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The synthesis of new fluorescent probes, based on biocompatible luminophors and exhibiting various specificities, is intensively developed worldwide. Many luminophors contain a hydrophobic group that limits their application for cell staining under vital conditions. Herein, we report the synthesis of two BODIPY molecules—BF2-meso-(4-butan/pentanamido-N-(((1S,5R)-6,6-dimethylbicyclo [3.1.1]hept-2-en-2-yl)methyl)-N,N-dimethylpropan-1-aminium)-3,3′,5,5′-tetramethyl-2,2′-dipyrromethene bromides—designed as 10, 11 with a spacer of either four or three CH2 groups in length, respectively. These molecules present conjugates of BODIPY luminophors with (+)-myrtenol via a quaternary ammonium group. Both terpene-BODIPY conjugates demonstrated high fluorescence efficiency in various solvents such as OctOH, DMSO and water, and were characterized by their stability at pH 1.65–9.18. The fusion of the myrtenol, a monocyclic terpene, to the BODIPY fluorophore in the meso-substituent facilitated their penetration into the filamentous fungi Fusarium solani, while impairing the binding of the latter with S. aureus, K. pneumoniae and P. aeruginosa. The additional quaternary ammonium group between the myrtenol and fluorophore moieties restored the bacterial cell-staining while it did not affect the staining of fungi. Finally, the BODIPY conjugate 11 was able to stain both Gram-positive and Gram-negative bacteria by its interaction with their cell wall (or the membrane), as well as penetrating into filamentous fungi F.solani and staining their mitochondria.

The present paper aims to study the biological properties of a series of bicyclic monoterpene alcohols. Firstly, we tested the obtained compounds for fungicidal activity against clinical and reference strains of microscopic fungi. Next, we determined the minimum inhibitory concentration of these compounds comparing to other drugs widely used in practical medicine (fluconazole, terbinafine). At this stage, we found that ( −)-myrtenol (47 MIC and 23.5 μg/ml) exhibits the most promising activity against filamentous and yeast fungi, respectively. Then, we have studied the membrane-protective and antioxidant activities of the obtained compounds and found out that ( −)-cis-verbenol and ( −)-myrtenol exhibit the highest activity on the model of erythrocytes oxidative hemolysis. Interestingly, among all the studied bicyclic monoterpene alcohols, the alcohols of the pinane series have been found to be the most promising. The obtained results from the present study suggest that ( −)-myrtenol would be a leading compound for further studies in terms of possible practical application.

This article describes the design and biological properties of a BODIPY FL-labeled monoterpenoid BF2-meso-(4-((1″R)-6″,6″-dimethylbicyclo[3.1.1]hept-2″-ene-2″)yl-methoxycarbonylpropyl)-3,3′,5,5′-te...

This paper is devoted to the design of a fluorescent probe based on meso-carboxysubstituted-BODIPY with a thioterpene fragment. The functional replacement of the methoxy group in the BODIPY molecule on a thioterpene fragment was carried out in order to find out the antiplatelet and anticoagulant action mechanisms of thioterpenoids and to assess the membrane and receptor factors contributions. The molecular structure of the conjugate was confirmed via UV/vis-, NMR- and MS-spectra. It is found that the probe is a high fluorescence quantum yield (to ∼100%) in the blue-green region at 509–516 nm. Molecular docking of all studied molecules showed that the BODIPY with terpenoid conjugation is an excellent way to increase their affinity to platelet receptor P2Y12.

In this article, we present synthesis, spectral characteristics, and results of DFT calculations of new CH(R)-bis(BODIPY) 1–3. They are characterized by the conformational mobility and sensitivity of fluorescence to polarity, proton-, electron donor ability and viscosity of the solvation environment. It is shown that fluorescence intensity of 1–3 increases in the homologous series of alcohols (ethanol, 1-propanol, 1-butanol, 1-octanol, 1-decanol) mainly due to decrease of medium acidic properties. The viscosity of the medium effects on the 1–3 fluorescence in a lesser degree. Compared to 1 and 2, the 3 is the most sensitive towards viscosity both in low-viscosity homologous alcohols and in high-viscosity ethanol-glycerol mixtures. In this regard, the sensitivity of fluorescence of CH(MeOPh)-bis(BODIPY) (compound 3) to the viscosity was studied in binary mixtures of polar DMF and low-polarity toluene with castor and vaseline oils, as well as to the macroviscosity of the solvate environment in mixtures of toluene with polystyrene. Prospects of the practical application of CH(R)-bis(BODIPY)s are proposed for the analysis of polarity, proton-donor properties and viscosity of the medium.

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.

It is common knowledge that Candida albicans are one of the main sources of fungal infections which may lead to inflammation or even threaten life. Until now, fungal infection treatment has been considered as a challenging task due to several problems associated with their application like toxicity, drug interactions, and resistance. This paper outlines a new approach to develop effective agents against Candida albicans biofilms. The impact of borneols and sulfur-containing terpenoids of bornane series on the in vitro formation and growth of clinical strain of C. albicans in biofilms has been studied and compared with modern antimycotics. As a result, thioterpenoid 4 minimum inhibitory concentrations for C. albicans strain plankton ranged from 100 to 200 μg/ml where biofilm growth inhibition occurred at the concentration of 200 μg/ml. It is generally accepted that fluconazole 7 is widely used in clinical practice but still not effective against biofilms of C. albicans fungi. Therefore, we believe that isoborneol 2 and thioterpenoids 3 and 4, as well as terbinafine 6, can be promising starting points for the development of new antifungal agents against the pathogenic activity of fungi including pathogens embedded in biofilms since they demonstrated an effective resistance against the formation of pseudomycelia.

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 design of new dual-function inhibitors simultaneously preventing hydrate formation and corrosion is a relevant issue for the oil and gas industry. The structure-property relationship for a promising class of hybrid inhibitors based on waterborne polyurethanes (WPU) was studied in this work. Variation of diethanolamines differing in the size and branching of N-substituents (methyl, n-butyl, and tert-butyl), as well as the amount of these groups, allowed the structure of polymer molecules to be preset during their synthesis. To assess the hydrate and corrosion inhibition efficiency of developed reagents pressurized rocking cells, electrochemistry and weight-loss techniques were used. A distinct effect of these variables altering the hydrophobicity of obtained compounds on their target properties was revealed. Polymers with increased content of diethanolamine fragments with n- or tert-butyl as N-substituent (WPU-6 and WPU-7, respectively) worked as dual-function inhibitors, showing nearly the same efficiency as commercial ones at low concentration (0.25 wt%), with the branched one (tert-butyl, WPU-7) turning out to be more effective as a corrosion inhibitor. Commercial kinetic hydrate inhibitor Luvicap 55 W and corrosion inhibitor Armohib CI-28 were taken as reference samples. Preliminary study reveals that WPU-6 and WPU-7 polyurethanes as well as Luvicap 55 W are all poorly biodegradable compounds, BODt/CODcr (ratio of Biochemical oxygen demand and Chemical oxygen demand) value is 0.234 and 0.294 for WPU-6 and WPU-7, respectively, compared to 0.251 for commercial kinetic hydrate inhibitor Luvicap 55 W. Since the obtained polyurethanes have a bifunctional effect and operate at low enough concentrations, their employment is expected to reduce both operating costs and environmental impact.

This study focuses on the behavior of a new fluorescent marker for labeling individual biomolecules and staining cell organelles developed on a meso-substituted BODIPY platform. Boron(III) complex with meso-4-methoxycarbonylpropylsubstituted 3,3&rsquo, 5,5&rsquo, tetramethyl-2,2&prime, dipyrromethene has been synthesized and identified via visible, UV-, NMR- and MS-spectra X-ray. The behavior of fluorophore in solutions has been studied with various experimental techniques. It has been found that luminophore exhibits a high quantum yield (almost ~100&ndash, 75%) in the blue-green region (513&ndash, 520 nm) and has high photostability. In addition, biological analysis indicates that the fluorophore exhibits a tendency to effectively penetrate into cell membranes. On the other hand, the proposed BODIPY can be used to study the significant differences among a large number of pathogens of mycotic infections, as well as to visualize structural changes in the plasma membrane, which is necessary for the clearance of mammalian cells undergoing apoptotic cell death.

A new efficient approach to the synthesis of 6-alkenyl substituted pyridoxine derivatives has been developed. A series of 31 novel alkenyl pyridoxine derivatives, stilbene-based bioisosteric analogs of estradiol, were synthesized. In vitro cytotoxicity of the obtained compounds against MCF-7 (ER+) breast cancer tumor cells was studied using the MTT assay. The most active compounds with IC50, MCF-7

Many pathogenic bacteria and microscopic fungi form rigid polymicrobial biofilms this way enhancing their resistant to treatment. A series of novel pyridoxine-based quaternary ammonium derivatives of terbinafine characterized by both antifungal and antibacterial activities was designed. The leading compound named KFU-127 exhibits promising antifungal and antibacterial activities against various bacteria and micromycetes in both planktonic and biofilm-embedded forms demonstrating MIC values comparable with those of conventional antifungals and antimicrobials. Similar to other antiseptics like benzalkonium chloride and miramistin, KFU-127 is considerably toxic for eukaryotic cells that limits is application to topical treatment options. On the other hand, KFU-127 reduces the number of viable biofilm-embedded bacteria and C. albicans by 3 orders of magnitude at concentrations 2-4 times lower than those of reference drugs and successfully eradicates S. aureus-C. albicans mixed biofilms. The mechanism of antimicrobial action of KFU-127 is bimodal including both membrane integrity damage and pyridoxal-dependent enzymes targeting. We expect that this bilateral mechanism would result in lower rates of resistance development in both fungal and bacterial pathogens. Taken together, our data suggest KFU-127 as a new promising broad spectrum topical antimicrobial capable of one-shot targeting of bacterial and fungal-bacterial biofilms.

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.

In this paper, detailed comparative analysis of the spectral properties of bis(BODIPY) dyes in various organic solvents: saturated aromatic hydrocarbons, homologous series of alcohols (CnOH, n = 2–4, 8, 10) and mixture of ethanol-glycerol with different viscosity was carried out. In bis(BODIPY) dimeric molecules, the BODIPY chromophore domains are linked by a methylene spacer at the 2,2-, 2,3-, or 3,3-positions (1, 2, and 3 respectively). The absorption spectra of the bis(BODIPY)s exhibit exciton splitting of band maxima. We showed that bis(BODIPY)s are sensitive to the polarity and acidity of media due to its structural features. The mechanism of fluorescence quenching of 1–3 in the series of alcohols are explained in detail. It has been established that the fluorescence quenching efficiency of dimeric dyes in alcohols is determined by both universal and specific interactions. The fluorescence quantum yield of bis(BODIPY)s is minimal in ethanol and increases in the alcohols homologous series due to a reduction in medium polarity and the stability of the bis(BODIPY)(Solv)2 supramolecular structures. In viscous ethanol-glycerol mixtures, fluorescence of 1–3 increases because of the limitation of the dye molecules conformational mobility. The results of the study allow us to predict the possibility of practical application of 1–3 as alcohols fluorescent sensors in various media.

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.

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.

A series of 108 novel quaternary bis-ammonium pyridoxine derivatives carrying various substituents at the quaternary nitrogen&rsquo, s and acetal carbon was synthesized. Thirteen compounds exhibited antibacterial and antifungal activity (minimum inhibitory concentration (MIC) 0.25&ndash, 16 &micro, g/mL) comparable or superior than miramistin, benzalkonium chloride, and chlorhexidine. A strong correlation between the lipophilicity and antibacterial activity was found. The most active compounds had logP values in the range of 1&ndash, 3, while compounds with logP &gt, 6 and logP &lt, 0 were almost inactive. All active compounds demonstrated cytotoxicity comparable with miramistin and chlorhexidine on HEK-293 cells and were three-fold less toxic when compared to benzalkonium chloride. The antibacterial activity of leading compound 5c12 on biofilm-embedded Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli or Pseudomonas aeruginosa was comparable or even higher than that of the benzalkonium chloride. In vivo 5c12 was considerably less toxic (LD50 1705 mg/kg) than benzalkonium chloride, miramistine, and chlorhexidine at oral administration on CD-1 mice. An aqueous solution of 5c12 (0.2%) was shown to be comparable to reference drugs efficiency on the rat&rsquo, s skin model. The molecular target of 5c12 seems to be a cellular membrane as other quaternary ammonium salts. The obtained results make the described quaternary bis-ammonium pyridoxine derivatives promising and lead molecules in the development of the new antiseptics with a broad spectrum of antimicrobial activity.

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.