Isatin-3-acylhydrazones with Enhanced Lipophilicity: Synthesis, Antimicrobial Activity Evaluation and the Influence on Hemostasis System.

Water-soluble trialkylammonium isatin-3-hydrazone derivatives bearing phenolic substituent were easily synthesized with high yields. XRD studies confirmed the presence of these compounds as trans-(Z)-isomers in a crystal. It was shown that an increase in the lipophilicity of the cationic center leads to an increase in activity against Gram-positive bacteria Staphylococcus aureus and Bacillus cereus, including methicillin-resistant Staphylococcus aureus (MRSA) strains. The MIC values of all compounds turned out to be 2-100 times higher than the MIC of norfloxacin against the MRSA strains in the absence of hemo- and cytotoxicity. Antiaggregation and anticoagulation properties were in vitro better than for acetylsalicylic acid and sodium heparin drugs. It has been shown by UV spectroscopy and fluorescence microscopy that the mechanism of antimicrobial action of new acylhydrazones is associated with their ability to destroy the bacterial cell membrane.

Bi-functional sterically hindered phenol lipid-based delivery systems as potential multi-target agents against Alzheimer's disease via an intranasal route.

New lipid-based nanomaterials and multi-target directed ligands (MTDLs) based on sterically hindered phenol, containing a quaternary ammonium moiety (SHP-s-R, with s = 2,3) of varying hydrophobicity (R = CH2Ph and CnH2n+1, with n = 8, 10, 12, 16), have been prepared as potential drugs against Alzheimer's disease (AD). SHP-s-R are inhibitors of human cholinesterases with antioxidant properties. The inhibitory potency of SHP-s-R and selectivity ratio of cholinesterase inhibition were found to significantly depend on the length of the methylene spacer (s) and alkyl chain length. The compound SHP-2-16 showed the best IC50 for human AChE and the highest selectivity, being 30-fold more potent than for human BChE. Molecular modeling of SHP-2-16 binding to human AChE suggests that this compound is a dual binding site inhibitor that interacts with both the peripheral anionic site and catalytic active site. The relationship between self-assembly parameters (CMC, solubilization capacity, aggregation number), antioxidant activity and a toxicological parameter (hemolytic action on human red blood cells) was investigated. Two sterically hindered phenols (SHP-2-Bn and SHP-2-R) were loaded into L-α-phosphatidylcholine (PC) nanoparticles by varying the SHP alkyl chain length. For the brain AChE inhibition assay, PC/SHP-2-Bn/SHP-2-16 nanoparticles were administered to rats intranasally at a dose of 8 mg kg-1. The Morris water maze experiment showed that scopolamine-induced AD-like dementia in rats treated with PC/SHP-2-Bn/SHP-2-16 nanoparticles was significantly reduced. This is the first example of cationic SHP-phospholipid nanoparticles for inhibition of brain cholinesterases realized by the use of intranasal administration. This route has promising potential for the treatment of AD.

Ammonium-Charged Sterically Hindered Phenols with Antioxidant and Selective Anti-Gram-Positive Bacterial Activity.

The increase in the resistance of pathogens, in particular Staphylococcus aureus, to the action of antibiotics necessitates the search for new readily available and non-toxic drugs. In solving this problem, phenolic acylhydrazones have high potential. In this communication, the synthesis of quaternary ammonium compounds containing a differently substituted phenolic moiety has been performed. An initial study of antimicrobial activity showed that these compounds are highly selective against S. aureus and B. cereus. The highest activity (MIC 2.0 µm) was shown by hydrazones containing a catechol fragment. These compounds are more than 3-fold more active against S. aureus and 3-10-fold more active against B. cereus than norfloxacin. Low hemolytic and high antioxidant activities of all new compounds were also established.

Design, synthesis, and biological activity of novel ammonium salts containing sterically hindered phenolic fragment and phosphoryl group.

Here, we present an approach to novel "hybrid" biologically active compounds based on a combination of sterically hindered phenol and ammonium pharmacophores in a single molecule. The novel target ammonium salts were obtained by the reaction of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-(2-(dimethylamino)alkyl)propanamide with aliphatic bromides or by the reaction of phosphorylated methylenequinones with diamines followed by alkylation with organic bromides. A series of twenty-three novel multifunctional ammonium salts that contain a sterically hindered phenolic fragment were assessed for antimicrobial, cytotoxic and antioxidant activity. The compounds exhibited antimicrobial activity against Staphylococcus aureus ATCC 209p, Bacillus cereus ATCC 8035, Escherichia coli CDC F-50, Pseudomonas aeruginosa ATCC 9027, Aspergillus niger BKMF-1119, Trichophyton mentagrophytes var. gypseum 1773, and Candida albicans 855-653 in the concentration range of 442-0.70 µM. The maximum activity of an ammonium salt among all the types of structure was observed in cases in which a decyl radical was present on the onium nitrogen atom. The most active compounds exhibited antioxidant activity at levels of 0.25 and 0.50 mM and did not display cytotoxic properties towards WI-38 (human embryonic lung cells) and Chang liver (human liver cells) cell lines in the concentration range of 0.70-11.3 µM.