New Class Of Heterocyclic Compounds Research Articles

A novel [4 + 2] cycloaddition reaction involving Lawesson’s reagent. Structure and specific fragmentations of a new cyclic 1,2-thiaphosphinane-4-one

A crude morpholine enamine of acetone treated with Lawesson’s reagent unexpectedly yielded a six-membered thiaphosphinane-4-one. This compound is the first example of a new class of heterocycles. It has been proven that it is formed from 4-methyl-2-morpholino-1,3-pentadiene which is usually present in crude morpholine enamine batches. A mechanism of this regioselective reaction was postulated and a characteristic chair-like conformation of the product was examined in detail. Additionally, some unusual primary fragmentations of the product with the loss of H2S and isobutylene were observed for positive and negative ESI ionization mode, respectively.

Electrochemical Reduction of 1H‐Thioxanthene‐1,4,9‐trione and 3‐Methyl‐1H‐thioxanthene‐1,4,9‐trione – Representatives of a New Class of Heterocycles Related to Thioxanthenone

AbstractA convenient synthetic route was proposed for the synthesis of 3‐methyl‐1H‐thioxanthene‐1,4,9‐trione. This compound and its 3‐H congener are representatives of a new class of thioxanthone‐like heterocycles, which can be used as building blocks for materials used in organic electronics. Electrochemical reduction (ECR) of 1H‐thioxanthene‐1,4,9‐trione and its 3‐methyl derivative in DMF and acetonitrile is a three‐stage process leading to the formation of the corresponding long‐lived radical anions and unstable dianions at the first and second stages, respectively. In a protolytic equilibrium, dianions are converted into 1‐oxy‐4‐hydroxy‐1H‐thioxanthene‐9‐one anions. Their one‐electron reversible ECR leads to the corresponding radical dianions, followed by the formation of (3‐methyl/H)‐1,4‐dihydroxy‐1H‐thioxantene‐9‐ones as the final products. The latter compounds can be converted into the initial (3‐methyl/H)‐1H‐thioxanthene‐1,4,9‐triones. The main intermediates were characterized using a combination of cyclic voltammetry, EPR spectroscopy, 3D spectroelectrochemistry, and DFT calculations at the (U)B3LYP/6‐31+G*/PCM level of theory. A general ECR scheme was proposed for both types of compounds.

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine Sulfonamides as an Important Scaffold for Anticancer Drug Discovery-In Vitro and In Silico Evaluation.

Pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides (MM-compounds) are a relatively new class of heterocyclic compounds that exhibit a wide variety of biological actions, including anticancer properties. Here, we used caspase enzyme activity assays, flow cytometry analysis of propidium iodide (PI)-stained cells, and a DNA laddering assay to investigate the mechanisms of cell death triggered by the MM-compounds (MM134, -6, -7, and -9). Due to inconsistent results in caspase activity assays, we have performed a bromodeoxyuridine (BrdU) incorporation assay, colony formation assay, and gene expression profiling. The compounds' cytotoxic and pro-oxidative properties were also assessed. Additionally, computational studies were performed to demonstrate the potential of the scaffold for future drug discovery endeavors. MM-compounds exhibited strong micromolar (0.06-0.35 µM) anti-proliferative and pro-oxidative activity in two cancer cell lines (BxPC-3 and PC-3). Activation of caspase 3/7 was observed following a 24-h treatment of BxPC-3 cells with IC50 concentrations of MM134, -6, and -9 compounds. However, no DNA fragmentation characteristics for apoptosis were observed in the flow cytometry and DNA laddering analysis. Gene expression data indicated up-regulation of BCL10, GADD45A, RIPK2, TNF, TNFRSF10B, and TNFRSF1A (TNF-R1) following treatment of cells with the MM134 compound. Moreover, in silico studies indicated AKT2 kinase as the primary target of compounds. MM-compounds exhibit strong cytotoxic activity with pro-oxidative, pro-apoptotic, and possibly pro-necroptotic properties that could be employed for further drug discovery approaches.

A comprehensive review on synthesis of dihydropyrimidione via Biginelli reaction catalyzed by reusable magnetic nanocatalyst (from 2020–till date)

The discovery of a new class of heterocyclic compounds by Pietro Biginelli in 1891 was regarded as a watershed point in the history of chemistry. Biginelli is a well‐known organic chemistry technique for generating dihydropyrimidones/thiones, which are important biological compounds. The chemistry of the Biginelli motifs has been studied in drug development because of the extensive use of multiple Biginelli adducts in various domains. The current review focuses on the magnetic reusable iron nanocatalysts, imparting their catalytic role in the Biginelli reaction, which can be impregnated with ionic liquids, Lewis's acids, metal (monometallic or bimetallic), or hybrid polymers as catalyst support. Our ongoing interest in developing environmentally friendly synthetic methodologies prompted us to investigate the utility of magnetically reusable catalysts where workup provides an eco‐friendly approach in comparison with traditional methods to provide a clear understanding of pathways leading to the formation of Biginelli adducts.

1,2,3,5-Tetrazines: A General Synthesis, Cycloaddition Scope, and Fundamental Reactivity Patterns.

Despite the explosion of interest in heterocyclic azadienes, 1,2,3,5-tetrazines remain unexplored. Herein, the first general synthesis of this new class of heterocycles is disclosed. Its use in the preparation of a series of derivatives, and the first study of substituent effects on their cycloaddition reactivity, mode, and regioselectivity provide the foundation for future use. Their reactions with amidine, electron-rich, and strained dienophiles reveal unique fundamental reactivity patterns (4,6-dialkyl-1,2,3,5-tetrazines > 4,6-diaryl-1,2,3,5-tetrazines for amidines but slower with strained dienophiles), an exclusive C4/N1 mode of cycloaddition, and dominant alkyl versus aryl control on regioselectivity. An orthogonal reactivity of 1,2,3,5-tetrazines and the well-known isomeric 1,2,4,5-tetrazines is characterized, and detailed kinetic and mechanistic investigations of the remarkably fast reaction of 1,2,3,5-tetrazines with amidines, especially 4,6-dialkyl-1,2,3,5-tetrazines, established the mechanistic origins underlying the reactivity patterns and key features needed for future applications.

Bromo‐Substituted Diazenyl‐pyrazolo[1,5‐a]pyrimidin‐2‐amines: Sonogashira Cross‐Coupling Reaction, Photophysical Properties, Bio‐interaction and HSA Light‐Up Sensor

A convenient synthesis of a broad series of thirteen examples of alkyne-spacer derivatives 2 from the well-known Sonogashira cross-coupling reaction on diazenyl-pyrazolo[1,5-a]pyrimidin-2-amine compounds 1 is reported. The reactivity of heterocycles 1 due the presence of selected electron-donor (EDG) and electron-withdrawing (EWG) groups attached to different alkynes was evaluated. Also, the reactional versatility due the position variation of the bromo atom at the scaffolds 1 was also investigated. In general, derivatives presented strong absorption bands at the 250-500 nm optical window and UV to cyan emission properties. Also, the redox analysis was recorded by electrochemical cyclic voltammetry technique. For HSA biomacromolecule assays, spectroscopic studies by UV-Vis, steady-state and time-resolved emission fluorescence, and molecular docking calculations evidenced the ability of each compound to establish interactions with human serum albumin (HSA). Finally, the behavior presented for this new class of heterocycles makes them a promising tool as optical sensors for albumins.

Synthesis and Characterization and Antifungal Screening Studies of Some Novel Imidazole Derivatives

Imidazole derivatives are five-mamboed heterocyclic having nitrogen, and oxygen atoms in their ring structure and exhibiting potent as well as wide range of pharmacological activities. Current investigations of imidazole derivatives have provided information that these derivatives may have applications in antimicrobial, antifungal, antiviral, as well as antidiabitic treatments. Fen bam is an imidazole derivative developed by McNeil Laboratories in the late 1970s as a novel anxiolytic drug with an at-the-time-unidentified molecular target in the brain. The imidazole ring system is present in important biological building blocks such as histamine, and the related hormone histamine. Imidazole can serve as a base and as a weak acid. Many antifungal drugs such as nitroimidazole contain an imidazole ring. Thus, varied pharmacological activities of 2-amino-1-methyl-1H-imidazol-4(5H)-one derivatives have encouraged us to design and synthesize some of new class of heterocycles containing imidazolering and its derivatives. Different isomeric secondary amine containing bicyclical aromatic heterocyclic compounds were treated with 2-amino1-methyl-1H-imidazol-4(5H)-one in presence of base by using DMF as solvent and HBTU as coupling agent to get target compounds. Pure target compounds were characterized by 1H NMR, 13C NMR and LC-MS. Some of the selected imidazole derivatives were screened for their antifungal activities.

Facile synthesis of C6-substituted benz[4,5]imidazo[1,2-a]quinoxaline derivatives and their anticancer evaluation.

Cancer remains a leading cause of death worldwide, resulting in continuous efforts to discover and develop highly efficacious anticancer drugs. High-throughput screening of heterocyclic compound libraries is one of the promising approaches that provided several new lead molecules with a novel mechanism of action. On the basis of the promising anticancer potential of imidazoquinoxaline as well as the structurally similar imidazoquinoline-derived scaffold, we prepared a set of C6-substituted benzimidazo[1,2-a]quinoxaline derivatives via two novel synthetic routes using commercially available starting materials, with good to excellent yields and evaluated their anticancer activity against the NCI-60 cancer cell lines. The one-dose (10 µM) anticancer screening of the synthesized compounds in the NCI-60 cell line panel revealed that the substituents have a significant role in the activity. In particular, the indole (7f), imidazole (7g),and benzimidazole (7h) derivatives showed significant activity against the triple-negative breast cancer cell line, MDA-MB-468. The lead compounds also exhibited notable IC50 values against another breast cancer cell line, MCF-7. Furthermore, it was observed that these compounds were relatively nontoxic to normal cell lines: HEK293 (human embryonic kidney cell line) and MCF12A (nontumorigenic human breast epithelial cell line). The IC50 values against healthy cells were at least 5- to 11-fold higher, offering a new class of heterocycles that can be further developed as promising therapeutics for cancer treatment.

Chemical targeting of NEET proteins reveals their function in mitochondrial morphodynamics.

Several human pathologies including neurological, cardiac, infectious, cancerous, and metabolic diseases have been associated with altered mitochondria morphodynamics. Here, we identify a small organic molecule, which we named Mito-C. Mito-C is targeted to mitochondria and rapidly provokes mitochondrial network fragmentation. Biochemical analyses reveal that Mito-C is a member of a new class of heterocyclic compounds that target the NEET protein family, previously reported to regulate mitochondrial iron and ROS homeostasis. One of the NEET proteins, NAF-1, is identified as an important regulator of mitochondria morphodynamics that facilitates recruitment of DRP1 to the ER-mitochondria interface. Consistent with the observation that certain viruses modulate mitochondrial morphogenesis as a necessary part of their replication cycle, Mito-C counteracts dengue virus-induced mitochondrial network hyperfusion and represses viral replication. The newly identified chemical class including Mito-C is of therapeutic relevance for pathologies where altered mitochondria dynamics is part of disease etiology and NEET proteins are highlighted as important therapeutic targets in anti-viral research.

Synthesis of a New Series of Nitrogen/Sulfur Heterocycles by Linking Four Rings: Indole; 1,2,4-Triazole; Pyridazine; and Quinoxaline.

A new series of nitrogen and sulfur heterocyclic systems were efficiently synthesized by linking the following four rings: indole; 1,2,4-triazole; pyridazine; and quinoxaline hybrids. The strength of the acid that catalyzes the condensation of 4-amino-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1 with aromatic aldehydes controlled the final product. Reflux in glacial acetic acid yielded Schiff bases 2–6, whereas concentrated HCl in ethanol resulted in a cyclization product at C-3 of the indole ring to create indolo-triazolo-pyridazinethiones 7–16. This fascinating cyclization approach was applicable with a wide range of aromatic aldehydes to create the target cyclized compounds in excellent yield. Additionally, the coupling of the new indolo-triazolo-pyridazinethiones 7–13 with 2,3-bis(bromomethyl)quinoxaline, as a linker in acetone and K2CO3, yielded 2,3-bis((5,6-dihydro-14H-indolo[2,3-d]-6-aryl-[1,2,4-triazolo][4,3-b]pyridazin-3 ylsulfanyl)methyl)quinoxalines 19–25 in a high yield. The formation of this new class of heterocyclic compounds in high yields warrants their use for further research. The new compounds were characterized using nuclear magnetic resonance (NMR) and mass spectral analysis. Compound 6 was further confirmed by the single crystal X-ray diffraction technique.

Aza-Morita–Baylis–Hillman Reaction with Vinyl-oxadiazoles: An Expeditious Approach to Access New Heterocyclic Arrangements

In this communication, we disclosed a new aza-MBH reaction in which traditional nucleophilic partners of these reactions (e.g., acrylates, nitroolefins or enones) were replaced by vinyl-1,2,4-oxadiazoles. Thus, the aza-MBH reaction between 5-aryl-3-vinyl-1,2,4-oxadiazoles and N-sulfonylimines, catalyzed by the mixture DABCO/AcOH, provides a class of new adduct in yields varying from 31% up to 93% in reaction times from 30 minutes to 24 hours. Due to the biological activities and technological applications associated with the 1,2,4-oxadiazole motifs, this new class of heterocycles offers great synthetic and commercial potentiality.

A General Synthesis of Benzoazepinoindoles – A New Class of Heterocycles

A new class of heterocyclic compounds, namely the benzoazepinoindolones, has been synthesised through a base-catalysed cyclisation reaction of 1,4-bis(2-aminophenyl)-2-phenylbutane-1,4-dione derivatives and features the prominent seven-membered azepine ring moiety. This synthesis has considerable scope for the rapid generation of more complex structures and is inexpensive and generally applicable.

ChemInform Abstract: Synthesis of Thiazolo[5,4‐d][1,2,4]triazolo[4,3‐a]pyrimidines as a New Class of Heterocyclic Compounds.

AbstractAn efficient synthetic pathway for the formation of derivatives of the novel title heterocyclic system (IX), potential templates in drug discovery, is given.

ChemInform Abstract: Synthesis of Oxazolo[5,4‐d][1,2,4]triazolo[4,3‐a]pyrimidines as a New Class of Heterocyclic Compounds.

AbstractThe oxazolopyrimidine ring formation is carried out through treatment of aminopyrimidine (I) with various carboxylic acids.

Synthesis of Thiazolo[5,4-d][1,2,4]Triazolo[4,3-a]Pyrimidines as a New Class of Heterocyclic Compounds

A new series of 2-aminothia zolo[5,4- d]pyrimidines has been synthesised by treating various amines with the new intermediate, 2,5-dichloro-7-methylthiazolo[5,4- d]pyrimidine. Sequential treatment of the amino derivatives with hydrazine hydrate and triethyl orthoesters gave thiazolo[5,4- d][1,2,4]triazolo[4,3- a]pyrimidines as derivatives of a novel heterocyclic system.

The combination of quinazoline and chalcone moieties leads to novel potent heterodimeric modulators of breast cancer resistance protein (BCRP/ABCG2)

During the last decade it has been found that chalcones and quinazolines are promising inhibitors of ABCG2. The combination of these two scaffolds offers a new class of heterocyclic compounds with potentially high inhibitory activity against ABCG2. For this purpose we investigated 22 different heterodimeric derivatives. In this series only methoxy groups were used as substituents as these had been proven superior for inhibitory activity of chalcones. All compounds were tested for their inhibitory activity, specificity and cytotoxicity. The most potent ABCG2 inhibitor in this series showed an IC50 value of 0.19 μM. It possesses low cytotoxicity (GI50 = 93 μM), the ability to reverse MDR and is nearly selective toward ABCG2. Most compounds containing dimethoxy groups showed slight activity against ABCB1 too. Among these three compounds (17, 19 and 24) showed even higher activity toward ABCB1 than ABCG2. All inhibitors were further screened for their effect on basal ATPase activity. Although the basal ATPase activity was partially stimulated, the compounds were not transported by ABCG2. Thus, quinazoline-chalcones are a new class of effective ABCG2 inhibitors.

Double cyclization of O-acylated hydroxyamides generates 1,6-dioxa-3,9-diazaspiro[4.4]nonanes a new class of oxy-oxazolidinones

This work explains preparation of a new class of heterocyclic compounds namely 1,6-dioxa-3,9-diazaspiro[4.4]nonanes triggered by the cyclization of acyloxy amides and their subsequent spirocyclization to generate densely functionalized 3-azaspirocyclic orthoamide compounds.

Synthesis, Biological Evaluation and Structure Activity Relationship of Substituted pyrazolo-, isoxazolo-, pyrimido- and mercaptopyrimidocycloocta[b]indoles

A new class of heterocycles, (3-7) specifically substituted pyrazolo-, isoxazolo- and pyrimidocycloocta[b]indoles, has been synthesized by condensation of substituted 7-(hydroxymethylene)-5,7,8,9,10,11-hexahydrocycloocta[b] indol-6-ones (2) with hydrazine hydrate, hydroxylamine hydrochloride, phenylhydrazine, urea and thiourea, respectively. The structures of the compounds were established by IR, 1H NMR, 13C NMR and the compounds have been screened for in vitro antibacterial and antitumor activities against two human cancer cell lines (A549 and MCF7). Among the compounds screened, 6b and 7b emerged as the most active anti bacterial and the most potent anti proliferative compounds against both the tested cell lines. Structure activity relationship (SAR) analyses confirmed that these two compounds are potential lead for future drug discovery studies.

Synthesis of Oxazolo[5,4‐d][1,2,4]triazolo[4,3‐a]pyrimidines as a New Class of Heterocyclic Compounds

Several new derivatives of oxazolo[5,4‐d]pyrimidine (3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h) have been synthesized through the reaction of 2,4‐dichloro‐6‐methyl‐5‐nitropyrimidine (2) with aryl carboxylic acids in refluxing POCl3. Further treatment of compounds (3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h) with hydrazine hydrate gave the hydrazine derivatives (4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h) that were subsequently cyclized into a novel heterocyclic system, oxazolo[5,4‐d][1,2,4]triazolo[4,3‐a]pyrimidine (5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5l, 5m, 5n, 5o, 5p) and (7a, 7b, 7c, 7d) on treatment with triethylorthoesters or carbondisulfide and alkylhalides, respectively.

ChemInform Abstract: Asymmetric Synthesis of Agrochemically Attractive Trifluoromethylated Dihydroazoles and Related Compounds under Organocatalysis

AbstractReview: [49 refs.