AcOH-Catalyzed Rearrangements of Benzo[e][1,4]diazepin-2(and 3)-ones: Easy Access to 1,4-Dihydroquinazolines and Their Condensed Analogues.

Presented herein is a novel synthesis of new 2-(quinolin-4-yl)-1,4-dihydroquinazoline systems 8, in which the acid-catalyzed rearrangement of spiro[benzo[e][1,4]diazepine-3,4'-quinolin]-2(1H)-ones generated in situ from 3-(2-aminophenyl)-5H-benzo[e][1,4]diazepin-2(1H)-ones 6 with acetone and alkylmethyl ketones has been realized as an important step. An attempt to synthesize isomeric 2-(2-aminophenyl)-5H-benzo[e][1,4]diazepin-3(4H)-one 6'a by hydrolysis of the corresponding N-{2-[5H-benzo[e][1,4]diazepin-3(4H)-on-2-yl]phenyl}acetamide 5'a led to a new heterocyclic system, 6-methyl-8,13-dihydro-13aH-quinazolino[4,3-b]quinazolin-5-ium 13a-carboxylate 14, as a result of an unexpected rearrangement. In addition, it is noteworthy that during the hydrolysis of N-{2-[5H-benzo[e][1,4]diazepin-2(1H)-on-3-yl]phenyl}acetamides 5, the not previously described 14-dihydro-5H-14,5a-(epimino[1,2]benzo)benzo[5,6][1,4]diazepin[2,1-b]quinazolin-6(7H)-ones 7 were unexpectedly obtained.

Discovery of Di(het)arylmethane and Dibenzoxanthene Derivatives as Potential Anticancer Agents.

A family of bifunctional dihetarylmethanes and dibenzoxanthenes is assembled via a reaction of acetals containing a 2-chloroacetamide moiety with phenols and related oxygen-containing heterocycles. These compounds demonstrated selective antitumor activity associated with the induction of cell apoptosis and inhibition of the process of glycolysis. In particular, bis(heteroaryl)methane containing two 4-hydroxy-6-methyl-2H-pyran-2-one moieties combine excellent in vitro antitumor efficacy with an IC50 of 1.7 µM in HuTu-80 human duodenal adenocarcinoma models with a high selectivity index of 73. Overall, this work highlights the therapeutic potential of dimeric compounds assembled from functionalized acetals and builds a starting point for the development of a new family of anticancer agents.

α-Umpolung/Michael Addition/Quaternization Tandem Reaction to provide α-Imido-ß-phosphonium Propanoates with Broad Spectrum of Biological Activity.

This paper has been supported by the Kazan Federal University Strategic Academic Leadership Program ('PRIORITY-2030'). HRMS data were obtained in the CSF-SAC FRC KSC RAS by support of the State Assignment of the Federal Research Center "Kazan Scientific Center", Russian Academy of Sciences. A.D.V, conducted studies of anticancer activity with financial support form the government assignment for FRC Kazan Scientific Center of RAS.

Towards Antibacterial Agents: Synthesis and Biological Activity of Multivalent Amide Derivatives of Thiacalix[4]arene with Hydroxyl and Amine Groups.

Antimicrobial resistance to modern antibiotics stimulates the search for new ways to synthesize and modify antimicrobial drugs. The development of synthetic approaches that can easily change different fragments of the molecule is a promising solution to this problem. In this work, a synthetic approach was developed to obtain multivalent thiacalix[4]arene derivatives containing different number of amine and hydroxyl groups. A series of macrocyclic compounds in cone, partial cone, and 1,3-alternate stereoisomeric forms containing -NHCH2CH2R (R = NH2, N(CH3)2, and OH) and -N(CH2CH2OH)2 terminal fragments, and their model non-macrocyclic analogues were obtained. The antibacterial activity against Gram-positive (Staphylococcus aureus, Bacillus cereus, and Enterococcus faecalis) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacterial strains and cytotoxicity of the obtained compounds were studied. Structure-activity relationships were established: (1) the macrocyclic compounds had high antibacterial activity, while the monomeric compounds had low activity; (2) the compounds in cone and partial cone conformations had better antibacterial activity compared to the compounds in 1,3-alternate stereoisomeric form; (3) the macrocyclic compounds containing -NHCH2CH2N(CH3)2 terminal fragments had the highest antibacterial activity; (4) introduction of additional terminal hydroxyl groups led to a significant decrease in antibacterial activity; (5) the compounds in partial cone conformation had significant bactericidal activity against all studied cell strains; the best selectivity was observed for the compounds in cone conformation. The mechanism of antibacterial activity of lead compounds with terminal fragments -NHCH2CH2N(CH3)2 was proved using model negatively charged POPG vesicles, i.e., the addition of these compounds led to an increase in the size and zeta potential of the vesicles. The obtained results open up the possibility of using the synthesized macrocyclic compounds as promising antibacterial agents.

Synthesis of D-π-A'-π-A Chromophores with Quinoxaline Core as Auxiliary Acceptor and Effect of Various Silicon-Substituted Donor Moieties on Thermal and Nonlinear Optical Properties at Molecular and Material Level.

Novel D-π-A'-π-A chromophores with quinoxaline cores as auxiliary acceptors and various donor moieties (aniline, carbazole, phenothiazine, tetrahydroquinoline) containing bulky tert-butyldimethylsilyloxy (TBDMSO) groups and tricyanofuranyl (TCF) acceptors with bulky cyclohexylphenyl substituents were synthesized via eight- to nine-step procedures, and their photo-physical and thermal properties were investigated. The values of the chromophores' first hyperpolarizabilities were calculated in the framework of DFT at the M06-2X/aug-cc-pVDZ computational level; the effect of the introduction of the TBDMSO group into the donor fragment is shown to be inessential, as this group is not coupled to the π-conjugated system of the chromophore. The chromophore with the tetrahydroquinoline donor has a first hyperpolarizability value of 937 × 10-30 esu, which is the highest for the studied chromophores. Atomistic modeling of composite materials with the studied chromophores as guests demonstrated that the presence of bulky substituent in the donor fragment prevents notable aggregation of chromophores, even at high chromophore content (40 wt.%). The nonlinear optical performance of guest-host materials with 25 and 40 wt.% of suggested chromophore content was studied using a second harmonic generation technique to give the NLO coefficient, d33 up to 52 pm/V.

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.

Switching Ion Binding Selectivity of Thiacalix[4]arene Monocrowns at Liquid-Liquid and 2D-Confined Interfaces.

Understanding the interaction of ions with organic receptors in confined space is of fundamental importance and could advance nanoelectronics and sensor design. In this work, metal ion complexation of conformationally varied thiacalix[4]monocrowns bearing lower-rim hydroxy (type I), dodecyloxy (type II), or methoxy (type III) fragments was evaluated. At the liquid-liquid interface, alkylated thiacalixcrowns-5(6) selectively extract alkali metal ions according to the induced-fit concept, whereas crown-4 receptors were ineffective due to distortion of the crown-ether cavity, as predicted by quantum-chemical calculations. In type-I ligands, alkali-metal ion extraction by the solvent-accessible crown-ether cavity was prevented, which resulted in competitive Ag+ extraction by sulfide bridges. Surprisingly, amphiphilic type-I/II conjugates moderately extracted other metal ions, which was attributed to calixarene aggregation in salt aqueous phase and supported by dynamic light scattering measurements. Cation-monolayer interactions at the air-water interface were monitored by surface pressure/potential measurements and UV/visible reflection-absorption spectroscopy. Topology-varied selectivity was evidenced, towards Sr2+ (crown-4), K+ (crown-5), and Ag+ (crown-6) in type-I receptors and Na+ (crown-4), Ca2+ (crown-5), and Cs+ (crown-6) in type-II receptors. Nuclear magnetic resonance and electronic absorption spectroscopy revealed exocyclic coordination in type-I ligands and cation-π interactions in type-II ligands.

Thermally Stable Nitrothiacalixarene Chromophores: Conformational Study and Aggregation Behavior.

Achieving high thermal stability and control of supramolecular organization of functional dyes in sensors and nonlinear optics remains a demanding task. This study was aimed at the evaluation of thermal behavior and Langmuir monolayer characteristics of topologically varied nitrothiacalixarene multichromophores and phenol monomers. A nitration/azo coupling alkylation synthetic route towards partially O-substituted nitrothiacalixarenes and 4-nitrophenylazo-thiacalixarenes was proposed and realized. Nuclear magnetic resonance (NMR) spectroscopy and X-ray diffractometry of disubstituted nitrothiacalix[4]arene revealed a rare 1,2-alternate conformation. A synchronous thermal analysis indicated higher decomposition temperatures of nitrothiacalixarene macrocycles as compared with monomers. Through surface pressure/potential-molecular area measurements, nitrothiacalixarenes were shown to form Langmuir monolayers at the air-water interface and, through atomic force microscopy (AFM) technique, Langmuir-Blodgett (LB) films on solid substrates. Reflection-absorption spectroscopy of monolayers and electronic absorption spectroscopy of LB films of nitrothiacalixarenes recorded a red-shifted band (290 nm) with a transition from chloroform, indicative of solvatochromism. Additionally, shoulder band at 360 nm was attributed to aggregation and supported by gas-phase density functional theory (DFT) calculations and dynamic light scattering (DLS) analysis in chloroform-methanol solvent in the case of monoalkylated calixarene 3. Excellent thermal stability and monolayer formation of nitrothiacalixarenes suggest their potential as functional dyes.