Targeting bacterial growth in biofilm conditions: rational design of novel inhibitors to mitigate clinical and food contamination using QSAR.

Antimicrobial resistance (AMR) is a pressing global issue exacerbated by the abuse of antibiotics and the formation of bacterial biofilms, which cause up to 80% of human bacterial infections. This study presents a computational strategy to address AMR by developing three novel quantitative structure-activity relationship (QSAR) models based on molecular topology to identify potential anti-biofilm and antibacterial agents. The models aim to determine the chemo-topological pattern of Gram (+) antibacterial, Gram (-) antibacterial, and biofilm formation inhibition activity. The models were applied to the virtual screening of a commercial chemical database, resulting in the selection of 58 compounds. Subsequent in vitro assays showed that three of these compounds exhibited the most promising antibacterial activity, with potential applications in enhancing food and medical device safety.

Drug screening of α-amylase inhibitors as candidates for treating diabetes.

In the present study, the identification of potential α-amylase inhibitors is explored as a potential strategy for treating type-2 diabetes mellitus. A computationally driven approach using molecular docking was employed to search for new α-amylase inhibitors. The interactions of potential drugs with the enzyme's active site were investigated and compared with the contacts established by acarbose (a reference drug for α-amylase inhibition) in the crystallographic structure 1B2Y. For this active site characterization, both molecular docking and molecular dynamics simulations were performed, and the residues involved in the α-amylase-acarbose complex were considered to analyse the potential drug's interaction with the enzyme. Two potential α-amylase inhibitors (AN-153I105594 and AN-153I104845) have been selected following this computational strategy. Both compounds established a large number of interactions with key binding site α-amylase amino acids and obtained a comparable docking score concerning the reference drug (acarbose). Aiming to further analyse candidates' properties, their ADME (absorption, distribution, metabolism, excretion) parameters, druglikeness, organ toxicity, toxicological endpoints and median lethal dose (LD50 ) were estimated. Overall estimations are promising for both candidates, and in silico toxicity predictions suggest that a low toxicity should be expected.

Ultrasound-assisted extraction followed by liquid chromatography coupled to tandem mass spectrometry for the simultaneous determination of multiclass herbicides in soil.

An analytical methodology based on ultrasound-assisted extraction (UAE) followed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) has been developed for the identification and quantification of 9 authorized herbicides in soil (dimethenamid-P, imazamox, S-metolachlor, nicosulfuron, pendimethalin, prosulfuron, bentazone, terbuthylazine, and mesotrione). Preliminary experiments dealing with solvent extraction, the extraction technique, and herbicide response comparison in soil, with and without organic amendments, were carried out with the purpose of obtaining high sample throughput and sensitivity. UAE and the solvent mixture water:methanol demonstrated higher efficiency and they were selected as sample treatment and extraction solvent, respectively. Critical parameters affecting UAE were optimized by experimental design. In the present research, the extraction technique used in the official EPA microwave-assisted extraction (MAE) methodology (United States Environmental Protection Agency) and UAE optimized methodology were compared. The results indicated that the developed method showed better efficacy since microwave extraction gave very poor responses for nicosulfuron and prosulfuron. The temperature extraction was also optimized; room temperature was the most suitable to work with. Under the optimized conditions, the proposed UAE-LC-MS/MS method was assessed in terms of linearity (R2 ≥ 0.9912), accuracy (recoveries around 100%), and precision (relative standard deviation, RSD < 13%). The absence of significant matrix effects allowed quantification in real samples by external calibration with standards prepared in water:methanol. Method sustainability was also evaluated using the metric tool AGREEPrep. Finally, the analysis of real contaminated samples revealed the presence of 7 out of the 9 studied herbicides with S-metolachlor at high concentrations in all samples.

In-syringe solid-phase extraction of polycyclic aromatic hydrocarbons using an iron-carboxylate metal-organic framework and hypercrosslinked polymer composite gelatin cryogel-modified cellulose acetate adsorbent.

Cellulose acetate fibers were modified with a gelatin cryogel adsorbent incorporating an iron-carboxylate metal-organic framework and hypercrosslinked polymer composite. The hybrid adsorption materials facilitated the adsorption ability toward polycyclic aromatic hydrocarbons and were entrapped into gelatin cryogel to be hierarchically coated on cellulose acetate fibers which helped to reduce the clogging problem of packed adsorbent. The composite adsorbent was employed as the solid phase of an in-syringe miniaturized solid-phase extraction system. The adsorbent was packed into the needle hub of a disposable syringe and used to extract and preconcentrate polycyclic aromatic hydrocarbons in water sample. The fabricated porous composite adsorbent was characterized and extraction conditions were optimized to achieve the best extraction performance. High-performance liquid chromatography was employed to separate and quantify extracted PAHs. The developed analysis method provided a linear range of 0.020-50 µg L-1 for phenanthrene and benzo(b)fluoranthene, 0.010-50 µg L-1 for pyrene, 0.0020-50 µg L-1 for benzo(a)anthracene, and 0.0050-50 µg L-1 for benzo(a)pyrene and dibenzo(a,h)anthracene. The limits of detection ranged from 0.5 to 5.0 ng L-1. Recoveries ranged from 89 to 98% with RSDs below 7%. The good stability of the adsorbent allowed up to 21 cycles of efficient extraction and desorption.

Macrolides May Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Entry into Cells: A Quantitative Structure Activity Relationship Study and Experimental Validation.

The global pandemic caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is threatening the health and economic systems worldwide. Despite the enormous efforts of scientists and clinicians around the world, there is still no drug or vaccine available worldwide for the treatment and prevention of the infection. A rapid strategy for the identification of new treatments is based on repurposing existing clinically approved drugs that show antiviral activity against SARS-CoV-2 infection. In this study, after developing a quantitative structure activity relationship analysis based on molecular topology, several macrolide antibiotics are identified as promising SARS-CoV-2 spike protein inhibitors. To confirm the in silico results, the best candidates were tested against two human coronaviruses (i.e., 229E-GFP and SARS-CoV-2) in cell culture. Time-of-addition experiments and a surrogate model of viral cell entry were used to identify the steps in the virus life cycle inhibited by the compounds. Infection experiments demonstrated that azithromycin, clarithromycin, and lexithromycin reduce the intracellular accumulation of viral RNA and virus spread as well as prevent virus-induced cell death, by inhibiting the SARS-CoV-2 entry into cells. Even though the three macrolide antibiotics display a narrow antiviral activity window against SARS-CoV-2, it may be of interest to further investigate their effect on the viral spike protein and their potential in combination therapies for the coronavirus disease 19 early stage of infection.

Targeting the JAK/STAT Pathway: A Combined Ligand- and Target-Based Approach.

Janus kinases (JAKs) are a family of proinflammatory enzymes able to mediate the immune responses and the inflammatory cascade by modulating multiple cytokine expressions as well as various growth factors. In the present study, the inhibition of the JAK-signal transducer and activator of transcription (STAT) signaling pathway is explored as a potential strategy for treating autoimmune and inflammatory disorders. A computationally driven approach aimed at identifying novel JAK inhibitors based on molecular topology, docking, and molecular dynamics simulations was carried out. For the best candidates selected, the inhibitory activity against JAK2 was evaluated in vitro. Two hit compounds with a novel chemical scaffold, 4 (IC50 = 0.81 µM) and 7 (IC50 = 0.64 µM), showed promising results when compared with the reference drug Tofacitinib (IC50 = 0.031 µM).

Miniaturized active air sampling method for the analysis of tire rubber pollutants from indoor and outdoor places.

An effective, quick, and sustainable air analysis method was developed to analyze 41 volatiles and semivolatile organic compounds present in tire rubber and crumb rubber materials. The proposed method, based on active sampling using a sorbent material followed by an ultrasound assisted extraction, was developed with the aim of obtaining a fast and simple procedure to determine polycyclic aromatic hydrocarbons, plasticizers, antioxidants, and vulcanization agents in air. A small amount of sorbent (25 mg) was used, and the analytes were recovered in only 1 mL of solvent. An experimental design was applied to study the influence of main factors such as type of sorbent and type of solvent, extraction technique (ultrasound-assisted extraction and vortex extraction), extraction time, as well as the factor interactions. Under optimal conditions, no breakthrough occurs in the studied interval (up to 4 m3 ). Linearity was demonstrated in a wide concentration range. Accuracy of the total sampling-extraction analysis was evaluated obtaining satisfactory recoveries as well as good precision. The method was successfully applied to different outdoor and indoor air environments, including a recycled rubber synthetic turf football pitch.

Occurrence of Fungicides in Vineyard and the Surrounding Environment.

Seventeen fungicides were determined in different matrices from vineyard areas, including vine leaves, soils, grapes and water, using gas chromatography coupled to tandem mass spectrometry (GC-MS/MS). For leaf analysis, ultrasound-assisted extraction (UAE) was performed evaluating different solvents. UAE was compared with other extraction techniques such as vortex extraction (VE) and matrix solid-phase dispersion (MSPD). The performance of the UAE method was demonstrated on vine leaf samples and on other types of samples such as tea leaves, underlining its general suitability for leaf crops. As regards other matrices, soils were analyzed by UAE and microwave-assisted extraction (MAE), grapes by UAE and waters by SPE using cork as the sorbent. The proposed method was applied to 17 grape leaf samples in which 14 of the target fungicides were detected at concentrations up to 1000 µg g-1. Furthermore, the diffusion and transport of fungicides was demonstrated not only in crops but also in environmental matrices.

Recent Advances in Sample Preparation for Cosmetics and Personal Care Products Analysis.

The use of cosmetics and personal care products is increasing worldwide. Their high matrix complexity, together with the wide range of products currently marketed under different forms imply a challenge for their analysis, most of them requiring a sample pre-treatment step before analysis. Classical sample preparation methodologies involve large amounts of organic solvents as well as multiple steps resulting in large time consumption. Therefore, in recent years, the trends have been moved towards the development of simple, sustainable, and environmentally friendly methodologies in two ways: (i) the miniaturization of conventional procedures allowing a reduction in the consumption of solvents and reagents; and (ii) the development and application of sorbent- and liquid-based microextraction technologies to obtain a high analyte enrichment, avoiding or significantly reducing the use of organic solvents. This review provides an overview of analytical methodology during the last ten years, placing special emphasis on sample preparation to analyse cosmetics and personal care products. The use of liquid-liquid and solid-liquid extraction (LLE, SLE), ultrasound-assisted extraction (UAE), solid-phase extraction (SPE), pressurized liquid extraction (PLE), matrix solid-phase extraction (MSPD), and liquid- and sorbent-based microextraction techniques will be reviewed. The most recent advances and future trends including the development of new materials and green solvents will be also addressed.

Identification of New Templates for the Synthesis of BEA, BEC, and ISV Zeolites Using Molecular Topology and Monte Carlo Techniques.

The presence of organic structure directing agents (templates) in the synthesis of zeolites allows the synthesis to be directed, in many cases, toward structures in which there is a large stabilization between the template and the zeolite micropore due to dispersion interactions. Although other factors are also important (temperature, pH, Si/Al ratio, etc.), systems with strong zeolite-template interactions are good candidates for an application of new computational algorithms, for instance those based in molecular topology (MT), that can be used in combination with large databases of organic molecules. Computational design of new templates allows the synthesis of existing and new zeolites to be expanded and refined. Three zeolites with similar 3-D large pore systems, BEA, BEC, and ISV, were selected with the aim of finding new templates for their selective syntheses. Using a training set of active and inactive templates (obtained from the literature) for the synthesis of target zeolites, it was possible to select chemical descriptors related to activity, meaning a good candidate template. With a discriminant function defined upon MT, the screening through a database of organic molecules led to a small subset (preselection) of candidate templates for the synthesis of BEA, BEC, and ISV. As far as we know, this is the first time that topological/topochemical descriptors, which do not consider 3-D information on the molecules, have been used to predict the activity of zeolite structure directing agents (SDAs). Following the prediction of SDAs using MT, an automated approach of sequential template filling of micropores based on a combination of Monte Carlo and lattice energy minimization was applied for all the candidate templates in the three zeolites. Two results can be obtained from this: an evaluation of the quality of the molecular topology QSAR models leading to the preselection of templates, and a final selection of candidate templates for the selective synthesis of BEA, BEC, and ISV. Regarding the latter, a good template will be that which maximizes the zeolite-template dispersion interactions with one, and only one, of the three zeolites. The presented methodology can be used to find alternative (maybe cheaper or perhaps more selective) templates than those already known.

Fabric phase sorptive extraction for the determination of 17 multiclass fungicides in environmental water by gas chromatography-tandem mass spectrometry.

A rapid environmental pollution screening and monitoring workflow based on fabric phase sorptive extraction-gas chromatography-tandem mass spectrometry (FPSE-GC-MS/MS) is proposed for the first time for the analysis of 17 widespread used fungicides (metalaxyl, cyprodinil, tolylfluanid, procymidone, folpet, fludioxonil, myclobutanil, kresoxim methyl, iprovalicarb, benalaxyl, trifloxystrobin, fenhexamid, tebuconazole, iprodione, pyraclostrobin, azoxystrobin and dimethomorph) in environmental waters. The most critical parameters affecting FPSE, such as sample volume, matrix pH, desorption solvent and time, and ionic strength were optimized by statistical design of experiment to obtain the highest extraction efficiency. Under the optimized conditions, the proposed FPSE-GC-MS/MS method was validated in terms of linearity, repeatability, reproducibility, accuracy and precision. To assess matrix effects, recovery studies were performed employing different water matrices including ultrapure, fountain, river, spring, and tap water at 4 different concentration levels (0.1, 0.5, 1 and 5 µg/L). Recoveries were quantitative with values ranging between 70-115%, and relative standard deviation values lower than 14%. Limits of quantification were at the low ng/L for all the target fungicides. Finally, the validated FPSE-GC-MS/MS method was applied to real water samples, revealing the presence of 11 out of the 17 target fungicides.

Molecular topology and QSAR multi-target analysis to boost the in silico research for fungicides in agricultural chemistry.

The aim of the present study is to show how molecular topology can be a powerful in silico tool for the prediction of the fungicidal activity of several diphenylamine derivatives against three fungal species (cucumber downy mildew, rice blast and cucumber gray mold). A multi-target QSAR model was developed, and two strategies were followed. First is the construction of a virtual library of molecules using DesMol2 program and a subsequent selection of potential active ones. Second is the selection of molecules from the literature on the basis of molecular scaffolds. More than 700 diphenylamine derivatives designed and other 60 fluazinam's derivatives with structural similarity higher than 80% were studied. Almost twenty percent of the molecules analyzed show potential activity against the three fungal species.

DesMol2, an Effective Tool for the Construction of Molecular Libraries and Its Application to QSAR Using Molecular Topology.

A web application, DesMol2, which offers two main functionalities, is presented: the construction of molecular libraries and the calculation of topological indices. These functionalities are explained through a practical example of research of active molecules to the formylpeptide receptor (FPR), a receptor associated with chronic inflammation in systemic amyloidosis and Alzheimer's disease. Starting from a data(base) of 106 dioxopiperazine pyrrolidin piperazine derivatives and their respective constant values of binding affinity to FPR, multilinear regression and discriminant analyses are performed to calculate several predictive topological-mathematical models. Next, using the DesMol2 application, a molecular library consisting of 6,120 molecules is built and performed for each predictive model. The best potential active candidates are selected and compared with results from other previous works.

Extreme cosmetics and borderline products: an analytical-based survey of European regulation compliance.

The cosmetic industry currently focuses on products with magnified or exaggerated effects or extremely long-lasting characteristics. There are also a number of related commercial products for which the regulatory framework is far from clear; they are called 'borderline', and the European authorities only recommend which regulations they need to comply with. In any case, all these products must be safe under reasonable conditions of use in accordance with the applicable laws in force in the European Union (EU) framework. In this context, adequate analytical methodology is needed to evaluate the degree of compliance. Ultrasound Assisted Extraction (UAE) procedures for the analysis of 70 cosmetic ingredients have therefore been developed in this work. Moreover, for cosmetics with plastic applicators, a Supported-UAE (Sup-UAE) method was also opportunely optimized to check if a partial transfer of plasticizers to the cosmetics-and thereby to the consumers-could happen. In a survey of 50 commercial products (30 'extreme' and 20 'borderline'), the methods afforded mean recoveries of about 100% and RSD values lower than 5% for UAE and 10% for Sup-UAE, and with detection limits far below the legal requirements, for all the target compounds, thereby demonstrating their analytical suitability. Results are discussed in detail for phthalates, fragrances (musks and allergens) and some frequent preservatives. Additionally, a labelling study was performed to check if the consumer is correctly and fully informed. Graphical abstract ᅟ.

Different miniaturized extraction methodologies followed by GC-MS/MS analysis for the determination of UV filters in beach sand.

Four different miniaturized methodologies were developed and applied to the analysis of 11 UV filters in sand samples. These approaches were based on ultrasound and vortex extractions, on-column lixiviation, and ultrasound extraction followed by solid-phase microextraction. Gas chromatography with tandem mass spectrometry was used for quantitative analysis. The analytical performance provided by the four methods was evaluated in terms of linearity, accuracy, precision, and limits of quantification. Lixiviation was discarded since it provided the lowest recoveries and the highest limits of quantification. In contrast, ultrasound and vortex extractions, and ultrasound extraction followed by solid-phase microextraction were suitable, with recoveries in general >85% and limits of quantification at the low ng/g level. Moreover, ultrasound extraction followed by solid-phase microextraction allowed using external calibration with aqueous standards and it provided higher sensitivity, with limits of quantification in general one order of magnitude lower than those achieved with the other techniques. The methodologies were applied for the analysis of four marine sand samples, and the results were statistically compared performing an analysis of variance. Eight out of the eleven target UV filters were detected. Octocrylene was found at very high concentrations (up to 1000 ng/g) followed by ethylhexyl salicylate, 4-methylbenzylidene camphor, homosalate, and 2-ethylhexyl methoxycinnamate.

Molecular topology: a strategy to identify novel compounds against ulcerative colitis.

In the present paper, a strategy to identify novel compounds against ulcerative colitis (UC) by molecular topology (MT) is presented. Several quantitative structure-activity relationship (QSAR) models based on molecular topology have been developed to predict inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha ([Formula: see text]) mediated anti-ulcerative colitis (UC) activity and protective activity against a dextran sulfate sodium (DSS)-induced UC model. Each one has been used for the screening of four previously selected compounds as potential therapeutic agents for UC: alizarin-3-methyliminodiacetic acid (AMA), Calcein, (+)-dibenzyl-L-tartrate, and Ro 41-0960. These four compounds were then tested in vitro and in vivo and confirmed AMA and Ro 41-0960 as the best lead candidates for further development against UC.

Predicting antiprotozoal activity of benzyl phenyl ether diamine derivatives through QSAR multi-target and molecular topology.

Multi-target QSAR is a novel approach that can predict simultaneously the activity of a given chemical compound on different pharmacological targets. In this work, we have used molecular topology and statistical tools such as multilinear regression analysis and artificial neural networks, to achieve a multi-target QSAR model capable to predict the antiprotozoal activity of a group of benzyl phenyl ether diamine derivatives. The activity was related to three parasites with a high prevalence rate in humans: Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani. The multi-target model showed a high regression coefficient (R(2) = 0.9644 and R(2) = 0.9235 for training and test sets, respectively) and a low standard error of estimate (SEE = 0.279). Model validation was performed with an external test (R(2) = 0.9001) and a randomization analysis. Finally, the model was applied to the search of potential new active compounds.

Molecular topology applied to the discovery of 1-benzyl-2-(3-fluorophenyl)-4-hydroxy-3-(3-phenylpropanoyl)-2H-pyrrole-5-one as a non-ligand-binding-pocket antiandrogen.

We report the discovery of 1-benzyl-2-(3-fluorophenyl)-4-hydroxy-3-(3-phenylpropanoyl)-2H-pyrrole-5-one as a novel non-ligand binding pocket (non-LBP) antagonist of the androgen receptor (AR) through the application of molecular topology techniques. This compound, validated through time-resolved fluorescence resonance energy transfer and fluorescence polarization biological assays, provides the basis for lead optimization and structure-activity relationship analysis of a new series of non-LBP AR antagonists. Induced-fit docking and molecular dynamics studies have been performed to establish a consistent hypothesis for the interaction of the new active molecule on the AR surface.