Design of novel water-soluble isoxazole-based antimicrobial agents and evaluation of their cytotoxicity and acute toxicity.

Based on the readily available 3-organyl-5-(chloromethyl)isoxazoles, a number of previously unknown water-soluble conjugates of isoxazoles with thiourea, amino acids, some secondary and tertiary amines, and thioglycolic acid were synthesized. The bacteriostatic activity of aforementioned compounds has been studied against Enterococcus durans B-603, Bacillus subtilis B-407, Rhodococcus qingshengii Ac-2784D, and Escherichia coli B-1238 microorganisms (provided by All-Russian Collection of Microorganisms, VKM). The influence of the nature of the substituents in positions 3 and 5 of the isoxazole ring on the antimicrobial activity of the obtained compounds has been determined. It is found that the highest bacteriostatic effect is observed for compounds containing 4-methoxyphenyl or 5-nitrofuran-2-yl substituents in position 3 of the isoxazole ring as well as methylene group in position 5 bearing residues of l-proline or N-Ac-l-cysteine (5a-d, MIC 0.06-2.5 µg/ml). The leading compounds showed low cytotoxicity on normal human skin fibroblast cells (NAF1nor) and low acute toxicity on mice in comparison with the well-known isoxazole-containing antibiotic oxacillin.

Pd-catalyzed cross-coupling of arabinogalactan propargyl ethers with 5-bromosalicylic acid.

New salicylate derivatives of arabinogalactan have been synthesized in up to 90% yield by cross-coupling of propargyl ethers of arabinogalactan with 5-bromosalicylic acid salts. The reaction proceeds in the presence of the catalytic system Pd(PPh3)4/PPh3 with CuBr (CuI), and piperidine or 1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU) as a base in DMSO at 70-95 °Ð¡. The propargyl groups of the starting arabinogalactan ethers are converted into propinylsalicylate ones with 35 and 50% conversion depending on the nature of the base used. Degree of arabinogalactan substitution with propynyl salicylate fragments reaches 1.0 and 0.7 in the reactions with piperidine and DBU, respectively. In the case of piperidine, along with the main process, intensive unprecedented (for Sonogashira reaction) hydroamination of propargyl groups is also observed, followed by hydrolysis of unstable enamines. The products have been characterized by IR, 1Н and 13С NMR, UV spectroscopy as well as elemental analysis and gel permeation chromatography. Salicylate derivatives of arabinogalactan show high activity in prolonging the activated partial thromboplastin time (APTT), whereas neither the arabinogalactan nor propargyl ethers of arabinogalactan nor salicylic acid salts have obvious effects.

Bactericidal action of Ag(0)-antithrombotic sulfated arabinogalactan nanocomposite: coevolution of initial nanocomposite and living microbial cell to a novel nonliving nanocomposite.

The first step of the interaction between Ag(0) nanocomposite with antiatherogenic anticoagulant sulfated arabinogalactan involves the transportation and concentration of antimicrobial nanosilver in the bacteria target (E. coli). Further, the silver ions in dynamic equilibrium with metal backbone of the nanoparticles (NPs) reach the membrane surface and bond with this surface. Simultaneously, the redox interaction of silver cations with main reducing components of the membrane surface is triggered to afford the zero-valence silver atoms that are stabilized to form metal clusters, or new NPs of silver. Size and morphology of these NPs are defined by specific conditions of their synthesis involving the microorganism membrane: The Ag(0) NPs formed on membranes and fragments of the destroyed bacteria have other morphology (including triangular) and smaller sizes in comparison with the initial nanocomposite that additionally enhances antimicrobial activity of such NPs. FROM THE CLINICAL EDITOR: This study investigates silver nanocompistes (Ag(0) NPs) and their interaction with antiatherogenic anticoagulant sulfated arabinogalactan. A complex set of interactions are described, leading to Ag(0)NPs formed on membranes and fragments of destroyed bacteria demonstrating altered morphology and smaller sizes in comparison with the initial nanocomposite that additionally enhances antimicrobial activity of such NPs.