Synthesis and diverse biological activity profile of triethyl-ammonium isatin-3-hydrazones

A series of biorelevant triethylammonium isatin hydrazones containing various substituents in the aromatic fragment have been synthesized. Their structure and composition were confirmed by NMR- and IR-spectroscopies, mass-spectrometry and elemental analysis. It was found that some representatives show activity against Staphylococcus aureus and Bacillus cereus higher or at the level of norfloxacin, including methicillin-resistant Staphylococcus aureus strains. The study also showed low hemo- and cytotoxicity (Chang Liver) and high antiaggregatory and anticoagulant activity of these compounds. The high potential of new ammonium isatin-3-acylhydrazones in the search for antimicrobial activity against phytopathogens of bacterial and fungal nature has been shown for the first time

Transdermal Delivery of 2-PAM as a Tool to Increase the Effectiveness of Traditional Treatment of Organophosphate Poisoning

For the first time, the efficacy of post-exposure treatment of organophosphate (OP) poisoning was increased by transdermal delivery of acetylcholinesterase (AChE) reactivator pyridine-2-aldoxime methochloride (2-PAM) as a preventive countermeasure. By selecting the optimal ratio of components, classical transfersomes (based on soybean phosphatidylcholine and Tween 20) and modified transfersomes (based on soybean phosphatidylcholine, Tween 20 and pyrrolidinium cationic surfactants with different hydrocarbon tail lengths) were obtained for 2-PAM encapsulation. Transfersomes modified with tetradecylpyrrolidinium bromide showed the best results in encapsulation efficiency and sustained release of 2-PAM from vesicles. Using Franz cells, it was found that the incorporation of surfactants into PC liposomes results in a more prolonged release of 2-PAM through the rat skin. Transfersomes containing 2-PAM, after exhaustive physical and chemical characterization, were embedded in a gel based on Carbopol® 940. A significantly high degree of erythrocyte AChE reactivation (23 ± 7%) was shown for 2-PAM in unmodified transfersomes in vivo. Preliminary transdermal administration of 2-PAM 24 h before emergency post-exposure treatment of OP poisoning leads to an increase in the survival rate of rats from 55% to 90%

Sterically Hindered Quaternary Phosphonium Salts (QPSs): Antimicrobial Activity and Hemolytic and Cytotoxic Properties

Structure–activity relationships are important for the design of biocides and sanitizers. During the spread of resistant strains of pathogenic microbes, insights into the correlation between structure and activity become especially significant. The most commonly used biocides are nitrogen-containing compounds; the phosphorus-containing ones have been studied to a lesser extent. In the present study, a broad range of sterically hindered quaternary phosphonium salts (QPSs) based on tri-tert-butylphosphine was tested for their activity against Gram-positive (Staphylococcus aureus, Bacillus cereus, Enterococcus faecalis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria and fungi (Candida albicans, Trichophyton mentagrophytes var. gypseum). The cation structure was confirmed to determine their biological activity. A number of QPSs not only exhibit high activity against both Gram-positive and -negative bacteria but also possess antifungal properties. Additionally, the hemolytic and cytotoxic properties of QPSs were determined using blood and a normal liver cell line, respectively. The results show that tri-tert-butyl(n-dodecyl)phosphonium and tri-tert-butyl(n-tridecyl)phosphonium bromides exhibit both low cytotoxicity against normal human cells and high antimicrobial activity against bacteria, including methicillin-resistant strains S. aureus (MRSA). The mechanism of QPS action on microbes is discussed. Due to their high selectivity for pathogens, sterically hindered QPSs could serve as effective tunable biocides

Novel Hybrid Compounds Containing Benzofuroxan and Aminothiazole Scaffolds: Synthesis and Evaluation of Their Anticancer Activity

A series of novel hybrid compounds containing benzofuroxan and 2-aminothiazole moieties are synthesized via aromatic nucleophilic substitution reaction. Possible reaction pathways have been considered quantum-chemically, which allowed us to suggest the most probable products. The quantum chemical results have been proved by X-ray data on one compound belonging to the synthesized series. It was shown that the introduction of substituents to both the thiazole and amine moieties of the compounds under study strongly influences their UV/Vis spectra. Initial substances and obtained hybrid compounds have been tested in vitro as anticancer agents. Target compounds showed selectivity towards M-HeLa tumor cell lines and were found to be more active than starting benzofuroxan and aminothiazoles. Furthermore, they are considerably less toxic to normal liver cells compared to Tamoxifen. The mechanism of action of the studied compounds can be associated with the induction of apoptosis, which proceeds along the mitochondrial pathway. Thus, new hybrids of benzofuroxan are promising candidates for further development as anticancer agents

Supramolecular Self-Assembly of Porphyrin and Metallosurfactant as a Drug Nanocontainer Design

The combined method of treating malignant neoplasms using photodynamic therapy and chemotherapy is undoubtedly a promising and highly effective treatment method. The development and establishment of photodynamic cancer therapy is closely related to the creation of sensitizers based on porphyrins. The present study is devoted to the investigation of the spectroscopic, aggregation, and solubilization properties of the supramolecular system based on 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (TSPP) and lanthanum-containing surfactant (LaSurf) in an aqueous medium. The latter is a complex of lanthanum nitrate and two cationic amphiphilic molecules of 4-aza-1-hexadecylazoniabicyclo[2.2.2]octane bromide. The mixed TSPP–LaSurf complexes can spontaneously assemble into various nanostructures capable of binding the anticancer drug cisplatin. Morphological behavior, stability, and ability to drug binding of nanostructures can be tailored by varying the molar ratio and the concentration of components. The guest binding is shown to be additional factor controlling structural rearrangements and properties of the supramolecular TSPP–LaSurf complexes

Silica-Supported Assemblage of CuII Ions with Carbon Dots for Self-Boosting and Glutathione-Induced ROS Generation

The present work introduces coordinative binding of CuII ions with both amino-functionalized silica nanoparticles (SNs) and green-emitting carbon dots (CDs) as the pregrequisite for the CuII-assisted self-assembly of the CDs at the surface of the SNs. The produced composite SNs exhibit stable in time stimuli-responsive green fluorescence derived from the CuII-assisted assemblage of CDs. The fluorescence response of the composite SNs is sensitive to the complex formation with glutathione (GSH), enabling them to detect it with the lower limit of detection of 0.15 μM. The spin-trap-facilitated electron spin resonance technique indicated that the composite SNs are capable of self-boosting generation of ROS due to CuII→CuI reduction by carbon in low oxidation states as a part of the CDs. The intensity of the ESR signals is enhanced under the heating to 38 °C. The intensity is suppressed at the GSH concentration of 0.35 mM but is enhanced at 1.0 mM of glutathione, while it is suppressed once more at the highest intracellular concentration level of GSH (10 mM). These tendencies reveal the concentrations optimal for the scavenger or reductive potential of GSH. Flow cytometry and fluorescence and confocal microscopy methods revealed efficient cell internalization of SNs-NH2-CuII-CDs comparable with that of “free” CDs

The Highly Regioselective Synthesis of Novel Imidazolidin-2-Ones via the Intramolecular Cyclization/Electrophilic Substitution of Urea Derivatives and the Evaluation of Their Anticancer Activity

A series of novel 4-(het)arylimidazoldin-2-ones were obtained by the acid-catalyzed reaction of (2,2-diethoxyethyl)ureas with aromatic and heterocyclic C-nucleophiles. The proposed approach to substituted imidazolidinones benefits from excellent regioselectivity, readily available starting materials and a simple procedure. The regioselectivity of the reaction was rationalized by quantum chemistry calculations and control experiments. The anti-cancer activity of the obtained compounds was tested in vitro

Therapy of Organophosphate Poisoning via Intranasal Administration of 2-PAM-Loaded Chitosomes

Chitosan-decorated liposomes were proposed for the first time for the intranasal delivery of acetylcholinesterase (AChE) reactivator pralidoxime chloride (2-PAM) to the brain as a therapy for organophosphorus compounds (OPs) poisoning. Firstly, the chitosome composition based on phospholipids, cholesterol, chitosans (Cs) of different molecular weights, and its arginine derivative was developed and optimized. The use of the polymer modification led to an increase in the encapsulation efficiency toward rhodamine B (RhB; ~85%) and 2-PAM (~60%) by 20% compared to conventional liposomes. The formation of monodispersed and stable nanosized particles with a hydrodynamic diameter of up to 130 nm was shown using dynamic light scattering. The addition of the polymers recharged the liposome surface (from −15 mV to +20 mV), which demonstrates the successful deposition of Cs on the vesicles. In vitro spectrophotometric analysis showed a slow release of substrates (RhB and 2-PAM) from the nanocontainers, while the concentration and Cs type did not significantly affect the chitosome permeability. Flow cytometry and fluorescence microscopy qualitatively and quantitatively demonstrated the penetration of the developed chitosomes into normal Chang liver and M-HeLa cervical cancer cells. At the final stage, the ability of the formulated 2-PAM to reactivate brain AChE was assessed in a model of paraoxon-induced poisoning in an in vivo test. Intranasal administration of 2-PAM-containing chitosomes allows it to reach the degree of enzyme reactivation up to 35 ± 4%

Synthesis, Self-Assembly in Crystalline Phase and Anti-Tumor Activity of 2-(2-/4-Hydroxybenzylidene)thiazolo[3,2-a]pyrimidines

A series of new thiazolo[3,2-a]pyrimidines different by aryl substituents in 2 and 5 positions are synthesized and characterized in solution as well as in the crystalline phase using 1H and 13C NMR-, IR-spectroscopies, mass-spectrometry methods, and single crystal X-ray diffraction (SCXRD). The SCXRD study revealed the role of intermolecular H-bonding in the formation of supramolecular architectures (racemic monomers, centrosymmetric racematic dimers, or homochiral 1D chains) of obtained thiazolo[3,2-a]pyrimidines derivatives depending on solvents (aprotic DMSO or protic EtOH) used upon the crystallization process. Moreover, the in vitro study of cytotoxicity toward different tumor cells showed their high or moderate efficiency with moderate cytotoxicity against normal liver cells which allows to consider the obtained thiazolo[3,2-a]pyrimidine derivatives as promising candidates for application as antitumor agents

Rational Design 2-Hydroxypropylphosphonium Salts as Cancer Cell Mitochondria-Targeted Vectors: Synthesis, Structure, and Biological Properties

It has been shown for a wide range of epoxy compounds that their interaction with triphenylphosphonium triflate occurs with a high chemoselectivity and leads to the formation of (2-hydroxypropyl)triphenylphosphonium triflates 3 substituted in the 3-position with an alkoxy, alkylcarboxyl group, or halogen, which were isolated in a high yield. Using the methodology for the disclosure of epichlorohydrin with alcohols in the presence of boron trifluoride etherate, followed by the substitution of iodine for chlorine and treatment with triphenylphosphine, 2-hydroxypropyltriphenylphosphonium iodides 4 were also obtained. The molecular and supramolecular structure of the obtained phosphonium salts was established, and their high antitumor activity was revealed in relation to duodenal adenocarcinoma. The formation of liposomal systems based on phosphonium salt 3 and L-α-phosphatidylcholine (PC) was employed for improving the bioavailability and reducing the toxicity. They were produced by the thin film rehydration method and exhibited cytotoxic properties. This rational design of phosphonium salts 3 and 4 has promising potential of new vectors for targeted delivery into mitochondria of tumor cells