Conjugates of amiridine and thiouracil derivatives as effective inhibitors of butyrylcholinesterase with the potential to block ß-amyloid aggregation.

New amiridine-thiouracil conjugates with different substituents in the pyrimidine fragment (R = CH3 , CF2 Н, CF3 , (CF2 )2 H) and different spacer lengths (n = 1-3) were synthesized. The conjugates rather weakly inhibit acetylcholinesterase (AChE) and exhibit high inhibitory activity (IC50 up to 0.752 ± 0.021 µM) and selectivity to butyrylcholinesterase (BChE), which increases with spacer elongation; the lead compounds are 11c, 12c, and 13c. The conjugates are mixed-type reversible inhibitors of both cholinesterases and practically do not inhibit the structurally related off-target enzyme carboxylesterase. The results of molecular docking to AChE and BChE are consistent with the experiment on enzyme inhibition and explain the structure-activity relationships, including the rather low anti-AChE activity and the high anti-BChE activity of long-chain conjugates. The lead compounds displace propidium from the AChE peripheral anion site (PAS) at the level of the reference compound donepezil, which agrees with the mixed-type mechanism of AChE inhibition and the main mode of binding of conjugates in the active site of AChE due to the interaction of the pyrimidine moiety with the PAS. This indicates the ability of the studied conjugates to block AChE-induced aggregation of ß-amyloid, thereby exerting a disease-modifying effect. According to computer calculations, all synthesized conjugates have an ADME profile acceptable for drugs.

Iodine-Catalyzed Radical C-H Amination of Nonaromatic Imidazole Oxides: Access to Cyclic α-Aminonitrones.

A straightforward cross-dehydrogenative coupling approach to incorporate alicyclic amino residues into the structure of model cyclic aldonitrones, 2H-imidazole oxides, is reported. The elaborated C(sp2)-H functionalization is achieved by employing cyclic amines in the presence of the I2-tert-butyl hydroperoxide (TBHP) reagent system. As a result, a series of 19 novel heterocyclic derivatives were obtained in yields of up to 97%. A mechanistic study involving electron paramagnetic resonance spectroscopic experiments allowed the radical nature of the reaction to be confirmed. In particular, the envisioned mechanistic rationale comprises N-iodination of a cyclic amine, followed by N-I bond homolysis of the resulting intermediate and subsequent amination of the nitrone moiety via the newly generated nitrogen-centered radical.

Novel Substituted Azoloazines with Anticoagulant Activity.

Hypercytokinemia, or cytokine storm, often complicates the treatment of viral and bacterial infections, including COVID-19, leading to the risk of thrombosis. However, the use of currently available direct anticoagulants for the treatment of COVID-19 patients is limited due to safety reasons. Therefore, the development of new anticoagulants remains an urgent task for organic and medicinal chemistry. At the same time, new drugs that combine anticoagulant properties with antiviral or antidiabetic activity could be helpfull in the treatment of COVID-19 patients, especially those suffering from such concomitant diseases as arterial hypertension or diabetes. We have synthesized a number of novel substituted azoloazines, some of which have previously been identified as compounds with pronounced antiviral, antibacterial, antidiabetic, antiaggregant, and anticoagulant activity. Two compounds from the family of 1,2,4-triazolo[1,5-a]pyrimidines have demonstrated anticoagulant activity at a level exceeding or at least comparable with that of dabigatran etexilate as the reference compound. 7,5-Di(2-thienyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine has shown the highest ability to prolong the thrombin time, surpassing this reference drug by 2.2 times. This compound has also exhibited anticoagulant activity associated with the inhibition of thrombin (factor IIa). Moreover, the anticoagulant effect of this substance becomes enhanced under the conditions of a systemic inflammatory reaction.

Synthesis and Assessment of Antiplatelet and Antithrombotic Activity of 4-Amino-Substituted 5-Oxoproline Amides and Peptides.

Venous thromboembolism is a serious problem because it significantly increases the risk of developing vascular complications in elderly patients with obesity or immobilization, cancer, and many other diseases. Thus, there is a need to study new therapeutic strategies, including new medicinal agents for the efficient and safe correction of thrombus disorders. In this work, we have synthesized a number of new amides and peptides of 4-amino-5-oxoprolines and studied their antiplatelet and antithrombotic activity in experiments in vitro and in vivo. It has been found that the newly obtained compounds slow down the process of thrombus formation in a model of arterial and venous thrombosis, without affecting plasma hemostasis parameters. (2S,4S)-4-Amino-1-(4-fluorophenyl)-5-oxoprolyl-(S)-phenylalanine proved to be the most efficient among the studied derivatives. The results obtained indicate the advisability of further studies on 5-oxoproline derivatives in order to design pharmaceutical agents for the prevention and treatment of the consequences of thrombosis.

Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit ß-amyloid self-aggregation: potential therapeutic agents for Alzheimer's disease.

We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of ß-amyloid (Aß42) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC50 = 2.90 ± 0.23 µM and 3.22 ± 0.25 µM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC50 = 6.90 ± 0.55 µM), consistent with docking results. Dihydroacridines inhibited Aß42 self-aggregation; 1d and 1e were the most active (58.9% ± 4.7% and 46.9% ± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTS•+-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood-brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Aß42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations.

(1-(4-(5-Phenyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)-methylenyls α,ω-Bisfunctionalized 3- and 4-PEG: Synthesis and Photophysical Studies.

Two new azaheterocycle-based bolas, such as (1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)-methylenyls α,ω-bisfunctionalized PEGs, were prepared via Cu-catalyzed click reaction between 2-(4-azidophenyl)-5-(aryl)-oxadiazole-1,3,4 and terminal ethynyls derived from PEG-3 and PEG-4. Due to the presence of two heteroaromatic cores and a PEG linker, these bola molecules are considered as promising fluorescent chemosensors for electron-deficient species. As a result of a well-pronounced "turn-off" fluorescence response towards common nitro-explosive components, such as 2,4-dinitrotoluene (DNT) and 2,4,6-trinitrotoluene (TNT), hard-to-detect pentaerythritol tetranitrate (PETN), as well as Hg2+ cation was observed.

Polyaromatic Hydrocarbon (PAH)-Based Aza-POPOPs: Synthesis, Photophysical Studies, and Nitroanalyte Sensing Abilities.

1,4-Bis(5-phenyl-2-oxazolyl)benzene (POPOP) is a common scintillation fluorescent laser dye. In this manuscript, the synthesis of 2-Ar-5-(4-(4-Ar'-1H-1,2,3-triazol-1-yl)phenyl)-1,3,4-oxadiazoles (Ar, Ar' = Ph, naphtalenyl-2, pyrenyl-1, triphenilenyl-2), as PAH-based aza-analogues of POPOP, by means of Cu-catalyzed click reaction between 2-(4-azidophenyl)-5-Ar-1,3,4-oxadiazole and terminal ethynyl-substituted PAHs is reported. An investigation of the photophysical properties of the obtained products was carried out, and their sensory response to nitroanalytes was evaluated. In the case of pyrenyl-1-substituted aza-POPOP, dramatic fluorescence quenching by nitroanalytes was observed.

3-Aryl-5-aminobiphenyl Substituted [1,2,4]triazolo[4,3-c]quinazolines: Synthesis and Photophysical Properties.

Amino-[1,1']-biphenyl-containing 3-aryl-[1,2,4]triazolo[4,3-c]quinazoline derivatives with fluorescent properties have been designed and synthesized. The type of annelation of the triazole ring to the pyrimidine one has been unambiguously confirmed by means of an X-ray diffraction (XRD) method; the molecules are non-planar, and the aryl substituents form the pincer-like conformation. The UV/Vis and photoluminescent properties of target compounds were investigated in two solvents of different polarities and in a solid state. The samples emit a broad range of wavelengths and display fluorescent quantum yields of up to 94% in toluene solutions. 5-(4'-Diphenylamino-[1,1']-biphenyl-4-yl)-3-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-c]quinazoline exhibits the strongest emission in toluene and a solid state. Additionally, the solvatochromic properties were studied for the substituted [1,2,4]triazolo[4,3-c]quinazolines. Moreover, the changes in absorption and emission spectra have been demonstrated upon the addition of water to MeCN solutions, which confirms aggregate formation, and some samples were found to exhibit aggregation-induced emission enhancement. Further, the ability of triazoloquinazolines to detect trifluoroacetic acid has been analyzed; the presence of TFA induces changes in both absorption and emission spectra, and acidochromic behavvior was observed for some triazoloquinazoline compounds. Finally, electronic-structure calculations with the use of quantum-chemistry methods were performed for synthesized compounds.

Mesomeric Betaines Based on Adamantylated 1,2,4-Triazolo[4,3-a]pyrimidin-5-ones: Synthesis, Structure and Conversion into Anionic N-Heterocyclic Carbenes.

The C-N coupling of 1,2,4-triazolo[1,5-a]pyrimidin-7-ones with 1-adamantanol/1-bromoadamantane leads to 1,2,4-triazolo[4,3-a]pyrimidinium-5-olates, which are represented as mesomeric betaines (MBs). The formation of MBs involves not only N-alkylation of heterocyclic framework but also the rearrangement leading to a change in the type of fusion between pyrimidine and 1,2,4-triazole fragments. The structures of the obtained products were confirmed by the X-ray analysis and measurements of 13 C-13 C (JCC ) coupling constants in the 1D 13 C NMR spectra of selectively 13 C-labeled samples. Treatment of the betaines with lithium bis(trimethylsilyl)amide (LiHMDS) gave anionic carbenes, which were detected by 13 C NMR spectroscopy and were trapped by reactions with phenyl isothiocyanate and sulfur. Density functional theory (DFT) and the quantum theory of atoms in molecules (QTAIM) analyses allowed for an insight into the electronic structure of the obtained betaines and N-heterocyclic carbene derivatives.

Triazavirin-A Novel Effective Antiviral Drug.

This review outlines the data of numerous studies relating to the broad-spectrum antiviral drug Triazavirin that was launched on the Russian pharmaceutical market in 2014 as an anti-influenza drug (the international non-patented name is Riamilovir). The range of antiviral activity of Triazavirin has been significantly expanded during recent years; in particular, it has been shown that Triazavirin exhibits activity against tick-borne encephalitis, Rift Valley fever, West Nile fever, and other infections of viral etiology. This drug has been approved for treatment of influenza and acute respiratory infections by the Russian Ministry of Health on the basis of comprehensive clinical trials involving over 450 patients. Triazavirin was found to be a highly effective and well-tolerated drug, allowing its over-the-counter sale. The recently published data on the use of Triazavirin in clinical practice for the treatment of patients with COVID-19 are discussed, with special attention paid to potential biological targets for this drug.

Push-Pull Structures Based on 2-Aryl/thienyl Substituted Quinazolin-4(3H)-ones and 4-Cyanoquinazolines.

Design and synthesis of 2-(aryl/thiophen-2-yl)quinazolin-4(3H)-ones and 4-cyano-2-arylquinazolines with Et2N-, Ph2N- or carbazol-9-yl- electron donating fragment are described. The key photophysical properties of these compounds have been studied by UV/Vis absorption and fluorescence spectroscopy in solvents of different polarity (toluene and MeCN). 2-(Aryl/thiophen-2-yl)quinazolin-4(3H)-ones show fluorescence in blue-green region in toluene solution with quantum yields up to 89% in the case of 2-(4'-N,N-diphenylamino[1,1'-biphenyl]-4-yl)-quinazolin-4(3H)-one. Moreover, triphenylamino derivative based on quinazolin-4(3H)-one with para-phenylene linker displays the highest quantum yield of 40% in powder. The fluorescence QY of Et2N and Ph2N derivatives decrease when going from toluene to MeCN solution, whereas carbazol-9-yl counterparts demonstrate strengthening of intensity that emphasizes the strong influence of donor fragment nature on photophysical properties. 4-Cyanoquinazolines are less emissive in both solvents, as well as, in solid state. The introduction of cyano group into position 4 leads to orange/red colored powder and dual emission bands. Some molecules demonstrate the increase in emission intensity upon addition of water to MeCN solution. According to frontier molecular orbitals (HOMO, LUMO) calculations, the energy gap of 4-cyanoquinazoline decreases by more than 1 eV compared to quinazolin-4-one, that is consistent with experimental data.

Effect of the Silica-Magnetite Nanocomposite Coating Functionalization on the Doxorubicin Sorption/Desorption.

A series of new composite materials based on Fe3O4 magnetic nanoparticles coated with SiO2 (or aminated SiO2) were synthesized. It has been shown that the use of N-(phosphonomethyl)iminodiacetic acid (PMIDA) to stabilize nanoparticles before silanization ensures the increased content of a SiO2 phase in the Fe3O4@SiO2 nanocomposites (NCs) in comparison with materials obtained under similar conditions, but without PMIDA. It has been demonstrated for the first time that the presence of PMIDA on the surface of NCs increases the level of Dox loading due to specific binding, while surface modification with 3-aminopropylsilane, on the contrary, significantly reduces the sorption capacity of materials. These regularities were in accordance with the results of quantum chemical calculations. It has been shown that the energies of Dox binding to the functional groups of NCs are in good agreement with the experimental data on the Dox sorption on these NCs. The mechanisms of Dox binding to the surface of NCs were proposed: simultaneous coordination of Dox on the PMIDA molecule and silanol groups at the NC surface leads to a synergistic effect in Dox binding. The synthesized NCs exhibited pH-dependent Dox release, as well as dose-dependent cytotoxicity in in vitro experiments. The cytotoxic effects of the studied materials correspond to their calculated IC50 values. NCs with a SiO2 shell obtained using PMIDA exhibited the highest effect. At the same time, the presence of PMIDA in NCs makes it possible to increase the Dox loading, as well as to reduce its desorption rate, which may be useful in the design of drug delivery vehicles with a prolonged action. We believe that the data obtained can be further used to develop stimuli-responsive materials for targeted cancer chemotherapy.

4-(Aryl)-Benzo[4,5]imidazo[1,2-a]pyrimidine-3-Carbonitrile-Based Fluorophores: Povarov Reaction-Based Synthesis, Photophysical Studies, and DFT Calculations.

A series of novel 4-(aryl)-benzo[4,5]imidazo[1,2-a]pyrimidine-3-carbonitriles were obtained through the Povarov (aza-Diels-Alder) and oxidation reactions, starting from benzimidazole-2-arylimines. Based on the literature data and X-ray diffraction analysis, it was discovered that during the Povarov reaction, [1,3] sigmatropic rearrangement leading to dihydrobenzimidazo[1,2-a]pyrimidines took place. The structures of all the obtained compounds were confirmed based on the data from 1H- and 13C-NMR spectroscopy, IR spectroscopy, and elemental analysis. For all the obtained compounds, their photophysical properties were studied. In all the cases, a positive emission solvatochromism with Stokes shifts from 120 to 180 nm was recorded. Aggregation-Induced Emission (AIE) has been illustrated for compound 6c using different water fractions (fw) in THF. The compounds 6c and 6f demonstrated changes in emission maxima or/and intensities after mechanical stimulation.

Carborane-Containing Folic Acid bis-Amides: Synthesis and In Vitro Evaluation of Novel Promising Agents for Boron Delivery to Tumour Cells.

The design of highly selective low-toxic, low-molecular weight agents for boron delivery to tumour cells is of decisive importance for the development of boron neutron capture therapy (BNCT), a modern efficient combined method for cancer treatment. In this work, we developed a simple method for the preparation of new closo- and nido-carborane-containing folic acid bis-amides containing 18-20 boron atoms per molecule. Folic acid derivatives containing nido-carborane residues were characterised by high water solubility, low cytotoxicity, and demonstrated a good ability to deliver boron to tumour cells in in vitro experiments (up to 7.0 µg B/106 cells in the case of U87 MG human glioblastoma cells). The results obtained demonstrate the high potential of folic acid-nido-carborane conjugates as boron delivery agents to tumour cells for application in BNCT.

Random Copolymers of Styrene with Pendant Fluorophore Moieties: Synthesis and Applications as Fluorescence Sensors for Nitroaromatics.

Five random copolymers comprising styrene and styrene with pendant fluorophore moieties, namely pyrene, naphthalene, phenanthrene, and triphenylamine, in molar ratios of 10:1, were synthesized and employed as fluorescent sensors. Their photophysical properties were investigated using absorption and emission spectral analyses in dichloromethane solution and in solid state. All copolymers possessed relative quantum yields up to 0.3 in solution and absolute quantum yields up to 0.93 in solid state, depending on their fluorophore components. Fluorescence studies showed that the emission of these copolymers is highly sensitive towards various nitroaromatic compounds, both in solution and in the vapor phase. The detection limits of these fluorophores for nitroaromatic compounds in dichloromethane solution proved to be in the range of 10-6 to 10-7 mol/L. The sensor materials for new hand-made sniffers based on these fluorophores were prepared by electrospinning and applied for the reliable detection of nitrobenzene vapors at 1 ppm in less than 5 min.

Mechanism, Kinetics and Thermodynamics of Decomposition for High Energy Derivatives of [1,2,4]Triazolo[4,3-b][1,2,4,5]tetrazine.

This paper presents the data of research studies on the mechanisms, kinetics and thermodynamics of decomposition of three high-energy compounds: [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine-3,6-diamine (TTDA), 3-amino-6-hydrazino[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (TTGA) and 3,6-dinitroamino[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (DNTT). The points of change of the reaction mechanisms under thermal effects with different intensities from 0.1 to 2000 s-1 have been established. The values of activation and induction energies for the limiting stages of decomposition have been obtained. The formation of nanostructured carbon nitride (α-C3N4) in condensed decomposition products, cyanogen (C2N2) and hydrogen cyanide (HCN) in gaseous products have been shown. Concentration-energy diagrams for the reaction products have been compiled. The parameters of heat resistance and thermal safety proved to be: 349.5 °C and 358.2 °C for TTDA; 190.3 °C and 198.0 °C for TTGA; 113.4 °C and 114.1 °C for DNTT. The energy and thermodynamic properties have also been estimated. This work found the activation energy of the decomposition process to be 129.0 kJ/mol for TTDA, 212.2 kJ/mol for TTGA and 292.2 kJ/mol for DNTT. The average induction energy of the catalytic process (Ecat) for TTGA was established to be 21 kJ/mol, and for DNTT-1500-1700 kJ/mol. The induction energy of the inhibition process (Eing) of TTDA was estimated to be 800-1400 kJ/mol.

Folic Acid Antimetabolites (Antifolates): A Brief Review on Synthetic Strategies and Application Opportunities.

Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common methods and approaches are presented for the synthesis of therapeutically significant antimetabolites of folic acid, which are Methotrexate (MTX), Raltitrexed (Tomudex, ZD1694), Pralatrexate, Pemetrexed, TNP-351, and Lometrexol. In addition, the applications or uses of these folic acid antimetabolites are also discussed.

Magnetic-Responsive Doxorubicin-Containing Materials Based on Fe3O4 Nanoparticles with a SiO2/PEG Shell and Study of Their Effects on Cancer Cell Lines.

Novel nanocomposite materials based on Fe3O4 magnetic nanoparticles (MNPs) coated with silica and covalently modified by [(3-triethoxysilyl)propyl]succinic acid-polyethylene glycol (PEG 3000) conjugate, which provides a high level of doxorubicin (Dox) loading, were obtained. The efficiency of Dox desorption from the surface of nanomaterials under the action of an alternating magnetic field (AMF) in acidic and neutral media was evaluated. Their high cytotoxicity against tumor cells, as well as the drug release upon application of AMF, which leads to an increase in the cytotoxic effect, was demonstrated.

Synthesis of Pyrimidine Conjugates with 4-(6-Amino-hexanoyl)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and Evaluation of Their Antiviral Activity.

A series of pyrimidine conjugates containing a fragment of racemic 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and its (S)-enantiomer attached via a 6-aminohexanoyl fragment were synthesized by the reaction of nucleophilic substitution of chlorine in various chloropyrimidines. The structures of the synthesized compounds were confirmed by 1H, 19F, and 13C NMR spectral data. Enantiomeric purity of optically active derivatives was confirmed by chiral HPLC. Antiviral evaluation of the synthesized compounds has shown that the replacement of purine with a pyrimidine fragment leads to a decrease in the anti-herpesvirus activity compared to the lead compound, purine conjugate. The studied compounds did not exhibit significant activity against influenza A (H1N1) virus.

Push-Pull Derivatives Based on 2,4'-Biphenylene Linker with Quinoxaline, [1,2,5]Oxadiazolo[3,4-B]Pyrazine and [1,2,5]Thiadiazolo[3,4-B]Pyrazine Electron Withdrawing Parts.

A series of novel V-shaped quinoxaline, [1,2,5]oxadiazolo[3,4-b]pyrazine and [1,2,5]thiadiazolo[3,4-b]pyrazine push-pull derivatives with 2,4'-biphenylene linker were designed and their electrochemical, photophysical and nonlinear optical properties were investigated. [1,2,5]Oxadiazolo[3,4-b]pyrazine is the stronger electron-withdrawing fragment as shown by electrochemical, and photophysical data. All compounds are emissive in a solid-state (from the cyan to red region of the spectrum) and quinoxaline derivatives are emissions in DCM solution. It has been found that quinoxaline derivatives demonstrate important solvatochromism and extra-large Stokes shifts, characteristic of twisted intramolecular charge transfer excited state as well as aggregation induced emission. The experimental conclusions have been justified by theoretical (TD-)DFT calculations.