A Novel Series of [1,2,4]Triazolo[4,3-a]Pyridine Sulfonamides as Potential Antimalarial Agents: In Silico Studies, Synthesis and In Vitro Evaluation.

For the development of new and potent antimalarial drugs, we designed the virtual library with three points of randomization of novel [1,2,4]triazolo[4,3-a]pyridines bearing a sulfonamide fragment. The library of 1561 compounds has been investigated by both virtual screening and molecular docking methods using falcipain-2 as a target enzyme. 25 chosen hits were synthesized and evaluated for their antimalarial activity in vitro against Plasmodium falciparum. 3-Ethyl-N-(3-fluorobenzyl)-N-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide and 2-(3-chlorobenzyl)-8-(piperidin-1-ylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one showed in vitro good antimalarial activity with inhibitory concentration IC50 = 2.24 and 4.98 µM, respectively. This new series of compounds may serve as a starting point for future antimalarial drug discovery programs.

Synthesis, analysis of mol-ecular and crystal structures, estimation of inter-molecular inter-actions and biological properties of 1-benzyl-6-fluoro-3-[5-(4-methylcyclohexyl)-1,2,4-oxadiazol-3-yl]-7-(piperidin-1-yl)quinolin-4-one.

The title compound, C30H33N4O2F, can be obtained via a two-step synthetic scheme involving 1-benzyl-6-fluoro-4-oxo-7-(piperidin-1-yl)-1,4-di-hydro-quino-line-3-carbo-nitrile as a starting compound that undergoes substitution with hydroxyl-amine and subsequent cyclization with 4-methyl-cyclo-hexane-1-carb-oxy-lic acid. It crystallizes from 2-propanol in the triclinic space group P with a mol-ecule of the title compound and one of 2-propanol in the asymmetric unit. After the mol-ecular structure was clarified using NMR and LC/MS, the mol-ecular and crystalline arrangements were defined with SC-XRD. A Hirshfeld surface analysis was performed for a better understanding of the inter-molecular inter-actions. One strong (O-H⋯O) and three weak [C-H⋯F (intra-molecular) and two C-H⋯O] hydrogen bonds were found. The contributions of short contacts to the Hirshfeld surface were estimated using two-dimensional fingerprint plots showing that O⋯H/H⋯O, C⋯H/H⋯C and C⋯C contacts are the most significant for the title compound and O⋯H for the 2-propanol. The crystal structure appears to have isotropically packed tetra-mers containing two mol-ecules of the title compound and two mol-ecules of 2-propanol as the building unit according to analysis of the distribution of pairwise inter-action energies. A mol-ecular docking study was carried out to evaluate the inter-actions of the title compound with the active centers of macromolecules corresponding to viral targets, namely, anti-hepatitis B activity [HBV, capsid Y132A mutant (VCID 8772) PDB ID: 5E0I] and anti-COVID-19 main protease activity (PDB ID: 6LU7). The data obtained revealed a noticeable affinity towards them that exceeded that of the reference ligands.

Synthesis, X-ray diffraction study, analysis of inter-molecular inter-actions and mol-ecular docking of ethyl 1-(3-tosyl-quinolin-4-yl)piperidine-4-carboxyl-ate.

The title compound, C24H26N2O4S, can be obtained via two synthetic routes. According to our investigations, the most suitable way is by the reaction of ethyl 2-bromo-acetate with sodium tosyl-sulfinate in dry DMF. It was crystallized from methanol into the monoclinic P21/n space group with a single mol-ecule in the asymmetric unit. Hirshfeld surface analysis was performed to define the hydrogen bonds and analysis of the two-dimensional fingerprint plots was used to distinguish the different types of inter-actions. Two very weak non-classical C-H⋯O hydrogen bonds were found and the contributions of short contacts to the Hirshfeld surface were determined. Mol-ecules form an isotropic network of inter-molecular inter-actions according to an analysis of the pairwise inter-action energies. A mol-ecular docking study evaluated the inter-actions in the title compound with the active centers of macromolecules of bacterial targets (Staphylococcus aureus DNA Gyrase PDB ID: 2XCR, Mycobacterium tuberculosis topoisomerase II PDB ID: 5BTL, Streptococcus pneumoniae topoisomerase IV PDB ID: 4KPF) and revealed high affinity towards them that exceeded the reference anti-biotics of the fluoro-quinolone group.

Synthesis, docking, and biological evaluation of novel 1-benzyl-4-(4-(R)-5-sulfonylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrrolidin-2-ones as potential nootropic agents.

In order to search for innovative nootropic agents, new 1-benzyl-4- (4- (R)-5-sulfonylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl) pyrrolidine-2-ones was synthesized by reacting benzylamine with itaconic acid to 1-benzyl-5-oxopyrrolidine-3-carboxylic acid, which was then subjected to hydrazinolysis followed by the addition of substituted isothiacyanate followed by cyclization of intermediate thiosemicarbazides. The structure and purity of the obtained substances were confirmed by elemental analysis, 1H NMR spectroscopy, 13C NMR spectroscopy and LC/MS. Docking studies were performed for the substances synthesized using Autodock 4.2 software. Approximate values of LD50 (in silico determination) are around 870-1000 mg/kg. All synthesized substances were tested for nootropic activity by the passive avoidance test on the scopolamine amnesia model in doses that are about 1/10 of the estimated LD50. Based on the results of docking and pharmacological experiment, the most promising substances 7a, as well as 7e, 7f were identified. The results of molecular docking (hit compound 7a) indicate a positive correlation between the obtained values of docking studies and experimental data.

Development of a New Approach for Standardization of the Herb Centaurium erythraea Rafn. by High Performance Liquid Chromatography.

OBJECTIVES: The aim of this study was the development a new, fully validated high performance liquid chromatography (HPLC) method for the quantitative analysis of secoiridoid glycosides by an active marker swertiamarin in the herb Centaurium erythraea Rafn. The article describes a new approach to the standardization of C. erythraea and more specifically the development of a new validated HPLC method for the quantitative determination of secoiridoid glycosides by swertiamarin. MATERIALS AND METHODS: The quantitative determination of swertiamarin was performed in isocratic mode on a Symmetry C18 column using water and acetonitrile as solvents for the mobile phase. RESULTS: Validation characteristics of the developed method showed that it was linear in the whole range of concentrations from 0.01 mg/mL to 0.05 mg/mL swertiamarin. All validation characteristics met the established acceptance criteria. CONCLUSION: This method can be used in the standardization of raw materials, as well as in the analysis of medicinal products and dietary supplements that include C. erythraea. The established chromatographic method was successfully applied for the analysis of raw materials of C. erythraea with the quantitative content determination of swertiamarin in the analyzed samples.

Synthesis, in vivo and in silico anticonvulsant activity studies of new derivatives of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetamide.

In order to expand the arsenal of biologically active substances of anticonvulsive action by the interaction of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetic acid with the corresponding amines in the presence of N,N'-carbonyldiimidazole in the dioxane medium, a systematic series of 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-N-R-acetamides was obtained. A novel approach to synthesis of the key intermediate - 2-(2,4-dioxo-1,4-dihydro-quinazolin-3(2H)-yl)acetic acid was developed. The structure and purity of the resulting substances was confirmed by elemental analysis, 1H NMR, 13C NMR spectroscopy and LC/MS. Based on the results of docking studies using SCIGRESS software, selected compounds with the best affinity for anticonvulsant protein biomes (PDB codes: 4COF, 3F8E and 1 EOU) are promising for experimental studies of anticonvulsant activity. A comparative analysis of the results of molecular docking and in vivo results suggests that there is a positive correlation between scoring protein inhibition and experimental data. Pharmacological studies have revealed the leader compound 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-N-[(2,4-dichlorophenyl)methyl]acet-amide, which improved all the experimental convulsive syndrome rates in mice without motor coordination impairment and may be recommended for further research. The lowest values of the scoring function of the ligand-peptide interaction are obtained for the synthesized compound and сarbonic anhydrase II (gene name CA2) (PDB code 1 EOU), so its inhibition is proposed by us as the most probable mechanism of the anticonvulsive effect of the leader compound.

Compounding in Nigeria.

Although the art of apothecary existed as early as the first settlers in the location known today as Nigeria, the practice of pharmacy has transformed from training of dispensers in the 17th century to compounding pharmacists. Compounding, currently carried out exclusively in hospital pharmacies in Nigeria, is a relatively small but significant part of pharmaceutical care since it is tailored to individual/ special patients for positive therapeutic outcomes. This aspect of pharmaceutical service suffers challenges in Nigeria.

Investigation of physical and chemical stability of ointment with herbals.

The physical and chemical stability of a stock preparation ointment with active ingredients-herbal tinctures of calendula and arnica-for the treatment of hemorrhoids was studied. Evaluations for physical and chemical stability were performed initially and throughout the storage period. Physical stability of the ointment was assessed by means of visual observation in normal room light. Throughout the study period, the physical appearance of the ointment did not change. The chemical stability of the ointment was evaluated by means of a stability-indicating, thin-layer chromatography analytical technique. The shelf-life was found to be one month at 25 degrees C +/- 2 degrees C/60% RH and two months at 5 degrees C +/- 3 degrees C, when protected from light.

Compounding in Ukraine.

Pharmaceutical compounding in modern Ukraine has a rich history and goes back to ancient times. Today in the Ukraine, there is a revival of compounding practice, the opening of private compounding pharmacies, updating of legislative framework and requirements of the State Pharmacopeia of Ukraine for compounding preparations, and the introduction of Good Pharmaceutical Practice.