From a humorous post to a detailed quantum-chemical study: isocyanate synthesis revisited.

Isocyanates play an essential role in modern manufacturing processes, especially in polyurethane production. There are numerous synthesis strategies for isocyanates both under industrial and laboratory conditions, which do not prevent searching for alternative highly efficient synthetic protocols. Here, we report a detailed theoretical investigation of the mechanism of sulfur dioxide-catalyzed rearrangement of phenylnitrile oxide into phenyl isocyanate, which was first reported in 1977. The DLPNO-CCSD(T) method and up-to-date DFT protocols were used to perform a highly accurate quantum-chemical study of the rearrangement mechanism. An overview of various organic and inorganic catalysts has revealed other potential catalysts, such as sulfur trioxide and selenium dioxide. Furthermore, the present study elucidated how substituents in phenylnitrile oxide influence reaction kinetics. This study was performed by a self-organized collaboration of scientists initiated by a humorous post on the VK social network.

6-Amino-4-aryl-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides: Synthesis, Biological Activity, Quantum Chemical Studies and In Silico Docking Studies.

New [1,2]dithiolo[3,4-b]pyridine-5-carboxamides were synthesized through the reaction of dithiomalondianilide (N,N'-diphenyldithiomalondiamide) with 3-aryl-2-cyanoacrylamides or via a three-component reaction involving aromatic aldehydes, cyanoacetamide and dithiomalondianilide in the presence of morpholine. The structure of 6-amino-4-(2,4-dichloro- phenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamide was confirmed using X-ray crystallography. To understand the reaction mechanism in detail, density functional theory (DFT) calculations were performed with a Grimme B97-3c composite computational scheme. The results revealed that the rate-limiting step is a cyclization process leading to the closure of the 1,4-dihydropyridine ring, with an activation barrier of 28.8 kcal/mol. Some of the dithiolo[3,4-b]pyridines exhibited moderate herbicide safening effects against 2,4-D. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) parameters were calculated and molecular docking studies were performed to identify potential protein targets.

Cyanoacetohydrazide as a Novel Derivatization Agent for the Determination of UHPLC-HRMS Steroids in Urine.

The possibility of cyanoacetohydrazide usage as a novel derivatizing agent is demonstrated in the presented article, and a comparison with hydroxylamine as the most commonly used reagent is provided. Optimal conditions for steroid derivatization with cyanoacetohydrazide are provided. According to the collected data, the maximum yield of derivatives was observed at pH 2.8 within 70 min at 40 °C with 5 ng/mL limit of detection for all investigated analytes. It was shown that cyanoacetohydrazide derivatives produces both syn- and anti-forms as well as hydroxylamine, and their ratios were evaluated and shown in presented work. An efficiency enchantment from two to up to five times was achieved with a novel derivatization reagent. Its applicability for qualitative analysis of steroids in urine was presented at real samples. Additionally, the reproducible fragmentation of the derivatizing agent in collision-induced dissociation offers opportunities for simplified non-targeted steroidomic screening. Furthermore, cyanoacetohydrazide increases ionization efficiency in positive mode, which can eliminate the need for redundant high-resolution instrument runs required for both positive and negative mode analyses.

Study of the Magnesium Comenate Structure, Its Neuroprotective and Stress-Protective Activity.

The crystal structure and the biological activity of a new coordination compound of magnesium ions with comenic acid, magnesium comenate, was characterized and studied. Quantitative and qualitative analysis of the compound was investigated in detail using elemental X-ray fluorescent analysis, thermal analysis, IR-Fourier spectrometry, UV spectroscopy, NMR spectroscopy, and X-ray diffraction analysis. Based on experimental analytical data, the empirical formula of magnesium comenate [Mg(HCom)2(H2O)6]·2H2O was established. This complex compound crystallizes with eight water molecules, six of which are the hydration shell of the Mg2+ cation, and two more molecules bind the [Mg(H2O)6]2+ aquacation with ionized ligand molecules by intermolecular hydrogen bonds. The packing of molecules in the crystal lattice is stabilized by a branched system of hydrogen bonds with the participation of solvate water molecules and oxygen atoms of various functional groups of ionized ligand molecules. With regard to the biological activity of magnesium comenate, a neuroprotective, stress-protective, and antioxidant effect was established in in vitro and in vivo models. In in vitro experiments, magnesium comenate protected cerebellar neurons from the toxic effects of glutamate and contributed to the preservation of neurite growth parameters under oxidative stress caused by hydrogen peroxide. In animal studies, magnesium comenate had a stress-protective and antioxidant effect in models of immobilization-cold stress. Oral administration of magnesium comenate at a dose of 2 mg/kg of animal body weight for 3 days before stress exposure and for 3 days during the stress period led to a decrease in oxidative damage and normalization of the antioxidant system of brain tissues against the background of induced stress. The obtained results indicate the advisability of further studies of magnesium comenate as a compound potentially applicable in medicine for the pharmacological correction of conditions associated with oxidative and excitotoxic damage to nerve cells.

Structure and Neuroprotector Properties of a Complex Compound of Lithium with Comenic Acid.

The structure, antioxidant and neuroprotective properties of lithium comenate (lithium 5-hydroxy-4-oxo-4H-pyran-2-carboxylate) were studied. Lithium comenate was obtained by reacting comenic acid (H2Com) with lithium hydroxide in an aqueous solution. The structure of lithium comenate was confirmed via thermal analysis, mass spectrometry, IR, NMR and UV spectroscopy. The crystal structure was studied in detail via X-ray diffraction. The compound crystallized in a non-centrosymmetric space group of symmetry of the orthorhombic system Pna21 in the form of a hydrate, with three water molecules entering the first coordination sphere of the cation Li+ and one molecule forming a second environment through non-valent contacts. The gross formula of the complex compound was established [Li(HCom)(H2O)3]·H2O. It has been established that lithium comenate has a pronounced neuroprotective activity under the excitotoxic effect of glutamate, increasing the survival rate of cultured rat cerebellar neurons more than two-fold. It has also been found that the pre-stress use of lithium comenate at doses of 1 and 2 mg/kg has an antioxidant effect, which is manifested in a decrease in oxidative damage to the brain tissues of mice subjected to immobilization stress. Based on the data available in the literature, we believe that the high neuroprotective and antioxidant efficacy of lithium comenate is a consequence of the mutual potentiation of the pharmacological effects of lithium and comenic acid.

Phthalylglycyl Chloride as a Derivatization Agent for UHPLC-MS/MS Determination of Adrenaline, Dopamine and Octopamine in Urine.

Dopamine, adrenaline and octopamine are small polar molecules that play a vital role in regulatory systems. In this paper, phthalylglycyl chloride was proposed as a derivatization agent for octopamine, adrenaline and dopamine determination in urine for the first time. The derivatization procedure facilitated the use of reversed-phase liquid chromatography with positive electrospray ionization-high-resolution mass spectrometry. An LC-HRMS method was developed that provided quantification limits of 5 ng/mL and detection limits of 1.5 ng/mL for all analytes. The 95-97% yield of derivates was observed after a 10 min derivatization with phthalylglycyl chloride at pH 6.5 and 30 °C. The proposed method was successfully applied to the analysis of human urine samples. The obtained results were compared with those of conventional derivatization procedures with 9-fluorenyl-methoxycarbonyl chloride and dansyl chloride.

New 6'-Amino-5'-cyano-2-oxo-1,2-dihydro-1'H-spiro[indole-3,4'-pyridine]-3'-carboxamides: Synthesis, Reactions, Molecular Docking Studies and Biological Activity.

The purpose of this work was to prepare new isatin- and monothiomalondiamide-based indole derivatives, as well as to study the properties of the new compounds. The four-component reaction of 5-R-isatins (R = H, CH3), malononitrile, monothiomalonamide (3-amino-3-thioxo- propanamide) and triethylamine in hot EtOH yields a mixture of isomeric triethylammonium 6'-amino-3'-(aminocarbonyl)-5'-cyano-2-oxo-1,2-dihydro-1'H- and 6'-amino-3'-(aminocarbonyl)- 5'-cyano-2-oxo-1,2-dihydro-3'H-spiro[indole-3,4'-pyridine]-2'-thiolates. The reactivity and structure of the products was studied. We found that oxidation of spiro[indole-3,4'-pyridine]-2'-thiolates with DMSO-HCl system produced only acidification products, diastereomeric 6'-amino-5'-cyano-5-methyl-2-oxo-2'-thioxo-1,2,2',3'-tetrahydro-1'H-spiro-[indole-3,4'-pyridine]- 3'-carboxamides, instead of the expected isothiazolopyridines. The alkylation of the prepared spiro[indole-3,4'-pyridine]-2'-thiolates upon treatment with N-aryl α-chloroacetamides and α-bromoacetophenones proceeds in a regioselective way at the sulfur atom. In the case of α-bromoacetophenones, ring-chain tautomerism was observed for the S-alkylation products. According to NMR data, the compounds consist of a mixture of stereoisomers of 2'-amino-6'-[(2-aryl-2-oxoethyl)thio]-3'-cyano-2-oxo-1'H-spiro[indoline-3,4'-pyridine]-5'-carboxamides and 5'-amino-3'-aryl-6'-cyano-3'-hydroxy-2-oxo-2',3'-dihydrospiro[indoline-3,7'-thiazolo[3,2-a]pyridine]-8'-carboxamides in various ratios. The structure of the synthesized compounds was confirmed by IR spectroscopy, HRMS, 1H and 13C DEPTQ NMR studies and the results of 2D NMR experiments (1H-13C HSQC, 1H-13C HMBC). Molecular docking studies were performed to investigate suitable binding modes of some new compounds with respect to the transcriptional regulator protein PqsR of Pseudomonas aeruginosa. The docking studies revealed that the compounds have affinity for the bacterial regulator protein PqsR of Pseudomonas aeruginosa with a binding energy in the range of -5.8 to -8.2 kcal/mol. In addition, one of the new compounds, 2'-amino-3'-cyano-5-methyl-2-oxo-6'-{[2-oxo-2-(p-tolylamino)ethyl]thio}-1'H-spiro-[indoline-3,4'-pyridine]-5'-carboxamide, showed in vitro moderate antibacterial effect against Pseudomonas aeruginosa and good antioxidant properties in a test with 1,1-diphenyl-2-picrylhydrazyl radical. Finally, three of the new compounds were recognized as moderately active herbicide safeners with respect to herbicide 2,4-D in the laboratory experiments on sunflower seedlings.

Alkyl 4-Aryl-6-amino-7- phenyl-3-(phenylimino)-4,7-dihydro- 3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxylates: Synthesis and Agrochemical Studies.

The reaction between dithiomalondianilide (N,N'-diphenyldithiomalondiamide) and alkyl 3-aryl-2-cyanoacrylates in the presence of morpholine in the air atmosphere leads to the formation of alkyl 6-amino-4-aryl-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]- pyridine-5-carboxylates in 37-72% yields. The same compounds were prepared in 23-65% yields by ternary condensation of aromatic aldehydes, ethyl(methyl) cyanoacetate and dithiomalondianilide. The reaction mechanism is discussed. The structure of ethyl 6-amino-4-(4-methoxyphenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxylate was confirmed by X-ray crystallography. Two of the prepared compounds showed a moderate growth-stimulating effect on sunflower seedlings. Three of the new compounds were recognized as strong herbicide safeners with respect to herbicide 2,4-D in the laboratory and field experiments on sunflower.

The Reactions of N,N'-Diphenyldithiomalondiamide with Arylmethylidene Meldrum's Acids.

The Michael addition reaction between dithiomalondianilide (N,N'-diphenyldithiomalondiamide) and arylmethylidene Meldrum's acids, accompanied by subsequent heterocyclization, was investigated along with factors affecting the mixture composition of the obtained products. The plausible mechanism includes the formation of stable Michael adducts which, under the studied conditions, undergo further transformations to yield corresponding N-methylmorpholinium 4-aryl-6-oxo-3-(N-phenylthio-carbamoyl)-1,4,5,6-tetrahydropyridin-2-thiolates and their oxidation derivatives, 4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-ones. The structure of one such product, N-methylmorpholinium 2,2-dimethyl-5-(1-(2-nitrophenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate, was confirmed via X-ray crystallography.

Probing chemical space of tick-borne encephalitis virus reproduction inhibitors with organoselenium compounds.

Tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, is the leading cause of arboviral neuroinfections in Europe. Only a few classes of the nucleoside and non-nucleoside inhibitors were investigated against TBEV reproduction. Paving the way to previously unexplored areas of anti-TBEV chemical space, we assessed the inhibition of TBEV reproduction in the plaque reduction assay by various compounds derived from cyanothioacetamide and cyanoselenoacetamide. Compounds from seven classes, including 4-(alkylthio)-2-aryl-3-azaspiro[5.5]undec-4-ene-1,1,5-tricarbonitriles, 3-arylamino-2-(selenazol-2-yl)acrylonitriles, ethyl 6-(alkylseleno)-5-cyano-2-oxo-1,2-dihydropyridine-3-carboxylates, 6-(alkylseleno)-2-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles, 2-(alkylseleno)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitriles, 8-selenoxo-3,5,7,11-tetraazatricyclo[7.3.1.02,7 ]tridec-2-ene-1,9-dicarbonitriles, and selenolo[2,3-b]quinolines, inhibited TBEV reproduction with EC50 values in the micromolar range while showing moderate cytotoxicity and no inhibition of enterovirus reproduction. Thus, new scaffolds with promising anti-TBEV activity were found.

Recognition capabilities of a Hopfield model with auxiliary hidden neurons.

We study the recognition capabilities of the Hopfield model with auxiliary hidden layers, which emerge naturally upon a Hubbard-Stratonovich transformation. We show that the recognition capabilities of such a model at zero temperature outperform those of the original Hopfield model, due to a substantial increase of the storage capacity and the lack of a naturally defined basin of attraction. The modified model does not fall abruptly into the regime of complete confusion when memory load exceeds a sharp threshold. This latter circumstance, together with an increase of the storage capacity, renders such a modified Hopfield model a promising candidate for further research, with possible diverse applications.

2-Amino-4,5-dihydrothiophene-3-carbonitriles: A New Synthesis, Quantum Chemical Studies, and Mannich-Type Reactions Leading to New Hexahydrothieno[2,3-d]pyrimidines.

trans-2-Amino-4-aryl-5-benzoyl-4,5-dihydrothiophene-3-carbonitriles were prepared either by the reaction of 3-aryl-2-cyanothioacrylamides with α-thiocyanatoacetophenone or by the Michael-type addition of cyanothioacetamide to α-bromochalcones followed by intramolecular cyclization. The mechanism of the first reaction was studied using high-level quantum chemical calculations. Density functional theory (DFT) studies were carried out to determine the mechanism of the first reaction. A new approach toward the construction of the thieno[2,3-d]pyrimidine core system was demonstrated by the reaction of the prepared dihydrothiophenes with HCHO and RNH2 under noncatalyzed Mannich conditions.

Unusual Oxidative Dimerization in the 3-Aminothieno[2,3-b]pyridine-2-carboxamide Series.

Noncatalyzed, regio- and stereoselective hypochlorite oxidation of 3-aminothieno[2,3-b]pyridine-2-carboxamides is presented. Unexpectedly, the oxidation proceeded by different mechanistic pathways, and different products were formed, depending on the nature of solvents used. A possible mechanism, the structure of products, kinetics and dynamics of intramolecular processes, and biological activity of products are discussed.

A chemical placebo: NaCl as an effective, cheapest, non-acidic and greener catalyst for Biginelli-type 3,4-dihydropyrimidin-2(1H)-ones (-thiones) synthesis.

Despite prior reports of several really effective catalytic and non-catalytic approaches towards Biginelli's 3,4-dihydropyrimidin-2(1H)-ones, an overwhelming number of new catalysts for the Biginelli reaction have been recently published. Most of the catalysts are somewhat exotic, expensive, harmful and even uneffective in the absence of acidic additives. Herein we reduce the "yet-another-one-catalyst" idea to absurdity by proposing NaCl promotes the reaction that actually requires no catalyst, neither rare nor expensive.

Self-averaging in the random two-dimensional Ising ferromagnet.

We study sample-to-sample fluctuations in a critical two-dimensional Ising model with quenched random ferromagnetic couplings. Using replica calculations in the renormalization group framework we derive explicit expressions for the probability distribution function of the critical internal energy and for the specific heat fluctuations. It is shown that the disorder distribution of internal energies is Gaussian, and the typical sample-to-sample fluctuations as well as the average value scale with the system size L like ∼Llnln(L). In contrast, the specific heat is shown to be self-averaging with a distribution function that tends to a δ peak in the thermodynamic limit L→∞. While previously a lack of self-averaging was found for the free energy, we here obtain results for quantities that are directly measurable in simulations, and implications for measurements in the actual lattice system are discussed.

2,2,2-Trifluoroethyl-thiadiazines: a patent evaluation of WO2016023927.

The Alzheimer's disease (AD) is acknowledged as the most common type of dementia in aging adults. It is characterized by the formation of intracellular neurofibrillary tangles and extracellular amyloid plaques. The latter insoluble deposits mainly consist of ß-amyloid peptides (Aß), which are the derivatives of the amyloid precursor protein (APP). The formation of neurotoxic Aß-peptides involves the cleavage of APP with beta-secretase enzyme (beta-site APP cleaving enzyme 1, BACE1) so the potential of BACE1 inhibitors as therapeutic agents for AD is now drawing much attention. The patent application WO2016023927 reports the preparation of new 1,2,4-thiadiazine inhibitors of BACE1 activity and their use as therapeutically active substances. Some of the new compounds are claimed to be good inhibitors with the IC50 values in the 0.000292-0.134165 µM range. Several pharmaceutical preparations based on these compounds are proposed for possible treatment and prevention of AD. Expert opinion: In light of the novelty from the chemical point of view and improved biological activity, the reported 2,2,2-trifluoroethylthiadiazines could be considered as promising BACE1 inhibitors. However, the available data are insufficient to make a recommendation if these compounds can be considered as drug candidates. Further studies with a larger number of compounds are required. The compounds described in the patent have to be characterized more thoroughly from the chemical viewpoint (e.g., by means of IR, 1H and 13C NMR spectroscopy, X-ray crystallography), especially as regards stereochemical details.

Universal free-energy distribution in the critical point of a random Ising ferromagnet.

We discuss the non-self-averaging phenomena in the critical point of weakly disordered Ising ferromagnet. In terms of the renormalized replica Ginzburg-Landau Hamiltonian in dimensions D<4, we derive an explicit expression for the probability distribution function (PDF) of the critical free-energy fluctuations. In particular, using known fixed-point values for the renormalized coupling parameters, we obtain the universal curve for such PDF in the dimension D=3. It is demonstrated that this function is strongly asymmetric: its left tail is much slower than the right one.

Design and synthesis of pyrido[2,1-b][1,3,5]thiadiazine library via uncatalyzed Mannich-type reaction.

This Research Article describes the synthesis of an over 700-member library of (8R/8S)-3-R-8-aryl-6-oxo-3,4,7,8-tetrahydro-2H,6H-pyrido[2,1-b][1,3,5]thiadiazin-9-carbonitriles by uncatalyzed Mannich-type reaction of N-methylmorpholinium (4R/4S)-4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridin-2-thiolates with a set of primary amines and excessive HCHO. The scope and limitations of the reaction were studied. Starting thiolates were obtained in yields of 53-82% by multicomponent reaction of aromatic aldehydes, cyanothioacetamide, 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid), and N-methylmorpholine, followed by heterocyclization of the resulting Michael adducts.

Two-temperature Langevin dynamics in a parabolic potential.

We study a planar two-temperature diffusion of a Brownian particle in a parabolic potential. The diffusion process is defined in terms of two Langevin equations with two different effective temperatures in the X and the Y directions. In the stationary regime the system is described by a nontrivial particle position distribution, P(x,y), which we determine explicitly. We show that this distribution corresponds to a nonequilibrium stationary state, characterized by the presence of space-dependent particle currents which exhibit a nonzero rotor. Theoretical results are confirmed by the numerical simulations.

Inhibitors of tick-borne flavivirus reproduction from structure-based virtual screening.

Flaviviruses form a large family of enveloped viruses affecting millions of people over the world. To date, no specific therapy was suggested for the infected people, making the treatment exclusively symptomatic. Several attempts were performed earlier for the design of fusion inhibitors for mosquito-borne flaviviruses, whereas for the tick-borne flaviviruses such design had not been performed. We have constructed homology models of envelope glycoproteins of tick-transmitted flaviviruses with the detergent binding pocket in the open state. Molecular docking of substituted 1,4-dihydropyridines and pyrido[2,1-b][1,3,5]thiadiazines was made against these models, and 89 hits were selected for the in vitro experimental evaluation. Seventeen compounds showed significant inhibition against tick-borne encephalitis virus, Powassan virus, or Omsk hemorrhagic fever virus in the 50% plaque reduction test in PEK cells. These compounds identified through rational design are the first ones possessing reproduction inhibition activity against tick-borne flaviviruses.