Vol 68, No 5 (2019)

Pyridoxine and its derivatives, pyridoxamine and pyridoxal, are the three main forms of vitamin B₆, which play exceptionally important biological roles in living organisms. The active endogenous metabolites of these molecules, pyridoxal phosphate and pyridoxamine phosphate, are the most important coenzymes involved in a wide range of biochemical reactions necessary for cell activity, due to which pyridoxine and its derivatives are regarded as biologically privileged molecules. Taking into account also the wide possibilities for chemical modification of the pyridoxine structure, it is only natural for medicinal chemists to explore them in the design of novel drugs. This review summarizes the data on the main pharmacologically significant pyridoxine derivatives (including pyridoxamine and pyridoxal derivatives) reported in modern scientifi c and patent sources. Methods for their synthesis, key pharmacological properties, and medicinal chemistry concepts underlying the design of the developing physiologically active compounds are presented. The promising directions for future development of chemistry of physiologically active pyridoxine derivatives are also discussed.

New biologically active substances isolated from natural sources provide valuable information on structural motifs that are important for a specific type of activity and can also be used as drugs or serve as raw materials for chemical modification in order to develop new pharmaceuticals. This review considers natural antibiotics combining two pharmacophores in their structure: a redox-active naphthoquinone moiety and a membrane-active polyol macrolide. Data on their structures and the spectrum of biological activity are summarized.

The products of the reaction between p-cresol and camphene were isolated and characterized. Their antiradical activity and toxicity were studied. The pharmacological activity of the most active stereoisomer of 2,6-diisobornyl-4-methyl phenol in rats with a model of streptozotocin diabetes was studied. Under these conditions, the investigated compound during course administration improves micro- and macrorheological parameters of blood, exhibits a membranestabilizing eff ect on erythrocytes, restricts platelet aggregation, and favors the preservation of the vasodilator function of endothelium.

A convenient method is proposed for the synthesis of N-unsubstituted spiroxindoles with different heterocyclic moieties (2-thiohydantoin, hydantoin, and thiazolidine) by the regio-selective 1,3-dipolar cycloaddition of azomethine ylides, generated from isatins and sarcosine, to arylidene derivatives of corresponding heterocycles. The cytotoxicity of compounds was tested by the MTT method against MCF7, A549, HEK, and VA13 cell lines and compared with the anticancer drug Nutlin-3a. The best bioactivity was observed for hydantoin-based dispiroindolinones, the most cytotoxic compound demonstrated selectivity against A549 lung cancer cells with an IC₅₀ value of 6.6±1.6 μmol L⁻¹.

The applicability of [2-(2-nitrophenyl)oxiran-1-yl](aryl(methyl))ketones in the synthesis of 3-hydroxyquinolin-4-ones and 2-arylquinolines was studied.

Pinane sulfi de obtained by the addition of methyl hydrosulfanylacetate at the double bond of β-pinene inhibits platelet receptor activity. It inhibits completely platelet aggregation induced by adrenaline, ADP, collagen, arachidonic acid, and also reduces the eff ect of ristomycin. This compound inhibits both platelet and coagulation hemostasis, which allows one to use it for creation promising antiaggregation drugs and for stabilization blood products.

N-Heterocycle-containing (1S)-(+)-camphor-10-sulfonamide derivatives were synthesized. Their antiviral activity against the Ebola and Marburg viruses was estimated using a pseudovirus system based on the vesicular stomatitis virus. The derivatives bearing morpholine and triazole moieties demonstrated the highest inhibitory activity towards the Ebola virus glycoprotein. A moderate activity against the Marburg virus was found for a compound containing the piperidine moiety. A molecular modeling of the interaction between the synthesized derivatives and the binding site of glycoprotein of the Ebola virus was performed.

The paper describes the synthesis of new tetrahydroberberrubine derivatives containing polyfl uorophenyl- or alkylsulfonate groups at the O(9) position as well as those containing or not containing a bromine atom at the C(12) position. In a model of acute Triton-induced hyperlipidemia, tetrahydroberberrubine 9-O-(heptafluoro-4’-toluene)sulfonate was shown to reduce the cholesterol level by 23.5%, which is comparable with the eff ect of Simvastatin. At a concentration of 32 μg mL⁻¹, tetrahydroberberrubine 9-O-pentafluorobenzenesulfonate inhibits the growth of the fungus Cryptococcus neoformans by 81.3±3.5%.

New p-tert-butyl thiacalix[4]arene derivative in the 1,3-alternate stereoisomeric form containing two diethylenetriamine groups and pentacosa-10,12-diynoic moieties on the opposide sides of macrocyclic cavity was synthesized using the copper(i)-catalyzed azide-alkyne cycloaddition. According to the dynamic and electrophoretic light scattering data, the synthesized macrocycle forms submicron particles with the sizes 200 nm and ζ-potential equal to 43 mV. The critical aggregation concentration of the macrocycle was 0.019 mmol L⁻¹. The obtained macrocycle intercalates into calf thymus DNA (CT DNA) to form a lipoplex. Using ethidium bromide as a fluorescent probe intercalation of obtained macrocycle into CT DNA with following formation of a lipoplex with the ζ-potential equal to −30 mV was found. The macrocycle was used for the synthesis of mixed polydiacetylene particles with N-(2-aminoethyl)pentacosa-10,12-diynamide (PCDA) as a base lipid. The highest degree of polymerization is achieved in the system with the macrocycle to PCDA ratio equal to 1 : 4. Macrocycle embedding into the polydiacetylene particles significantly increases their colorimetric response to CT DNA. The response to CT DNA as a change in the color of a solution of particles from blue to red is seen by naked eye at the CT DNA concentration starting from 20 µmol L₋₁, which makes the obtained particles promising for bioanalytical application.

A galvanochemical method for the synthesis of iron lignosulfonate was developed. Metallic iron is gradually dissolved in a solution of lignosulfonates on contact with the material acting as a cathode of the short-circuited galvanic pair. The effect of the cathode material as well as duration and temperature of the process on the anodic dissolution of iron was studied under dynamic and static conditions. Anodic dissolution occurs in a solution of lignosulfonic acids approximately 5 times more rapidly than in a solution of lignosulfonates. Iron lignosulfonate synthesized using the galvanochemical method have high biological activity. Under vegetative conditions, they can be used as an anti-chlorosis preparation to prevent glandular deficiency in plants growing on carbonate soils. Unlike complexonates based on synthetic complexones, iron lignosulfonates are biodegradable and environmentally friendly.

A method is proposed for immobilization of anti-ischemic drug phosphocreatine on the surface of aminated silica and magnetite nanoparticles of similar size and shape. The synthesis of spacer and the coordination-ionic drug immobilization technique are described. Magnetite nanoparticles demonstrated much more efficient chemisorption of phosphocreatine than silica nanoparticles. The method was recommended for practical application.

Reaction of 4″O,5O-bis(chloroacetyl)ivermectin with amines in the presence of sulfur provided the corresponding bis(2-amino-2-thioxoacetyl) derivatives that are potential antiparasitics.