical parameters and selectivity toward multidrug-resistant (MDR) cancer cells. Objectives: To synthesize a series of 8-hydroxyquinoline–phthalimide hybrids and their Mannich base derivatives and evaluate their cytotoxic activity and resistance-selective properties against sensitive Colo205 and resistant Colo320 cancer cell lines. Methods: Four hybrid compounds were synthesized by reacting 5-amino-8-hydroxyquinoline with different phthalic anhydride derivatives. Twelve fine-tuned derivatives were prepared by using the modified Mannich reaction. Cytotoxic activity was measured using the MTT assay, and relative resistance (RR) was calculated to determine selectivity toward the resistant cell line. P-glycoprotein (Pgp) ATPase activity was evaluated for the most active compounds. Results: All derivatives displayed cytotoxic activity, with higher potency toward the resistant Colo320 cell line. Compounds 2 and 4 showed the strongest activity against both cell lines (IC₅₀ down to 4.88 µM). Compounds 5, 8a, 9a, and 9c retained potent activity against Colo320 (IC₅₀ = 9.89–22.79 µM). Incorporating a CH₂–N group at position C7 substantially enhanced the selectivity for MDR cells. Compounds 9c, 9a, and 8a exhibited the highest selectivity, with RR values of 0.29, 0.33, and 0.35, respectively. Compounds 2, 4, 5, 8a, and 9a showed inhibitory effects on Pgp ATPase activity. Conclusions: The newly synthesized HQ–phthalimide hybrids represent promising candidates for targeting MDR in colorectal cancer, with Mannich modification enhancing the selectivity toward resistant cells. Full article

Background: Silver(I) complexes with aromatic heterocyclic ligands are well known for their broad antimicrobial potential, largely attributed to their ability to interact with biomolecular targets. Results and Discussion: In this study, a new polynuclear silver(I) complex with N-(3′-phenylpropyl)quinoxaline-2-carboxamide (pqx-2ca), [Ag(NO₃)(pqx-2ca)]_n, was synthesized. Its structure was confirmed by single-crystal X-ray diffraction and comprehensively characterized using NMR, IR, and UV–Vis spectroscopy, while its behavior in solution was further elucidated through density functional theory (DFT) calculations combined with spectral simulations. The complex demonstrated significantly enhanced antimycobacterial activity compared with the free ligand when tested against the avirulent Mycobacterium tuberculosis H37Ra, fast-growing model organisms M. smegmatis and M. aurum, as well as the nontuberculous species M. avium and M. kansasii. Experimental and docking studies confirmed stable binding of the complex to subdomain III of bovine serum albumin (BSA) and to the minor groove of DNA. Furthermore, docking to validated mycobacterial targets revealed inhibitory potential toward the InhA and MmpL3 proteins, with binding affinities comparable to those of standard inhibitors. Conclusions: These results highlight [Ag(NO₃)(pqx-2ca)]_n as a promising candidate for the development of silver-based antimycobacterial agents with a dual mechanism of action involving both DNA and protein targets. Full article

Background: Gold (Au) complexes have emerged as promising anticancer candidates due to their distinct coordination chemistry and ability to modulate thiol-dependent and redox-regulated cellular pathways, particularly thioredoxin reductase (TrxR). In recent years, structurally diverse Au(I) and Au(III) complexes have been reported with potent in vitro anticancer activity; however, cross-study comparability and design principles remain unclear. Aim: This systematic review critically evaluates anticancer Au(I/III) complexes reported since 2016, with the specific aim of identifying how oxidation state, coordination geometry, and ligand class influence in vitro potency, selectivity, and translational potential. Methods: A PRISMA-guided literature search was performed in Scopus, Web of Science, PubMed, and ScienceDirect for studies published between January 2016 and March 2025. Two independent reviewers screened titles/abstracts and full texts according to predefined inclusion criteria. Only original studies reporting anticancer activity of structurally characterized Au(I/III) complexes in human cancer models were included. After the removal of duplicates, 1100 records were screened at the title and abstract level. Of these, 240 articles were assessed in full text for eligibility. Ultimately, 128 studies reporting anticancer activity of structurally characterized Au(I/III) complexes met the inclusion criteria and were included in the qualitative synthesis. Biological potency data were harmonized to μM units where applicable, and results were synthesized qualitatively due to heterogeneity in experimental design. Results: A total of 128 studies met the inclusion criteria. Au(I) complexes—particularly phosphine- and N-heterocyclic carbene (NHC)-based compounds—consistently showed sub-micromolar cytotoxicity in TrxR-dependent cancer cell lines, whereas Au(III) complexes displayed greater structural diversity but variable stability and redox behavior. In vivo efficacy was reported for a limited subset of compounds and was frequently constrained by solubility, systemic toxicity, or metabolic instability. Conclusions: The available evidence indicates that anticancer activity of gold complexes is strongly dependent on oxidation state, ligand environment, and redox stability. While Au(I) scaffolds show more reproducible in vitro potency, successful translation to in vivo models remains limited. This review defines structure–activity and structure–liability relationships that can guide the rational design of next-generation gold-based anticancer agents. Full article

This study aimed to analyze the volatile organic compounds (VOCs) for different rice aroma types using sensory evaluation, headspace solid-phase microextraction gas chromatography mass spectrometry (HS-SPME-GC-MS), and gas chromatography-ion mobility spectrometry (GC-IMS) techniques, and to explore the material basis for the flavor differences. Based on the sensory evaluation results, rice aroma was categorized into three types, distinguished by their unique aroma compounds. Type A was characterized by a prominent sweet, popcorn aroma, type B by a more prominent cereal and starchy flavor, and type C by a more complex aroma. Untargeted metabolomics analysis using HS-SPME-GC-MS identified and characterized 74 volatile compounds. A comparison of A versus B versus C revealed 8 key aroma compounds, primarily alkanes, aldehydes, ketones, alcohols, and heterocyclic compounds. (E)-2-Octenal, 6-Undecanone, 2-Acetyl-1h-pyrrole, and P-menthan-1-ol in type A gave it a better sweet aroma, Dodecane, 2,6,10-trimethyl-, 1-Octen-3-one, and 2-Methyldecane in type B gave it a better starchy and cereal flavor. 2-Acetyl-1h-pyrrole, Heptacosane, and 1-Propanol in type C contributed to a complex aroma. GC-IMS analysis showed that the fingerprints of rice with different aroma types were significantly different. The VOCs of aroma type A contained (+)-limonene, 2-methylpyrazine, 2-pentanone, ethyl butanoate, n-pentanal, styrene, 1-butanol, 3-methyl-, acetate, 1-hexanal, 1-pentanol, and 2-heptanone, which gave it a better sweet aroma. The VOCs of aroma type C contained 1-octen-3-ol, 2,6-dimethyl pyrazine, 2-acetylpyridine, and ethyl hexanoate, which gave it a better complex aroma. Full article

Three Schiff base fluorescent probes 3a–3c with N-heterocyclic structure were designed and synthesized by using the reaction of 4-diethylaminosalicylaldehyde with different N-heterocyclic amines, such as 2-aminobenzimidazole, 2-aminobenzothiazole, and 2-amino-6-methylpyridine. Compound 3a exhibited excellent selectivity towards Hg²⁺, with a detection limit of 3.21 × 10⁻⁷ M and a response time of only 30 s. It could be used as a fluorescent probe for detecting Hg²⁺. Meanwhile, compounds 3b and 3c exhibited excellent selectivity towards Zn²⁺, with detection limits of 1.61 × 10⁻⁷ M and 2.03 × 10⁻⁷ M, respectively, and response times of only 30 s. They could serve as fluorescent probes for detecting Zn²⁺. Using probe 3a for Hg²⁺ as an example, the detecting mechanism was further elucidated through ¹H NMR, ESI-MS testing, and DFT calculation analysis. For compound 3a, the coordination stoichiometry between compound 3a and Hg²⁺ was verified to be 1:1 through a Job’s plot. After coordination with Hg²⁺, the molecular rigidity of compound 3a was enhanced, which inhibited the non-radiative decay process and led to the closure of the excited-state intramolecular proton transfer (ESIPT) effect. At the same time, the fluorescence intensity was significantly increased through the chelation-enhanced fluorescence (CHEF) mechanism, which was confirmed by density functional theory (DFT) calculations. In addition, compounds 3a–3c were successfully applied in practical water samples and test strips for the detection of Hg²⁺/Zn²⁺. Full article

Background: A benzotriazole is a heterocycle frequently used in medicinal chemistry to obtain potent drug candidates, including anticancer agents. Nonetheless, the available literature lacks a comprehensive review of the in vitro and in vivo studies regarding these derivatives. Thus, our study aims to review the preclinical evidence on benzotriazole derivatives that showed potential as anticancer candidates, focusing on the cytotoxicity, mechanisms of action, structure–activity relationship, and methodological rigor of the included studies. Methods: We searched PubMed, Scopus, and Web of Science and included 41 studies in our analysis following the selection process. Additionally, we assessed the risk of bias using the QUIN tool for in vitro and the SYRCLE tool for in vivo studies in order to assess the methodological rigor of the included studies. Results: The benzotriazole derivatives were classified according to their structure in four classes, namely N-derivatives, C-derivatives, fused derivatives, and organometallic compounds. The in vitro results showed that certain derivatives, such as halogen, alkyl-aryl, or natural-base hybrids, can have superior cytotoxicity compared to parent molecules, exerted through multiple mechanisms, such as apoptosis and cell cycle arrest. Additionally, the in vivo analysis highlighted that benzotriazole derivatives can reduce tumor mass in a dose-dependent manner, with only a slight degree of hepatotoxicity reported in one case. However, histopathological data were generally absent or limited and based on a very limited number of in vivo studies. Conclusions: Overall, benzotriazole derivatives remain promising candidates for cancer treatment. However, limited mechanistic and toxicity data, as well as the moderate risk of bias identified across studies, may limit our assessment. Therefore, future studies should employ more rigorous methodologies and explore the underlying anticancer and toxicity mechanisms to fully assess the therapeutic potential of benzotriazole derivatives. Full article

Perimidine derivatives are versatile heterocycles with growing significance in medicinal chemistry and materials sciences. However, their structural variety remains limited. This study focused on the synthesis and crystal structure characterization of a new perimidine-based molecule. A bicyclic perimidine lactone, (1S,4R)-4,7,7-trimethyl-1-(1H-perimidin-2-yl)-2-oxabicyclo[2.2.1]heptan-3-one (1), was synthesized through an intramolecular dehydration of a monoamide intermediate formed from 1,8-diaminonaphthalene and (1S)-(–)-camphanic chloride under basic conditions. The product was purified and crystallized from acetone, giving single crystals suitable for X-ray diffraction. Structural analysis revealed two stereogenic centers and crystallization in the chiral tetragonal P4₃2₁2 space group, with stabilization through N—H···O and C—H···N hydrogen bonds as well as C—H···π interactions. Full article