Six-membered Heterocyclic Ring Research Articles

A Route to Two-Dimensional Room-Temperature Organometallic Multiferroics: The Marriage of d-p Spin Coupling and Structural Inversion Symmetry Breaking.

Two-dimensional (2D) room-temperature multiferroic materials are highly desirable but still very limited. Herein, we propose a potential strategy to obtain such materials in 2D metal-organic frameworks (MOFs) by utilizing the d-p direct spin coupling in conjunction with center-symmetry-breaking six-membered heterocyclic rings. Based on this strategy, a screening of 128 2D MOFs results in the identification of three multiferroics, that is, Cr(1,2-oxazine)2, Cr(1,2,4-triazine)2, and Cr(1,2,3,4-trazine)2, simultaneously exhibiting room-temperature ferrimagnetism and ferroelectricity/antiferroelectricity. The room-temperature ferrimagnetic order (306-495 K) in these MOFs originates from the strong d-p direct magnetic exchange interaction between Cr cations and ligand anions. Specifically, Cr(1,2-oxazine)2 exhibits ferroelectric behavior with an out-of-plane polarization of 4.24 pC/m, whereas the other two manifest antiferroelectric characteristics. Notably, all three materials present suitable polarization switching barriers (0.18-0.31 eV). Furthermore, these MOFs are all bipolar magnetic semiconductors with moderate band gaps, in which the spin direction of carriers can be manipulated by electrical gating.

The use of simple structural parameters of energetic metal-organic frameworks to assess their density

A new method is presented for accurately estimating the density (D) of energetic material-organic frameworks (EMOFs), which has vital role in determining their performance. The experimental density data for 124 EMOFs, which are composed of five or six-membered heterocyclic rings, has been used to develop and analyze the model. The model is constructed based on simple structural parameters and can be easily applied to EMOFs with complex compositions and structures. The performance of the new model in estimating density has been compared to the Dalirandeh et al. model. The values of statistical factors comprising mean absolute error (MAE), maximum absolute error (AEmax), root mean square error (RMSE), mean absolute percent error (MAPE), and coefficient of determination (R2) for Dalirandeh et al./new model are 0.09/0.07, 0.33/0.23, 0.12/0.10, 4.21/3.50, and 0.94/0.96, respectively. Statistical validations and applicability domain (AD) assessments have confirmed that the new model provides high accuracy, precision, reliability, and goodness-of-fit.

Rational design for novel heterocyclic based Donepezil analogs for Alzheimer’s disease: an in silico approach

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and has devastating impacts on the elderly population. During the last two decades, there has been a significant focus on developing effective and safe treatments for AD. Acetylcholinesterase (AChE) has been identified as one of the primary therapeutic targets for developing drug candidates for AD. However, there is still a need for more efficient therapies. In this study, our aim is to design a new series of heterocyclic-based AChE inhibitors inspired by a standard drug. Here, we carried out molecular docking, drug-likeliness characteristics, and molecular dynamics (MD) to predict important pharmacophore features and understand the inhibitory mechanism of the designed inhibitors towards the AChE. We have designed 112 new derivatives by replacing the piperidine moiety of Donepezil with the different five and six-membered heterocyclic rings and selected 15 compounds that show higher or comparable docking scores as compared to standard Donepezil and pose no risk for carcinogenicity. Furthermore, MD results imply the structural stability of the selected docked complexes and seven exhibit a stronger binding affinity towards the AChE than Donepezil. Thus, heterocyclic-based derivatives based on oxazole, pyrazole, and tetrahydropyran may be potential therapeutic candidates for AD. Our structure-based drug design approach allows us to identify and gain insight into the structural stability of the inhibitor-protein complex and the inhibition mechanism of the newly designed inhibitors. The present finding might be an initial selection for developing a new inhibitor for AD and provide a direction for further experiments on its biological activities. Communicated by Ramaswamy H. Sarma

Natural Products-Pyrazine Hybrids: A Review of Developments in Medicinal Chemistry.

Pyrazine is a six-membered heterocyclic ring containing nitrogen, and many of its derivatives are biologically active compounds. References have been downloaded through Web of Science, PubMed, Science Direct, and SciFinder Scholar. The structure, biological activity, and mechanism of natural product derivatives containing pyrazine fragments reported from 2000 to September 2023 were reviewed. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. The results of research work show that pyrazine-modified natural product derivatives have a wide range of biological activities, including anti-inflammatory, anticancer, antibacterial, antiparasitic, and antioxidant activities. Many of these derivatives exhibit stronger pharmacodynamic activity and less toxicity than their parent compounds. This review has a certain reference value for the development of heterocyclic compounds, especially pyrazine natural product derivatives.

Synthesis, In Vitro, and In Vivo Investigations of Pterostilbene-Tethered Analogues as Anti-Breast Cancer Candidates.

Pterostilbene has been found to be an active scaffold with anti-breast cancer (BC) action. In this study, fourteen pterostilbene-tethered analogues (2A-2N) were prepared and screened in vitro against MDA-MB-231 and MCF-7 cells. Meanwhile, their structures were characterized using 1H-NMR, 13C-NMR, and HRMS (ESI) spectroscopy techniques. Among them, analogue 2L displayed the most potent anti-proliferation effect on MDA-MB-231 (IC50 = 10.39 μM) and MCF-7 cells (IC50 = 11.73 μM). Furthermore, the meaningful structure-activity relationships suggested that the introduction of a saturated six-membered nitrogen heterocyclic ring into the side chain favored anti-BC capacity. Biological observations indicated that 2L could cause the typical morphological changes in apoptosis, namely an increase in reactive oxygen species level and a loss of mitochondrial membrane potential in BC cells. Importantly, 2L could induce mitochondrial-mediated apoptosis by regulating the expression of caspase-related proteins. Consistent with the results of our in vitro study, 2L apparently inhibited tumor growth in MDA-MB-231 xenograft mice without obvious toxicity. These findings revealed that 2L is expected to be a promising anti-BC lead compound that merits further investigations.

The Neuropharmacological Potential of Piperazine Derivatives: A Mini- Review

Abstract: Piperazine is a six-membered heterocyclic ring with two nitrogen atoms at positions one and four. This piperazine moiety can be present in a slew of well-known medicines that have pharmacophoric effects on a variety of receptors. Various piperazine analogs have core biological activities involving the activation of monoamine pathways, primarily on neurotransmitter receptors. As a result, piperazine analogs have a wide range of central clinical uses, including anxiolytic, antipsychotic, and antidepressant. Due to its stimulant and euphoric effects, benzyl-piperazine is the prototype of piperazine analogs, and this molecule is the main substance of recreational drugs. This review focuses on the activity of piperazine pharmacophore on diverse neurotransmitter receptors used therapeutically as anxiolytics (buspirone), antidepressants (vortioxetine), antipsychotics (clozapine), and other drugs.

DFT, hirshfeld and molecular docking studies of a hybrid compound - 2,4-Diamino-6-methyl-1,3,5-triazin-1-ium hydrogen oxalate as a promising anti -breast cancer agent

The six-membered heterocyclic ring - 1,3,5-triazine and its derivatives have garnered a lot of attention because they're good bioactive herbicides, cancer agents, and other things. One such triazine derivative, 2,4-diamino-6-methyl-1,3,5-triazin-1-ium hydrogen oxalate (DMTHO), was produced in this work, and the structure was optimised using density functional theory's B3LYP functional and the basis set 6–31++G (d,p). Additionally, the chemical underwent in-depth research using molecular docking analysis, Hirshfeld, and density functional theory. The electron densities distribution in the atoms is provided by natural orbital analysis, which also characterises the chemical bonding and reaction behaviour of the compound. The calculated HOMO and LUMO energies indicate that charge transfer occurs inside the molecule. Chemical reactivity traits including HOMO-LUMO energy gaps, softness, total energy, chemical hardness, electronic chemical potential, and electrophilicity of bioactive substances have all been subjected to analytical investigation. Total dipole moment (μ) and first-order hyperpolarizability (β) measurements for the investigated chemical indicate that DMTHO may exhibit microscopic nonlinear optical (NLO) behaviour with nonzero values. A quantitative description about intermolecular interactions in the produced crystal is provided by the Hirshfeld surface analysis. Further docking studies of the compound have been performed and the results reveals that the compound inhibit the breast cancer related protein - casein kinase (CK2) – and the possibility of developing as a potential anti breast cancer lead.

Indolyl-4H-chromenes: Multicomponent one-pot green synthesis, in vitro and in silico, anticancer and antioxidant studies

The present work describes the simple, economical and eco-friendly multicomponent one-pot synthesis of indolyl-4H-chromene derivatives. It is being achieved by reacting benzaldehydes, nitroketene N,S-acetals and indoles in the presence of 1,4-diazabicyclo[2.2.2]octane as catalyst and ethanol, a green solvent. In this domino transformation, a new 4H-chromene, a six-membered heterocyclic ring has been generated by the concurrent formation of two CC and one CO bond. The rampant spread of cancer and disorders associated with cancers necessitated us to evaluate the dual active potentials of these new indolyl-4H-chromenes derivatives as anticancer and anti-oxidant agents. In silico assay of C2-N-phenyl substituted indolyl-4H-chromene against laryngeal (1sa0), breast (5nwh), and cervical carcinoma (4 giz) proteins. From DFT studies, we have analyzed the R and S isomers of compound 4a-l and also the MO of all the compounds analyzed. The in vitro and in silico results taken together indicate that the compound 4e is the promising dual active lead with IC50 values at 0.75 ± 0.06 µM, 0.75 ± 0.04 µM and 10 ± 0.91 µM concentrations against Hep2, A549 and HeLa, respectively and 84.96% anti-oxidant activity.

Construction and Functionalization of Highly Strained N -Doped Zigzag Hydrocarbon Belts

Open AccessCCS ChemistryCOMMUNICATION18 May 2022Construction and Functionalization of Highly Strained N-Doped Zigzag Hydrocarbon Belts Ming Xie, Shuo Tong and Mei-Xiang Wang Ming Xie MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084 Google Scholar More articles by this author , Shuo Tong MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084 Google Scholar More articles by this author and Mei-Xiang Wang *Corresponding author: E-mail Address: [email protected] MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202202008 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Recent years have witnessed breakthroughs in the study of zigzag hydrocarbon belts. However, the synthesis of heterocycle-containing zigzag molecular belts remains very rare and challenging despite their interesting structures and potential applications in chemistry and materials science. Here, we report the expeditious construction of a highly strained belt[4]arene[4](1,4-dihydropyridine) structure using the fjords-stitching strategy. The synthesis comprised four-fold abnormal m-bromination of four N-pivaloylaniline units and Pd2(dba)3/4-Me2NC6H4PtBu2-catalyzed intramolecular C–N bond-forming reactions. Subsequent functionalization through N-arylations produced a variety of tetraza-embedded octahydrobelt[8]arenes. Further oxidation of p-methoxyphenyl-substituted belt[4]arene[4](1,4-dihydropyridine) with Ag[Al(OtBuF)4] yielded a singlet diradical dication N-doped zigzag belt. Download figure Download PowerPoint Introduction Zigzag hydrocarbon belts such as belt[n]arenes or [n]cyclacenes A (Figure 1) are composed of linearly fused benzene rings in a macrocyclic fashion. They initially appeared in the literature more than six decades ago as fictional molecules.1 Later, in the 1980s and 1990s, they were proposed as synthetic targets, along with partly hydrogenated derivatives, including collarenes B and beltenes C (Figure 1).2 Despite their unique structures, tantalizing physical properties, and potential applications in materials science and nanotechnology, the synthesis of these double-stranded macrocycles remains challenging.2–5 One of the insurmountable hurdles is the ramp-up of macrocyclic strain during the construction of belt structures.6 The presumed open-shell electronic characteristics of the fully conjugated structures7 might also impose difficulty in making them. The breakthroughs in the synthesis have been reported very recently.8–15 Starting with readily available resorcin[n]arene (n = 4, 6) derivatives, we achieved an efficient synthesis of partly hydrogenated belt[n]arene (n = 8, 12) derivatives by means of stitching all fjords through multiple intramolecular alkylation and acylation reactions.8–10 Oxidation of an octahydrobelt[8]arene with excess amounts of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) led to a belt[8]arene-(DDQ)4 adduct, following tandem quadruple aromatization and Diels-Alder reactions. A fully conjugated belt[8]arene derivative was observed in the matrix-assisted laser desorption ionization (MALDI) mass spectrum when the belt[8]arene-(DDQ)4 adduct was subjected to laser irradiation and underwent most probably step-wise retro-Diels-Alder reactions.8 Later, Itami et al.14 and Chi et al.15 independently reported the synthesis of stable and isolable benzannulated analogs of belt[18]arene and belt[12]arene, respectively, using a similar iterative Diels-Alder reaction sequence, followed by reductive aromatization of oxygen-bridged moieties. Figure 1 | Structures of zigzag hydrocarbon belts and heteroatom-embedded analogs. Download figure Download PowerPoint Figure 2 | X-ray crystallographic molecular structure of 3a with the top (left) and side (right) views. Hydrogen atoms and solvent molecules are omitted for clarity. Download figure Download PowerPoint In contrast to the resurgence of interest in zigzag hydrocarbon belts,2–5 construction of heterocycle-containing zigzag molecular belts did not draw attention until recently.16–20 Conceivably, introducing heteroatoms generated a diversity of novel zigzag belt structures. Most importantly, precise inlaying of various heteroatoms or site-selective replacement of the carbon atoms with different heteroatoms would permit fine-tuning of the physical and chemical properties of molecular belts, leading to tailor-made materials useful in the field of supramolecular chemistry and advanced materials. Through repetitive and two-directional condensation reactions between o-arylenediamine derivatives and C-shaped bis(o-benzoquinone)s, Wang and Miao16 synthesized a box-like tetraepoxy nanobelt consisting of tetrazapentacene subunits. Reductive aromatization reactions gave a pyrazine-embedded belt[18]arene derivative, characterized using the MALDI time-of-flight (MALDI-TOF) mass spectrum. Zhu and co-workers19,20 reported the construction of benzo[b][1,4]oxathiine- and benzo[b][1,4]dithiine constituted belt[16]arene derivatives from Ullmann coupling reactions and post-macrocyclization intramolecular electrophilic sulfurization reactions. Wu et al.21 reported very recently the synthesis of nitrogen-doped [(6.)m8]ncyclacenes; the introduction of eight-membered tub-shaped 1,5-diazocine units mitigates substantially the strain of belt[n]arenes which are composed of all six-membered aromatic rings. After successful development of the fjords-stitching strategy in the synthesis of a variety of zigzag hydrocarbon belts, starting from readily available resorcin[n]arenes,8–10 we launched a project to explore the chemistry of heteroatom-embedded zigzag hydrocarbon belts D (Figure 1). Very recently, we17 have shown that the fjords-stitching strategy worked efficiently in the construction of tetraoxa (D, X = Y = Z = O), diazadixoa (D, X = O, Y = Z = NR) and azatrioxa (D, X = Y = O, Z = NR) doped octahydrobelt[8]arene compounds through intramolecular nucleophilic aromatic substitutions and palladium-catalyzed intermolecular C–N bond formations.17 Unfortunately, straightforward transition metal-catalyzed quadruple acridinations of pertriflated resorcin[4]arenes with primary amines did not yield tetraza-linked octahydrobelt[8]arene products (D, X = Y = Z = NAr).17 Also, this type of belt molecules was not delivered by other methods such as intramolecular nitrene insertions to Ar-H bonds and the N-centered radical cyclization reactions of resorcin[4]arene-derived C4-symmetric tetraazides and tetraamines, respectively.22 Aiming at the synthesis of desired N-doped highly strained belt molecules, we exploited multiple Buchwald-Hartwig reactions as means to close all fjords of resorcin[4]arenes.23 Herein, we report the unusual four-fold meta-selective bromination reactions of C4-symmetric 1,3,5,7(1,3)-tetrabenzenacyclooctaphane tetraamides and their efficient conversion to highly strained belt[4]arene[4](1,4-dihydropyridine)s or octahydrobelt[4]arene[4]pyridines. As a useful synthetic platform, the acquired NH-linked belt molecules underwent straightforward N-arylations to produce various functional N-doped zigzag hydrocarbon belts. Oxidation of N-para-methoxyphenyl-substituted belt[4]arene[4](1,4-dihydropyridine) with silver salt furnished a diradical dication belt. Results and Discussion We commenced our study preparing compounds 4, the crucial intermediates for Pd-catalyzed intramolecular C–N bond coupling reactions. Selective meta-brominations of tetramines were not feasible as electrophilic bromination of aniline moiety within macrocycle 1 took place dominantly on the ortho position. On the other hand, under forceful conditions, bromination reactions of 1 failed to afford perbrominated products. These compounds were also anticipated to have the potential to undergo cyclization reactions to form belt structures. To circumvent unfavorable ortho-bromination reactions or non-selective and excessive bromination reactions of 1, we decided to conduct bromination reactions of N-acylated derivatives of 2, assuming that the introduction of an electron-withdrawing N-acyl group would alleviate the reactivity of aromatic ring toward electrophiles. More importantly, if the nitrogen lone pair electrons conjugated with the carbonyl rather than the arene ring, the directing effect of the amino group would probably be overridden by another two alkyl substituents and result in site-selective substitution meta to an amino group. Furthermore, using a sterically bulky acyl group would also aid in driving and directing the position from ortho to meta. Following these guidelines, we acylated compounds 1 with pivaloyl chloride. As illustrated in Scheme 1, in the presence of triethylamine as an acid scavenger, the reaction of 1 with eight equivalents of pivaloyl chloride afforded tetraamide products 2 in excellent yields. Favorably, the AlCl3-promoted bromination reaction of 2 with large excess bromine (16 equiv) in CS2 at ambient temperature indeed led to meta-brominated compounds 3 as the major products in 45% yield. It is important to note that the use of 4 and 8 equiv of bromine resulted in the formation of an inseparable mixture, containing presumably various brominated compounds. Substantiated by the single-crystal X-ray molecular structure of 3a (Figure 2 and Supporting Information Figure S1 and Table S1), a macrocyclic molecule adopting a pinched cone conformation or a boat conformation was observable. Noticeably, most of the pivalamido fragments were not coplanar with their benzene rings, indicating that there was no conjugation between the nitrogen and benzene moieties. Such macrocyclic conformation-governed stereoelectronic effect of pivalamido was most likely responsible for electrophilic bromination at the meta position. The removal of pivaloyl groups was achieved efficiently. Under acidic conditions at 150 °C, tetraamides 3 underwent exhaustive amide hydrolysis to furnish compounds 4 almost quantitatively (Scheme 1). Scheme 1 | Synthesis of 4 from 1 via meta-selective bromination of pivalamidobeneze units. Download figure Download PowerPoint The boat conformation rendered macrocyclic compounds 4 ideal precursors for belt structure through stitching all fjords using intramolecular C–N bond formation. In the presence of 6 equiv of tBuONa and a catalytic amount of Pd2(dba)3 and tBu3P, both 4a and 4b underwent quadruple Buchwald-Hartwig cross-coupling reactions smoothly in refluxing toluene (for 4a) or xylene (for 4b). Gratifyingly, the desired tetraaza-doped zigzag belt molecules, namely, belt[4]arene[4](1,4-dihydropyridine)s or octahydrobelt[4]arene[4]pyridines 5a and 5b were isolated as major products in 63% and 61% yields, respectively (Scheme 2). It is worth addressing that an overall 63% chemical yield of 5a implied a nearly 90% yield for each of the C–N bond-forming reactions. The one-step synthesis of compounds 5 again highlighted the generality and efficiency of the fjords-stitching strategy in constructing zigzag molecular belts from macrocyclic precursors. Scheme 2 | Synthesis of octahydrobelt[4]arene[4]pyridines 5a and 5b. Download figure Download PowerPoint The single-crystal X-ray molecular structure illustrated in Figure 3 and Supporting Information Figure S2 ( Supporting Information Table S2) shows that belt[4]arene[4](1,4-dihydropyridine) 5a adopted a highly symmetric square prism-shaped belt structure. The distances between two distal benzene centroids ranged from 5.68–5.79 Å, while the height was ∼ 2.67–2.79 Å. All six-membered heterocyclic rings were boat-configured, with alkyl substituents being equatorially orientated. The macrocyclic strain forces nitrogen atoms out of the planes of their neighboring benzene rings, and the conjugation of aromatic rings with nitrogen lone-pair electrons were weakened. Consequently, the mean C–N bond length within 5a was 1.43 Å, that is, in between the typical C–N bond length of aromatic amines (1.39 Å) and aliphatic amines (1.47 Å). Figure 3 | X-ray crystallographic molecular structure of 5a with the top (left) and side (right) views. Solvent molecules are omitted for clarity. Distances are given in Å. Download figure Download PowerPoint Belt[4]arene[4](1,4-dihydropyridine)s 5 are versatile building blocks in the fabrication of N-doped zigzag hydrocarbon belts because the secondary amine moieties provide invaluable handles for derivatization. To showcase their synthetic utility and also construct belt molecules of expanded cavities, the synthesis of N-functionalized belt[4]arene[4](1,4-dihydropyridine)s 7 was investigated. A survey of the conditions for the reaction of 5a with bromobenzene 6a indicated that the catalyst or the ligand was crucial for the C–N bond formation. For instance, in the presence of Pd2(dba)3 as a transition metal catalyst and tBuONa as a base, the use of BINAP as a ligand led to the formation of 7a in 38% yield. The chemical yield was improved to 68% when the biphenyl phosphine ligand, XPhos, was used. While 1,3-bis(diphenylphosphino)propane (dppp) appeared detrimental to the reaction from which only a trace amount of 7a was observed, 1,1′-bis(diphenylphosphino)ferrocene (dppf) was beneficial to the catalysis leading to the production of 7a in 89% yield. An excellent yield (94%) of 7a was achieved when 4-(di-tert-butylphosphaneyl)-N,N-dimethylaniline24 was employed as a ligand. Under the optimized catalytic conditions, the reaction of both 5a and 5b with various arylbromides 6 (12 equiv) proceeded efficiently to afford the corresponding N-aryl-substituted belt[4]arene[4](1,4-dihydropyridine)s 7 (Scheme 3). For example, N-arylated belt products bearing either an electron-donating or electron-withdrawing group on the para position of the benzene ring were obtained with yields ranging from 55% to 77%. Meta- and ortho-methoxylated arylbromides reacted equally well to produce belts 7d and 7e in 99% and 77%, respectively. Sterically bulky 2,4-dimethoxyphenyl and 2,4,6-trimethoxyphenyl groups were also readily installed on the rim of the belt[4]arene[4](1,4-dihydropyridine) to give products 7f and 7g (Scheme 3). Scheme 3 | Synthesis of functional belt[4]arene[4](1,4-dihydropyridine)s 7 from fourfold N-arylation reactions of 5. Download figure Download PowerPoint The structures of products 7 were supported by their spectroscopic data. The observation of single sets of 1H and 13C NMR spectra indicated the symmetric structures of all N-arylated belts in solution. In the solid-state, highly C4-symmetric structures were also determined unambiguously, employing single-crystal X-ray diffraction analysis. Molecular structures of 7a, 7c, and 7h in Figure 4 and Supporting Information Figures S3–S7 ( Supporting Information Tables S3–S7) showed convincingly that the installation of aryl groups on the nitrogen atoms around the rim increased the cavity substantially. In the case of 7a, for instance, the distance between the distal phenyls at the open rim and between the far end carbon of the N-phenyl and the plane, defined by lower rim carbons, were 11.07 and 6.36 Å, respectively. Scrutiny of all C–N bond lengths also revealed that each N-aryl substituent formed conjugation with the nitrogen inlayed in the skeleton of the belt structure. In the case of 7f and 7g, however, each plane of N-2,4-dimethoxyphenyl and N-2,4,6-trimethoxyphenyl rings was nearly in the bisector plane of each boat-configured 1,4-dihydropyridine ring. Such conformation could prevent steric repulsion between the proximal N-2,4-dimethoxyphenyl substituents in 7f and N-2,4,6-trimethoxyphenyl substituents in 7g. The steric interaction between bulky N-2,4,6-trimethoxyphenyl substituents or between methoxy groups on the ortho positions of the phenyls even caused distinct deformation of the square prism-shaped belt structure of 7g. Consequently, the lone-pair electrons of the inlaid nitrogen atom were unable to conjugate with the aryl group on the rim. Figure 4 | X-ray crystallographic molecular structure of 7a (a), 7c (b), 7f (c), and 7g (d) with top (top) and side (bottom) views. Solvent molecules are omitted for clarity. Distances are given in Å. Download figure Download PowerPoint We then attempted the oxidation of the N-doped hydrocarbon belts. While oxidative aromatization of 5 with DDQ resulted in an insoluble mixture, we found that electrooxidation of belt compounds substituted with a p-methoxy group such as 7c, 7e, and 7f led to the development of blue, purple, and red color of their dichloromethane (DCM) solutions, respectively ( Supporting Information Figure S9). They also underwent oxidation rapidly with Ag[Al(OtBuF)4] to form colorful solutions. Gratifyingly, the oxidation product of 8 precipitated as single crystals in 60% yield (Scheme 4). Compound 8 was stable under atmospheric conditions. X-ray diffraction experiment, electron paramagnetic resonance (EPR), and superconducting quantum interference device (SQUID) measurements indicated that product 8 was a diradical dication salt ( 7c++.)2[Al(OtBuF)4]−. As illustrated in Figure 5 and Supporting Information Figure S8 ( Supporting Information Table S8), the bond lengths of a pair of distal CPMP-N+. (1.350 Å) and C–O (1.325–1.329 Å) bonds were markedly shorter than that of other pairs of CPMP-N (1.410–1.425 Å) and C–O (1.365–1.373 Å) bonds. In the solid-state, two diradical dication belts were head-to-tail arrayed; in between, there were two anions [Al(OtBuF)4]− ( Supporting Information Figure S8): One of the bulky anions was accommodated nicely by the cavity formed by four p-methoxyphenyl (PMP) segments (Figure 5). Zero-field splitting, accompanied by the forbidden Δms = ±2, was shown by EPR spectroscopy ( Supporting Information Figure S10), and antiferromagnetic intra- and intermolecular interaction revealed by SQUID measurement ( Supporting Information Figure S11) indicated that compound 8 was a singlet diradical dication species. The average spin–spin distance was calculated as 8.65 Å, close to the distance between two distal PMP carbons attached to single-electron-oxidized nitrogen atoms (Figure 5). Scheme 4 | Formation of diradical dication salt 8 from oxidation of 7c. Download figure Download PowerPoint Conclusion We have developed an efficient fjords-stitching method to construct a highly strained belt[4]arene[4](1,4-dihydropyridine)s from readily available macrocyclic reactants. The synthesis featured abnormal meta-bromination of each pivalamidobeneze subunits of C4-symmetric calixarenes and four-fold palladium-catalyzed intramolecular C–N bond coupling reactions. We have also demonstrated that the acquired belt[4]arene[4](1,4-dihydropyridine)s provided an invaluable springboard for the convenient fabrication of novel zigzag molecular belts with varied cavity structures and desired functions. Further applications of the products are being actively pursued in our laboratory, and the results will be reported in due course. Figure 5 | X-ray crystallographic molecular structure of 8 with the top (left) and side (right) views. For clarity, two anions and a solvent molecule are omitted for the top view, while the side view shows one included anion. Distances are given in Å. Download figure Download PowerPoint Supporting Information Supporting Information is available and includes all experimental details and copies of 1H-, 13C-NMR, and EPR spectra of products. X-ray crystallographic data were submitted as Crystallographic Information Files (CIFs) to the Cambridge Crystallographic Data Centre (CCDC). Conflict of Interest The authors declare no competing interests. Acknowledgments We thank the National Natural Science Foundation of China (grant nos. 22050005, 21732004, and 21821001) and the Tsinghua University Initiative Scientific Research Program (grant no. 2019Z07L01004) for generous financial support.

Explorations of novel pyridine-pyrimidine hybrid phosphonate derivatives as aurora kinase inhibitors

For developing novel therapeutic agents with good anticancer activities, a series of novel pyridine-pyrimidine hybrid phosphonate derivatives4(a–q) were synthesized by the Kabachnik-Fields method using CAN as catalyst. The compound 4o exhibited the most potent anticancer activity with an IC50 value of 13.62 μM, 17.49 μM, 5.81 μM, 1.59 μM and 2.11 μM against selected cancer cell lines A549, Hep-G2, HeLa, MCF-7, and HL-60, respectively. Compound 4o displayed seven times more selectivity towards Hep-G2 cancer cell lines compared to the human normal hepatocyte cell line LO2 (IC50 value 95.33 μM). Structure-Activity Relationship (SAR) studies were conducted on the variation in the aromatic ring (five-membered heterocyclic ring, six-membered heterocyclic ring) and the variation of substituents on the phenyl ring (electron donating groups, electron withdrawing groups). Furthermore, the mechanism of anticancer activity was clarified by further explorations in bioactivity by using in vitro aurora kinase inhibitory activity and molecular docking studies. The results showed that the compound 4o at IC50concentrationdemonstrated distinctive morphological changes such as cell detachment, cell wall deformation, cell shrinkage and reduced number of viable cells in cancer cell lines. Compound 4o induced early apoptosis and late apoptosis of 27.7% and 6.1% respectively.

Graph-theoretical exploration of the relation between conductivity and connectivity in heteroatom-containing single-molecule junctions.

In this study, we employ the Sachs graph theory to formulate the conduction properties of a single-molecular junction consisting of a molecule in which one carbon atom of an alternant hydrocarbon is replaced with a heteroatom. The derived formula includes odd and even powers of the adjacency matrix, unlike the graph of the parental structure. These powers correspond to odd- and even-length walks. Furthermore, because the heteroatom is represented as a self-loop of unit length in the graph, an odd number of passes of the self-loop will change the parity of the length of the walk. To confirm the aforementioned effects of heteroatoms on conduction in an actual sample, the conduction behavior of meta-connected molecular junctions consisting of a heterocyclic six-membered ring, whose conductive properties have already been experimentally determined, was analyzed based on the enumerated number of walks.

Recent Advances in the Biological Activity of s-Triazine Core Compounds.

An effective strategy for successful chemotherapy relies on creating compounds with high selectivity against cancer cells compared to normal cells and relatively low cytotoxicity. One such approach is the discovery of critical points in cancer cells, i.e., where specific enzymes that are potential therapeutic targets are generated. Triazine is a six-membered heterocyclic ring compound with three nitrogen replacing carbon-hydrogen units in the benzene ring structure. The subject of this review is the symmetrical 1,3,5-triazine, known as s-triazine. 1,3,5-triazine is one of the oldest heterocyclic compounds available. Because of its low cost and high availability, it has attracted researcher attention for novel synthesis. s-Triazine has a weak base, it has much weaker resonance energy than benzene, therefore, nucleophilic substitution is preferred to electrophilic substitution. Heterocyclic bearing a symmetrical s-triazine core represents an interesting class of compounds possessing a wide spectrum of biological properties such as anti-cancer, antiviral, fungicidal, insecticidal, bactericidal, herbicidal and antimicrobial, antimalarial agents. They also have applications as dyes, lubricants, and analytical reagents. Hence, the group of 1,3,5-triazine derivatives has developed over the years. Triazine is not only the core amongst them, but is also a factor increasing the kinetic potential of the entire derivatives. Modifying the structure and introducing new substituents makes it possible to obtain compounds with broad inhibitory activity on processes such as proliferation. In some cases, s-triazine derivatives induce cell apoptosis. In this review we will present currently investigated 1,3,5-triazine derivatives with anti-cancer activities, with particular emphasis on their inhibition of enzymes involved in the process of tumorigenesis.

Catalytic Enantioselective Diels Alder Reaction: Application in the Synthesis of Antiviral Agents

The Diels–Alder reaction (DAR) is one of the most effective and reliable strategies for the construction of six-membered carbocyclic and heterocyclic rings, and it is widely used in the synthesis of organic molecules and drugs. Due to the high regio- and stereo-selectivity and its versatility, DARs have represented a powerful tool for organic chemistry for many years. In addition, the asymmetric DAR has become a fundamental synthetic approach in the preparation of optically active six-membered rings and natural compounds. The COVID-19-related pandemic requires continuous research; DAR represents an useful method to obtain optically active intermediates for the synthesis of antiviral agents under different catalytic conditions. We would like to highlight an intriguing synthetic procedure applied to the development of novel synthetic protocols that are potentially useful against a large panel of viruses and other unmet diseases.

Insight in triazine chromatographic and microbiological analysis: A brief review

Triazine is the six-membered heterocyclic ring that contains three nitrogen?s instead of the carbon- hydrogen unit in the benzene. The triazine derivatives are very attractive from the perspective of agriculture, pharmacology and medicine for a long period of time. They possess a versatile pharmacophore which enables them to express diverse biological activities such as pesticidal, antibacterial, antifungal, antiendotoxin, antileishmanial, antitubercular and anticancer activity. This review represents a summarized report of the chromatographic and microbiological analysis of the triazine derivatives published in past five years.

Effect of a Solid-Hydrogen Environment on UV-Induced Hydrogen-Atom Transfer in Matrix-Isolated Heterocyclic Thione Compounds.

To shed more light on the mechanisms of UV-induced hydrogen-atom-transfer processes in heterocyclic molecules, phototautomeric thione → thiol reactions were investigated for thione compounds isolated in low-temperature Ar as well as in n-H2 (normal hydrogen) matrices. These studies concerned thione compounds with a five-membered heterocyclic ring and thione compounds with a six-membered heterocyclic ring. The experimental investigation of 2-thioimidazole and 3-thio-1,2,4-triazole (thione compounds with a five-membered heterocyclic ring) revealed that for the compounds isolated in solid n-H2 only trace amounts of thiol photoproducts were photogenerated; even though for the same compounds isolated in the solid Ar matrix, the thione → thiol photoconversion was nearly total. In contrast to that, for 3-thiopyridazine and 2-thioquinoline (thione compounds with a six-membered heterocyclic ring) isolated in solid n-H2, the UV-induced thione → thiol conversion occurred with the yield reaching 25–50% of the yield of the analogous process observed for the same species isolated in solid Ar. The obtained experimental results allow us to conclude that the dissociation–association mechanism nearly exclusively governs the phototransformation in thione heterocycles with high barriers for tautomerization (such as thione compounds with a five-membered ring), whereas the strictly intramolecular hydrogen-atom shift contributes to the mechanism of hydrogen-atom transfer in thione heterocycles with lower barriers (such as thione compounds with a six-membered ring).

Nitrite-mediated photodegradation of sulfonamides and formation of nitrated products

In this study, we systematically investigated the indirect photolysis of five SAs, i.e., sulfamethazine (SMZ), sulfamethoxazole (SMX), sulfathiazole (STZ), sulfapyridine (SPD), and sulfamethizole (SMT), under UV-A irradiation (365 nm) and mediated by nitrite (NO2‾) at environmentally relevant concentrations (0.005–0.1 mM). The SAs that are resistant to direct photolysis can be effectively removed in UV/NO2‾ system. SAs with a six-membered heterocyclic ring (i.e., SMZ and SPD) were degraded more quickly than those with a five-membered heterocyclic ring (i.e., SMX, STZ and SMT). The pseudo-first-order rate constants (k) at nitrite concentration of 0.1 mM followed the order of kSPD (0.0265 min−1) > kSMZ (0.0245 min−1) > kSMX (0.0184 min−1) > kSTZ (0.0176 min−1) > kSMT (0.0154 min−1). A kinetic model was developed and the contributions of direct UV photolysis, OH, and RNS to SAs degradation in UV/NO2‾ system were calculated. At NO2‾ concentration of 0.1 mM, the contributions of OH and RNS for SAs removal were 29.17–46.53% and 52.33–63.28%, respectively. Main transformation pathways including hydroxylation and nitration were proposed, based on liquid chromatography mass spectrometry analysis of the degradation products and density functional theory calculation. However, Smile-type rearrangement which generated a SO2-extrusion product was only observed in the degradation of SAs with a six-membered ring, which explains their higher degradation rate than those with a five-membered ring. The presence of natural organic matter (NOM) decreased the formation of nitrated products. Overall, these results will be helpful to understand the fate and the potential ecological risks of SAs in sunlit aquatic environments.

Synthesis and Biological Activity Evaluation of Polyfunctionalized Anthraquinonehydrazones

Background : Anthraquinone derivatives, frequently occurring motifs in many various natural compounds, have attracted a great deal of interest as compounds with a wide spectrum of biological activities. Introduction: The hybrid pharmacophore approach has become an object of considerable interest due to the incorporation of a five- or six-membered heterocyclic rings in the structure of various natural compounds, especially anthraquinone derivatives. Methods: A series of polyfunctionalized anthraquinonehydrazones have been synthesized via the azo-coupling reaction between anthraquinone-based triazenes and methylene active compounds. The structures of synthesized compounds were confirmed by spectral data. Some of the synthesized compounds were screened for their in vitro anticancer activity according to US NCI protocols. The screening of antimicrobial and antifungal activities against Candida albicans and Lactobacillus sp. was carried out. The synthesized compounds were evaluated for their antioxidant (DPPH free radical scavenging assay) and herbicidal activity. Results: The synthesized 1-[N'-(5-oxo-2-thioxoimidazolidin-4-ylidene)-hydrazino]-anthraquinone 1.5 displayed a high level of antimitotic activity against tested human tumor cells with mean GI50/TGI values 4.06/78.52μM. The screening of antimicrobial and antifungal activities led to the identification of 1.8 and 1.9 with a moderate effect on Candida albicans and Lactobacillus sp. Antioxidant activity evaluation allowed the identification of 1-[N'-(3-methyl-5-oxo-1-phenyl-1,5- dihydropyrazol-4-ylidene)-hydrazino]-anthraquinone 1.8 with an IC50 value of 3.715 mM. The herbicidal activity screening led to compound identification 1.8 with growth inhibition of Agrostis stolonifera at 25 %. Conclusion: The obtained anthraquinonehydrazones constitute an interesting template for the design of new synthetic agents with polypharmacological activities.

Chemistry of Substituted Thiazinanes and Their Derivatives.

Thiazinanes and its isomeric forms represent one of the most important heterocyclic compounds, and their derivatives represented a highly potent drug in disease treatment such as, 1,1-dioxido-1,2-thiazinan-1,6-naphthyridine, which has been shown to have anti-HIV activity by a mechanism that should work as anti-AIDS treatment, while (Z)-methyl 3-(naphthalen-1-ylimino)- 2-thia-4-azaspiro[5 5]undecane-4-carbodithioate showed analgesic activity, cephradine was used as antibiotic and chlormezanone was utilized as anticoagulants. All publications were interested in the chemistry of thiazine (partially or fully unsaturated heterocyclic six-membered ring containing nitrogen and sulfur), but no one was dealing with thiazinane itself which encouraged us to shed new light on these interesting heterocycles. This review was focused on the synthetic approaches of thiazinane derivatives and their chemical reactivity.

A DFT quest for effects of fused rings on the stability of remote N-heterocyclic carbenes

Assuming aromaticity (cyclic continuous conjugation, planarity, and obeying the Huckel 4n + 2 rule), effects of one and two fused six-membered heterocyclic rings are investigated on the energy lowering (stabilization) of 22 novel singlet (s) and triplet (t) carbenes, at B3LYP/AUG-cc-pVTZ and M06-2X/AUG-cc-pVTZ. Results display that (1) exclusive of triplet pyridine-4-ylidene, and s and t states, other species appear as ground state, so every s Hammick carbene exhibits more stability than its corresponding t state; (2) the highest stability is demonstrated by unsubstituted pyridine-4-ylidene as reference carbene, and the lowest stability is shown by carbene situated between two nitrogen heteroatoms of two fused rings, in a “W” arrangement; (3) regarding the relationship between carbenic center (CC) and substituted heteroatom, the order of stabilization for fused rings is meta > para > ortho; (4) regardless of how organized, fusion of one six-membered ring, in a given arrangement, has more stabilizing effect than two six-membered rings; (5) contrary to our expectation, t Hammick carbenes show higher band gap (ΔEHOMO-LUMO) than their corresponding s species; (6) based on the NICS (nuclear independent chemical shift) results, the least stable carbene has the most aromaticity in its pyridine ring; and (7) according to proposed homomolecular isodesmotic reactions, all s states are stabilized via π-donor/σ-acceptor substitution more than the t states.

Structure-lock induced phosphorescence lifetime enhancing of (9H-carbazol-9-yl)(phenyl)methanone: An organic phosphorescent materials

Different molecular design strategies have been performed to study purely organic materials with room-temperature phosphorescence (RTP) by suppressing nonradiative deactivation and facilitating intersystem crossing. In this work, a synthetic strategy based on CPM ((9H-carbazol-9-yl)(phenyl)methanone) has been performed to achieve long lived RTP by immobilizing the torsion of benzophenone moiety and forming a six-membered heterocyclic ring containing nitrogen element. This synthesized locked-CPM (8H-indolo[3,2,1-de]phenanthridin-8-one) with higher rigidity has planar configuration both in the singlet state and the triplet state, whose locking configuration effectively inhibits the twist intramolecular charge transfer (TICT) of CPM and significantly reduces the energy gap between the singlet and triplet states to 0.89 ev. This change facilitates intersystem crossing and the generalization of triplet excitons. By fitting the phosphorescence decay curves, we demonstrate that the phosphorescence lifetime of the locked-CPM has increased by nearly forty times compared with that of the CPM, indicating that the presented strategy will bring insight into the developing long lived RTP materials. It is noted that suppress the vibration and torsion of molecular and reduce the energy gap between single-triplet states will favors of long phosphorescence lifetime.