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Conditions have been established for the direct reaction of thiosemicarbazides with carboxylic acids in the presence of polyphosphate ester (PPE) to synthesize 1,2,4-triazole-3-thiol derivatives. The synthesis involves two consecutive steps: (i) acylation of the thiosemicarbazide with a carboxylic acid in chloroform in the presence of PPE at 90 °C using a hydrothermal reaction vessel, followed by (ii) cyclodehydration of the acylation product by treatment with an aqueous alkali solution. Using this new synthetic approach, 15 derivatives of 1,2,4-triazole-3-thiol were obtained, five of which were synthesized for the first time. The structures of the synthesized compounds were confirmed by NMR spectroscopy and mass spectrometry.

Amoxicillin is one of the most widely used antibacterial drugs. It is known to be the first reason of adverse effects caused by medications in human and animals. Antibacterial drugs, combined with a delivery agent, could provide desirable therapeutic effects with decreased toxicity and reduce the emergence of antimicrobial resistant bacteria. The aim of this study was to compare the toxicity of amoxicillin, polyphosphate ester amoxicillin complex and phosphate ester on mice. Synthesis of the polyphosphate ester (P4) was performed via polycondensation technique, using PEG-400. Animal studies were performed in accordance with the European Convention for the Protection of Vertebrate Animals (Strasbourg, 1986). BALB/c mice were treated by intramuscular injection with saline 0.2 mL (control), amoxicillin 0.2 mL (15 mg/kg); polyphosphate ester complex with amoxicillin 0.2 mL (with amoxicillin content 15 mg/kg) and polyphosphate ester 0.2 mL. Blood biochemical analysis and histology of liver, spleen and kidney were used to assess toxicity. Blood biochemical analysis indicates that P4 did not induce changes in liver and kidneys. Specifically, blood biochemical indicis that represent functional state and cell structure of these organs were within normal physiological values: ALT (56 ± 15.96 U/L), AST (265 ± 37.50U/L), urea (4.4 ± 1.45 mmol/L), creatinine 62.8 ± 5.17 mmol/L, cholesterol 3.5 ± 0.56 mmol/L, total protein 55.9 ± 4.60 g/L, glucose 8.1 ± 0.55 mmol/L. However, the analysis of organ to body weight ratio showed decreased liver ratio (p ≤ 0.05) in mice injected with polyphosphate ester (P4). Histological examination of the liver didn’t show severe pathological changes. There were single places with mild portal vein inflammation in liver of mice receiving amoxicillin and amoxicillin complexed with polyphosphate ester. P4 separately in some places caused cell cytoplasm granulation in liver. No spleen alterations were observed. Overall, the results of this study showed that P4 polyphosphate ester alone and in complex with amoxicillin does not cause renal, hepatic and splenic toxicity in mice. Thus, polyphosphate ester P4 can serve as a safe drug carrier for antimicrobial drugs. It is planned to carry out more extensive studies on other animal species to study its biocompatibility and effectiveness of antimicrobial activity in a complex with antimicrobials.

The main purpose of the study was the development of a new method for synthesis of 1,3,4-thiadiazol-2-amine derivatives in a one-pot manner using the reaction between a thiosemicarbazide and carboxylic acid without toxic additives such as POCl3 or SOCl2. The reaction was investigated in the presence of polyphosphate ester (PPE). It was found that, in the presence of PPE, the reaction between the thiosemicarbazide and carboxylic acid proceeds in one-pot through three steps with the formation of corresponding 2-amino-1,3,4-thiadiazole. Using the developed approach five, 2-amino-1,3,4-thiadiazoles were synthesized. The structures of all compounds were proven by mass spectrometry, IR, and NMR spectroscopies.

Hydrogen-bonding catalytic reactions have gained great interest. Herein, a hydrogen-bond-assisted three-component tandem reaction for the efficient synthesis of N-alkyl-4-quinolones is described. This novel strategy features the first proof of polyphosphate ester (PPE) as a dual hydrogen-bonding catalyst and the use of readily available starting materials for the preparation of N-alkyl-4-quinolones. The method provides a diversity of N-alkyl-4-quinolones in moderate to good yields. The compound 4h demonstrated good neuroprotective activity against N-methyl-ᴅ-aspartate (NMDA)-induced excitotoxicity in PC12 cells.

Prolonged use of antibiotics can cause toxicity in human and animal cells and lead to the development of antibiotic resistance. The development of drug delivery systems for enhanced antibacterial properties of antibiotics could reduce toxic effects and minimize the development of resistance. The aim of this study was to evaluate the effectiveness of oxytetracycline in complexes with new polyphosphate ester-type transporters and to investigate the antimicrobial effect of these complexes on Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus growth in vitro. Two polyphosphate ester-type transporters with different molecular weights were synthesized, and oxytetracycline was attached through the phosphorus groups. To determine the sensitivities of microorganisms, oxytetracycline hydrochloride and oxytetracycline complexes with polyphosphate ester-type transporters (P4 and P6) were added to liquid and solid media with E. coli, P. aeruginosa, and S. aureus in different doses. Oxytetracycline in complex with polyphosphate ester-type transporters at low doses (2.3 to 3.8 μg/disk or μg/mL) in both solid and liquid media inhibits the growth of S. aureus more effectively than oxytetracycline alone. The maximum influence on E. coli growth on solid media is observed at a dose of 8 μg/disk of oxytetracycline in combination with both P4 and P6 polyphosphate ester-type transporters. P. aeruginosa growth under the influence of oxytetracycline in combination with polyphosphate-ester type transporters in a liquid medium depends on the dose of antibiotic and the day of cultivation.

Amidoalkyl naphthols are synthesized via a simple, one-pot, three-component reaction between aldehydes, 2-naphthol and amides or ureas using polyphosphate ester (PPE) as a reaction mediator under solvent-free conditions in good to excellent yields. High yields, short reaction time, easy work-up, elimination of solvents and toxic catalysts are the advantages of this procedure.

In this investigation, a novel compound (NCSAPP) based on chitosan (CS) and ammonium polyphosphate (APP) was synthesized by employing solutions of chitosan and ammonium polyphosphate. The synthesized compound was characterized using FTIR, PXRD, XPS, FESEM, EDX, TGA and a Micro Calorimeter. Finally, NCSAPP was inserted into vinyl ester resin and study the thermal and flammable properties. The FTIR spectrum of NCSAPP suggested the reaction between chitosan and APP and that formation of –NH 3+ –O − P– bonds with the –NH 3 + peak at 1533 cm −1 . The XPS spectrum showed a characteristic peak at 401.36 eV corresponding to the N 1s of –NH 3+ . PXRD suggested the amorphous nature of NCSAPP. FESEM coupled with EDX depicted a rough morphological pattern for NCSAPP with C, N, O and P. The thermal decomposition of NCSAPP was observed to be active at lower temperatures. However, at elevated temperatures (> 315 °C), a slow degradation rate with significantly higher thermal stability than that of CS was observed. The peak release rate (16.9 w/g) and total heat release (0.9 kJ/g) were significantly lower than those of CS. Besides, vinyl ester composite of NCSAPP obtained superior fire-retardant properties than vinyl ester composites of CS and APP. The obtained results indicate that NCSAPP can be applied in thermal applications operating at high temperatures.

Inositol tris/tetrakis phosphate kinases (IP3-4K) in the human fungal priority pathogens, Cryptococcus neoformans (CnArg1) and Candida albicans (CaIpk2), convey numerous virulence functions, yet it is not known whether the IP3-4K catalytic activity or a scaffolding role is responsible. We therefore generated a C. neoformans strain with a non-functional kinase, referred to as the dead-kinase (dk) CnArg1 strain (dkArg1). We verified that, although dkARG1 cDNA cloned from this strain produced a protein with the expected molecular weight, dkArg1 was catalytically inactive with no IP3-4K activity. Using recombinant CnArg1 and CaIpk2, we confirmed that, unlike the IP3-4K homologs in humans and Saccharomyces cerevisiae, CnArg1 and CaIpk2 do not phosphorylate the lipid-based substrate, phosphatidylinositol 4,5-bisphosphate, and therefore do not function as class I PI3Ks. Inositol polyphosphate profiling using capillary electrophoresis-electrospray ionization-mass spectrometry revealed that IP3 conversion is blocked in the dkArg1 and ARG1 deletion (Cnarg1Δ) strains and that 1-IP7 and a recently discovered isomer (4/6-IP7) are made by wild-type C. neoformans. Importantly, the dkArg1 and Cnarg1Δ strains had similar virulence defects, including suppressed growth at 37°C, melanization, capsule production, and phosphate starvation response, and were avirulent in an insect model, confirming that virulence is dependent on IP3-4K catalytic activity. Our data also implicate the dkArg1 scaffold in transcriptional regulation of arginine metabolism but via a different mechanism to S. cerevisiae since CnArg1 is dispensable for growth on different nitrogen sources. IP3-4K catalytic activity therefore plays a dominant role in fungal virulence, and IPK pathway function has diverged in fungal pathogens.IMPORTANCEThe World Health Organization has emphasized the urgent need for global action in tackling the high morbidity and mortality rates stemming from invasive fungal infections, which are exacerbated by the limited variety and compromised effectiveness of available drug classes. Fungal IP3-4K is a promising target for new therapy, as it is critical for promoting virulence of the human fungal priority pathogens, Cryptococcus neoformans and Candida albicans, and impacts numerous functions, including cell wall integrity. This contrasts to current therapies, which only target a single function. IP3-4K enzymes exert their effect through their inositol polyphosphate products or via the protein scaffold. Here, we confirm that the IP3-4K catalytic activity of CnArg1 promotes all virulence traits in C. neoformans that are attenuated by ARG1 deletion, reinforcing our ongoing efforts to find inositol polyphosphate effector proteins and to create inhibitors targeting the IP3-4K catalytic site, as a new antifungal drug class.

The src homology 2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 are two proteins involved in intracellular signaling pathways and have been linked to the pathogenesis of several diseases. Both protein paralogs are well known for their involvement in the formation of various kinds of cancer. SHIP1, which is expressed predominantly in hematopoietic cells, has been implicated as a tumor suppressor in leukemogenesis especially in myeloid leukemia, whereas SHIP2, which is expressed ubiquitously, has been implicated as an oncogene in a wider variety of cancer types and is suggested to be involved in the process of metastasis of carcinoma cells. However, there are numerous other diseases, such as inflammatory diseases as well as allergic responses, Alzheimer’s disease, and stroke, in which SHIP1 can play a role. Moreover, SHIP2 overexpression was shown to correlate with opsismodysplasia and Alzheimer’s disease, as well as metabolic diseases. The SHIP1-inhibitor 3-α-aminocholestane (3AC), and SHIP1-activators, such as AQX-435 and AQX-1125, and SHIP2-inhibitors, such as K161 and AS1949490, have been developed and partly tested in clinical trials, which indicates the importance of the SHIP-paralogs as possible targets in the therapy of those diseases. The aim of this article is to provide an overview of the current knowledge about the involvement of SHIP proteins in the pathogenesis of cancer and other human diseases and to create awareness that SHIP1 and SHIP2 are more than just tumor suppressors and oncogenes.

This study focused on the effects of novel chitosan-ammonium polyphosphate, chitosan, and ammonium polyphosphate additives on the flammable properties of a vinyl ester matrix. A general mechanical process used for reinforcing additives within the matrix, and composites fabricated by the solution casting method through a general mechanical process. The influence of the additives on the resin observed through Fourier transform infrared spectroscopy, field-emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, and pore size/surface area evaluation of the additives using the Brunauer–Emmett–Teller analysis. The effect of the different amounts (1, 2, and 3 wt%) of additives on the flammability (horizontal and vertical burn test [UL94], LOI and microcalorimeter test), thermal, and mechanical (dynamic mechanical analysis and flexural test) properties of the vinyl ester composites were investigated. Reinforcement by 3 wt% NCSAPP resulted in an excellent fire extinguishing property (UL-94) with a low peak heat release rate (451 W/g) and appreciably improved mechanical properties. Hence, this study is suitable for the development of sub-structural materials.