AlCl3-Promoted Intramolecular Indolinone-Quinolone Rearrangement of Spiro[indoline-3,2'-quinoxaline]-2,3'-diones: Easy Access to Quinolino[3,4-b]quinoxalin-6-ones.

A facile and direct intramolecular indolinone-quinolone rearrangement was developed for the synthesis of quinolino[3,4-b]quinoxalin-6-ones from spiro[indoline-3,2'-quinoxaline]-2,3'-diones, which are readily available with use of isatines, malononitrile, and 1,2-phenylenediamines under quite mild conditions. This efficient approach provides excellent yields and could potentially be used for the construction of a diverse library of quinolino[3,4-b]quinoxalin-6-ones for high-throughput screening in medicinal chemistry. The reaction mechanism is explored by extensive DFT calculations.

Divergent Synthesis of 3-(Indol-2-yl)quinoxalin-2-ones and 4-(Benzimidazol-2-yl)-3-methyl(aryl)cinnolines via Polyphosphoric Acid (PPA)-Mediated Intramolecular Rearrangements of 3-(Methyl/aryl(2-phenylhydrazono)methyl)quinoxalin-2-ones.

Herein, we report a polyphosphoric acid (PPA)-mediated divergent metal-free operation to access a diverse collection of 3-(indol-2-yl)quinoxalin-2-ones and 4-(benzimidazol-2-yl)-3-methylcinnolines in moderate to excellent overall yields. The described process involves two distinct, and competing rearrangements of 3-(methyl(2-phenylhydrazono)methyl)quinoxalin-2-ones, namely [3,3]-sigmatropic Fischer rearrangement with the formation of an indole ring to produce 3-(indol-2-yl)-quinoxalin-2-ones, and Mamedov rearrangement with simultaneous construction of benzimidazole and cinnoline rings to form the new biheterocyclic system─4-(benzimidazol-2-yl)-3-methylcinnolines. The reaction mechanism of both rearrangement channels is explored by extensive dispersion-corrected DFT calculations. It is partcularly remarkable that when 3-(aryl(2-phenylhydrazono)methyl)quinoxalin-2-ones is used, instead of 3-(methyl(2-phenylhydrazono)methyl)quinoxalin-2-ones, reactions proceed regioselectively with the formation of only rearrangement products─4-(benzimidazol-2-yl)-3-arylcinnolines with high yields. This operationally simple protocol enables a rapid access to these scaffolds and is compatible with a wide scope of starting materials. In addition, the new rearrangement found features a promising approach for the design of unique compound libraries for drug design and discovery programs.

One-Step Synthesis of Functionalized Pyrazolo[3,4-b]pyridines via Ring Opening of the Pyrrolinium Ion.

Herein, we report a highly regioselective one-pot synthesis of pyrazolo[3,4-b]pyridines via the reaction of 3-arylidene-1-pyrrolines with aminopyrazoles. The reaction proceeds through the sequential nucleophilic addition/electrophilic substitution/C-N bond cleavage and provides easy access to pyrazolo[3,4-b]pyridine derivatives featuring a primary amino group. Moreover, the reaction can be terminated at the electrophilic substitution stage, thus providing convenient entry to the hardly accessible pyrazolopyrrolopyridine scaffold.

Supramolecular Optimization of Sensory Function of a Hemicurcuminoid through Its Incorporation into Phospholipid and Polymeric Polydiacetylenic Vesicles: Experimental and Computational Insight.

This work presents the synthesis of a new representative of hemicurcuminoids with a nonyloxy substituent (HCur) as a fluorescent amphiphilic structural element of vesicular aggregates based on phosphatidylcholine (PC), phosphatidylserine (PS), and 10,12-pentacosadiynoic acid (PCDA). Both X-ray diffraction analysis of the single crystal and 1H NMR spectra of HCur in organic solvents indicate the predominance of the enol-tautomer of HCur. DFT calculations show the predominance of the enol tautomer HCur in supramolecular assemblies with PC, PS, and PCDA molecules. The results of the molecular modeling show that HCur molecules are surrounded by PC and PS with a rather weak exposure to water molecules, while an exposure of HCur molecules to water is enhanced under its supramolecular assembly with PCDA molecules. This is in good agreement with the higher loading of HCur into PC(PS) vesicles compared to PCDA vesicles converted into polydiacetylene (PDA) ones by photopolymerization. HCur molecules incorporated into HCur-PDA vesicles exhibit greater planarity distortion and hydration effect in comparison with HCur-PC(PS) ones. HCur-PDA is presented as a dual fluorescence-chromatic nanosensor responsive to a change in pH within 7.5-9.5, heavy metal ions and polylysine, and the concentration-dependent fluorescent response is more sensitive than the chromatic one. Thus, the fluorescent response of HCur-PDA allows for the distinguishing between Cd2+ and Pb2+ ions in the concentration range 0-0.01 mM, while the chromatic response allows for the selective sensing of Pb2+ over Cd2+ ions at their concentrations above 0.03 mM.

Calix[4]Resorcinarene Carboxybetaines and Carboxybetaine Esters: Synthesis, Investigation of In Vitro Toxicity, Anti-Platelet Effects, Anticoagulant Activity, and BSA Binding Affinities.

As a result of bright complexation properties, easy functionalization and the ability to self-organize in an aqueous solution, amphiphilic supramolecular macrocycles are being actively studied for their application in nanomedicine (drug delivery systems, therapeutic and theranostic agents, and others). In this regard, it is important to study their potential toxic effects. Here, the synthesis of amphiphilic calix[4]resorcinarene carboxybetaines and their esters and the study of a number of their microbiological properties are presented: cytotoxic effect on normal and tumor cells and effect on cellular and non-cellular components of blood (hemotoxicity, anti-platelet effect, and anticoagulant activity). Additionally, the interaction of macrocycles with bovine serum albumin as a model plasma protein is estimated by various methods (fluorescence spectroscopy, synchronous fluorescence spectroscopy, circular dichroic spectroscopy, and dynamic light scattering). The results demonstrate the low toxicity of the macrocycles, their anti-platelet effects at the level of acetylsalicylic acid, and weak anticoagulant activity. The study of BSA-macrocycle interactions demonstrates the dependence on macrocycle hydrophilic/hydrophobic group structure; in the case of carboxybetaines, the formation of complexes prevents self-aggregation of BSA molecules in solution. The present study demonstrates new data on potential drug delivery nanosystems based on amphiphilic calix[4]resorcinarenes for their cytotoxicity and effects on blood components.

Synthesis of Morpholine-, Piperidine-, and N-Substituted Piperazine-Coupled 2-(Benzimidazol-2-yl)-3-arylquinoxalines as Novel Potent Antitumor Agents.

A novel series of 2-(benzimidazol-2-yl)quinoxalines with three types of pharmacophore groups, namely, piperazine, piperidine, and morpholine moieties, which are part of known antitumor drugs, was designed and synthesized. The compounds have been characterized by NMR and IR spectroscopy, high- and low-resolution mass spectrometry, and X-ray crystallography. 2-(Benzimidazol-2-yl)quinoxalines with N-methylpiperazine substituents showed promising activity against a wide range of cancer lines, without causing hemolysis and showing little cytotoxicity against normal human Wi-38 cells (human fetal lung). A mixture of regioisomers 2-(benzimidazol-2-yl)-3-(4-fluorophenyl)-6(and 7)-(4-methylpiperazin-1-yl)quinoxalines (mri BIQ 13da/14da) showed a highly selective cytotoxic effect against human lung adenocarcinoma (cell line A549) with a half-maximal inhibitory concentration at the level of doxorubicin with a selectivity index of 12. The data obtained by flow cytometry, fluorescence microscopy, and multiparametric fluorescence analysis suggested that the mechanism of the cytotoxic effect of the mri BIQ 13da/14da on A549 cells may be associated with the stopping of the cell cycle in phase S and inhibition of DNA synthesis as well as with the induction of mithochondrial apoptosis. Thus, mri BIQ 13da/14da can be considered as a leading compound deserving further study, optimization, and development as a new anticancer agent.

Modulating the Inclusive and Coordinating Ability of Thiacalix[4]arene and Its Antenna Effect on Yb3-Luminescence via Upper-Rim Substitution.

The present work introduces the series of thiacalix[4]arenes (H4L) bearing different upper-rim substituents (R = H, Br, NO2) for rational design of ligands providing an antenna-effect on the NIR Yb3+-centered luminescence of their Yb3+ complexes. The unusual inclusive self-assembly of H3L- (Br) through Brπ interactions is revealed through single-crystal XRD analysis. Thermodynamically favorable formation of dimeric complexes [2Yb3+:2HL3-] leads to efficient sensitizing of the Yb3+ luminescence for H4L (Br, NO2), while poor sensitizing is observed for ligand H4L (H). X-ray analysis of the single crystal separated from the basified DMF solutions of YbCl3 and H4L(NO2) has revealed the transformation of the dimeric complexes into [4Yb3+:2L4-] ones with a cubane-like cluster structure. The luminescence characteristics of the complexes in the solutions reveal the peculiar antenna effect of H4L(R = NO2), where the triplet level at 567 nm (17,637 cm-1) arisen from ILCT provides efficient sensitizing of the Yb3+ luminescence.

Bromine-Promoted One-Pot Furo[b]annulation and α-C(sp2)-Thiomethylation Cascade of (E)-3-Styrylquinoxalin-2(1H)-ones with Dimethyl Sulfoxide.

A new process has been developed for the bromine-promoted sequential (sp2)C = (sp2)C bond functionalization of (E)-3-styrylquinoxalin-2(1H)-ones and furo[b]annulation via the 5-exo-cyclization in dimethyl sulfoxide (DMSO). The reaction represents a novel strategy for the synthesis of 2-aryl-3-(methylthio)furo[2,3-b]quinoxalines and involves 3-(1,2-dibromo-2-arylethyl)quinoxalin-2(1H)-ones and 2-arylfuro[2,3-b]quinoxalines as key intermediates. Furthermore, DMSO was converted to dimethyl sulfide in situ, which served as the methylthiolation reagent in the reaction. This protocol constitutes an efficient and convenient method for the annulation and methylthiolation of (E)-3-styrylquinoxalin-2(1H)-ones bearing a wide range of functional groups in high yields at room temperature.

Enamine-mediated Mannich reaction of cyclic N,O-acetals and amido acetals: the multigram synthesis of pyrrolidine alkaloid precursors.

The cooperative L-proline/Brønsted acid/base promoted reaction of 2-ethoxypyrrolidines or N-substituted 4,4-diethoxybutan-1-amines with methyl(alkyl/aryl)ketones for the synthesis of 2-(acylmethylene)pyrrolidine derivatives is reported. The key features of the developed protocol are gram-scale synthesis of the target compounds, easily available starting materials, operational simplicity and usage of non-expensive reagents.

Role of PSS-based assemblies in stabilization of Eu and Sm luminescent complexes and their thermoresponsive luminescence.

The present work introduces self-assembled polystyrenesulfonate (PSS) molecules as soft nanocapsules for incorporation of Eu3+-Sm3+ complexes by the solvent exchange procedure. The high levels of Eu3+- and Sm3+-luminescence of the complexes derives from the ligand-to-metal energy transfer, in turn, resulted from the complex formation of Eu3+and Sm3+ ions with the three recently synthesized cyclophanic 1,3-diketones. The structural features of the ligands are optimized for the high thermal sensitivity of Eu3+- luminescence in DMF solutions. The PSS-nanocapsules (∼100 nm) provide both colloid and chemical stabilization of the ultrasmall (3-5 nm) nanoprecipitates of the complexes, although their luminescence spectra patterns and excited state lifetimes differ from the values measured for the complexes in DMF solutions. The specific concentration ratio of the Eu3+-Sm3+ complexes in the DMF solutions allows to tune the intensity ratio of the luminescence bands at 612 and 650 nm in the heterometallic Eu3+-Sm3+ colloids. The thermal sensitivity of the Eu3+- and Sm3+-luminescence of the complexes derives from the static quenching both in PSS-colloids and in DMF solutions, while the thermo-induced dynamic quenching of the luminescence is significant only in DMF solutions. The reversibility of thermo-induced luminescence changes of the Eu3+-Sm3+ colloids is demonstrated by six heating-cooling cycles. The DLS measurements before and after the six cycles reveal the invariance of the PSS-based capsule as the prerequisite for the recyclability of the temperature monitoring through the ratio of Eu3+-to- Sm3+ luminescence.

Supramolecular Self-Assembly of Porphyrin and Metallosurfactant as a Drug Nanocontainer Design.

The combined method of treating malignant neoplasms using photodynamic therapy and chemotherapy is undoubtedly a promising and highly effective treatment method. The development and establishment of photodynamic cancer therapy is closely related to the creation of sensitizers based on porphyrins. The present study is devoted to the investigation of the spectroscopic, aggregation, and solubilization properties of the supramolecular system based on 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (TSPP) and lanthanum-containing surfactant (LaSurf) in an aqueous medium. The latter is a complex of lanthanum nitrate and two cationic amphiphilic molecules of 4-aza-1-hexadecylazoniabicyclo[2.2.2]octane bromide. The mixed TSPP-LaSurf complexes can spontaneously assemble into various nanostructures capable of binding the anticancer drug cisplatin. Morphological behavior, stability, and ability to drug binding of nanostructures can be tailored by varying the molar ratio and the concentration of components. The guest binding is shown to be additional factor controlling structural rearrangements and properties of the supramolecular TSPP-LaSurf complexes.

Cationic Imidazolium Amphiphiles Bearing a Methoxyphenyl Fragment: Synthesis, Self-Assembly Behavior, and Antimicrobial Activity.

Novel cationic amphiphiles of the 3-alkyl-1-(4-methoxyphenyl)-1H-imidazol-3-ium bromide series bearing methoxyphenyl fragments (MPI-n) have been synthesized. Their aggregation properties in aqueous solutions, solubilization capacity, and hemolytic and antimicrobial activities have been investigated by a number of physicochemical methods. Using tensiometry, conductometry, and fluorescence spectroscopy, it was shown that the MPI-n have lower CMCs than their nonfunctionalized counterparts. The unusual alkyl-chain-length-dependent morphology of aggregates is testified for this homological series. Amphiphiles with 12, 14, and 16 alkyl tails are characterized by the formation of micellar aggregates, while a surfactant with a decyl tail is characterized by the formation of larger aggregates with lower surface curvature. The MPI-10 aggregate morphology was rationalized in terms of the packing parameter consideration and was supported by size measurements and the fluorescence probe techniques, which showed that vesicle-like aggregates in close-packing mode probably occur. MPI-n aggregates have exhibited a high solubilization capacity toward hydrophobic azo dye Orange OT. Importantly, amphiphiles studied showed (i) high bacteriostatic activity at the level of ciprofloxacin; (ii) high bactericidal action against all Gram-positive bacteria, including methicillin-resistant strains; (iii) bactericidal properties against Gram-negative bacteria; and (iv) low hemolytic activity.

Interaction of mucin with viologen and acetate derivatives of calix[4]resorcinols.

The mucus layer acts as a selective diffusion barrier that has an important effect on the efficiency of drug delivery systems in the human body. In this regard, currently the drug nanocarriers of various sizes and compositions are being widely developed to study their mucoadhesive properties i.e., the ability to interact with mucin. However, the effective interaction of drug composition with mucin does not guarantee the success due to the fact that there is a further barrier in the form of epithelial cells retained by calcium ions under the mucus layer. In this work, the interaction of mucin (porcine gastric mucin) with calixarenes is considered for the first time. The study of interaction between calixarenes, mucin and calcium ions by a complex of physicochemical methods showed that effective interaction with mucin requires cationic fragments, and binding with calcium is realized due to anionic fragments in the calixarene structure. Therefore, the combination of different chemical groups in the structure of drug nanocarrier plays an important role in successful mucosal drug delivery. Taking into account the wide possibilities of synthetic modification of the macrocyclic platform, calixarenes can find the application in the drug delivery across mucous barriers.

The Highly Regioselective Synthesis of Novel Imidazolidin-2-Ones via the Intramolecular Cyclization/Electrophilic Substitution of Urea Derivatives and the Evaluation of Their Anticancer Activity.

A series of novel 4-(het)arylimidazoldin-2-ones were obtained by the acid-catalyzed reaction of (2,2-diethoxyethyl)ureas with aromatic and heterocyclic C-nucleophiles. The proposed approach to substituted imidazolidinones benefits from excellent regioselectivity, readily available starting materials and a simple procedure. The regioselectivity of the reaction was rationalized by quantum chemistry calculations and control experiments. The anti-cancer activity of the obtained compounds was tested in vitro.

Correction: A simple synthetic approach to enhance the thermal luminescence sensitivity of Tb3+ complexes with thiacalix[4]arene derivatives through upper-rim bromination.

Correction for 'A simple synthetic approach to enhance the thermal luminescence sensitivity of Tb3+ complexes with thiacalix[4]arene derivatives through upper-rim bromination' by Sergey N. Podyachev, et al., Dalton Trans., 2020, 49, 8298-8313, DOI: 10.1039/D0DT00709A.

A simple synthetic approach to enhance the thermal luminescence sensitivity of Tb3+ complexes with thiacalix[4]arene derivatives through upper-rim bromination.

The present work for the first time reports an application of the thiacalix[4]arene scaffold for the preparation of Tb3+ complexes possessing high thermal luminescence sensitivity in the physiological temperature range of 20-50 °C. Non-substituted thiacalix[4]arenes form luminescent complexes with Tb3+ ions, but they do not reveal any meaningful thermal sensitivity. To solve this problem, an upper-rim bromination of thiacalix[4]arenes, as well as distal bromination along with the embedding of two 1,3-diketone substituents are proposed as new simple synthetic approaches to enhance the thermal luminescence sensitivity of the Tb3+ complexes. A combination of mass spectrometry, NMR, UV-Vis and luminescence spectroscopy with quantum chemical calculations reveals a dimeric structure of the complexes formed by thiacalix[4]arenes with Tb3+ ions in DMF solutions. The steady-state luminescence of the Tb3+ complexes has demonstrated more than one order higher thermal sensitivity for the complexes of bromo-substituted ligands in comparison with the non-substituted thiacalix[4]arenes. The reasons for such behavior are discussed. The results highlight new opportunities for the thiacalix[4]arene platform for controlling ligand-to-metal energy transfer in terbium complexes and tuning their thermo-responsive luminescence properties.

Acid-Catalyzed Rearrangement of 3-Cyanoquinoxalin-2(1H)-ones When Exposed to 1,2-Diaminobenzenes: Synthesis of 2,2'-Bibenzimidazoles.

A novel and efficient protocol for the synthesis of diversely substituted 2,2'-bibenzimidazoles from the reaction of 3-cyanoquinoxalin-2(1H)-ones with 1,2-diaminobenzenes has been developed, which proceeds through sequential nucleophilic addition and electrophilic substitution followed by a Mamedov rearrangement. The synthetic utility of this strategy was illustrated by the concise, one-pot synthesis of 5,5'-bi(2,2'-bibenzimidazoles) and aza-analogues of 2,2'-bibenzimidazole.

N-Methyl-d-glucamine-Calix[4]resorcinarene Conjugates: Self-Assembly and Biological Properties.

Deep insight of the toxicity of supramolecular systems based on macrocycles is of fundamental interest because of their importance in biomedical applications. What seems to be most interesting in this perspective is the development of the macrocyclic compounds with biocompatible fragments. Here, calix[4]resorcinarene derivatives containing N-methyl- d-glucamine moieties at the upper rim and different chemical groups at the lower rim were synthesized and investigated. These macrocycles showed a tendency to self-aggregate in aqueous solution, and their self-assembly abilities depend on the structure of the lower rim. The in vitro cytotoxic and antimicrobial activity of the calix[4]resorcinarenes revealed the relationship of biological properties with the ability to aggregate. Compared to macrocycles with methyl groups on the lower rim, calix[4]resorcinarenes with sulfonate groups appear to possess very similar antibacterial properties, but over six times less hemolytic activity. In some ways, this is the first example that reveals the dependence of the observed hemolytic and antibacterial activity on the lipophilicity of the calix[4]arene structure.

Structural and photophysical properties of Tb3+-tetra-1,3-diketonate complexes controlled by calix[4]arene-tetrathiacalix[4]arene scaffolds.

The present work highlights the key aspects of the influence of calix[4]arene and tetrathiacalix[4]arene scaffolds on the structural and photophysical properties of Tb3+ complexes with tetra-1,3-diketone derivatives of the macrocycles in DMF solutions. The equilibrium forms of Tb3+ complexes with unsubstituted and functionalized by acetylacetonyl groups at the upper rim of calix[4]arenes and thiacalix[4]arenes are revealed from UV-, NMR, MALDI TOF mass spectroscopy, quantum-chemical calculations at the DFT level and luminescence spectroscopy data. In alkaline DMF solutions, the ligands form predominantly 1 : 1 complexes with Tb3+ ions. However, the replacement of a calix[4]arene-scaffold by a thiacalix[4]arene-scaffold in the tetra-1,3-diketone derivatives shifts the equilibrium forms of Tb3+ complexes from monomeric to the dimeric ones. DFT calculations in combination with experimental data reveal the most reliable structures of complexes. The quantitative analysis of the photophysical parameters in correlation with the structural features of the complexes highlights the specific inner-sphere environment of Tb3+ ions in the dimeric complexes with the thiacalix[4]arene derivatives as a reason for greater sensitization of Tb3+-centered luminescence.

One-Pot Synthesis of 7-(Benzimidazol-2-yl)thioxolumazine and -lumazine Derivatives via H2SO4-Catalyzed Rearrangement of Quinoxalinones When Exposed to 5,6-Diamino-2-mercapto- and 2,5,6-Triaminopyrimidin-4-ols.

A facile approach to a range of substituted 7-(benzimidazol-2-yl)thioxolumazines [7-(benzimidazol-2-yl)-2-thioxo-2,3-dihydropteridin-4(1 H)-ones] and 7-(benzimidazol-2-yl)lumazines [7-(benzimidazol-2-yl)pteridine-2,4(1 H,3 H)-diones] is described. These new biheterocyclic systems are obtained via H2SO4-catalyzed rearrangement of quinoxalin-2-ones in the presence of 5,6-diamino-2-mercapto- and 2,5,6-triaminopyrimidin-4-ols. Thus, benzimidazole and pteridine rings are constructed in one synthetic step. A plausible ANRORC ( addition of nucleophile, ring opening and ring closure)-type reaction mechanism is proposed. Applying the rearrangement to the aza-analogue of 3-benzoylquinoxalin-2(1 H)-one-i.e., 3-benzoylpyrido[2,3- b]pyrazin-2(1 H)-one-with 5,6-diamino-2-mercaptopyrimidin-4-ol makes it possible to synthesize inaccessible 7-(1 H-imidazo[4,5- b]pyridin-2-yl)-6-phenyl-2-thioxo-2,3-dihydropteridin-4(1 H)-one. 7-(Benzimidazol-2-yl)-6-(2-fluorophenyl)-2-thioxo-2,3-dihydropteridin-4(1 H)-ones undergoes intramolecular nucleophilic substitution of fluorine by a nitrogen of the benzimidazole fragment with the formation of benzo[4',5']imidazo[1',2':1,2]quinolino[4,3- g]pteridine-2,4(1 H,3 H)-diones as new heterocyclic systems.