The index of ideality of correlation: improvement of models for toxicity to algae

Toxicity to algae is important characteristic of substances from ecologic point of view. The CORAL software (http://www.insilico.eu/coral) gives possibility to build up model of toxicity to algae using data on the molecular architecture and experimental toxicity, without additional data on physicochemical and/or biochemical parameters. Considerable improvement of the model is observed in the case of using the index of ideality of correlation (IIC) in the role of additional criterion of predictive potential. The IIC is calculated with using of the correlation coefficient between experimental and calculated values of endpoint for the calibration set, with taking into account the positive and negative dispersions between experimental and calculated values. The best model calculated with use the IIC is characterized (the validation set) by n?=?50, r²?=?0.947, RMSE?=?0.401 whereas, model calculated without use the IIC is characterized by n?=?50, r²?=?0.805, and RMSE?=?0.539. The suggested models are built up in accordance to five OECD principles.

     

Design of (quinolin-4-ylthio)carboxylic acids as new Escherichia coli DNA gyrase B inhibitors: machine learning studies,molecular docking,synthesis and biological testing

Spread of multidrug‐resistant Escherichia coli clinical isolates is a main problem in the treatment of infectious diseases. Therefore, the modern scientific approaches in decision this problem require not only a prevention strategy, but also the development of new effective inhibitory compounds with selective molecular mechanism of action and low toxicity. The goal of this work is to identify more potent molecules active against E. coli strains by using machine learning, docking studies, synthesis and biological evaluation. A set of predictive QSAR models was built with two publicly available structurally diverse data sets, including recent data deposited in PubChem. The predictive ability of these models tested by a 5-fold cross-validation, resulted in balanced accuracies (BA) of 59–98% for the binary classifiers. Test sets validation showed that the models could be instrumental in predicting the antimicrobial activity with an accuracy (with BA = 60–99 %) within the applicability domain. The models were applied to screen a virtual chemical library, which was designed to have activity against resistant E. coli strains. The eight most promising compounds were identified, synthesized and tested. All of them showed the different levels of anti-E. coli activity and acute toxicity. The docking results have shown that all studied compounds are potential DNA gyrase inhibitors through the estimated interactions with amino acid residues and magnesium ion in the enzyme active center The synthesized compounds could be used as an interesting starting point for further development of drugs with low toxicity and selective molecular action mechanism against resistant E. coli strains. The developed QSAR models are freely available online at OCHEM http://ochem.eu/article/112525 and can be used to virtual screening of potential compounds with anti-E. coli activity.     

Synthesis and psychotropic properties of furyl- and thienyl-germatranes

Trihalogermyl-furans and -thiophenes were prepared by inserting germanium dibromide (GeBr₂) generated from the dibromogermane(II) dioxanate complex into the carbon-halogen bond of halo-furans and -thiophenes. Their ethanolysis and transesterification by triethanolamine yielded the germatranes which were subjected to psychotropic activity assays. The psychotropic properties of germatranes were found to depend on the type of the heterocycle and on the position of the germatrane moiety.     

Evidence of steric factors in the fungitoxic mechanisms of 8-quinolinol and its 2-, 3-, 4-, 5-, 6-and 7-chloro and bromo analogues

Summary A study was made of the fungitoxicity of 2-, 3-, 4-, 5-, 6- and 7-chloro and bromo-8-quinolinols againstAspergillus niger,A. oryzae,Myrothecium verrucaria,Trichoderma viride andTrichophyton mentagrophytes in Sabouraud dextrose broth and in Yeast Nitrogen Base supplemented with 1%D-glucose and 0.088%L-asparagine. Based on the presence or absence of synergism between pairs of substituted 8-quinolinols and reversal or nonreversal of toxicity byL-cysteine or N-acetyl-L-cysteine, the following conclusions were reached: (1) substituents on the quinoline ring change the site(s) of action of the toxicant; (2) the sites of action of the 5-, 6-, and 7-chloro-8-quinolinols are different from each other and from 8-quinolinol and its 2-, 3-, and 4-chloro analogues, and the same is true for the corresponding bromo compounds; (3) 8-quinolinol and its 3- and 4-chloro and bromo analogues appear to share common sites of action; (4) for good antifungal activity the 2 position of the ring must not be substituted by sterically bulky groups; (5) the geometry of the binding sites of action are not so constrained that they cannot accommodate the analogously substituted chloro- and bromo-8-quinolinols.

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Nachweis sterischer Faktoren bei der Fungitoxizität von 8-Chinolinol und seinen 2-, 3-, 4-, 5-, 6- und 7-Chlor- und -Brom-Analogen

Zusammenfassung Es wurde eine Studie der Fungitoxizität von 2-, 3-, 4-, 5-, 6- und 7-Chlor- und-Brom-8-chinolinol gegenüberAspergillus niger,A. oryzae,Myrothecium verrucaria,Trichoderma viride undTrichphyton mentagrophytes in Sabouraud Dextrose Nährmedium und in Hefe-N-Base mit 1%D-Glucose und 0.088%L-Asparagin unternommen. Auf der Basis des Zutreffens oder der Abwesenheit eines Synergismus zwischen Paaren von substituierten 8-Chinolinolen und der Umkehrung oder Nichtumkehrung der Toxizität durchL-Cystein oder N-Acetyl-L-cystein wurden folgende Schlußfolgerungen abgeleitet: (1) Substituenten am Chinolin-Ring ändern die Aktionsstelle(n) des Toxikans; (2) Die Angriffsstellen der 5-, 6- und 7-Chlor-8-chinolinole sind untereinander und von 8-Chinolinol und seinen 2-, 3- und 4-Chlor-Analogen verschieden, wobei das auch für die entsprechenden Brom-Verbindungen gilt; (3) 8-Chinolinol und seine 3- und 4-Chlor- und -Brom-Analogen scheinen gemeinsame Aktionsstellen zu teilen; (4) für eine gute antifungale Aktivität darf die 2-Position des Rings nicht mit sterisch anspruchsvollen Gruppen besetzt sein; (5) Die Geometrie des Bindungsstellen der Wirkung ist nicht so gespannt, daß nicht sowohl analoge Chlor- oder Brom-8-chinolinole Platz finden.

     

Speciation analysis of platinum antitumoral drugs in impacted tissues

Chemical compounds containing platinum have been employed since 1978 as drugs to beat certain type of tumours. Nevertheless, besides of their exceptional antitumoral properties, these drugs also have important deleterious side effects, such as, nephrotoxicity and ototoxicity.A study of Pt accumulation and a speciation analysis has been performed by ICP-MS in samples from kidney and inner ear in a controlled population of Wistar rats treated with, either, cisplatin, carboplatin or oxaliplatin. The results on Pt accumulation point out to drug structure and not only to Pt content as the responsible for the alteration of organ functionality.Speciation studies in the samples from kidney and inner ear were performed coupling two-dimensional liquid chromatography (2D-LC) to ICP-MS. Size exclusion (SEC) and anion exchange fast protein liquid chromatography (FPLC) was employed for 2D orthogonal separation. After these separations, free drug peaks were not observed in any of the samples.The binding of Pt to biomolecules was demonstrated by SEC and, independently of the drug used, Pt eluted as two main bands with molecular weights of 12 kDa and 25-65 kDa for inner ear samples, and as two different bands with 20 kDa and 50-60 kDa in the samples from kidney. However, the relative band intensity presented important differences for the three drugs. Using the same chromatographic conditions, it was shown that a metallothionein (MT) standard eluted in the same position as some of the cytosolic Pt-biomolecules.High Pt-containing fractions eluting from the SEC column were analysed by anion exchange FPLC after a preconcentration step. Among the different preconcentration methods tested, sample focusing on the head of the FPLC column shows main advantages. In this way, the separation by 2D chromatography of the high molecular Pt-species has been considerably improved.     

A new method for the synthesis of silicon-and germanium-containing 2-acetylfurans and 2-acetylthiophenes

A new method was developed for the synthesis of silicon-and germanium-containing acetylfurans and acetylthiophene by metallation of 2-acetylfuran or 2-acetylthiophene with n-BuLi at low temperature after protection of the carbonyl group with lithium N-methylpiperazide and reaction of the lithium derivative with various trialkyl-, alkylphenyl-, and cycloalkylchlorosilanes or trialkylchloro(bromo)germanes. The cytotoxic activity of the new compounds was studied, and it was established that the silicon-and germanium-containing acetylfurans and acetylthiophenes are substances with low toxicity (LD₅₀ 312->2000 mg/kg) and have low cytotoxicity toward HT-1080 and MG-22A tumor cells. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 192–199, February, 2007.     

Analysis of Toxic Aluminium Species in Natural Waters

Aluminium is known to be toxic to a wide range of aquatic organisms under certain conditions. Monomeric hydroxy ions have been found to be primarily responsible for aluminium aquatic toxicity.A survey of aluminium toxicity and a brief discussion of speciation schemes are presented. The fast reaction of Al³⁺ with pyrocatechol violet (PCV) followed by spectrophotometric analysis is a frequently used method for aluminium speciation. By using a flow system, one obtains fairly exact and reproducible control of the reaction time, and as a result it provides a direct method of analysis for free aluminium (including inorganic monomeric aluminium).The PCV-method has been adapted for the determination of aluminium in carbonate-rich natural waters using an improved buffering system. Thus it is possible to monitor aluminium concentrations in lake water as well as in pore water of the sediments of eutrophicated hardwater lakes that has been treated with aluminium salts as a restoration measure.     

Size fractionation of aquatic colloids and particles by cross-flow filtration: analysis by scanning electron and atomic force microscopy

The suitability of the combined application of environmental scanning electron microscopy (ESEM), scanning electron microscopy (SEM) and atomic force microscopy (AFM) for the evaluation of the ability of cross-flow filtration (CFF) to perform adequate size fractionation of freshwater colloids and particles was examined. ESEM and SEM imaging provided reference images of the CFF-generated fractions and, in estimating the experimental cut-off diameter of the membrane, provided evidence that separation was not consistent with nominal pore sizes of the membranes. However, analysis of the images showed that size distribution of CFF-generated fractions and the estimated cut-off diameter of the membranes were dependent on the advantages and limitations of the two imaging techniques. With both ESEM and SEM, best estimates of size cut-offs were lower than the nominal pore size of the membrane in the case of 0.45 μm membranes, but roughly accurate in the case of 0.1 μm pore size membranes. The results also suggested that the effectiveness of CFF may benefit from a pre-separation step using a minimally perturbing technique such as split thin-flow fractionation. AFM demonstrated the presence of colloids smaller than 50 nm in all fractions including the retentates, showing that CFF fractionation is not fully quantitative and not based on size alone. The results indicate that previous studies investigating trace element partitioning using CFF may need re-evaluation as the importance of particles and large colloids may be over-estimated.     

Synthetic and structural carboxylate chemistry of neurotoxic aluminum in relevance to human diseases

The contact of Al(III) with biological components in human physiology has increased significantly over the years, due to a number of factors, prominent among which stands the rapid acidification of the environment and the concomitant introduction of that abundant metal ion in human biological fluids. As a result, pathophysiological aberrations in humans have arisen due to Al(III) (neuro)toxicity. Among the efforts targeting the elucidation of the factors responsible for Al(III) toxicity is the exploration of the requisite Al(III)-carboxylate chemistry in aqueous media, and its relevance to soluble, potentially bioavailable species capable of exerting toxic effects. A detailed synthetic, structural, and spectroscopic account of the Al(III)-carboxylate complexes, purported to exist as components in aqueous Al(III)-carboxylic acid speciation, is presented. The structures described are classified as mononuclear, dinuclear, trinuclear, tetranuclear, and polynuclear species, arising from various aqueous and non-aqueous Al(III)-carboxylate ligand reactions. Moreover, the solution chemistry and kinetic behavior of the so far reported complexes is given, with the specific aim of comparing their solid state and solution chemical and structural properties. In this sense, a comprehensive picture on the Al(III) speciation, in the presence of various physiological or biologically relevant carboxylate ligands, appears to emerge, which is expected to contribute to the understanding of Al(III) (neuro)toxicity and its consequence(s) in a multitude of human diseases. Carboxylate containing low and high molecular mass components stand prominent in their chemical preference to react with Al(III) in biological fluids. In this context, factors considered to influence the aqueous low molecular mass Al(III)-carboxylate chemistry, thus affecting the solubility and possibly the bioavailability of the resulting species, are discussed as potential research links to the ultimate manifestation of Al(III) toxicity at the cellular level.