Combined drug delivery for Alzheimer's disease (AD) treatment is a promising area of research. It is known that the positive charge on the liposome surface increases their affinity for negatively charged biological barriers. The simultaneous inclusion of both cationic and nonionic surfactants in a vesicular nanocontainer can lead to increased intranasal penetration of active pharmaceutical substances. In this study, a homologous series of isothiuronium surfactants (S-alkylisothiuronium bromides, CnSUBr, where n =10, 12, 14, 16) was selected to obtain ultra-deformable liposomes (transfersomes) for intranasal therapy of AD. The cationic transfersomes were loaded with a combination of substrates, donepezil hydrochloride (DNP) and alpha-tocopherol (Toc). The study consisted of the following stages: (i) assessment of liposome hydrodynamic diameter, zeta potential, morphology; (ii) evaluation of transfersome binding to mucin, determination of substrate encapsulation efficiency (& IEcy;& IEcy;), and study of DNP release kinetics; (iii) estimation of cytotoxicity, antioxidant activity, hemolysis, and hemagglutination; (iv) pharmacokinetic experiments and a novel object recognition test on transgenic mice with AD model. For PC/TW20/Toc/C16SUBr/DNP transfersomes the following results were obtained: Dh =104 f 1 nm, PdI = 0.067 f 0.010, zeta = 40.3 f 0.1 mV, & IEcy;& IEcy;& Tcy;& ocy;& scy; = 98.5 f 0.6 %, & IEcy;& IEcy;DNP = 70 f 1 %, twofold increase in antioxidant activity compared to free & Tcy;& ocy;& scy;, the preference index of a new object over a familiar one is equal to 65 f 9 % (p = 0.03), Cmax = 228 f 21 ng/g (15 min after intranasal administration) and t1/2 = 64 min.

The search for new systems for drug delivery to the brain is stimulated by the low ability of medicines to overcome the blood-brain barrier (BBB). Liposomes modified with cationic surfactants are promising systems from this point of view. Therefore, new cationic lipid-like surfactants with hexadecyl hydrocarbon tail and different head group structures were synthesized for modification of phosphatidylcholine-based liposomes. To obtain the optimal composition, the surfactant/lipid molar ratio was varied. Modified vesicular nanocontainers were used to load the acetylcholinesterase reactivator, pralidoxime chloride (2-PAM). The physicochemical parameters (hydrodynamic diameter, zeta potential, polydispersity index, aggregate morphology), substrate release profile in vitro, hemolytic activity and hemagglutination ability, as well as 2-PAM pharmacokinetics and AChE reactivation in vivo were examined. The optimized liposomal formulations demonstrated long-term stability. Subsequent evaluation of BBB penetration, 2-PAM pharmacokinetic profile, and in vivo AChE reactivation revealed that the top-performing systems achieved notable brain uptake and reactivated rat brain AChE by 25-38 %.

Twenty triphenylphosphonium (TPP) conjugates in which 1-alkynyl-substituted nucleic bases (uracil, thymine) and their analogues (6-methyluracil, quinazoline-2,4-dione) were connected to the TPP cation via an octyl or decyl linker were synthesized. In vitro evaluation of their antibacterial activity against five Gram-positive bacteria, two Gram-negative bacteria and fungus C. albicans revealed six lead compounds which exhibited high bacteriostatic activity (MIC 0.2–0.9 μM) against Gram-positive bacteria S. aureus, B. cereus, E. faecalis, as well as MRSA strains. These lead compounds are TPP-conjugates in which 1-alkynylquinazoline-2,4-dione moiety is bound to the TPP cation via the decyl (4 d, 4 f) or octyl (4e) linker and biscationic TPP-conjugates in which two TPP cations are attached to the N-1 and N-3 atoms of 5-alkynylquinazoline-2,4-dione moiety via the decyl (5 d, 5 f) or octyl (5e) linkers. Biscations 5 d and 5e showed high in vitro bacteriostatic and bactericidal activity (MIC/MBC 0.2–7.8 μM) against Gram-negative bacteria E. coli and P. aeruginosa. In addition, biscations 5 d and 5 f exhibited noticeable in vitro fungistatic and fungicidal activity against fungus C. albicans. Using colorimetric and fluorimetric methods, it was found that all lead compounds at concentrations corresponding to the MIC and MBC values caused cytoplasmic membrane damage and depolarization, without violating the integrity of the S. aureus cell wall. In addition, all lead compounds inhibited the formation of S. aureus biofilm by 80-100

Meldrum's acid-based multi-component reactions have emerged as a highly versatile and valuable tool, offering simple access to numerous classes of pharmaceutically and industrially valuable heterocyclic and acyclic organic compounds. The vast majority of these reactions employ a carbonyl compound as one of the reagents and utilize the electrophilic reactivity of transient arylidene malonates. This necessarily requires a third nucleophilic reagent and represents the general limitation of these reactions. Herein, we proposed an approach to a reactivity umpolung of arylidene malonates via a visible light-driven SET/PT sequence, enabling the radical chemistry in Meldrum's acid-based MCRs. The viability of the proposed approach was demonstrated by the three-component synthesis of hitherto unknown imidazolinone malonic acids. The radical chain mechanism was evidenced for the disclosed transformation by mechanistic experiments and density functional calculations.

In this work, we designed and synthesized 12 triphenylphosphonium (TPP) conjugates of acetylenated nucleic bases (uracil, thymine) and their analogues (6-methyluracil, quinazoline-2,4-dione) and evaluated their in vitro cytotoxicity against 9 human cancer cell lines M-HeLa, HuTu 80, MCF-7, T 98 G, A 549, DU-145, SK-OV-3, PC-3, A-375 and two lines of normal human cells RPMI 1788 and WI-38. All synthesized TPP-conjugates showed high cytotoxicity (IC50 values in the range of 0.1–7.3 µM) against all used human cancer cell lines. The mechanisms of cytotoxic action were studied for the lead compounds 2c,d, 4c,d which exhibited very high cytotoxicity (IC50 = 0.2–0.3 μM) against PC-3 cancer cells. The flow cytometry method using Annexin V and propidium iodide (PI) has shown that the lead compounds cause apoptosis of PC-3 cells. With the help of flow cytometry using cationic carbocyanine dye JC-1, it was found that the lead compounds cause a significant dose-dependent decrease in the mitochondrial membrane potential of PC-3 cancer cells, that induces apoptosis along the mitochondrial pathway. Significant ROS production in PC-3 cells after their treatment with the lead compounds 2c,d was detected by flow cytometry using CellROX® Deep Red fluorogenic probe. Enzyme-linked immunosorbent assay (ELISA) found that the lead compounds activated apoptosis-initiating caspase-9 and blocked anti-apoptotic Bcl-2 protein in PC-3 cancer cells. This experimental fact was explained by molecular docking.

This study evaluates the antibacterial and antifungal effects of ethanol extracts from Gnaphalium uliginosum L. derived from freshly harvested plant biomass, including stems, leaves, flowers, and roots. The extract was analyzed using gas chromatography-mass spectrometry (GC-MS) to determine its antimicrobial activity against phytopathogenic bacteria and fungi. Two methods were used in the experiments: agar well diffusion and double serial dilution. Extraction was carried out using the maceration method with different temperature regimes (25 °C, 45 °C, and 75 °C) and the ultrasonic method at various powers (63–352 W) for different durations (5 and 10 min). It was found that the 70% ethanol extract obtained through the ultrasonic experiment at 189 W power for 10 min and at 252 W power for 5 min had the highest antimicrobial activity compared to the maceration method. The most sensitive components of the extracts were the Gram-positive phytopathogenic bacteria Clavibacter michiganensis and the Gram-negative phytopathogenic bacteria Erwinia carotovora spp., with MIC values of 156 μg/mL. Among the fungi, the most sensitive were Rhizoctonia solani and Alternaria solani (MIC values in the range of 78–156 µg/mL). The evaluation of the antimicrobial activity of extracts using the diffusion method established the presence of a growth suppression zone in the case of C. michiganensis (15–17 mm for flowers, leaves, and total biomass), which corresponds to the average level of antimicrobial activity. These findings suggest that G. uliginosum has potential as a source of biologically active compounds for agricultural use, particularly for developing novel biopesticides.

The biodegradation of petroleum by Aspergillus niger strain AM1 VKM F-4815D is studied. Visual observation and gas chromatography–mass spectrometry (GC-MS) showed that petroleum undergoes partial destruction, but cannot serve as the only source of carbon: the culture medium must contain glucose. An interesting fact is the change in consistency and hardening of petroleum under the influence of A. niger. This allows us to consider the possibility of using the strain for bioremediation of soils and waters contaminated with petroleum. No less interesting is that even earlier the strain was found to be able to metabolize a number of toxic phosphorus compounds, including even white and red phosphorus. However, most organic solvents have a noticeable toxic effect, slowing growth in the presence of glucose and not becoming sources of carbon in the absence of glucose.

In this work, we describe a mild electro-oxidative metal-, oxidant- and acid-free direct amidation of aromatic C–H bonds using nitrile solvents as a source of amide and amine moieties.

In this research, using the thia-Michael reaction, cationic amphiphilic meroterpenoids containing fragments of mono- and sesquiterpenoids were synthesized. The bacteriostatic and fungistatic activity of synthesized meroterpenoids against the fungi Saccharomyces cerevisiae and Candida sp., Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis) and Gram-negative (Salmonella typhimurium, Klebsiella pneumoniae, Pseudomonas aeruginosa) bacteria was studied. The compound containing the farnesyl fragment was most active against Saccharomyces cerevisiae (MIC 0.039 mg/mL), Candida sp. (MIC 0.078 mg/mL), Gram-positive bacteria Staphylococcus epidermidis (MIC 0.02 mg/mL) and Gram-negative Salmonella typhimurium (MIC 0.078 mg/mL). Besides, the Ames test demonstrated the absence of direct mutagenic action in all the studied compounds.

A novel organonickel sigma-complex [NiBr(Tcpp)(bpy)], where Tcpp is 2,4,6-tricyclopentylphenyl, bpy is 2,2'-bipyridine has been generated in solution by electrochemical macroscale synthesis. The monitoring of the macroscale electrosynthesis and also the cyclic voltammetric measurements have shown that the organonickel sigma-complex is formed at the electrolysis but, in contrast to its analogues with ortho -substituted aromatic fragments, is unstable and decomposes to the homo-coupling product, namely, the earlier unknown sterically hindered biaryl derivative 2,2',4,4',6,6'-hexacyclopentyl-1,1'-biphenyl, the molecular and crystal structure of which are described by NMR spectroscopy and X-ray diffraction techniques.

Currently, special attention is paid to the study of the mechanisms of stress resistance of extremophile organisms that can survive in extreme conditions. Such organisms include lichens, which are symbiotic associations of fungi and algae and/or cyanobacteria. The high stress resistance of lichens is due to the presence of a wide range of biologically active metabolites, including sterols. It is known that lichens have a diverse and unique sterol composition, different from that of fungi and algae. Sterol-mediated biochemical mechanisms of stress resistance in lichens have not been fully studied and not systematized. Temperature stress is quite common for lichens, which often grow in unfavorable conditions. It is known that dry lichen thalli are able to withstand temperature changes over large ranges, while hydrated thalli are much more sensitive to unfavorable temperatures. In this work, stress-induced changes in respiratory activity and membrane stability index (MSI), as well as the sterol profile of hydrated lichen thalli, of Peltigera canina (L.) Willd. under the influence of elevated (+40°С) and low (–20°С) temperatures was investigated. It was shown that unfavorable temperatures caused a suppression of respiration rate and a decrease in the MSI of lichen thalli. Chromatomass spectrometric analysis showed the presence of P. canina ergosterol, dehydroergosterol, episterol, lichesterol, and fungisterol. Under the influence of both stress factors, there was a decrease in the level of ergosterol and an increase in the proportion of episterol. Under cold stress conditions, the proportion of dehydroergosterol also increased, the proportion of lichesterol decreased, and the relative content of the more saturated sterol fungisterol remained at the control level. It can be assumed that stress-induced changes in the sterol profile of lichens under low-temperature exposure create an optimal balance of sterols in membranes, which provides conditions for the deployment of a successful strategy leading to the adaptation of the lichen to the action of a stressor.

An Erratum to this paper has been published: https://doi.org/10.1134/S1023193524010087

Currently, special attention is paid to the study of the mechanisms of stress resistance of extremophile organisms that can survive in extreme conditions. Such organisms include lichens, which are symbiotic associations of fungi and algae and/or cyanobacteria. The high stress resistance of lichens is due to the presence of a wide range of biologically active metabolites, including sterols. It is known that lichens have a diverse and unique sterol composition, different from that of fungi and algae. Sterol-mediated biochemical mechanisms of stress resistance in lichens have not been fully studied and not systematized. Temperature stress is quite common for lichens, which often grow in unfavorable conditions. It is known that dry lichen thalli are able to withstand temperature changes over large ranges, while hydrated thalli are much more sensitive to unfavorable temperatures. In this work, stress-induced changes in respiratory activity and membrane stability index (MSI), as well as the sterol profile of hydrated lichen thalli, of Peltigera canina (L.) Willd. under the influence of elevated (+40°С) and low (–20°С) temperatures was investigated. It was shown that unfavorable temperatures caused a suppression of respiration rate and a decrease in the MSI of lichen thalli. Chromatomass spectrometric analysis showed the presence of P. canina ergosterol, dehydroergosterol, episterol, lichesterol, and fungisterol. Under the influence of both stress factors, there was a decrease in the level of ergosterol and an increase in the proportion of episterol. Under cold stress conditions, the proportion of dehydroergosterol also increased, the proportion of lichesterol decreased, and the relative content of the more saturated sterol fungisterol remained at the control level. It can be assumed that stress-induced changes in the sterol profile of lichens under low-temperature exposure create an optimal balance of sterols in membranes, which provides conditions for the deployment of a successful strategy leading to the adaptation of the lichen to the action of a stressor.

Cerasomes are a promising modification of liposomes with covalent siloxane networks on the surface that provide outstanding morphological stability while maintaining all the useful traits of liposomes. Herein, thin film hydration and ethanol sol injection methods were utilized to produce cerasomes of various composition, which were then evaluated for the purpose of drug delivery. The most promising nanoparticles obtained by the thin film method were studied closely using MTT assay, flow cytometry and fluorescence microscopy on T98G glioblastoma cell line and modified with surfactants to achieve stability and the ability to bypass the blood-brain barrier. An antitumor agent, paclitaxel, was loaded into cerasomes, which increased its potency and demonstrated increased ability to induce apoptosis in T98G glioblastoma cell culture. Cerasomes loaded with fluorescent dye rhodamine B demonstrated significantly increased fluorescence in brain slices of Wistar rats compared to free rhodamine B. Thin film hydration with Tween 80 addition was established as a more reliable and versatile method for cerasome preparation. Cerasomes increased the antitumor action of paclitaxel toward T98G cancer cells by a factor of 36 and were able to deliver rhodamine B over the blood-brain barrier in rats.

This work presents the synthesis of a new representative of hemicurcuminoids with a nonyloxy substituent (HCur) as a fluorescent amphiphilic structural element of vesicular aggregates based on phosphatidylcholine (PC), phosphatidylserine (PS), and 10,12-pentacosadiynoic acid (PCDA). Both X-ray diffraction analysis of the single crystal and 1H NMR spectra of HCur in organic solvents indicate the predominance of the enol-tautomer of HCur. DFT calculations show the predominance of the enol tautomer HCur in supramolecular assemblies with PC, PS, and PCDA molecules. The results of the molecular modeling show that HCur molecules are surrounded by PC and PS with a rather weak exposure to water molecules, while an exposure of HCur molecules to water is enhanced under its supramolecular assembly with PCDA molecules. This is in good agreement with the higher loading of HCur into PC(PS) vesicles compared to PCDA vesicles converted into polydiacetylene (PDA) ones by photopolymerization. HCur molecules incorporated into HCur-PDA vesicles exhibit greater planarity distortion and hydration effect in comparison with HCur-PC(PS) ones. HCur-PDA is presented as a dual fluorescence-chromatic nanosensor responsive to a change in pH within 7.5–9.5, heavy metal ions and polylysine, and the concentration-dependent fluorescent response is more sensitive than the chromatic one. Thus, the fluorescent response of HCur-PDA allows for the distinguishing between Cd2+ and Pb2+ ions in the concentration range 0–0.01 mM, while the chromatic response allows for the selective sensing of Pb2+ over Cd2+ ions at their concentrations above 0.03 mM.

Amphiphilic calix[4]resorcinarenes are a class of macrocyclic compounds with broad potential utility including nanomedicine. Here the synthesis of new carboxybetaine and carboxybetaine ester calix[4]resorcinarene bearing 4-(dodecyloxy)phenyl groups on the lower rim is presented. The compounds were characterized by 1H-NMR, 13C-NMR, 2D NMR, IR, ESI and elemental analysis. The critical association concentration values are 1.00 × 10−5 and 1.18 × 10−5 mol·L−1 for carboxybetain and ester, respectively. The hemolytic activity of the macrocycles and their cytotoxicity against normal (WI-38, Chang liver) and tumor cells (M-HeLa) are also estimated.

A series of new uncharged conjugates of adenine, 3,6-dimetyl-, 1,6-dimethyl- and 6-methyluracil with 1,2,4-triazole-3-hydroxamic and 1,2,3-triazole-4-hydroxamic acid moieties were synthesized and studied as reactivators of organophosphate-inhibited cholinesterase. It is shown that triazole-hydroxamic acids can reactivate acetylcholinesterase (AChE) inhibited by paraoxon (POX) in vitro, offering reactivation constants comparable to those of pralidoxime (2-PAM). However, in contrast to 2-PAM, triazole-hydroxamic acids demonstrated the ability to reactivate AChE in the brain of rats poisoned with POX. At a dose of 200 mg/kg (i.v.), the lead compound 3e reactivated 22.6 ± 7.3% of brain AChE in rats poisoned with POX. In a rat model of POX-induced delayed neurodegeneration, compound 3e reduced the neuronal injury labeled with FJB upon double administration 1 and 3 h after poisoning. Compound 3e was also shown to prevent memory impairment of POX-poisoned rats as tested in a Morris water maze.

The present work introduces the solvent exchange procedure as a route for conversion of the Cu4I4L2 complex, where the Cu4I4 cluster core is coordinated with two P,N-ligands (L), into an aqueous colloid. The analysis of both colloidal and supernatant phases revealed some losses in CuI going from the initial Cu4I4L2 complex to Cu2I2L3-based nanoparticles. The comparative analysis of IR, 31P NMR spectroscopy, ESI mass-spectrometry and luminescence data argued for a contribution of the “butterfly”-like structures of the Cu2I2 cluster core to Cu2I2L3-based nanoparticles, although the amorphous nature of the latter restricted structure evaluation from the PXRD data. The green luminescence of the colloids revealed their chemical stability under pH variations in the solutions of some amino acids and peptides, and to specify the temperature and concentration conditions triggering the oxidative degradation of the nanoparticles. The spin trap-facilitated ESR study indicated that the oxidative transformations were followed by the generation of reactive oxygen species (ROS). The physiological temperature level (310 K) enhanced the ROS generation by nanoparticles, but the ROS level was suppressed in the solution of GSH at pH = 7.0. The cytotoxicity of nanoparticles was evaluated in the M-HeLa cell line and is discussed in correlation with their cell internalization and intracellular oxidative transformations.

Antimicrobial resistance to modern antibiotics stimulates the search for new ways to synthesize and modify antimicrobial drugs. The development of synthetic approaches that can easily change different fragments of the molecule is a promising solution to this problem. In this work, a synthetic approach was developed to obtain multivalent thiacalix[4]arene derivatives containing different number of amine and hydroxyl groups. A series of macrocyclic compounds in cone, partial cone, and 1,3-alternate stereoisomeric forms containing -NHCH2CH2R (R = NH2, N(CH3)2, and OH) and -N(CH2CH2OH)2 terminal fragments, and their model non-macrocyclic analogues were obtained. The antibacterial activity against Gram-positive (Staphylococcus aureus, Bacillus cereus, and Enterococcus faecalis) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacterial strains and cytotoxicity of the obtained compounds were studied. Structure-activity relationships were established: (1) the macrocyclic compounds had high antibacterial activity, while the monomeric compounds had low activity; (2) the compounds in cone and partial cone conformations had better antibacterial activity compared to the compounds in 1,3-alternate stereoisomeric form; (3) the macrocyclic compounds containing -NHCH2CH2N(CH3)2 terminal fragments had the highest antibacterial activity; (4) introduction of additional terminal hydroxyl groups led to a significant decrease in antibacterial activity; (5) the compounds in partial cone conformation had significant bactericidal activity against all studied cell strains; the best selectivity was observed for the compounds in cone conformation. The mechanism of antibacterial activity of lead compounds with terminal fragments -NHCH2CH2N(CH3)2 was proved using model negatively charged POPG vesicles, i.e., the addition of these compounds led to an increase in the size and zeta potential of the vesicles. The obtained results open up the possibility of using the synthesized macrocyclic compounds as promising antibacterial agents.