Antioxidants in the retina and vitreous — current state of knowledge

In the healthy organism, there is a constant balance between the formation and neutralization of free radicals. Oxidative stress is a result of free radicals’ production and naturalization imbalance, in favor of the free radicals’ high concentration. Literature suggests the existence of the relationship between decreased intraocular antioxidant capacity and ocular diseases. Retina and the photoreceptors in particularl, are susceptible to oxygen deficiency due to their great oxygen consumption. The aim of this review was to describe the relationship between oxidative stress and the most common vitreoretinal disorders. The authors focused on four ocular diseases such as vitreous degeneration, rhegmatogenous retinal detachment, age-related macular degeneration and diabetic retinopathy. It was widely proven that high oxidative stress damages retina by the acceleration of photoreceptors and ganglion cells apoptosis. Available data suggesting that substances scavenging oxidative stress may be effective in slowing down the progression of these degenerative ocular diseases. However, the effects of antioxidants treatment are ambiguous, successful results of experimental studies lead straight to clinical use in human in the future

Combined Micellar Liquid Chromatography Technique and QSARs Modeling in Predicting the Blood–Brain Barrier Permeation of Heterocyclic Drug-like Compounds

The quantitative structure–activity relationship (QSAR) methodology was used to predict the blood–brain permeability (log BB) for 65 synthetic heterocyclic compounds tested as promising drug candidates. The compounds were characterized by different descriptors: lipophilicity, parachor, polarizability, molecular weight, number of hydrogen bond acceptors, number of rotatable bonds, and polar surface area. Lipophilic properties of the compounds were evaluated experimentally by micellar liquid chromatography (MLC). In the experiments, sodium dodecyl sulfate (SDS) as the effluent component and the ODS-2 column were used. Using multiple linear regression and leave-one-out cross-validation, we derived the statistically significant and highly predictive quantitative structure–activity relationship models. Thus, this study provides valuable information on the expected properties of the substances that can be used as a support tool in the design of new therapeutic agents

An Insight into Fluorinated Imines and Hydrazones as Antibacterial Agents

Fluorinated imines (Schiff bases) and fluorinated hydrazones are of particular interest in medicinal chemistry due to their potential usefulness in treating opportunistic strains of bacteria that are resistant to commonly used antibacterial agents. The present review paper is focused on these fluorinated molecules revealing strong, moderate or weak in vitro antibacterial activities, which have been reported in the scientific papers during the last fifteen years. Fluorinated building blocks and reaction conditions used for the synthesis of imines and hydrazones are mentioned. The structural modifications, which have an influence on the antibacterial activity in all the reported classes of fluorinated small molecules, are highlighted, focusing mainly on the importance of specific substitutions. Advanced research techniques and innovations for the synthesis, design and development of fluorinated imines and hydrazones are also summarized

Anti-Tumor Active Isopropylated Fused Azaisocytosine-Containing Congeners Are Safe for Developing <i>Danio rerio</i> as Well as Red Blood Cells and Activate Apoptotic Caspases in Human Breast Carcinoma Cells

New isopropylated fused azaisocytosine-containing congeners (I–VI) have previously been reported as promising anticancer drug candidates, so further research on these molecules in the preclinical development phase is fully justified and necessary. For this reason, in the present paper, we assess the toxicity/safety profiles of all the compounds using Danio rerio and red blood cell models, and examine the effect of the most selective congeners on the activation of apoptotic caspases in cancer and normal cells. In order to evaluate the effect of each molecule on the development of zebrafish embryos/larvae and to select the safest compounds for further study, various phenotypic parameters (i.e., mortality, hatchability, heart rate, heart oedema, yolk sac utilization, swim bladder development and body shape) were observed, and the half maximal lethal concentration, the maximal non-lethal concentration and no observed adverse effect concentration for each compound were established. The effect of all the isopropylated molecules was compared to that of an anticancer agent pemetrexed. The lipophilicity-dependent structure–toxicity correlations were also determined. To establish the possible interaction of the compounds with red blood cells, an ex vivo hemolysis test was performed. It was shown that almost all of the investigated isopropylated congeners have no adverse phenotypic effect on zebrafish development during five-day exposure at concentrations up to 50 μM (I–III) or up to 20 μM (IV–V), and that they are less toxic for embryos/larvae than pemetrexed, demonstrating their safety. At the same time, all the molecules did not adversely affect the red blood cells, which confirms their very good hemocompatibility. Moreover, they proved to be activators of apoptotic caspases, as they increased caspase-3, -7 and -9 levels in human breast carcinoma cells. The conducted research allows us to select—from among the anticancer active drug candidates—compounds that are safe for developing zebrafish and red blood cells, suitable for further in vivo pharmacological tests

TG-DSC and TG-FTIR Studies of Annelated Triazinylacetic Acid Ethyl Esters—Potential Anticancer Agents

To avoid problems associated with the storage and processing of newly developed potential medicines, there is a need to carry out thermal studies in the preclinical phase of drug development. The thermal behaviour and decomposition pathway of a whole novel class of patented potential molecular pharmaceutics, i.e., ethyl 2-[4-oxo-8-(R-phenyl)-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl]acetates (1–6) were reported for the first time in inert and oxidative atmospheres. The experiments were conducted with the use of simultaneous thermogravimetry/differential scanning calorimetry (TG-DSC) and simultaneous thermogravimetry coupled with Fourier transform infrared spectroscopy (TG-FTIR). The decomposition pathways of compounds 1–6 were found to be different under oxidative and inert conditions. It was proven that the investigated molecules reveal higher thermal stability under a synthetic air atmosphere than under a nitrogen atmosphere, and their decomposition is preceded by the melting process. Among all the investigated compounds, only the meta-chloro derivative (4) was found to exhibit interesting polymorphic behaviour at a low heating rate (10 °C min−1). It was proven that the oxidative decomposition process of the studied molecules proceeds in three overlapping stages accompanied by strong exothermic effects. Additionally, it was concluded that the title compounds were stable up to a temperature of 195–216 °C in an atmosphere of synthetic air, and their thermal stability decreased in the order of R at the benzene ring: 4-CH3 > 3,4-Cl2 > 4-Cl > H > 2-OCH3 > 3-Cl

Sensitive and Selective Voltammetric Sensor Based on Anionic Surfactant-Modified Screen-Printed Carbon for the Quantitative Analysis of an Anticancer Active Fused Azaisocytosine-Containing Congener

3-(4-Nitrophenyl)-8-(2,3-dimethylphenyl)-7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-one (NDIT) is one of the most promising candidates for anticancer agents. Hence, a sensitive and selective sodium dodecyl sulfate-modified screen-printed carbon sensor (SPCE/SDS) was used for its quantitative analysis. The SPCE/SDS, in contrast to the SPCE, showed excellent behavior in the electrochemical reduction of NDIT by differential-pulse adsorptive stripping voltammetry (DPAdSV). Cyclic voltammetric (CV) studies reveal an irreversible, two-stage and not purely diffusion-controlled reduction process in 0.01 M HNO3. The sensor was characterized by CV and electrochemical impedance spectroscopy (EIS). Under the optimized conditions (t 45 s, ΔE 175 mV, ν 150 mV/s, and tm 5 ms), the DPAdSV procedure with the SPCE/SDS presented a very wide linear range from 1 to 2000 nM and a low detection limit of 0.29 nM. A 1000-fold excess concentration of potential interferents commonly present in biological samples did not significantly alter the peak current of NDIT. The practical application of the proposed DPAdSV procedure with the SPCE/SDS was successfully checked by analyzing spiked human serum samples

Thermal Investigations of Annelated Triazinones—Potential Analgesic and Anticancer Agents

In this article, for the first time, TG-DSC and TG-FTIR investigations of potential pharmaceutics, i.e., analgesic and anticancer active annelated triazinones (1–9) have been presented. The thermal behaviour of these molecules was established in oxidative and inert conditions. The solid–liquid phase transition for each compound (1–9) was documented by one sharp DSC peak confirming the high purity of each sample studied. All the molecules were characterised in terms of calorimetric changes and mass changes during their heating. They revealed high thermal stability in oxidative and inert conditions. The observed tendency in thermal stability changes in relation to a substituent present at the phenyl moiety was found to be similar in air and nitrogen. It was confirmed that annelated triazinones 1–9 were stable up to a temperature range of 241–296 °C in air, and their decomposition process proceeded in two stages under oxidative conditions. In addition, it was established that their thermal stability in air decreased in the following order of R at the phenyl moiety: 4-Cl > 3,4-Cl2 > H > 3-Cl > 4-CH3 > 2-CH3 > 3-CH3 > 2-Cl > 2-OCH3. The volatile decomposition products of the investigated molecules were proposed by comparing the FTIR spectra collected during their thermogravimetric analysis in nitrogen with the spectra from the database of reference compounds. None of annelated triazinones 1–9 underwent any polymorphic transformation during thermal studies. All the compounds proved to be safe for erythrocytes. In turn, molecules 3, 6, and 9 protected red blood cells from oxidative damage, and therefore may be helpful in the prevention of free radical-mediated diseases

Biologically and chemically important hydrazino-containing imidazolines as antioxidant agents

<p>Biologically and chemically useful hydrazinoimidazolines were evaluated as antioxidant and antihaemolytic agents. 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH^•), galvinoxyl radical (GOR), nitric oxide (NO) and hydrogen peroxide (H₂O₂) scavenging assays, ferric ions reducing power assay, and <i>ex vivo</i> model of rat erythrocytes exposed to 2,2′-azobis(2-methylpropionamidine)dihydrochloride (AAPH) or H₂O₂ were used. The most potent DPPH^• scavengers proved to be hydrazinoimidazolines <b>3</b>, <b>2</b>, and <b>4</b>, revealing excellent antiradical effects – superior or comparable to that of all antioxidant standards used. Moreover, these molecules showed strong NO neutralising potencies – better to that of ascorbic acid (AA) (<b>3</b>), 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) (<b>3</b> and <b>2)</b>, butylated hydroxytoluene (BHT) (<b>3</b> and <b>2</b>), and butylated hydroxyanisole (BHA) (<b>3</b>, <b>2</b>, and <b>4</b>). Compound <b>4</b> was also effective in GOR scavenging. The excellent scavenger of GOR, NO, and H₂O₂ proved to be structure <b>5</b>, with the potency superior or comparable to the majority of antioxidant standards used. In turn, compound <b>9</b> was effective in H₂O₂ and GOR neutralisation. All hydrazinoimidazolines revealed the reducing power that is higher than BHT. Moreover, the protective effects of most test compounds on oxidatively stressed erythrocytes were observed. Some structure–activity relationships were disclosed. A significance of the primary hydrazino group on antioxidant effects was confirmed. The most likely DPPH^• and GOR scavenging mechanisms for test compounds were propound. Among all the investigated molecules, hydrazinoimidazolines <b>5</b>, <b>3</b>, <b>2</b>, <b>4</b>, and <b>9</b>, due to their excellent or good antiradical activities, can represent promising antioxidant candidates with prospective utility for prevention of diseases related to reactive oxygen/nitrogen species.</p

A Screen-Printed Sensor Coupled with Flow System for Quantitative Determination of a Novel Promising Anticancer Agent Candidate

A carbon nanofibers modified screen-printed carbon sensor (SPCE/CNFs) was applied for the determination of a novel promising anticancer agent candidate (ethyl 8-(4-methoxyphenyl)-4-oxo-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3-carboxylate, EIMTC) using square-wave voltammetry (SWV). It is the first method for the quantitative determination of EIMTC. The modified screen-printed sensor exhibited excellent electrochemical activity in reducing EIMTC. The peak current of EIMTC was found to be linear in two concentration ranges of 2.0 &times; 10&minus;9 &ndash; 2.0 &times; 10&minus;8 mol L&minus;1 and 2.0 &times; 10&minus;8 &ndash; 2.0 &times; 10&minus;7 mol L&minus;1, with a detection limit of 5.0 &times; 10&minus;10 mol L&minus;1. The connection of flow-cell for the SPCE/CNFs with SWV detection allowed for the successful determination of EIMTC in human serum samples. Ultra-high-performance liquid chromatography coupled to electrospray ionization triple quadrupole mass spectrometry (UHPLC-ESI-MS/MS) acted as a comparative method in the serum samples analysis