Identification of structural fingerprints for in vivo toxicity by using Monte Carlo based QSTR modeling of nitroaromatics.

Monte Carlo based method by using either SMILES based or combination of SMILES and Graph-based descriptors is an important strategy to build the QSAR/QSTR model for prediction of different biological endpoints. In this study, Monte Carlo based QSTR approach was applied to the dataset of 90 nitroaromatic compounds related to their in vivo toxicity, represented by 50% lethal dose concentration for rats (LD50). Both classification and regression-based QSTR models were developed to get an idea about different fingerprints for promoters and hinderers of nitroaromatics toxicity. The best classification model was obtained by using SMILES and graph-based (GAO) descriptor with 1ECK connectivity (sensitivity = 0.7143, specificity = 1.0000, accuracy = 0.8889, and MCC = 0.7774). The best regression model calculated by using SMILES and hydrogen-suppressed graph descriptors with 0ECk connectivity (R2 = 0.7386, Q2 = 0.6315, S = 0.467, and MAE = 0.340). Finally, a consensus QSTR model was generated to predict efficiently the toxicity of new compounds. The study highlighted that the comparative QSTR models by using the Monte Carlo method can also be generated and will be a useful tool for structural fingerprint analysis in case of nitroaromatics for preliminary evaluation of its toxicity to mammals.

A simple approach for assessment of toxicity of nitroaromatic compounds without using complex descriptors and computer codes.

A simple approach is introduced to assess the toxicity of nitroaromatic compounds in terms of an oral LD50 dose (50% lethal dose) for rats. Most of the presented Quantitative Structure-Activity Relationship (QSAR) models for prediction of in vivo toxicity of nitroaromatics are calculated by quantum computing descriptors which are more difficult to interpret and apply, while the new model requires only the molecular structure of a desirable nitroaromatic compound. The novel model is based on the constitutional descriptors, such as the number of oxygen, sulphur, phosphorous and molecular fragments. Experimental data of 90 nitroaromatics are used to derive and test the new model as the logarithm of LD50 values, i.e. -log (LD50). Although it is based on only simple structural parameters, the reliability of the new model is also higher than the complex QSAR model because the values of the root-mean-square deviation (RMSD) of -log (LD50) for the new and the outputs of the latest QSAR method are 0.342 and 0.377, respectively.

Prediction of the adsorption coefficients of some aromatic compounds on multi-wall carbon nanotubes by the Monte Carlo method.

In this investigation, quantitative structure-property relationship (QSPR) modelling of adsorption coefficients of 69 aromatic compounds on multi-wall carbon nanotubes (MWCNTs) was studied using the Monte Carlo method. QSPR models were calculated with CORAL software, and optimal descriptors were calculated with the simplified molecular input line entry system (SMILES) and hydrogen-suppressed molecular graphs (HSGs). The aromatic compound data set was randomly split into training, invisible training, calibration and validation sets. Analysis of three probes of the Monte Carlo optimization with three random splits was done. The results from three random splits displayed robust, very simple, predictable and reliable models for the training, invisible training, calibration and validation sets with a coefficient of determination (r2) equal to 0.9463-0.8528, 0.9020-0.8324, 0.9606-0.9178 and 0.9573-0.8228, respectively. As a result, the models obtained help to identify the hybrid descriptors for the increase and the decrease of the adsorption coefficient of aromatic compounds on MWCNTs. This simple QSPR model can be used for the prediction of the adsorption coefficient of numerous aromatic compounds on MWCNTs.

Four selected high molecular weight heterocyclic aromatic hydrocarbons: Ecotoxicological hazard assessment, environmental relevance and regulatory needs under REACH.

Little is known about the ecotoxicity of heterocyclic aromatic hydrocarbons (NSO-HETs) to aquatic organisms. In the environment, NSO-HETs have been shown to occur in a strong association with their unsubstituted carbocyclic analogues, the polycyclic aromatic hydrocarbons (PAH), for which much more information is available. The present study addressed this issue by investigating the toxicity of four selected NSO-HETs in green algae (Desmodesmus subspicatus), daphnids (Daphnia magna) and fish embryos (Danio rerio). The four high molecular weight NSO-HETs dibenz[a,j]acridine (DBA), 7H-dibenzo[c,g]carbazole (DBC), benzo[b]naphtho[2,1-d]thiophene (BNT) and benzo[b]naphtho[1,2-d]furan (BNF) were selected, based on the results of a previous research project, indicating a lack of toxicity data and a high potential for persistence and bioaccumulation. The solubilities of the NSO-HETs in the test media were determined and turned out to be comparatively low (2.7-317 µg/L) increasing in the following order: DBA < BNT « DBC « BNF. Exposure concentrations during the toxicity tests were quantified with GC-MS and decreased strongly possibly due to sorption or metabolising during the test periods (48-96 h). Therefore, the estimated effect concentrations were related to the mean measured concentrations, as endpoints related to nominal concentrations would have underestimated the toxicity many times over. Within the range of the substance solubilities, BNF affected all test organisms with fish embryos being the most sensitive (fish: EC50 6.7 µg/L, algae: EC10 17.8 µg/L, daphnids: EC50 55.8 µg/L). DBC affected daphnids (EC50 2.5 µg/L,) and algae (EC10 3.1 µg/L), but not fish embryos. The lowest toxicity endpoint was observed for BNT affecting only algae (NOEC 0.556 µg/L) and neither daphnids nor fish embryos. DBA did not show any effects on the tested organisms in the range of the water solubility. However, we would expect effects in long-term toxicity studies to fish and aquatic invertebrates for all substances at lower concentrations, which needs further investigation. All four NSO-HETs were identified in mussels (Mytilus edulis) from the German coasts, in green kale (Brassica oleracea var. acephala) and in freshwater harbor sediment in concentrations between 0.07 and 2 µg/kg, highlighting their relevance as environmental contaminants. There is a need to regulate the four NSO-HETs within the REACH regulation due to their intrinsic properties and their environmental relevance. However, acquisition of additional experimental data appears to be pivotal for a regulation under REACH.

Toxicological Assessment of Mineral Hydrocarbons in Foods: State of Present Discussions.

The evaluation of mineral oils by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) provided high acceptable daily intakes for classes largely falling into the mass range strongly accumulated by humans. Because they are roughly 2 orders of magnitude above the present exposure, they authorize strongly increased exposure. An approach based on accumulation seems more adequate. Increased organ weights might be more critical than granulomas. Aromatic hydrocarbons with 1-2 aromatic rings should be distinguished from those with at least 3 aromatic rings. If mineral oil saturated hydrocarbon limits were low, no limit might be needed for the 1-2 ring aromatics. It should be considered to phase out substantial use of mineral oils in food application.

Low-Cost Perovskite Solar Cells Employing Dimethoxydiphenylamine-Substituted Bistricyclic Aromatic Enes as Hole Transport Materials.

The synthesis, characterization and photovoltaic performance of series of novel molecular hole transport materials (HTMs) based on bistricyclic aromatic enes (BAEs) are presented. The new derivatives were obtained following a simple and straightforward procedure from inexpensive starting reagents mimicking the synthetically challenging 9,9'-spirobifluorene moiety of the well-studied spiro-OMeTAD. The novel HTMs were tested in mixed cations and anions perovskite solar cells (PSCs) yielding a power conversion efficiency (PCE) of 19.2 % under standard global 100 mW cm-2 AM1.5G illumination using 9-{2,7-bis[bis(4-methoxyphenyl)amino]-9H-fluoren-9-ylidene}-N2 ,N2 ,N7 ,N7 -tetrakis(4-methoxyphenyl)-9H-thioxanthene-2,7-diamine (coded as KR374). The power conversion efficiency data confirms the easily attainable heteromerous fluorenylidenethioxanthene structure as valuable core for low-cost and highly efficient HTM design and paves the way towards cost-effective PSC technology.

The Effects of Molecular Properties on Ready Biodegradation of Aromatic Compounds in the OECD 301B CO2 Evolution Test.

Ready biodegradation is the primary biodegradability of a compound, which is used for discriminating whether a compound could be rapidly and readily biodegraded in the natural ecosystems in a short period and has been applied extensively in the environmental risk assessment of many chemicals. In this study, the effects of 24 molecular properties (including 2 physicochemical parameters, 10 geometrical parameters, 6 topological parameters, and 6 electronic parameters) on the ready biodegradation of 24 kinds of synthetic aromatic compounds were investigated using the OECD 301B CO2 Evolution test. The relationship between molecular properties and ready biodegradation of these aromatic compounds varied with molecular properties. A significant inverse correlation was found for the topological parameter TD, five geometrical parameters (Rad, CAA, CMA, CSEV, and N c), and the physicochemical parameter K ow, and a positive correlation for two topological parameters TC and TVC, whereas no significant correlation was observed for any of the electronic parameters. Based on the correlations between molecular properties and ready biodegradation of these aromatic compounds, the importance of molecular properties was demonstrated as follows: geometrical properties > topological properties > physicochemical properties > electronic properties. Our study first demonstrated the effects of molecular properties on ready biodegradation by a number of experiment data under the same experimental conditions, which should be taken into account to better guide the ready biodegradation tests and understand the mechanisms of the ready biodegradation of aromatic compounds.

Metal catalysts for steam reforming of tar derived from the gasification of lignocellulosic biomass.

Biomass gasification is one of the most important technologies for the conversion of biomass to electricity, fuels, and chemicals. The main obstacle preventing the commercial application of this technology is the presence of tar in the product gas. Catalytic reforming of tar appears a promising approach to remove tar and supported metal catalysts are among the most effective catalysts. Nevertheless, improvement of catalytic performances including activity, stability, resistance to coke deposition and aggregation of metal particles, as well as catalyst regenerability is greatly needed. This review focuses on the design and catalysis of supported metal catalysts for the removal of tar in the gasification of biomass. The recent development of metal catalysts including Rh, Ni, Co, and their alloys for steam reforming of biomass tar and tar model compounds is introduced. The role of metal species, support materials, promoters, and their interfaces is described.

What does the aromatic ring number mean for drug design?

INTRODUCTION: During the last decade, there has been an increased focus on understanding the factors that influence the chance of success of a drug molecule in development. Recent publications have highlighted that the aromatic ring count of a drug molecule also has an influence on its developability profile. AREAS COVERED: This article reviews both the positive and negative consequences of including aromatic rings in drug molecules based on the recent literature and presents a thorough review of recent publications describing the influence of aromatic ring count on compound developability. These conclusions are analysed alongside their implications for the medicinal chemist. The authors also highlight the limitations of recent analyses; this includes a particular emphasis on the restricted diversity of the compound collections used. EXPERT OPINION: Modern medicinal chemists work in a very restricted area of the available drug-like chemical space, although there is evidence that safe compounds can be identified outside of conventional drug-like chemical space. It is true that current evidence implies that drug molecules with > 3 aromatic rings in are undesirable and that heteroaromatics perform better than carboaromatic overall. However, the analyses performed so far have only used compounds designed for oral administration, which were provided from pharmaceutical companies' collections, and were therefore limited in diversity.

Assessment of soil pollution based on total petroleum hydrocarbons and individual oil substances.

Different oil products like gasoline, diesel or heavy oils can cause soil contamination. The assessment of soils exposed to oil products can be conducted through the comparison between a measured concentration and an intervention value (IV). Several national policies include the IV based on the so called total petroleum hydrocarbons (TPH) measure. However, the TPH assessment does not indicate the individual substances that may produce contamination. The soil quality assessment can be improved by including common hazardous compounds as polycyclic aromatic hydrocarbons (PAHs) and aromatic volatile hydrocarbons like benzene, toluene, ethylbenzene and xylenes (BTEX). This study, focused on 62 samples collected from different sites throughout The Netherlands, evaluates TPH, PAH and BTEX concentrations in soils. Several indices of pollution are defined for the assessment of individual variables (TPH, PAH, B, T, E, and X) and multivariables (MV, BTEX), allowing us to group the pollutants and simplify the methodology. TPH and PAH concentrations above the IV are mainly found in medium and heavy oil products such as diesel and heavy oil. On the other hand, unacceptable BTEX concentrations are reached in soils contaminated with gasoline and kerosene. The TPH assessment suggests the need for further action to include lighter products. The application of multivariable indices allows us to include these products in the soil quality assessment without changing the IV for TPH. This work provides useful information about the soil quality assessment methodology of oil products in soils, focussing the analysis into the substances that mainly cause the risk.

The organic contamination survey and health risk assessment of 16 source water reservoirs in Haihe River basin.

Although contamination by organic pollutants has previously been reported to occur in the Haihe River basin, few studies have been carried out on the levels of source water reservoir contamination and the health risk in the Haihe River basin. To understand the organic pollution status of the reservoirs in the Haihe River basin, samples were collected from 16 source water reservoirs. The samples were analyzed for the representative organic pollutants, which included benzene homologues, chlorobenzene compounds, organophosphorus pesticides, and nitrobenzene compounds, a total in all of 17 compounds. It was observed that the concentrations of the 17 compounds in the 16 reservoirs were all less than the limit laid down by Chinese surface water quality standards. In addition, benzene, toluene, nitrobenzene, p-nitrochlorobenzene, 2,4-dinitrotoluene and 2,4-dinitrochlorobenzene, dichlorvos, demeton, dimethoate methyl parathion, malathion and parathion were frequently detected in the 16 source water reservoirs, especially the organophosphorus pesticides; the detection rates of dichlorvos, dimethoate, methyl parathion, malathion and parathion were all 100% in the 16 source water reservoirs. The detection rate of target compounds suggested that organic pollution had been common in the source water of the Haihe River basin. The health risk assessment results suggested that the noncarcinogenic risk hazard quotient values of the target compounds were less than one, and the cancer risk values were all below 1 × 10(-6), which indicated that the heath risk produced by the target compounds in the 16 reservoirs was at an acceptable level.

Efficient synthesis of 16 aromatic Morita-Baylis-Hillman adducts: Biological evaluation on Leishmania amazonensis and Leishmania chagasi.

Sixteen aromatic Morita-Baylis-Hillman adducts (MBHA) 1-16 were efficiently synthesized in a one step Morita-Baylis-Hillman reaction (MBHR) involving commercial aldehydes with methyl acrylate or acrylonitrile (81-100% yields) without the formation of side products on DABCO catalysis and at low temperature (0°C). The toxicities of these compounds were assessed against promastigote form of Leishmania amazonensis and Leishmania chagasi. The low synthetic cost of these MBHA, green synthetic protocols, easy one-step synthesis from commercially available and cheap reagents as well as the very good antileishmanial activity obtained for 14 and 16 (IC50 values of 6.88µgmL⁻¹ and 11.06µgmL⁻¹ respectively on L. amazonensis; 9.58µgmL⁻¹ and 14.34µgmL⁻¹ respectively on L. chagasi) indicates that these MBHA can be a novel and promising class of anti-parasitic compounds.

Developing tools for risk assessment in protected species: Relative potencies inferred from competitive binding of halogenated aromatic hydrocarbons to aryl hydrocarbon receptors from beluga (Delphinapterus leucas) and mouse.

Persistent organic pollutants such as halogenated aromatic hydrocarbons (HAHs) biomagnify in food webs and accumulate to high concentrations in top predators like odontocete cetaceans (toothed whales). The most toxic HAHs are the 2,3,7,8-substituted halogenated dibenzo-p-dioxins and furans, and non-ortho-substituted polychlorinated biphenyls (PCBs), which exert their effects via the aryl hydrocarbon receptor (AHR). Understanding the impact of HAHs in wildlife is limited by the lack of taxon-specific information about the relative potencies of toxicologically important congeners. To assess whether Toxic Equivalency Factors (TEFs) determined in rodents are predictive of HAH relative potencies in a cetacean, we used beluga and mouse AHRs expressed in vitro from cloned cDNAs to measure the relative AHR-binding affinities of ten HAHs from five different structural classes. The rank order of mean IC(50)s for competitive binding to beluga AHR was: TCDD

Aromatic amines: mechanisms of carcinogenesis and implications for risk assessment.

Carcinogenic aromatic amines are widespread and need to be regulated. Genotoxic and non-genotoxic effects are both necessary for tumor development. The common mode of action includes metabolic activation, the reaction of metabolites with nucleic acids and cellular macromolecules as well as toxic effects. The dose-response relationship of irreversible DNA damage is linear down to background concentrations and a no-effect level (NEL) cannot be defined. The dose-response relationships of reversible toxic effects are often non-linear and have been used to derive no-observed adverse effect levels (NOAEL). However, this procedure does not account for background exposure, the activity of structurally related, and those structurally unrelated chemicals which compete for the same biochemical systems. Fixed limit values for acceptable risk are therefore unacceptably uncertain. The perspective should change from "risk" to the "contribution to risk". The ALARA principle (as low as reasonably achievable) is part of such an approach. It does not say how much exposure is acceptable. Scientific risk assessment and risk management should be kept distinct and the input of scientific data and expert judgement documented.

Identification of intermediates and assessment of ecotoxicity in the oxidation products generated during the ozonation of clofibric acid.

The degradation of an aqueous solution of clofibric acid was investigated during catalytic and non-catalytic ozonation. The catalyst, TiO(2), enhanced the production of hydroxyl radicals from ozone and raised the fraction or clofibric acid degraded by hydroxyl radicals. The rate constant for the reaction of clofibric acid and hydroxyl radicals was not affected by the presence of the catalyst. The toxicity of the oxidation products obtained during the reaction was assessed by means of Vibrio fischeri and Daphnia magna tests in order to evaluate the potential formation of toxic by-products. The results showed that the ozonation was enhanced by the presence of TiO(2,) the clofibric acid being removed completely after 15 min at pH 5. The evolution of dissolved organic carbon, specific ultraviolet absorption at 254 nm and the concentration of carboxylic acids monitored the degradation process. The formation of 4-chlorophenol, hydroquinone, 4-chlorocatechol, 2-hydroxyisobutyric acid and three non-aromatic compounds identified as a product of the ring-opening reaction was assessed by exact mass measurements performed by liquid chromatography coupled to time-of-flight mass spectrometry (LC-TOF-MS). The bioassays showed a significant increase in toxicity during the initial stages of ozonation following a toxicity pattern closely related to the formation of ring-opening by-products.

Free volume analysis and gas transport mechanisms of aromatic polyimide membranes: a molecular simulation study.

Molecular simulation techniques were adopted to investigate membrane free volume morphologies and gas-transport mechanisms in the aromatic polyimide (PI) membranes composed of various diamines and dianhydrides. A molecular dynamics (MD) technique was adopted to analyze the fractional free volume (FFV), fractional accessible volume (FAV), free volume size and shape, and diffusion mechanisms. A Monte Carlo (MC) method was used to analyze the gas sorption behaviors in the membranes. The FFV, FAV, and free volume morphology analyses reveal that bulky groups in the PI membranes contributed to the formation of a larger and more continuous free volume. The thermal motion analysis shows that a greater effective free volume in the membranes promoted effective motion, such as jumping and diffusive motions. The sorption analysis indicates that the larger free volume provides more sites for gas molecule absorption. The MD and MC results provide good agreement with the experimental data from past reports, which validates the feasibility of molecular simulation techniques in gas separation membranes at a molecular scale.

Assessment and use of two silicon carbide multi-well plates for library synthesis and proteolytic digests using microwave heating.

The use of two silicon carbide plates is reported for the preparation of three libraries of organic molecules using microwave heating. In addition, a preliminary study has been carried out, showing that one of the plates can also be used in a proteomics setting. Both the 24-position and 48-position plates heated evenly when irradiated with microwave energy. The 48-position plate was used to prepare a library of N-aryl functionalized beta-amino esters via an aza-Michael reaction between anilines and Michael acceptors. The 24-position plate was used to prepare a library of biaryls via a Suzuki coupling methodology and a library of 1,4-dihydropyridines via a Hantzsch synthesis. The 48-position plate was also used to perform the proteolytic digestion of insulin chain B by trypsin.

Efficient iron/copper cocatalyzed S-arylations of thiols with aryl halides.

A practical and promising protocol was developed for S-arylations of various thiols with different substituted aryl halides. The reactions were readily facilitated to afford desired thioethers under mild conditions in good to excellent yields. The versatility, air-stability, operational simplicity of this method, in addition to the higher yields and shorter reaction time it provides, highlight the potential of using this method in large scale library synthesis involving carbon-heteroatom formation.

New one-pot four-component synthesis of disubstituted pyrido[2,3-d]pyrimidine-6-carboxamide derivatives.

In this work, 1,2,3,4,5,8-hexahydro-1,3,7-trimethyl-2,4-dioxopyrido[2,3-d]pyrimidine-6-carboxamide derivatives were synthesized in a simple and efficient method from the four-component condensation reaction of diketene, an aliphatic or aromatic amine, an aromatic aldehyde, and 6-amino-1,3-dimethyluracil in the presence of a catalytic amount of p-toluenesulfonic acid under mild conditions at ambient temperature in high yields.

Palladium-catalysed direct 3- or 4-arylation of 2,5-disubstituted pyrrole derivatives: an economically and environmentally attractive procedure.

Straight to the point: The direct 3- or 4-arylation of pyrrole derivatives through C--H bond activation proceeds in moderate to good yields using Pd(OAc)(2) as catalyst. In contrast to classical coupling procedures, the preparation of an organometallic derivative is not required and the major by-products are AcOH/KBr instead of metallic salts.