QSAR models for biocides: The example of the prediction of Daphnia magna acute toxicity

ABSTRACT

Biocides are multi-component products used to control undesired and harmful organisms able to affect human or animal health or to damage natural and manufactured products. Because of their widespread use, aquatic and terrestrial ecosystems could be contaminated by biocides. The environmental impact of biocides is evaluated through eco-toxicological studies with model organisms of terrestrial and aquatic ecosystems. We focused on the development of in silico models for the evaluation of the acute toxicity (EC₅₀) of a set of biocides collected from different sources on the freshwater crustacean Daphnia magna, one of the most widely used model organisms in aquatic toxicology. Toxicological data specific for biocides are limited, so we developed three models for daphnid toxicity using different strategies (linear regression, random forest, Monte Carlo (CORAL)) to overcome this limitation. All models gave satisfactory results in our datasets: the random forest model showed the best results with a determination coefficient r² = 0.97 and 0.89, respectively, for the training (TS) and the validation sets (VS) while linear regression model and the CORAL model had similar but lower performance (r² = 0.83 and 0.75, respectively, for TS and VS in the linear regression model and r² = 0.74 and 0.75 for the CORAL model).     

Expanding the Scope of Arylsulfonylacetylenes as Alkynylating Reagents and Mechanistic Insights in the Formation of Csp2?Csp and Csp3?Csp Bonds from Organolithiums

We describe the unexpected behavior of the arylsulfonylacetylenes, which suffer an “anti‐Michael” addition of organolithiums producing their alkynylation under very mild conditions. The broad scope, excellent yields, and simplicity of the experimental procedure are the main features of this methodology. A rational explanation of all these results can be achieved by theoretical calculations, which suggest that the association of the organolithiums to the electrophile is a previous step of their intramolecular attack and is responsible for the unexpected “anti‐Michael” reactions observed for substituted sulfonylacetylenes.     

Gas-liquid chromatographic evaluation of fenquizone in biological samples for pharmacokinetic investigations

Extractive alkylation was carried out on fenquizone, a sulphonamide diuretic, in order to devise a suitable method for its determination in pharmacokinetic and bioavailability studies. After extraction as a tetramethyl derivative, fenquizone was evaluated by gas-liquid chromatography with a 63Ni electron-capture detector, which enables a limit of detection of 2 ng/ml of plasma or urine to be achieved. Linearity was verified in a range of 50- 10,000 pg for each injection with a fenquizone/internal standard ratio ranging from 4:1 to 1:4. Determination is very rapid, as one analysis only takes 5 min. The preliminary results of the pharmacokinetic study performed in a volunteer human subject after a single oral administration of the drug are presented in this paper in terms of the plasma levels and the cumulative urinary excretion.     

Enantioselective synthesis of 3(S)-hydroxy polygodial derivatives and evaluation of their vanilloid activity

The enantioselective synthesis of 3(S)-hydroxy polygodial and its acetyl derivative is described. The construction of the 3-hydroxy drimane skeleton was based on the titanium-catalyzed radical cyclization of (10S)-10, 11-epoxy-farnesyl acetate. Only underivatized 3(S)-hydroxy polygodial showed activity in assays on VR1 vanilloid receptor in HEK cells transfected with the human VR1.     

One-pot synthesis of sulfonamides from methyl sulfinates using ultrasound

Room temperature ultrasonic irradiation of neat mixtures of methyl sulfinates and primary or secondary amines (1.5 equiv) produced sulfinamides, which on m-CPBA oxidation (in dichloromethane) were converted into the corresponding sulfonamides. The two steps can be accomplished in one pot, in good overall yields, when using secondary amines, but primary amines give better sulfonamide yields when the peracid oxidation is effected on the purified sulfinamide. This constitutes a mild, efficient, and potentially scalable route to sulfonamides, which obviates the use of water sensitive, often lachrymatory sulfonyl chlorides and large reagent excesses.     

Gas--liquid chromatographic evaluation of lofemizole in biological samples for pharmacokinetic investigations. Comparison of two analytical methods

The present paper reports the analytical conditions allowing lofemizole, a new non-steroidal anti-inflammatory drug, to be evaluated in biological fluids for pharmacokinetic and bioavailability investigations. The first approach led to an N-methyl derivative of lofemizole which could be successfully analysed by gas--chromatography employing a flame-ionization detector, reaching a sensitivity of 2 micrograms/ml. The second approach led to the N-(2-chlorobenzoyl) derivative of lofemizole which was suitable for pharmacokinetic investigation using gas--liquid chromatography with electron-capture detection, and reaching a much higher sensitivity of 10 ng/ml of plasma. Recovery of the extraction, reproducibility and specificity were all satisfactory with both methods. Since the first method employing flame-ionization detection was suitable for pharmacokinetic investigations in animal species, this paper describes both methods on a comparative basis.     

Visible‐Light Photocatalysis: Does It Make a Difference in Organic Synthesis?

Visible‐light photocatalysis has evolved over the last decade into a widely used method in organic synthesis. Photocatalytic variants have been reported for many important transformations, such as cross‐coupling reactions, α‐amino functionalizations, cycloadditions, ATRA reactions, or fluorinations. To help chemists select photocatalytic methods for their synthesis, we compare in this Review classical and photocatalytic procedures for selected classes of reactions and highlight their advantages and limitations. In many cases, the photocatalytic reactions proceed under milder reaction conditions, typically at room temperature, and stoichiometric reagents are replaced by simple oxidants or reductants, such as air, oxygen, or amines. Does visible‐light photocatalysis make a difference in organic synthesis? The prospect of shuttling electrons back and forth to substrates and intermediates or to selectively transfer energy through a visible‐light‐absorbing photocatalyst holds the promise to improve current procedures in radical chemistry and to open up new avenues by accessing reactive species hitherto unknown, especially by merging photocatalysis with organo‐ or metal catalysis.