Search Results (230)

This review summarises the possible applications and basic methodologies for the synthesis of six-membered polyazo heterocycles, namely, diazines, triazines, and tetrazines. The time period covered by the analysed works ranges from the beginning of the 20th century to the present day. This period was chosen because it was during this time that synthetic chemistry, as defined by physicochemical research methods, became capable of solving such complex problems as efficiently as possible. The first part of the review describes the applications of polyazo heterocyclic compounds, whose frameworks are found in the composition of drugs, dyes, and functional molecules for materials chemistry, as well as in a wide variety of natural compounds and their synthetic analogues. The review also systematises the methods for assembling six-membered aromatic polyazo heterocycles, including intramolecular and sequential cyclisation, which determine the possible structural and functional diversity based on the presence and arrangement of nitrogen atoms and the position of the corresponding substituents. Full article

Fused and spiro nitrogen-containing heterocycles play an important role as structural motifs in numerous biologically active natural products and pharmaceuticals. The review summarizes various approaches to the synthesis of three-, four-, five-, and six-membered fused and spiro heterocycles with one or two nitrogen atoms. The assembling of the titled compounds via cycloaddition, oxidative cyclization, intramolecular ring closure, and insertion of sextet intermediates—carbenes and nitrenes—is examined on a vast number of examples. Many of the reactions proceed with high regio-, stereo-, or diastereoselectivity and in excellent, up to quantitative, yield, which is of principal importance for the synthesis of chiral drug-like compounds. For most unusual and hardly predictable transformations, the mechanisms are given or referred to. Full article

In this study, the design and synthesis of a novel series of cinnamic acid and 1,2,4-triazole hybrids were reported, aiming to enhance antioxidant and lipoxygenase inhibitory activities through pharmacophore combination. Cinnamic acid derivatives and 1,2,4-triazoles exhibit a broad spectrum of biological activities; therefore, by synthesizing hybrid molecules, we would like to exploit the beneficial characteristics of each scaffold. The general synthetic procedure comprises three synthetic steps, starting from the reaction of appropriate substituted cinnamic acid with hydrazine monohydrate in acetonitrile with cyclohexane and resulting in the formation of hydrazides. Consequently, the hydrazides reacted with phenylisothiocyanate under microwave irradiation conditions. Then, cyclization proceeded to the 1,2,4-triazole after the addition of NaOH solution and microwave irradiation. All the synthesized derivatives have been studied for their ability (a) to interact with the free radical DPPH, (b) inhibit lipid peroxidation induced by AAPH, and (c) inhibit soybean lipoxygenase. The synthesized derivatives have shown significant antioxidant activity and have been proved to be very good lipoxygenase inhibitors. Compounds 4b and 4g (IC₅₀ = 4.5 μM) are the most potent within the series followed by compound 6a (IC₅₀ = 5.0 μM). All the synthesized derivatives have been subjected to docking studies related to soybean lipoxygenase. Compound 4g exhibited a docking score of −9.2 kcal/mol and formed hydrophobic interactions with Val126, Tyr525, Lys526, Arg533, and Trp772, as well as a π−cation interaction with Lys526. Full article

Heterocyclic compounds are a common subject in the field of medicinal chemistry due to their numerous pharmaceutical applications. Among these, nitrogen- and oxygen-containing five-membered heterocyclic rings, namely oxazole and isoxazole, are particularly significant, exhibiting a broad spectrum of biological activities. Molecular hybridization, the process that enables the fusion of bioactive scaffolds, is a powerful strategy for the development of novel compounds characterized by enhanced or multitarget activities. This review focuses on hybrids incorporating linked oxazole and/or isoxazole moieties (i.e., isoxazole–oxazole and isoxazole–isoxazole hybrids), drawing upon peer-reviewed research articles and international patents from 1995 to the end of 2024. The overview systematically presents the diverse biological activities reported for the isoxazole–(iso)oxazole hybrids, including anticancer, antibacterial, antitubercular, anti-inflammatory, and antidepressant effects, alongside their corresponding chemical structures. Our analysis of the literature highlights the structural versatility and therapeutic potential of this important class of heterocyclic hybrids. Full article

Background: α-Hydroxyphosphonates, one of the most prominent classes of phosphonates, remain of utmost importance because of their potential and real biological activity as pharmaceutical or pesticide agents. The effect is the consequence of their enzyme inhibitory properties. Objectives: It was planned to make available new heterocyclic hydroxyphosphonate derivatives with cytotoxic activity. Methods: After optimizing the synthesis, 23 members of a new family, α-hydroxy-α-(benzothiophen-2-yl)-methylphosphonates, were prepared by the Pudovik reaction of benzo[b]thiophene-2-carboxaldehydes and diethyl phosphite. The addition was performed at 26 °C in the presence of triethylamine as the catalyst. One of the products was also characterized by single-crystal X-ray analysis. Results: The cytotoxic effect of the α-hydroxy-α-benzothiophenyl-methylphosphonates was tested on U266 myeloma, A2058 melanoma, HT-29 colon, and EBC-1 lung cancer cell lines. Most of the molecules showed significant activity; the greatest effects were seen after treatment with hydroxyphosphonates with a trifluoromethyl group in the benzene ring. Conclusions: The cytotoxic activity of the newly synthesized α-hydroxyphosphonates is encouraging to find even better derivatives. Full article

1,3-Dipolar cycloadditions on nitrone dipoles are key reactions to access five-membered heterocycles, which are useful intermediates in the synthesis of biologically relevant glycomimetics. The good atomic balance and high stereoselectivity characteristic of such reactions make them good candidates for the development of green protocols. In the present work, these features were maximized by avoiding the use of organic solvents and considering starting materials derived from biomass. Reactions involving (acyclic and cyclic) carbohydrate-derived nitrones as dipoles and levoglucosenone as dipolarophile were considered. Performing selected 1,3-dipolar cycloadditions in neat conditions showed reduced reaction times, maintaining similar selectivity and yields with respect to the classical protocols. The use of microwave irradiation and orbital shaking were also exploited to increase the sustainability of the synthetic protocols. The collected results highlight the potential of solvent-free 1,3-dipolar cycloadditions in the design of efficient synthetic routes according to green chemistry principles, such as prevention, atom economy, safer solvents and auxiliaries, and use of renewable feedstocks. Full article

In this study, we use coal as a carbon source from Zhangjiamao and doped with different nitrogen sources for co-pyrolysis. Nitrogen-rich tar was successfully prepared, and the content and variety were also increased. From the elemental analysis, the nitrogen content of all the tars was significantly enhanced, among which the nitrogen content of the tars after co-pyrolysis with melamine was enhanced by 5.21%, and the nitrogen content of coke was enhanced by 10.87%. According to the GC/MS results, it was found that the nitrogen compounds in the tar after full pyrolysis were richer and more abundant than those in Py-GC/MS. For the free radical reaction, the reaction process is extremely rapid, and the ¹⁵N substitution product after isotope labeling was successfully captured by adding ¹⁵NH₄Cl for isotope labeling, which can be more intuitively and accurately illustrated from the m/z change. Among them, 26 nitrogen-containing compounds were screened out, which accounted for 66.28% of the content, and they were categorized. It was found that the five-membered nitrogen heterocycles were the most abundant, accounting for 34.88%. In addition, five other nitrogen-containing compounds containing different functional groups and the tar from the co-pyrolysis of tar-rich coal were also analyzed by GC/MS, among which the tar from melamine had the highest content of nitrogen-containing compounds, with 70.48%. Finally, the functional groups of nitrogen-containing compounds were further analyzed by XPS and FTIR, and the results were consistent with those of GC/MS analysis. In this paper, nitrogen-rich tar was prepared by co-pyrolysis of tar-rich coal and nitrogen compounds. This achievement provides a valuable reference for the high-value utilization of coal tar. Full article

In this study, we develop a concise and efficient synthetic strategy for the construction of eight-membered cyclic diaryl sulfides by undertaking [3+2] cycloaddition, 1,2-hydrogen shift, and C(sp²)-S bond cleavage steps on 2-methylenebenzothiophene-3-ones with aryne, using TBAT as the fluorine source. This transformation proceeds well under mild conditions and affords the target products in high to excellent yields (up to 93% yields). The process provides a practical route to achieving sulfur-containing medium-sized heterocycles. Full article

Imidazole is a five-membered heterocyclic system featuring two nitrogen heteroatoms at the 1- and 3-positions of the ring. The imidazole scaffold is particularly suited for kinase inhibition concepts. This further confirms that this scaffold is a privileged structure in the development of anticancer drugs. Considering these key factors and the recent focus of scientists on imidazole compounds, we discuss the anticancer activities of imidazole-containing hybrids and related compounds, highlighting articles published in 2023 that serve as a basis for medicinal chemistry leads. From a chemical perspective, the present review emphasizes hybrid molecules with an imidazole ring in the side chain, imidazole-centered hybrid molecules, condensed imidazole hybrids, hybrid compounds containing two or more imidazole rings, polycyclic imidazole hybrids, imidazole-containing metal complexes, and benzimidazole hybrids. Full article

The transforming growth factor-β (TGF-β) signaling pathway is involved in various cellular functions, including immunological response, extracellular matrix formation, differentiation, growth and development, and cell cycle regulation. The TGF β receptor type 1 (TGF-βR1) has emerged as a key component of this pathway, exhibiting significant overexpression in diverse malignancies, including hepatocellular carcinoma, gastric cancer, breast cancer, and colon cancer. Multiple therapeutic targets have been identified for the TGF-β signaling pathway, encompassing antibodies, ligand traps, vaccines, antisense oligonucleotides, and small-molecule TGF-βR1 kinase inhibitors. This review delineates the structural and functional characteristics of the small-molecule TGF-βR1 kinase inhibitors. The inhibitors discussed herein are categorized based on shared pharmacophoric features, notably a five-membered heterocyclic ring linked to three distinct features (R1, R2, and R3). These features interact with amino acids within the selectivity pocket, hinge region, or solvent-exposed area, respectively. These insights contribute to a clearer understanding of the structural requirements for selective TGF-βR1 inhibition. The presented findings in this review article offer a valuable foundation for future drug discovery efforts targeting the TGF-β signaling pathway. Full article

Background: KRAS-G12D mutations drive 20–50% of pancreatic/biliary cancers yet remain challenging to target due to GTP-pocket conservation and high cellular GTP levels. While allosteric inhibitors targeting the SWII pocket (e.g., MRTX1133) show promise, limited chemical diversity and paradoxical cellular/enzymatic activity relationships necessitate the exploration of novel scaffolds. This study aims to develop KRAS-G12D inhibitors and PROTACs to offer a selection of new chemical entities through systematic structure–activity optimization and evaluate their therapeutic potential through PROTAC derivatization. Methods: Eleven compounds featuring heterocyclic cores (pyrimidine/pyrido[4,3-d]pyrimidine/5,6,7,8-tetrahydroprodo[3,4-d]pyrimidine) were designed via structure-based drug design. Antiproliferative activity against KRAS-G12D (Panc1), KRAS-G13D (HCT116) and wild-type (A549) cells was assessed using the CCK-8 assay. KRAS-G12D enzymatic inhibition was measured using a GTPase activity assay. Molecular docking simulations (Sybyl 2.0; PDB:7RPZ) elucidated binding modes. Two PROTACs were synthesized from lead compounds by conjugating E3 ligase linkers. All the novel inhibitors and PROTACs were characterized by means of NMR or HRMS. Results: Compound 10c demonstrated selective anti-proliferation in Panc1 cells (IC₅₀ = 1.40 μM) with 4.9-fold greater selectivity over wild-type cells, despite weak enzymatic inhibition (IC₅₀ > 10 μM). Docking revealed critical hydrogen bonds between its protonated 3,8-diazabicyclo[3.2.1]octane moiety and Asp12/Gly60. The enzymatic inhibitor 10k showed potent KRAS-G12D inhibition (IC₅₀ = 0.009 μM) through homopiperazine-mediated interactions with Glu92/His95. Derived PROTACs 26a/b exhibited reduced potency (IC₅₀ = 3–5 μM vs. parental 10k: 2.22 μM), potentially due to impaired membrane permeability. Conclusions: Eleven novel KRAS-G12D inhibitors with a seven-membered ring pharmacophore were synthesized. Compound 10c showed strong anti-proliferative activity, while 10k exhibited potent enzymatic inhibition. Two PROTACs were designed but showed no clear advantage over 10k. This study provides valuable insights for KRAS-targeted drug development. Full article

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

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

Mustard gas (HD) is a well-known chemical warfare agent, recognized for its extreme toxicity and severe hazards. Metal–organic frameworks (MOFs), with their unique structural properties, show significant potential for HD adsorption applications. Due to the extreme hazards of HD, most experimental studies focus on its simulants, but molecular simulation research on these simulants remains limited. Simulation analyses of simulants can uncover structure–performance relationships and enable experimental validation, optimizing methods, and improving material design and performance predictions. This study integrates molecular simulations, machine learning (ML), and molecular fingerprinting (MFs) to identify MOFs with high adsorption performance for the HD simulant diethyl sulfide (DES), followed by in-depth structural analysis and comparison. First, MOFs are categorized into Top, Middle, and Bottom materials based on their adsorption efficiency. Univariate analysis, machine learning, and molecular fingerprinting are then used to identify and compare the distinguishing features and fingerprints of each category. Univariate analysis helps identify the optimal structural ranges of Top and Bottom materials, providing a reference for initial material screening. Machine learning feature importance analysis, combined with SHAP methods, identifies the key features that most significantly influence model predictions across categories, offering valuable insights for future material design. Molecular fingerprint analysis reveals critical fingerprint combinations, showing that adsorption performance is optimized when features such as metal oxides, nitrogen-containing heterocycles, six-membered rings, and C=C double bonds co-exist. The integrated analysis using HTCS, ML, and MFs provides new perspectives for designing high-performance MOFs and demonstrates significant potential for developing materials for the adsorption of CWAs and their simulants. Full article

Nitrogen-rich heterocycles constitute a family of high energy density materials (HEDMs) that have been developing intensively in recent years. A representative of this class is 1,2,4,5-tetrazine, a six-membered aromatic compound containing four nitrogen atoms in the ring. Many energetic compounds with this scaffold exhibit thermal stability, high density, and insensitivity to various stimuli, including friction, impact, and electrostatic discharge. This review presents methods for constructing 1,2,4,5-tetrazine precursors from acyclic reagents and describes their chemical modifications, leading to new energetic compounds with potential applications in the industry as explosives, propellants, or pyrotechnics. Synthetic procedures and reaction conditions are discussed, along with the detonation parameters of new nitrogen-rich tetrazine-based products, which allow estimation of their application potential. Full article