Six-membered Heterocycles Research Articles

Exploring the Diverse Therapeutic Applications of 1, 3-Thiazine: A Comprehensive Review

Thiazine, a six-membered heterocycle containing nitrogen and sulfur atoms, is of paramount importance due to its diverse biological functions and broad therapeutic effects. The pharmacological attributes of 1,3-thiazine span a wide range of activities, including antileukemic, antimycobacterial, anti-inflammatory, sedative, hypnotic, anti-influenza, antituberculosis, melanogenesis inhibition, BACE1 inhibition (with anti-Alzheimer's potential), growth promotion, neuroprotective, and anticonvulsant properties. Consequently, novel synthetic methodologies and the design of new 1,3-thiazine derivatives are significantly influenced by recent research findings. This comprehensive review explores both in vivo and in vitro preclinical studies on the biomedical and therapeutic applications of 1,3-thiazine, highlighting its extensive medical relevance. It is anticipated that derivatization strategies for 1,3-thiazine will open new avenues for the development of innovative biological agents. This review aims to engage researchers, stimulating the creation of promising new treatments and preventive measures for various diseases.

Synthesis of fluorinated six-membered nitrogen heterocycles using microwave irradiation

Synthesis of fluorinated six-membered nitrogen heterocycles using microwave irradiation

Modeling Ligand Exchange Kinetics in Iridium Complexes Catalyzing SABRE Nuclear Spin Hyperpolarization.

Large signal enhancements can be obtained for NMR analytes using the process of nuclear spin hyperpolarization. Organometallic complexes that bind parahydrogen can themselves become hyperpolarized. Moreover, if parahydrogen and a to-be-hyperpolarized analyte undergo chemical exchange with the organometallic complex it is possible to catalytically sensitize the detection of the analyte via hyperpolarization transfer through spin-spin coupling in this organometallic complex. This process is called Signal Amplification By Reversible Exchange (SABRE). Signal intensity gains of several orders of magnitude can thus be created for various compounds in seconds. The chemical exchange processes play a defining role in controlling the efficiency of SABRE because the lifetime of the complex must match the spin-spin couplings. Here, we show how analyte dissociation rates in the key model substrates pyridine (the simplest six-membered heterocycle), 4-aminopyridine (a drug), and nicotinamide (an essential vitamin biomolecule) can be examined. This is achieved for the most widely employed SABRE motif that is based on IrIMes-derived catalysts by 1H 1D and 2D exchange NMR spectroscopy techniques. Several kinetic models are evaluated for their accuracy and simplicity. By incorporating variable temperature analysis, the data yields key enthalpies and entropies of activation that are critical for understanding the underlying SABRE catalyst properties and subsequently optimizing behavior through rational chemical design. While several studies of chemical exchange in SABRE have been reported, this work also aims to establish a toolkit on how to quantify chemical exchange in SABRE and ensure that data can be compared reliably.

The retention features of nitrogen-containing heterocyclic compounds in reversed-phase and hydrophilic HPLC-MS modes

Aromatic five- and six-membered nitrogen-containing heterocyclic compounds are biologically active substances and are widely used in biochemistry and medicine. In addition, such compounds are known as ecotoxicants formed during oxidation processes in industrial wastewater. High-performance liquid chromatography-mass spectrometry is widely used to determine nitrogen-containing heterocycles in various complex mixtures. Octadecyl silica gel is the main sorbent for chromatographic separation. However, octadecyl silica gel does not always enable satisfactory separation in the presence of highly polar isomeric molecules, and more selective chromatographic approaches are required. One of these is hydrophilic chromatography, which facilitates the separation of polar compounds. The aim of the study was to comparatively characterize the retention of a number of five- and six-membered nitrogen-containing heterocyclic compounds during reversed-phase and hydrophilic liquid chromatography with mass spectrometric detection. In addition, spectrophotometric detection at a wavelength of 210 nm was carried out. In the study, we used sorbents based on octadecyl silica gel and unmodified silica gel. High-resolution mass spectrometry was used in the electrospray ionization mode. We studied 19 nitrogen-containing heterocyclic compounds. We used aqueous acetonitrile mobile phases with added aqueous solutions of formic acid and diethylamine as acid-base modifiers. An ammonium formate solution was used as a modifier during hydrophilic chromatography. Reversed-phase chromatography showed that the introduction of 0.1% aqueous formic acid solution increased the ionization and the mass spectrometer signal intensity, but did not always result in a satisfactory separation of isomers upon elution from the octadecyl silica gel surface. The introduction of 0.01% diethylamine solution provided no significant improvement in the separation compared to the mobile phase without modifiers. The use of unmodified silica gel in hydrophilic chromatography mode allowed us to separate isomeric five-membered heterocycles, which was demonstrated by narrow symmetric peaks, but did not result in selective separation of isomeric diazines. Thus, we studied the retention of 19 nitrogen-containing heterocyclic compounds using reversed-phase and hydrophilic liquid chromatography with electrospray ionisation. It was determined that hydrophilic chromatography on unmodified silica gel could be used for satisfactory separation of isomeric five-membered heterocyclic compounds of different classes. For six-membered heterocycles, satisfactory separation was achieved by elution from the surface of octadecyl silica gel using aqueous acetonitrile mobile phase without modifiers.

Evaluating the antibacterial and antibiofilm activities of chitosan derivatives containing six-membered heterocyclics against E. coli and S. aureus

Chitosan exhibits good biocompatibility and some antibacterial activity, making it a popular choice in biomedicine, personal care products, and food packaging. Despite its advantages, the limited antibacterial effectiveness of chitosan hinders its widespread use. Introducing a six-membered heterocyclic structure through chemical modification can significantly enhance its antimicrobial properties and broaden its potential applications. In order to explore the effect of six-membered heterocyclic structure on the antibacterial and antibiofilm activities of chitosan. In this study, seven chitosan derivatives containing six-membered heterocyclics were prepared. They were characterized using Fourier transform infrared (FT-IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and elemental analysis. Cell viability assay showed that they were non-toxic. The antibacterial and antibiofilm activities against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were evaluated. Our research findings demonstrate that increasing the hydrophobicity, alkalinity and charge density of the substitute groups improved the antibacterial and antibiofilm activities of chitosan. This study also offers valuable insights into the quantitative structure-activity relationships of chitosan derivatives in terms of antibacterial and antibiofilm activities.

Recent Advances in Synthetic Strategies of Piperazine & its Analogs Via Rearrangement Reactions: A Review

Abstract: In the six-membered heterocyclic compound piperazine, two nitrogen atoms are positioned within the ring at 1 and 4 positions. Numerous studies have shown that piperazine has the potential to be a useful pharmacophore in many harmful pharmacological conditions such as microbiocidal, antiinflammatory, anticancer, antioxidant, etc. In this present review, we highlighted the synthetic protocols for piperazine and its analogs, as well as the synthetic protocol for piperazine via rearrangement reaction, which have been adopted in recent years. The study also involved a listing of several patents (granted), which comprised important work on piperazine and its derivatives. Among all the methods, the most commonly adopted synthetic methods included the synthesis of piperazine analogs by dizacope, hydrolytic, mumm, multi-component, ugi-smiles, [2+3]-stevens, aza-Wittig, Curtius, Schmidt rearrangement reactions, etc. These synthetic protocols have also been compared based on different reaction conditions, feasibility, and economy to help the researchers in designing their work.

Elucidating the potential of nitrogen-containing heterocyclic core-based non-fullerene acceptors for organic photovoltaic applications

Intramolecular noncovalent interactions are recognized as an efficient route to construct non-fused-core-based non-fullerene acceptors (NFAs) for efficient and cost-effective organic solar cells (OSCs). Herein, we engineered ten distinct structured NFAs molecules based on nitrogen-containing six-membered heterocycle cores. We incorporated various efficient functional groups into the synthetic reference molecule (RM) to design a new efficient series of NFAs (RM1-RM10). These materials are intensively investigated by performing advanced quantum chemical simulations, and the results are compared with those of synthetic RM molecules. We revealed the potential of these materials by investigating their optical, electronic, optoelectronic, and photovoltaic characteristics. By implementing various theoretical models, we explore the inner hidden potential of this designed series (RM1-RM10), such as density of state, transition density matrix, and electrostatic potential studies have been performed. Our applied theoretical modeling approach enables these photovoltaic materials (RM1-RM10) to have customized attributes by tuning their energy levels, binding energy, optical features, and also the photovoltaic characteristics of these materials. Newly developed molecules (RM1-RM10) show promising optoelectronic properties, including a lower energy gap (ranging from 1.81 eV to 1.63 eV) and an absorbed maximum absorption wavelength (760.36 nm), compared to the reference values, which have an energy gap of 1.81 eV and a wavelength of 684.16 nm. Moreover, to demonstrate the charge transfer behavior of these materials, a donor: acceptor (PTB7-Th:RM9) complex study is also performed to reveal the charge transfer phenomenon at the donor: acceptor interface. Therefore, our presented molecular modeling strategy holds significant potential for manufacturing materials with tailored qualities, which is crucial in advancing the organic photovoltaics field.

Solvent Free Potassium 3,5-dinitro-6-oxo-1,6-dihydropyrazin-2-olate 3D EMOF as Thermally Stable Energetic Material.

Heat-resistant explosives play a vital role in indispensable applications. For this, we have synthesized a novel, three-dimensional, solvent-free energetic metal-organic framework (EMOF) potassium 3,5-dinitro-6-oxo-1,6-dihydropyrazin-2-olate (KDNODP) straightforwardly. The synthesized EMOF was characterized through IR, NMR spectroscopy, elemental analysis, and differential scanning calorimetry studies. Furthermore, single-crystal X-ray diffraction provided a complete description of KDNODP. It exhibits a three-dimensional EMOF structure with remarkably balanced properties such as high density (2.11 g cm-3), excellent thermal stability (291 °C), good detonation performance (8127 m s-1 and 26.94 GPa) and low mechanical sensitivity (IS=35 J; FS=360 N) than the commonly used heat-resistant explosives HNS (density=1.74 g cm-3; VOD=7164 m s-1, DP=21.65 GPa, IS=5 J) as well as the similar reported energetic potassium MOFs. To gain insights into the packing and intermolecular interactions, the Hirshfeld surface and a 2D fingerprint analysis were examined. Additionally, scanning electron microscopy was used to investigate the particle size and morphological characteristics of KDNODP. These outcomes highlight a successful method for creating 3D EMOF based on a six-membered heterocycle as a potential heat-resistant energetic material.

2-(Pyridin-4-yl)-2,3-di-hydro-1H-naphtho-[1,8-de][1,3,2]di-aza-borinine.

The title compound, C15H12BN3, is a type of di-aza-borinane featuring substitution at 1, 2, and 3 positions in the nitro-gen-boron six-membered heterocycle. It is comprised of two almost planar units, the pyridyl ring and the Bdan (dan = 1,8-di-aminona-phtho) group, which subtend a dihedral angle of 24.57 (5)°. In the crystal, the mol-ecules are linked into R 4 4(28) hydrogen-bonding networks around the fourfold inversion axis, giving cyclic tetra-mers. The mol-ecules form columnar stacks along the c axis.

Two-Dimensional Cu(II)-MOF with Lewis Acid-Base Bifunctional Sites for Chemical Fixation of CO2 and Bioactive 1,4-DHP Synthesis via Hantzsch Condensation.

Five- and six-membered heterocycles containing nitrogen or oxygen have been considered as privileged scaffolds in organic chemistry and the chemical industry because of their usage in high-value commodities. Herein, we report a two-dimensional (2D) Cu(II)-based MOF catalyst, IITKGP-40, via the strategic employment of ample Lewis acid-base bifunctional sites (open metal nodes and free pyrazine moieties) along the pore wall. IITKGP-40 could convert toxic CO2 to cyclic carbonates in an atom-economical manner under solvent-free conditions and aromatic aldehyde to bioactive 1,4-DHPs via Hantzsch condensation. Exceptional catalytic performance (99%) and turnover number under mild reaction conditions for CO2 fixation using sterically hindered styrene oxide, and good-to-excellent yields for a wide range of aromatic aldehydes toward 1,4-dihydropyridines (1,4-DHPs) make IITKGP-40 promising as a multipurpose heterogeneous catalyst. Moreover, to demonstrate the practical utility of the catalyst, two biologically important drug molecules, diludine and nitrendipine analogue, have also been synthesized. IITKGP-40 is recyclable for at least three consecutive runs without significant loss of activity, making it promising for real-time applications.

Synthesis and polyester printing applications of transition metal complexes of tridentate 5-(m-tolyldiazenyl)salicylaldehyde thiosemicarbazone derivatives

Thiosemicarbazone metal complexes are intriguing molecules with a variety of applications in several fields, including the pharmaceutical sector, analytical chemistry, and textile industries. Here, we designed and synthesized 12 transition metal complexes based on thiosemicarbazone as a tridendate group and azo moiety as a chromophore part, in addition to evaluating their color strength and fastness properties. The tridentate ligand derivatives of 5-(m-tolyldiazenyl)salicylaldehyde thiosemicarbazone reacted with four transition metal salts (copper, cobalt, nickel, and iron salts) in refluxing alkaline ethanol to afford the corresponding thiosemicarbazone complexes. The ligands behaved as double-deprotonated tridentate ligands that connected to the transition metal ions through the deprotonation of phenolic-OH and thiol-SH, as well as the azomethine nitrogen atom, to generate fused five- and six-membered heterocycle rings. The obtained metal complexes were characterized by elemental analyses, atomic absorption, IR, and UV–Vis spectra. The color strength and fastness properties of the printed fabrics were tested, showing good to excellent properties.

4-(1H-2,3-Dihydro-naphtho-[1,8-de][1,3,2]di-aza-borinin-2-yl)-1-ethylpyridin-1-ium iodide.

The title compound, C17H17BN3I, is a type of di-aza-borinane featuring substitution at the 1, 2, and 3 positions of the nitro-gen-boron six-membered heterocycle. The organic mol-ecule has a planar structure, the dihedral angle between the pyridyl ring and the fused ring system being 3.46 (4)°. In the crystal, mol-ecules are stacked in a head-to-tail manner. The iodide ion makes close contacts with three organic mol-ecules and supports the alternating stack.

4-(1H-2,3-Dihydronaphtho-[1,8-de][1,3,2]di-aza-borinin-2-yl)-1-ethylpyridin-1-ium iodide monohydrate.

The cation of the title hydrated salt, C17H17BN3 +·I-·H2O, is a di-aza-borinane featuring substitution at the 1, 2, and 3 positions in the nitro-gen-boron six-membered heterocycle. The cation is approximately planar with a dihedral angle between the pyridyl ring and the di-aza-borinane ring system of 5.40 (5)°. In the crystal, the cations stack along [100] in an alternating head-to-tail manner, while the iodide ion and water mol-ecule form one-dimensional hydrogen-bonded chains beside the cation stack. The cation stacks and I--water chains are crosslinked by N-H⋯I and N-H⋯O hydrogen bonds.

Butadienyl Ketene: An Unexplored Intermediate in Organic Synthesis

AbstractButadienyl ketene is a useful intermediate because of its role as a 2p-component in cycloaddition reactions with a variety of substrates such as simple or conjugated imines and dienes. This review article summarizes recent reports on the generation of butadienyl ketene in situ and their cycloaddition reactions to afford heterocyclic systems. The chemistry of butadienyl ketene is explored with a focus on its [2+2] and [4+2] cycloaddition reactions with a variety of imines and azadiene derivatives such as 1,3-diazabuta-1,3-dienes, for the synthesis of four- and six-membered heterocycles, respectively.

Synthesis and insecticidal activity of N-(5-phenylpyrazin-2-yl)-benzamide derivatives: Elucidation of mode of action on chitin biosynthesis through symptomology and genetic studies

Among the six-membered heterocycles, the pyrazine ring is poorly explored in crop protection and does not feature in any product listed in the current IRAC MoA classification. In an effort to identify new leads for internal research, we synthesized a series of N-(5-phenylpyrazin-2-yl)-benzamide derivatives and evaluated them for their insecticidal activity. N-(5-phenylpyrazin-2-yl)-benzamide derivatives 3 were prepared using an automated two-step synthesis protocol. These compounds were tested for their initial biological activity against a wide range of sucking and chewing insect pests and found to be active against lepidopterans only. More detailed experiments, including symptomology studies on the diamondback moth, Plutella xylostella (L.) and the Egyptian cotton leafworm, Spodoptera littoralis (Boisduval) showed that analog 3q causes severe abnormalities in the lepidopteran cuticle leading to larval mortality. Compound 3q shows strong potency against both P. xylostella and S. littoralis, whereas analog 3i shows better potency against S. littoralis causing also impaired cuticular structure and death of the larvae. Additionally, P. xylostella genetic studies showed that compound 3q resistance is linked to Chitin Synthase 1. Our studies show that N-(5-phenylpyrazin-2-yl)-benzamide derivatives 3, and in particular analogs 3i and 3q, act as insect growth modulator insecticides. Conformational similarities with lufenuron are discussed.

Cyclic Hydrocarbon Frameworks Containing Two Bismuth Atoms: Towards 9,10-Dibismaanthracene.

When bismuth atoms are incorporated into cyclic organic systems, this commonly goes along with strained or distorted molecular geometries, which can be exploited to modulate the physical and chemical properties of these compounds. In six-membered heterocycles, bismuth atoms are often accompanied by oxygen, sulfur or nitrogen as a second hetero-element. In this work, we present the first examples of six-membered rings, in which two CH units are replaced by BiX moieties (X=Cl, Br, I), resulting in dihydro-anthracene analogs. Their behavior in chemically reversible reduction reactions is explored, aiming at the generation of dibisma-anthracene (bismanthrene). Heterometallic compounds (Bi/Fe, Bi/Mn) are introduced as potential bismanthrene surrogates, as supported by bismanthrene-transfer to selenium. Analytical techniques used to investigate the reported compounds include NMR spectroscopy, high-resolution mass spectrometry, single-crystal X-ray diffraction analyses, and DFT calculations.

Recent advances in site-selective transformations of β-enaminones via transition-metal-catalyzed C-H functionalization/annulation.

β-Enaminone transformation strategies are widely employed in the synthesis of numerous biologically active drugs and natural products, highlighting their significance in medicinal chemistry. In recent years, various strategies have been developed for synthesizing several five- and six-membered heterocycles, as well as substituted polyaromatic scaffolds, which serve as crucial synthons in drug development, from β-enaminones. Among these approaches, site-selective transformations of β-enaminones via C-H activation and annulation have been particularly well explored. This review summarizes the most recent literature (over the past eight years) on β-enaminone transformations for developing bioactive scaffolds through site-selective C-H bond functionalization and annulation.

Synthesis of benzimidazole-fused 1,4-benzoxazepines and benzosultams spiro-connected to a 2-oxindole core via a tandem epoxide-opening/SNAr approach.

While hundreds of literature reports describe the preparation of spirooxindole-based five- and six-membered heterocycles, the construction of seven-membered heterocyclic rings spiro-connected to a 2-oxindole core has so far been less developed. Herein, we disclose a base-mediated (4 + 3) annulation of spiro-epoxyoxindoles and 2-(2-fluoroaryl)-1H-benzoimidazoles or 2-fluoro-N-arylbenzenesulfonamides toward the synthesis of two new classes of spirooxindole-based polycyclic systems. Mechanistically, this conceptually simple and high atom-economical reaction proceeds via an SN2-like intermolecular epoxide ring-opening, accompanied by a concomitant intramolecular SNAr reaction. From a synthetic aspect, the notable features of the process are its full regioselectivity, operational simplicity using readily available substrates under transition-metal-free conditions, high yields, and broad substrate scope.

Molecular Fe(II)-Ln(III) dyads for luminescence reading of spin-state equilibria at the molecular level.

Due to the primogenic effect, the valence shells of divalent iron Fe(II) ([Ar]3d6) and trivalent lanthanides Ln(III) ([Xe]4fn) are compact enough to induce spin-state equilibrium for the 3d-block metal and atom-like luminescence for the 4f-block partner in Fe(II)-Ln(III) dyads. In the specific case of homoleptic pseudo-octahedral [Fe(II)N6] units, programming spin crossover (SCO) around room temperature at normal pressure requires the design of unsymmetrical didentate five-membered ring chelating N∩N' ligands, in which a five-membered (benz)imidazole heterocycle (N) is connected to a six-membered pyrimidine heterocycle (N'). Benefiting from the trans influence, the facial isomer fac-[Fe(II)(N∩N')3]2+ is suitable for inducing SCO properties at room temperature in solution. Its connection to luminescent [LnN6O3] chromophores working as non-covalent podates in the triple-stranded [Fe(II)Ln(L10)3]5+ helicates (Ln = Nd, Eu) controls the facial arrangement around Fe(II). The iron-based SCO behaviour of the 3d-4f complex mirrors that programmed in the mononuclear scaffold. Because of the different electronic structures of high-spin and low-spin [Fe(II)N6] units, their associated absorption spectra are different and modulate the luminescence of the appended lanthanide luminophore via intramolecular intermetallic energy transfers. It thus becomes possible to detect the spin state of the Fe(II) center, encoded by an external perturbation (i.e. writing), by lanthanide light emission (i.e. reading) in a single molecule and without disturbance. Shifting from visible emission (Ln = Eu) to the near-infrared domain (Ln = Nd) further transforms a wavy emitted signal intensity into a linear one, a protocol highly desirable for future applications in data storage and thermometry.

Straight-chain ω-amino-α,β-unsaturated carbonyl compounds: versatile synthons for the synthesis of nitrogen-containing heterocycles via organocatalytic reactions

In this review, we elaborate and discuss the recent applications of straight-chain amino-α,β-unsaturated carbonyl compounds as versatile synthons in organocatalytic reactions for the creation of five- and six-membered saturated nitrogen-containing heterocycles.