IN SILICO MODELLING, SYNTHESIS, AND ANTI-DIABETIC EVALUATION OF BENZOTHIAZOLE SUBSTITUTED OXADIAZOLE DERIVATIVES

Objective: The study contemplates in silico modeling, synthesis and in-vitro anti-diabetic evaluation of benzothiazole substituted oxadiazole derivatives. [{5-[(1, 3-benzothiazol-2-ylsulfanyl) methyl]-1, 3, 4-oxadiazol-2-yl} sulfanyl) methyl] derivatives were synthesized by a conventional method. Methods: All the newly synthesized derivatives were characterized by determining their melting point, retention factor from thin-layer chromatography, and spectral methods (Infrared, 1H NMR spectroscopy, 13C NMR spectroscopy, Mass spectroscopy) and evaluated for their anti-diabetic activity. Results: [{5-[(1, 3-benzothiazol-2-ylsulfanyl) methyl]-1, 3, 4-oxadiazol-2-yl} sulfanyl) methyl] derivatives have been made and characterized using physical and spectral methods. The in-vitro anti-diabetic screening study revealed that BZT1 and BZT4 exhibited high inhibition against glucose uptake assay and alpha-amylase enzyme. But only the derivative BZT4 showed inhibition against alpha-glucosidase enzyme. Conclusion: Various benzothiazole substituted oxadiazole derivatives were synthesized, characterized by spectral studies. The anti-diabetic studies revealed that the synthesized derivatives have significant anti-diabetic properties and further structure-activity relationship studies may develop more potent and less toxic molecules.

Metal storage capacity evaluation of humic and himatomelanic acids hydroxymethyl derivatives obtained from brown coal

Humic substances represent the most extensive and reactive class of natural compounds. A more nature-saving way is to obtain humus substances from solid combustible minerals and waste from their processing. The ability of these compounds to form stable complexes with heavy metals, which increases with their directed chemical modification, has been experimentally confirmed. The effectiveness of the phenol-formaldehyde condensation method for the modification of initial humus substances has been confirmed. The interaction of humic and himatomelanic acids with formaldehyde leads to an increase in sorption activity in comparison with the initial humic acids with respect to heavy metals. This aspect has been studied and confirmed in model experiments with copper ions. Key words: humic substances, brown coal, humic and himatomelanic acids, directed chemical modification, hydroxymethyl (methyl) derivatives, heavy metals, copper ions, complex formation.

In vitro Effect of Harmine Alkaloid and Its N-Methyl Derivatives Against Toxoplasma gondii

Toxoplasmosis is one of the most prevalent and neglected zoonotic global diseases caused by Toxoplasma gondii. The current pharmacological treatments show clinical limitations, and therefore, the search for new drugs is an urgent need in order to eradicate this infection. Due to their intrinsic biological activities, β-carboline (βC) alkaloids might represent a good alternative that deserves further investigations. In this context, the in vitro anti-T. gondii activity of three βCs, harmine (1), 2-methyl-harminium (2), and 9-methyl-harmine (3), was evaluated herein. Briefly, the three alkaloids exerted direct effects on the parasite invasion and/or replication capability. Replication rates of intracellular treated tachyzoites were also affected in a dose-dependent manner, at noncytotoxic concentrations for host cells. Additionally, cell cycle analysis revealed that both methyl-derivatives 2 and 3 induce parasite arrest in S/M phases. Compound 3 showed the highest irreversible parasite growth inhibition, with a half maximal inhibitory concentration (IC50) value of 1.8 ± 0.2 μM and a selectivity index (SI) of 17.2 at 4 days post infection. Due to high replication rates, tachyzoites are frequently subjected to DNA double-strand breaks (DSBs). This highly toxic lesion triggers a series of DNA damage response reactions, starting with a kinase cascade that phosphorylates a large number of substrates, including the histone H2A.X to lead the early DSB marker γH2A.X. Western blot studies showed that basal expression of γH2A.X was reduced in the presence of 3. Interestingly, the typical increase in γH2A.X levels produced by camptothecin (CPT), a drug that generates DSB, was not observed when CPT was co-administered with 3. These findings suggest that 3 might disrupt Toxoplasma DNA damage response.

Condensation Reactions of Methyl Derivatives of Quinoxaline-1,4-Dioxide with 4,4'-Biphenyl Carboxaldehyde

Aims: To synthesis new compounds via condensation reactions between 2-methyl quinoxaline-1,4-dioxide derivatives 4,4'-biphenyl carboxaldehyde. Methodology: The Quinoxalines derivatives were prepared from 2-nitroaniline derivatives using the Beirut reaction, and the condensation reaction was carried out at room temperature in absolute methanol. Based on IR and NMR spectroscopic techniques, the structures of all products have been suggested. For their synthesis, suitable mechanisms have been suggested. Results: In this work, condensation reactions involving 2-methyl quinoxaline-1,4-dioxide derivatives and 4,4'-biphenyl carboxaldehyde were performed. Conclusion: The final compounds, we suppose, have considerable applications in fluorescent and chromophoric activities. In all known solvents, the products were just slightly soluble. Products have been subjected to sulfonation reactions, although with limited success.

Metabolism of 2,3-Dehydrosilybin A and 2,3-Dehydrosilybin B: A Study with Human Hepatocytes and Recombinant UDP-glucuronosyltransferases and Sulfotransferases

2,3-Dehydrosilybin A and 2,3-dehydrosilybin B are a pair of enantiomers formed by the oxidation of the natural flavonolignans silybin A and silybin B, respectively. However, the antioxidant activity of 2,3-dehydrosilybin molecules is much stronger than that of their precursors. Here, we investigated the biotransformation of pure 2,3-dehydrosilybin A and 2,3-dehydrosilybin B in isolated human hepatocytes, and we also aimed to identify human UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) with activity toward their respective enantiomers. After incubation with hepatocytes, both 2,3-dehydrosilybin A and 2,3-dehydrosilybin B were converted to hydroxyl derivatives, methylated hydroxyl derivatives, methyl derivatives, sulfates, and glucuronides. The products of direct conjugations predominated over those of oxidative metabolism, and glucuronides were the most abundant metabolites. Furthermore, we found that recombinant human UGTs 1A1, 1A3, 1A7, 1A8, 1A9, and 1A10 were capable of catalyzing the glucuronidation of both 2,3-dehydrosilybin A and 2,3-dehydrosilybin B. UGTs 1A1 and 1A7 showed the highest activity toward 2,3-dehydrosilybin A, and UGT1A9 showed the highest activity toward 2,3-dehydrosilybin B. The sulfation of 2,3-dehydrosilybin A and B was catalyzed by SULTs 1A1*1, 1A1*2, 1A2, 1A3, 1B1, 1C2, 1C4, and 1E1, of which SULT1A3 exhibited the highest activity toward both enantiomers. We conclude that 2,3-dehydrosilybin A and B are preferentially metabolized by conjugation reactions, and that several human UGT and SULT enzymes may play a role in these conjugations.

Morphofunctional changes in cells of Tetrahymena pyriformis W infusoria under the influence of plant growth regulators — derivatives of pyridine-n-oxide

The aim of the Research. To identify morphological changes in Tetrahymena pyriformis W infusoria under the acute exposure to plant growth regulators (PGR) — derivatives of pyridine-N-oxide and compare them to functional disorders of cells. Materials and Methods. In the research we used the 2-methylpyridine-N-oxide, 2,6-dimethylpyridine-N-oxide and their complexes with organic acids (succinic, maleic) or metal salts (ZnCl2, ZnI 2, CoCl2, MnCl2) (a total of 15 substances), synthesized at the Institute of Bioorganic chemistry and Petrochemistry, NAS, Ukraine. Studies were performed on Tetrahymena pyriformis W infusoria in isotoxic doses — at the level of toxic concentrations — LC50, LC16 and inactive concentrations (LC0). Morphological changes in cells of infusoria were assessed visually with the use of a light microscope. Structural changes in infusoria were compared to functional changes in cells (motor activity and energy state) obtained under the same experiment. Results and Conclusions. It is demonstrated that 2-methylpyridine-N-oxide, 2,6-dimethylpyridine-N-oxide and their complexes with organic acids (succinic, maleic) or metal salts (ZnCl2, ZnI2, CoCl 2, MnCl2) cause functional and morphostructural changes in infusoria, the extent of which depends on the current concentration. Morphostructural changes in infusoria under the influence of the studied PGRs are characterized by a change of shape, growth of the contractile vacuole, vesiculation, damage to the integrity of the cytoplasmic membrane, emission of cytoplasm and structural elements of cells into the nutrient medium. Complexes of methyl derivatives of pyridine-N-oxide with metal salts in the studied concentrations reduce speed and increase energy expenditure on movement, cause changes in behavioural reactions and structure of cells to a greater extent than 2-methylpyridine-N-oxide, 2,6-dimethylpyridine-N-oxide and their complexes with organic acids. Both functional and morphological changes in infusoria are more evident under the influence of studied PGR occurring at concentrations corresponding to LC50. At lower concentrations the changes in the functional activity of infusoria were observed. Comparison of the obtained functional and morphostructural indicators of the state of infusoria shows that complexes of methyl derivatives of Pyridine-N-oxide with metal salts have more toxic effects on infusoria than complexes of methyl derivatives of pyridine-N-oxide with organic acids. Reduced motor activity and an increase in energy consumption per a unit of a path of motion, together with the morphological changes of cell structure, are the indicators of toxicity of xenobiotics for infusoria and criteria for assessing their viability. Key Words: methyl derivatives of Pyridine-N-oxide, Tetrahymena pyriformis W, morphofunctional changes.

Mesoionic tetrazolium-5-aminides: Synthesis, molecular and crystal structures, UV–vis spectra, and DFT calculations

Tetrazolium-5-aminides have been prepared by the tert-butylation of 5-aminotetrazole and its N-methyl derivatives by the t-BuOH/HClO4 system followed by the treatment of the tetrazolium salts by alkali. The mesoionic compounds have been found to show a higher reactivity of the exocyclic N atom in comparison with 5-aminotetrazoles. The compounds reacted with 1,2-dibromoethane and 5-(methylsulfonyl)-1-phenyl-1H-tetrazole with substitution of bromine and methylsulfonyl groups giving the corresponding tetrazolium salts or conjugate aminides. The obtained mesoionic tetrazoles have been characterized by elemental analysis, FTIR, NMR, and UV–vis spectroscopy, TGA/DSC analysis and for 1,3-di-tert-butyltetrazolium-5-aminide, its N,N’-ethylene-bridged bis-derivative and (1,3-di-tert-butyl-1H-tetrazol-3-ium-5-yl)(1-phenyl-1H-tetrazol-5-yl)amide by single crystal X-ray analysis. The structural and spectral features of the tetrazolium-5-aminides are discussed by using quantum-chemical calculations.

Reductively disilylated N-heterocycles as versatile organosilicon reagents

The reductively disilylated N-heterocyclic systems 1,4-bis(trimethylsilyl)-1-aza-2,5-cyclohexadiene (1Si), 1,4-bis(trimethylsilyl)-1,4-dihydropyrazine (2Si) and its methyl derivatives (3Si and 4Si), and 1,1’-bis(trimethylsilyl)-4,4’-bipyridinylidene (5Si) are proficient organosilicon reagents owing to their low first vertical ionization...