Physicochemical Properties Of Conjugates Research Articles

New Multifunctional Agents for Potential Alzheimer's Disease Treatment Based on Tacrine Conjugates with 2-Arylhydrazinylidene-1,3-Diketones.

Alzheimer's disease (AD) is considered a modern epidemic because of its increasing prevalence worldwide and serious medico-social consequences, including the economic burden of treatment and patient care. The development of new effective therapeutic agents for AD is one of the most urgent and challenging tasks. To address this need, we used an aminoalkylene linker to combine the well-known anticholinesterase drug tacrine with antioxidant 2-tolylhydrazinylidene-1,3-diketones to create 3 groups of hybrid compounds as new multifunctional agents with the potential for AD treatment. Lead compounds of the new conjugates effectively inhibited acetylcholinesterase (AChE, IC50 0.24-0.34 µM) and butyrylcholinesterase (BChE, IC50 0.036-0.0745 µM), with weak inhibition of off-target carboxylesterase. Anti-AChE activity increased with elongation of the alkylene spacer, in agreement with molecular docking, which showed compounds binding to both the catalytic active site and peripheral anionic site (PAS) of AChE, consistent with mixed type reversible inhibition. PAS binding along with effective propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. All of the conjugates demonstrated metal chelating ability for Cu2+, Fe2+, and Zn2+, as well as high antiradical activity in the ABTS test. Non-fluorinated hybrid compounds 6 and 7 also showed Fe3+ reducing activity in the FRAP test. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters acceptable for potential lead compounds at the early stages of anti-AD drug development.

Effects of Grafting Degree on the Physicochemical Properties of Egg White Protein-Sodium Carboxymethylcellulose Conjugates and Their Aerogels

To improve the mechanical strength and oil-loading performances of egg white protein (EWP) aerogel, the effects of different grafting degrees on the modification of EWP by sodium carboxymethylcellulose (CMC-Na) were investigated. After different dry-heat treatment durations (0, 12, 24, 36, and 48 h), the EWP/CMC-Na conjugates with different grafting degrees (noted as EC0, EC12, EC24, EC36, and EC48, respectively) were obtained. Subsequently, the physicochemical properties of the conjugates, as well as the microstructure, mechanical properties, pore parameters, emulsification properties and oil-carrying properties of the conjugated aerogels, were characterized. The results showed that EC12 (with a grafting degree of 8.35%) aerogel possessed a uniform structure, the largest specific surface area, and the best emulsification performance. This facilitated a more robust aerogel (2.05 MPa) with nearly three times the mechanical strength of EWP aerogel. Moreover, this had a positive influence on the efficient loading and stable retention of oil. EC12 aerogel thus achieved an oil absorption capacity of 5.46 g/g aerogel and an oil holding capacity of 31.95%, and both values were nearly 1.7 times higher than those of EWP aerogel. In general, the EWP-based aerogel with a grafting degree of 8.35% had the best mechanical and oil-loading properties.

Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer's disease treatment

We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC50 for AChE = 1.83 ± 0.03 μM (Ki = 1.50 ± 0.12 and αKi = 2.58 ± 0.23 μM). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 ± 0.03 and 0.39 ± 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pKa values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development.

Structural and physicochemical properties of soya bean protein isolate/maltodextrin mixture and glycosylation conjugates

AbstractThe effect of mixture and conjugation with maltodextrin (MD) in aqueous solution on the structural and physicochemical properties of soya bean protein isolate (SPI) was investigated. Although the mixing of MD would not change the distribution of secondary structure and tertiary conformation of SPI, the protein aggregation was promoted through hydrophobic interaction, which resulted in the decrease in solubility and the improvement of gel strength and water holding capacity (WHC) of SPI/MD mixture. However, glycosylation decreased α‐helix and increased β‐structure. The bathochromic shift of the fluorescence emission maximum wavelength for SPI/MD conjugates was promoted, resulting in less compact tertiary conformation. These structural modifications might be the reason for the changes in the physicochemical properties of conjugates. After glycosylation, the surface hydrophobicity and solubility were increased, the average particle size was decreased, and the gelation properties were weakened including gel strength and WHC.

Preparation of an optimized ciprofloxacin-loaded chitosan nanomicelle with enhanced antibacterial activity

Objective: The objective of this study was to evaluate the effect of lipid structure on physicochemical properties of chitosan-fatty acid nanomicelles and prepare an optimum ciprofloxacin-loaded formulation from these conjugates which could enhance the antibacterial effects of drug against some important pathogens like P. aeruginosa.Significance: Nowadays, resistance in infectious diseases is a growing worldwide concern. Nanocarriers can increase the therapeutic index and consequently reduce the antibiotic resistance. By site-specific delivery of drug, the adverse effects of broad-spectrum antibiotics such as ciprofloxacin would be reduced.Methods: Fatty acid grafted chitosan conjugates were synthetized in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. The effects of fatty acid type (stearic acid, palmitic acid, and linoleic acid) on physicochemical properties of conjugates were investigated. Ciprofloxacin was encapsulated in nanomicelles by thin film hydration method. Also, the preparation process was optimized with a central composite design. The antibacterial effect of optimum formulation against P. aeruginosa, K. pneumoniae, and S. pneumoniae species was determined.Results: All conjugates were synthetized with high yield values and the substitution degrees ranged between 2.13 and 35.46%. Ciprofloxacin was successfully encapsulated in nanomicelles. The optimum formulation showed high drug loading (≈ 19%), with particle size of about 260 nm and a sustained release profile of ciprofloxacin. The minimum inhibitory concentrations of ciprofloxacin in optimum formulation against P. aeruginosa and K. pneumoniae species were 4 and 2 times lower in comparison with the free drug, respectively.Conclusions: The antibacterial effect of ciprofloxacin was improved by encapsulation of drug in chitosan nanomicelles.

Synthesis of MCC–PEG Conjugate and Its Evaluation as a Superdisintegrant

PEGylated conjugate of microcrystalline cellulose (MCC) was synthesized by reacting MCC with polyethylene glycol (PEG) 200 in the presence of catalyst at elevated temperature. Conjugation between MCC and PEG was confirmed by FT-IR and (1)H NMR studies. The conjugate showed 61% PEG content increase in molecular weight determined by mass spectroscopy. PEGylation did not improve solubility of cellulose significantly. The physico-chemical properties of conjugate were compared against MCC. This conjugate was evaluated for water vapor uptake isotherms, maximum water saturation, water penetration rate, disintegration time, superdisintegration power, and dissolution study. After comparing its results with that of commercial superdisintegrants, it can be concluded that MCC-PEG conjugate can prove to be a good superdisintegrant.

Effect of Ultrasonic Treatment on the Graft Reaction between Soy Protein Isolate and Gum Acacia and on the Physicochemical Properties of Conjugates

Soy protein isolate (SPI) was grafted with gum acacia (GA) in this work. In comparison with classical heating at high water activity, ultrasound could accelerate the graft reaction between SPI and GA. A degree of graft (DG) of 34 was obtained by ultrasonic treatment for 60 min, whereas 48 h was required with classical heating. Ultrasonic treatment improved the concentration of available free amino groups of SPI. The grafted SPI showed significantly (p < 0.05) higher levels of emulsifying activity index, emulsifying stability index, and surface hydrophobicity than native SPI. The droplet size (D[3,2] and D[4,3]) of SPI emulsion decreased from 8.3 to 2.3 microm and from 25.7 to 7.1 microm through ultrasound-assisted grafting, respectively. Moreover, SPI-GA conjugates gave emulsions exhibiting more stability against creaming than those prepared with only SPI during ambient temperature storage (20 days). Decreases of lysine and arginine contents during the graft reaction indicated that these two amino acid residues attended the covalent linkage between SPI and GA. The results of secondary structure suggested that grafted SPI had decreased alpha-helix and beta-sheet levels and increased unordered coils level.