Cardioprotective Effect of 2-Ethyl-3-Hydroxy-6-Methylpyridinium 2-Nitroxysuccinate Against Adrenaline/Hydrocortisone-Induced Myocardial Ischemia in Mice: Modulation of Free-Radical Processes in Biomembranes and Monoamine Oxidase A Activity.

Oxidative stress (OS) plays a key role in the development of cardiovascular diseases (CVD) in three major ways: reactive oxygen species (ROS)-induced reduction of nitric oxide (NO) bioavailability, ROS-induced inflammation and ROS-induced mitochondrial dysfunction. Oxidation of lipid molecules under the action of ROS leads to damage to membrane structures, changes the functioning of membrane-bound enzymes, and impairs membrane permeability and stability. An increase in OS results in the occurrence of endothelial dysfunction and drug tolerance, side effects, requiring discontinuation of drugs. All of these are significant problems of cardiotherapy. Therefore, the search for new alternative NO donors continues. The present research was aimed at studying the protective effect of 2-ethyl-3-hydroxy-6-methylpyridinium 2-nitroxysuccinate (NS) on the cardiovascular system on mouse myocardial ischemia (MI) model. The NS hybrid molecule includes a synthetic vitamin B6 analog 2-ethyl-3-hydroxy-6-methylpyridine (an antioxidant) and 2-nitroxysuccinic acid (a source of nitric oxide). Using the electron paramagnetic resonance (EPR) method and biochemical methods, we showed that the pronounced ability of NS to release NO is favorably combines with the capacity to prevent OS due to mechanisms such as suppression of the lipid peroxidation (LPO) process, antiradical activity and inhibition of the mitochondrial membrane-bound monoamine oxidase A (MAO-A). Using histological methods, we established that the administration of NS (10 mg/kg, i.p.) reduces the number of ischemic fibers and protects cardiomyocytes against ischemia injury. Thus, the complex protective effect allows us to consider NS as an alternative NO donor and a candidate for the development of a new pharmaceutical agent for the treatment of CVD.

Synthesis and antifungal activity of new hybrids thiazolo[4,5-d]pyrimidines with (1H-1,2,4)triazole.

Synthesis and antifungal activity of hybrids of thiazolo[4,5-d]pyrimidines with (1H-1,2,4)triazoles are presented. The solubility and lipophilicity of compounds was assessed and it was discovered that compounds with piperazine linker exhibited significant antifungal activity against filamentous and yeast fungi.

Understanding of Relationship between Phospholipid Membrane Permeability and Self-Diffusion Coefficients of Some Drugs and Biologically Active Compounds in Model Solvents.

In this work we measured self-diffusion coefficients of 5 drugs (aspirin, caffeine, ethionamide, salicylic acid, and paracetamol) and 11 biologically active compounds of similar structure in deuterated water and 1-octanol by NMR. It has been found that an increase in the van der Waals volume of the molecules of the studied substances result in reduction of their diffusion mobility in both solvents. The analysis of the experimental data showed the influence of chemical nature and structural isomerization of the molecules on the diffusion mobility. Apparent permeability coefficients of the studied compounds were determined using an artificial phospholipid membrane made of egg lecithin as a model of in vivo absorption. Distribution coefficients in 1-octanol/buffer pH 7.4 system were measured. For the first time the model of the passive diffusion through the phospholipid membrane was validated based on the experimental data. To this end, the passive diffusion was considered as an additive process of molecule passage through the aqueous boundary layer before the membrane and 1-octanol barrier simulating the lipid layer of the membrane.

Solubility, lipophilicity and membrane permeability of some fluoroquinolone antimicrobials.

Aqueous solubility and distribution of ciprofloxacin, enrofloxacin, norfloxacin and levofloxacin antimicrobials drugs in octanol/buffer system has been measured by the isothermal saturation method using buffer solutions pH2.0 and 7.4 in the temperature range of 293.15-313.15K. Thermophysical characteristics for the compounds have been determined by the DSC method. It has been established that the solubility of levofloxacin in these buffers is higher than that of the other fluoroquinolones. HYBOT descriptors for biologically active compounds have been calculated and the impact of the donor-acceptor capacity of the molecules on drugs solubility has been studied. According to the lipophilicity parameter fluoroquinolones are ranged in the following order: enrofloxacin>levofloxacin>ciprofloxacin>norfloxacin. The thermodynamic solubility and distribution functions of the studied compounds have been obtained. The permeability coefficients of the substances through an artificial phospholipid membrane were determined. The drugs with a lower aqueous solubility were estimated to have higher distribution coefficients and membrane permeability.

Synthesis, biological activity, distribution and membrane permeability of novel spiro-thiazines as potent neuroprotectors.

New spiro-derivatives of 1,3-thiazine - potential neuroprotectors have been synthesized. It has been determined that the obtained compounds are biologically active and capable of blocking the glutamate-induced calcium ion uptake into synaptosomes of rat brain cortex. The inhibitory activity of the test substances was shown to depend on the chemical nature and structure of the substituents bound with an exocyclic nitrogen atom. Non-polar alkyl and polar radicals with halogen, oxygen and nitrogen atoms were used as substituents. It is typical of the active spiro-thiazines to have alkyl substituents in ortho- and para-position of the benzene ring. Among the investigated spiro-thiazines it is the derivatives with ethyl- and isopropyl-groups in the aril part of the molecules that are the lead-compounds with a high inhibitory ability. We measured the distribution coefficients of the substances in octanol/buffer and hexane/buffer systems and made conclusions about the ability of the investigated drug-like compounds to penetrate the biological membranes. By using the parabolic model we derived a quadratic equation that allowed us to evaluate quantitatively the inhibitory activity of spiro-thiazines with hydrophobic substituents based on lipophilicity data. We also studied the permeability through the phospholipidic membrane and introduced a correlation equation describing the dependence of the investigated spiro-thiazines activity on the descriptors characterizing the donor-acceptor properties.

Thermodynamics of sorption in the binary liquid crystalline system composed of the poly(propyleneimine) dendrimer and p-n-pentyloxy-p'-cyanobyphenyl by inverse gas chromatography.

A binary system composed of the liquid crystalline poly(propyleneimine) dendrimer and nematic p-n-pentyloxy-p'-cyanobyphenyl has been studied by thermomicroscopy, scanning calorimetry, and inverse gas chromatography. In this system, there is the columnar phase being stable within broad ranges of temperature and component ratio. Dependences of the retention volumes of various solutes, namely, hydrocarbons, alcohols, and amines, on composition of the sorbents are revealed to exhibit the maximum. Thermodynamic functions of sorption of n-alkanes and n-alcohols on the binary sorbents composed of the said liquid crystals have been calculated specifically. Thermodynamic solute-sorbent compatibility characterized by the activity coefficients of the solutes is dependent on the sorbent composition; namely, it is controlled by counterbalancing of the enthalpy or entropy factors. The nonadditive mode of the solute-sorbent interaction is explained by arising of the microdomain nematic structure enclosed in the columnar structure of the dendrimer.