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Background: Adamantane derivatives possess multiple pharmacological activities such as antiviral, anticancer, antimycobacterial, antidiabetic, antiparkinsonian and others. The interest of medicinal chemists in adamantane compounds is due to their unique spatial structure, high lipophilicity, and carbon cage rigidity. As a result, these molecules can easily penetrate biological lipid membranes and often have unique target-specific activity profile. Another pharmacophore studied in this work is pyridoxine (vitamin B6). Pyridoxine plays highly important roles in living cells as a key cofactor of many enzymes. On the other hand, its molecular scaffold is a valuable structural platform which has led to the development of several launched drugs (Pyritinol, Pirisudanol, Cycletanine, Mangafodipir) and a wide number of preclinical and clinical drug candidates. Objective: The objective of this study is a synthesis of pyridoxine-adamantane and pyridoxinecyclooctane dipharmacophore molecules. The underlying idea was to assess the antibacterial and antiviral potential of such dipharmacophores, based on multiple examples of promising antiinfective agents which have in their structures adamantane and pyridoxine moieties. Another specific reason was to explore the ability of pyridoxine pharmacophore to suppress the potential of microbial pathogens to develop resistance to drug molecules. Methods: In this study, a series of pyridoxine-adamantane and pyridoxine-cyclooctane dipharmacophore molecules were synthesized based on reactions of three different cycloalkyl amines with the corresponding electrophilic derivatives of pyridoxine aldehydes, chlorides and acetates. All synthesized compounds have been tested for their in vitro activity against M. tuberculosis H37Rv strain and H3N2 (A/Aichi/2/68) influenza virus. Results: Series of pyridoxine-adamantane and pyridoxine-cyclooctane dipharmacophore molecules were synthesized based on reactions of three different cycloalkylamines with the corresponding electrophilic derivatives of pyridoxine aldehydes, chlorides and acetates. Reaction of cycloalkylamines with pyridoxine derivatives, in which meta-hydroxyl and ortho-hydroxymethyl groups are protected by acetyl groups, represents a useful alternative to reductive amination of aldehydes and nucleophilic substitution of alkyl halides. According to a tentative mechanism, it proceeds via paraand ortho-pyridinone methides which readily react with nucleophiles. None of the synthesized dipharmacophore compounds showed activity against M. tuberculosis H37Rv strain. At the same time, three compounds demonstrated some antiviral activity against H3N2 (A/Aichi/2/68) influenza virus (EC50 52-88 µg/mL) that was comparable to the activity of Amantadine, though lower than the activity of Rimantadine. The results of this work can be useful in the design of physiologically active derivatives of pyridoxine and adamantane. Conclusion: The results of this work can be useful in the design of physiologically active derivatives of pyridoxine and adamantane.

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.

The physico-chemical characteristics and crystal structure of newly synthesized isobornanyl sulfoxides and sulfone are presented. After purification, diastereomeric sulfoxides were obtained in a 2:1 eutectic ratio, which did not allow either separation or enrichment of the mixture. Based on thermochemical data, the form of the phase diagram of the system was reconstructed, showing that diastereomers have significantly different melting points. According to the X-ray data, the same supramolecular open–chain S=O⋅⋅⋅H–O synthon is built up in the crystals of diastereomeric sulfoxides. The isobornanyl sulfone crystal is formed in a complex way – two crystallographically independent molecules playing different roles in the formation of H-bonds. The IR spectra of a diastereomeric sulfoxides mixture demonstrate the averaging of the synthon-forming functional groups bands. In a counterbalance, the IR spectrum of isobornanyl sulfone shows a doubling of the key bands of synthon-forming functional groups belonging to homochirally homogeneous but crystallographically nonequivalent molecules.

Wittig reactions of a bis-triphenylphosphonium pyridoxine derivative with five aromatic and aliphatic aldehydes led to a series of mono- and bis-alkenyl substituted products. The reactions also demonstrated unusual reactivity patterns leading to unexpected products, including a Z-shaped hyperconjugated structure with trans-configuration for all three alkene fragments, and a tricyclic 9,10-dihydro-1H-[1,3]dioxino[4,5-c]quinoline formed as a result of non-symmetric Wittig olefination followed by a rare type of intramolecular cyclization. The obtained products represent prospective biologically active agents, while one compound is a potential microenvironment- and interaction-sensitive molecular probe.

A series of trans-6-phenylethenyl substituted pyridoxine derivatives, novel bioisosteric analogs of drugs based on trans-stilbene scaffold, were synthesized using the Wittig reaction of a bis-triphenylphosphonium pyridoxine derivative with various aromatic aldehydes. Two compounds demonstrated high activity against the estrogen-dependent MCF-7 (breast cancer) cell line with IC50 in the range of 1.9–7.9 µM and very good selectivity for other studied normal and tumor cells, including the estrogen receptor negative MDA-MB-231 breast cancer cells. The active compounds possessed an intense blue fluorescence, and this feature allowed us to effectively visualize them in cytoplasm and in nucleus. The obtained results make the described chemotype a promising starting point for the development of new anticancer agents for the therapy of estrogen-dependent malignancies.

Experimental investigation of hexachlorocyclopentadiene [4+2]-cycloaddition to 2-substituted 4,7-dihydro-1,3-dioxepins revealed an atypical stereochemical effect. Clear experimental evidence was obtained that more bulky C2 substituents favour the thermodynamically and sterically less favourable endo -isomers. The possible reasons for such behaviour are secondary interactions of the highest occupied and lowest unoccupied orbitals in the transition state for endo- cycloaddition, diastereotopic solvation and coordination of the attacking diene reagent to the acetal oxygens. The reaction stereoselectivity also depends on the solvent nature and reaction temperature. We have also found that microwave irradiation significantly influences the [4+2]-cycloaddition yields and stereochemistry, though the nature of the underlying effects remains unclear.

An approach to the synthesis of epoxides based on 6-hydroxymethylpyridoxine acetals was developed. The epoxides obtained were involved in the ring opening reactions by nitrogen-, oxygen-, and sulfur-containing nucleophiles. Cytotoxicity and antiadrenergic properties of some synthesized compounds were studied on the models in situ and in vivo.

A convenient method for the synthesis of pyridoxine alkenyl derivatives by the Wittig reaction of [(2,8-dimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methyl]triphenylphosphonium chloride with aldehydes was suggested. Some of the compounds obtained exhibit antitumor activity in vitro.

A fluorescent biomarker based on the boron(III) complex with meso-4-methoxycarbonylbutyl-substituted 3,3',5,5'-tetramethyl-2,2′-dipyrromethene (BODIPY) was synthesized. The BODIPY exhibits a large extinction coefficient (lgɛ ∼4.82–5.00) at 496–501 nm and high fluorescence quantum yield (∼77–100%) in the blue-green region of the spectrum (509–518 nm). The maximal fluorescence quantum yield (φ) is observed in non-polar media (∼100%) while φ slightly decreases to ∼90% in alcohols (with the exception of octanol-1) and to ∼77% in electron-donating dimethyl sulfoxide (DMSO). The BODIPY fluorophore demonstrates high photostability with the half-life of 41.4 and 91 hours in toluene and cyclohexane, respectively. The proposed luminophore preferentially stains gram-positive bacteria and can be used for differential staining of gram-positive and gram-negative bacteria in mixed cultures. BODIPY also accumulates in the cytoplasm of the mammalian cells giving polar micro-speckled staining pattern which is more intensive in the tumor cells when compared to the fibroblasts. The pronounced affinity of BODIPY to mitochondria of eukaryotic cells could be used for specific staining of these organelles.

In this work, we propose the synthesis of new thioterpenoids of a bornane series and study the influence of these compounds on hemostasis. The results from this study suggest that among all investigated terpenoids, sodium ([(1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]thio) acetate may be the most promising for further development due to enhanced inhibition of the spontaneous aggregation compared with isoborneol, and because of its higher solubility in water compared with ([(1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]thio) acetic acid, which has approximately the same antiaggregatory and anticoagulant properties. In accordance with one hypothesis, the distribution of the studied bioactive molecules within the cellular lipid membrane can directly influence the anticoagulant properties. In the current work, the interactions of thioterpenoids with phospholipid membranes have been studied using various NMR techniques. The findings of this study indicate that sodium ([(1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]thio) acetateexhibits a membrane location, which is shifted somewhat in the direction of the lipid-water interface. Such a location may shield the compound from interactions with hydrophobic lipid segments. In contrast, isoborneol is more deeply immersed in the membrane. These results represent an initial step toward developing new drugs based on the synthesized thioterpenoids in order to increase the effectiveness of treatment and prevention of several human diseases accompanying disorders in the hemostasis system.

Two series of novel pyridoxine-based azaheterocyclic analogs of feruloyl methane (Dehydrozingerone, DZG) were synthesized, and their biological activity against a panel of tumor and normal cell lines was evaluated in vitro. The most active compounds possessed expressed cytotoxic activity, which was comparable to cytotoxic activity of doxorubicin and significantly higher than that of DZG, and a remarkable selectivity for the studied cancer cell lines as compared to the normal cells. The leading compound and DZG initiated arrest of the cell cycle in the G2/M phase, preventing normal division and further transition of daughter cells to the G0/G1 phase. Similar to DZG, but with higher efficiency, the leading compound was able to inhibit migration activity and, therefore, invasiveness of tumor cells. It also increased concentration of reactive oxygen species in tumor cells, induced depolarization of mitochondrial membranes and initiated apoptosis accompanied by disruption of integrity of cytoplasmic cell membranes. By contrast to DZG, the leading compound did not possess antioxidant properties. The obtained data make the described chemotype a promising starting point for the development of new anticancer agents.

Synthesis of β-hydroxysulfides of 1,3-dioxepane series and their further functionalization were performed. Chiral β-hydroxysulfides were separated into enantiomers using enzymatic acylation by lipase PS. Study of antifungal activity of the obtained compounds showed that some enantiomerically pure 6-arylthio-1,3-dioxepan-5-ols represent promising antifungal drug candidates.