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Levulinic acid, which can be obtained from biomass, has sparked great interest as a biologically-based chemical building block with wide versatility and potential. Its esterification with alcohols of different chain lengths is a promising valorization process for obtaining esters with various applications in the areas of biofuels/biolubricants, food and cosmetics, among others. In this work, the enzymatic esterification of levulinic acid and 1-octanol using a biocatalyst derived from Araujia sericifera latex was studied in systems with and without solvent. The influence of the molar ratio between alcohol and acid (ranging from 2:1-1:9), the biocatalyst loading (between 7.5 % and 17.5 % relative to the acid), the volume of n-heptane used as reaction solvent (from 0 to 4 ml), and the reaction time (6 hours) were investigated. The activity and stability of the biocatalyst in successive uses were also analyzed. A conversion of 49 % was achieved when the reaction was carried out in a solvent-free system, using an alcohol/acid molar ratio of 1:7 and after 5 h of reaction. On the other hand, the conversion was 65.1 % when the reaction was conducted in a system containing 1 ml of n-heptane as solvent, an alcohol/acid molar ratio of 1:8, and 5 h of reaction. In both cases, a temperature as low as 30 °C and an agitation speed of 300 RPM were used., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Daniel Sanchez reports financial support was provided by National Agency for the Promotion of Research Technological Development and Innovation. Gabriela Tonetto reports financial support was provided by National Scientific and Consejo Nacional de Investigaciones Científicas y Técnicas. Gabriela Tonetto reports financial support was provided by National University of the South Department of Chemical Engineering. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, a simple, sensitive, and rapid method called green hydrophobic deep eutectic solvent-based liquid-liquid microextraction was developed to extract Brilliant Blue FCF dye from beverages. This method utilizes hydrophobic DES obtained by forming tetrabutylammonium bromide and 1-octanol in a 1:5 ratio as green extraction solvent. The transition of Brilliant Blue FCF to the DES phase occurred on its own, without the need for any reagents such as added salt or tetrahydrofuran. Several crucial factors were tried to get the best extraction efficiency, including species, DES volume and molar ratio, solution pH, ultrasonication, and centrifugation time. Under optimum conditions, extraction recoveries were achieved in the range of 95.1-101.3 % with the method developed for Brilliant Blue FCF. The detection and determination limits were observed to be 4.1 μg l -1 and 12.1 μg l -1 , respectively. In addition, the relative standard deviation values for the method's accuracy were found to be 2.23 % and 3.48 % within and between days, respectively. It has been established that the developed method is highly environmentally friendly thanks to the application of the Analytical GREENness (AGREE) and Green Analytical Procedure Index (GAPI) tools. This study shows that DES applications can be carried out without the use of emulsifiers and dispersants by prioritizing the use of hydrophobic DES compounds as environmentally friendly and green extraction solvents in food samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study pioneers a comparison of the application of biomimetic techniques, immobilised artificial membrane liquid chromatography (IAM LC) and liposome electrokinetic capillary chromatography (LEKC), for the prediction of pulmonary drug permeability. The pulmonary absorption profiles of 26 structurally unrelated drug-like molecules were evaluated using their IAM hydrophobicity index (CHI IAM) measured in IAM LC, and the logarithm of distribution constants (log K LEKC ) derived from the LEKC experiments. Lipophilicity (phospholipids) parameters obtained from IAM LC and most LEKC analyses were linearly related to the n-octanol/water partitioning coefficients of the neutral forms (i.e., log P o/w values) to a moderate extent. However, the relationship with distribution coefficients at the experimental pH (7.4) (i.e., log D 7.4 ) were weaker overall for IAM LC data and sigmoidal for some liposome compositions (phosphatidyl choline (PC): phosphatidyl inositol (PI) 85:15 mol% and 90:10 mol%) and concentrations (4 mM) in LEKC. This suggests that phospholipid partitioning supports both hydrophobic and electrostatic interactions occurring between ionised drugs and charged phospholipid moieties. The latter interactions are original when compared to those taking place in the more established n-octanol/water partitioning systems. A stronger correlation (R 2 > 0.65) was identified between the LEKC retention parameters, and the experimental apparent lung permeability (i.e., log P app values) as opposed to the values obtained by IAM LC. Therefore, LEKC offers unprecedented advantages over IAM LC in simulating cell membrane partitioning processes in the pulmonary delivery of drugs. Although LEKC has the advantage of more effectively simulating the electrostatic and hydrophobic forces in drug/pulmonary membrane interactions in vitro, the technique is unsuitable for analysing highly hydrophilic neutral or anionic compounds at the experimental pH. Conversely, IAM LC is useful for analysing compounds spanning a wider range of lipophilicity. Its simpler and more robust implementation, and propensity for high-throughput automation make it a favourable choice for researchers in drug development and pharmacological studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The bacteriophage F8 belongs to the Myoviridae group of phages and is a pathogen of Pseudomonas aeruginosa. Since Pseudomonas aeruginosa is a multidrug-resistant opportunistic bacterium and can cause serious challenges for health services, studying the potential use of phages against them is a promising approach. Pseudomonas aeruginosa can be found on medical devices because bacteria can attach to surfaces and develop biofilms, which are difficult to eradicate because of their high resistance to environmental conditions and antimicrobial therapeutics. Phage therapy is becoming promising as an alternative for the treatment of antibiotic-resistant infections, but there is still a lack of standardized protocols approved by health organizations for possible use in the clinic. In our research, we focused on the potential use of 1-octanol, which was previously used by our team to develop a method for phage purification from bacterial lysate. 1-octanol is a fatty alcohol that is mostly used in the cosmetics industry, and its advantage is that it is approved by the FDA as a food additive. In this paper, we studied the protective properties of the addition of 1-octanol for storing phage liquid preparations. We demonstrated the stabilization effect of 1-octanol addition on F8 bacteriophage preparation during storage under various conditions. Interestingly, more effective biofilm reduction was observed after treatment with the purified bacteriophage and with 1-octanol addition compared to crude lysate., (© 2024. The Author(s).)

Background: Droplet microfluidics with push-pull and microdialysis sampling from brain slices, cultured cells and engineered tissues produce low volume mass limited samples containing analytes sampled from the extracellular space. This sampling approach coupled to mass spectrometry (MS) detection allows evaluation of time-dependent chemical changes. Our goal is an approach for continuous sampling and segregation of extracellular samples into picoliter droplets followed by the characterization of the droplets using nanoelectrospray ionization (nESI) MS. The main focus here is the optimization of the carrier oil for the microfluidic device that neither affects the stability of picoliter droplets nor compatibility with MS detection of a range of analytes., Results: We developed and characterized a 1-octanol-assisted ultra-small volume droplet microfluidic nESI MS system for the analysis of neurotransmitters in distinct samples including cerebrospinal fluid (CSF). The use of a 1-octanol oil phase was effective for generation of aqueous droplets as small as 65 pL and enabled detection of acetylcholine (ACh) and gamma-aminobutyric acid (GABA) in water and artificial CSF. Continuous MS analysis of droplets for extended periods up to 220 min validated the long-term stability of droplet generation and analyte detection by nESI-MS. As an example, ACh response demonstrated a linear working range (R 2  = 0.99) between 0.4 μM and 25 μM with a limit of detection of 370 nM (24 amol), enabling its quantitation in rodent CSF., Significance: The established droplet microfluidics - nESI MS approach allows the analysis of microenvironments at high spatiotemporal resolution. The approach may allow microsampling and monitoring of spatiotemporal dynamics of neurochemicals and drugs in the brain and spinal cord of live animals., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jonathan Sweedler reports financial support was provided by National Institutes of Health. Yurii Vlasov reports financial support was provided by National Institutes of Health. Rashid Bashir reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Per- and polyfluorinated alkyl substances (PFAS), known for their widespread environmental presence and slow degradation, pose significant concerns. Of the approximately 10,000 known PFAS, only a few have undergone comprehensive testing, resulting in limited experimental data. In this study, we employed a combination of physics-based methods and data-driven models to address gaps in PFAS bioaccumulation potential. Using the COnductor-like Screening MOdel for Realistic Solvents (COSMO-RS) method, we predicted n-octanol/water partition coefficients (logK OW ), crucial for PFAS bioaccumulation. Our developed Quantitative Structure-Property Relationship (QSPR) model exhibited high accuracy (R 2  = 0.95, RMSE C  = 0.75) and strong predictive ability (Q 2 LOO  = 0.93, RMSE CV  = 0.83). Leveraging the extensive NORMAN, we predicted logK OW for over 4,000 compounds, identifying 244 outliers out of 4519. Further categorizing the database into eight Organisation for Economic Co-operation and Development (OECD) categories, we confirmed fluorine atoms role in enhanced bioaccumulation. Utilizing predicted logK OW , water solubility logS W , and vapor pressure logVP values, we calculated additional physicochemical properties that are responsible for the transport and dispersion of PFAS in the environment. Parameters such as Henry's Law (k H ), air-water partition coefficient (K AW ), octanol-air coefficient (K OA ), and soil adsorption coefficient (K OC ) exhibited favorable correlations with literature data (R 2  > 0.66). Our study successfully filled data gaps, contributing to the understanding of ubiquitous PFAS in the environment and estimating missing physicochemical data for these compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The potential of Micellar Liquid Chromatography (MLC) to model ecotoxicological endpoints for a series of pesticides was investigated. To exploit the flexibility in MLC conditions, different surfactants were employed and retention mechanism was tracked and compared to Immobilized Artificial Membrane (IAM) chromatographic retention and n-octanol- water partitioning, logP. Neutral polyoxyethylene (23) lauryl ether (Brij-35), anionic sodium dodecyl sulfate (SDS) and cationic cetyltrimethylammonium bromide (CTAB) were used in presence of PBS at pH=7.40 and acetonitrile as organic modifier when necessary. Similarities/ dissimilarities between MLC retention and IAM or logP were investigated by Principal Component Analysis (PCA) and Liner Solvation Energy Relationships (LSER). LSER revealed that hydrogen bonding acidity is the most important factor for differentiation between MLC and IAM or logP. The impact of hydrogen bonding is exemplified in the relationships of MLC retention factors with IAM or logP, which necessitate the inclusion of a relevant descriptor. PCA further revealed that MLC retention factors are clustered together with IAM indices and logP within a broader ellipse formed by ecotoxicological endpoints, involving LC 50 / EC 50 values of six aquatic organisms namely Rainbow Trout, Fathead Minnow, Bluegill Sunfish, Sheepshead Minnow, Eastern Oyster and Water Flea as well as LD 50 values of Honey Bee, thus justifying their use to construct relevant models. Satisfactory specific models for individual organisms, as well as general fish models, were obtained, in most cases, upon combination of MLC retention factors with Molecular Weight (MW) or/ and hydrogen bond parameters. All models were evaluated and compared to previously reported IAM and logP based models using an external validation data set. Predictions with Brij-35 and SDS based models were comparable, although slightly inferior than those obtained with IAM, while they were in all cases better than those obtained with logP. CTAB led to a satisfactory prediction model for Honey Bee, but it was found less suitable for aquatic organisms., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Liquid-liquid partition coefficient is a useful tool to predict biological and environmental fate of organic compounds, for example bioaccumulation or toxicity of lipophilic contaminants. Conversely, the partitioning of ionizable compounds is poorly studied in contrast to that of neutral compounds. Yet, such topic deserves attention, since numerous organic contaminants are ionizable as well as their degradation products. Hence, the contribution of charged species has to be considered in order to model accurately the mass balance or partition of ionizable compounds. In this context, we investigated the liquid-liquid partition of 13 ionizable compounds (oxalic acid, histidine, benzimidazole, etc.), covering various classes of compounds (carboxylic acids, amino-acids, etc.). The n-octanol/water partition coefficient was measured from pH 1 up to 13, in order to fully gather the distribution of both neutral and charged species. Empirical models describing these results are reviewed and partition parameters adjusted for charged species. The study of benzoic acid derivatives (benzoic, salicylic, ortho- and iso-phthalic acids) provides insights on the influence of chemical groups on the partitioning. In the case of tryptophan, the use of acid/base microconstants allowed to estimate the partition of both the zwitterion and its neutral tautomer. Despite a major zwitterionic form (log P Z (tryptophan) = -1.58 ± 0.30), the minor but neutral tautomer (log P N (tryptophan) = +0.03 ± 0.30) drives the partition equilibrium. Overall, the provided data may be useful to assess the retention of contaminants, its dependency on pH and salinity variations, and thus understanding their environmental fate. Such data may also be useful as well for molecular simulation involving solvation of organic ions in aqueous and non-aqueous solvents., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The important physicochemical properties of three novel bioactive hybrid compounds with different groups (-CH 3 , -F and -Cl) were studied, including kinetic and thermodynamic solubility in pharmaceutically relevant solvents (buffer solutions and 1-octanol) as well as partition coefficient in system 1-octanol/buffer pH 7.4. The aqueous solubility of these chemicals is poor and ranged from 0.67 × 10 -4 to 1.98 × 10 -3 mol·L -1 . The compounds studied are more soluble in the buffer pH 2.0, simulating the gastrointestinal tract environment (by an order of magnitude) than in the buffer pH 7.4 modelling plasma of blood. The solubility in 1-octanol is significantly higher; that is because of the specific interactions of the compounds with the solvent. The prediction solubility behaviour of the hybrid compounds using Hansen's three-parameter approach showed acceptable results. The experimental solubility of potential drugs was successfully correlated by means of two commonly known equations: modified Apelblat and van't Hoff. The temperature dependencies of partition coefficients of new hybrids in the model system 1-octanol/buffer pH 7.4 as a surrogate lipophilicity were measured by the shake flask method. It was found that compounds demonstrated a lipophilic nature and have optimal values of partition coefficients for oral absorption. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than fluconazole. In addition, the thermodynamic aspects of dissolution and partition processes have been examined. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than the reference drug.

The experimental and theoretical description of premelting behavior is one of the most challenging tasks in contemporary material science. In this paper, n-octanol was studied using a multi-method approach to investigate it at macroscopic and molecular levels. The experimental infrared (IR) spectra were collected in the solid state and liquid phase at temperature range from -84∘C to -15 ∘C to detect temperature-related indicators of pretransitional phenomena. Next, the nonlinear dielectric effect (NDE) was measured at various temperatures (from -30 ∘C to -15 ∘C) to provide insight into macroscopic effects of premelting. As a result, a two-step mechanism of premelting in n-octanol was established based on experimental data. It was postulated that it consists of a rotator state formation followed by the surface premelting. In order to shed light onto molecular-level processes, classical molecular dynamics (MD) was performed to investigate the time evolution of the changes in metric parameters as a function of simulation temperature. The applied protocol enabled simulations in the solid state as well as in the liquid (the collapse of the ordered crystal structure). The exact molecular motions contributing to the rotator state formation were obtained, revealing an enabling of the rotational freedom of the terminal parts of the chains. The Car-Parrinello molecular dynamics (CPMD) was applied to support and interpret experimental spectroscopic findings. The vibrational properties of the stretching of OH within the intermolecular hydrogen bond were studied using Fourier transformation of the autocorrelation function of both dipole moments and atomic velocity. Finally, path integral molecular dynamics (PIMD) was carried out to analyze the quantum effect's influence on the bridged proton position in the hydrogen bridge. On the basis of the combined experimental and theoretical conclusions, a novel mechanism of the bridged protons dynamics has been postulated-the interlamellar hydrogen bonding pattern, resulting in an additional OH stretching band, visible in the solid-state experimental IR spectra.

Blind predictions of octanol/water partition coefficients at 298.15 K for 22 drug-like compounds were made for the SAMPL7 challenge. The octanol/water partition coefficients were predicted using solvation free energies computed using molecular dynamics simulations, wherein we considered the use of both pure and water-saturated 1-octanol to model the octanol-rich phase. Water and 1-octanol were modeled using TIP4P and TrAPPE-UA, respectively, which have been shown to well reproduce the experimental mutual solubility, and the solutes were modeled using GAFF. After the close of the SAMPL7 challenge, we additionally made predictions using TIP4P/2005 water. We found that the predictions were sensitive to the choice of water force field. However, the effect of water in the octanol-rich phase was found to be even more significant and non-negligible. The effect of inclusion of water was additionally sensitive to the chemical structure of the solute., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

A protein precipitation technique was optimized to produce biophysically stable 'protein microbeads', applicable to highly concentrated protein formulation. Initially, production of BSA microbeads was performed using rapid dehydration by vortexing in organic solvents followed by cold ethanol treatment and a vacuum drying. Out of four solvents, n-octanol produced the most reversible microbeads upon reconstitution. A Shirasu porous glass (SPG) membrane emulsification technique was utilized to enhance the size distribution and manufacturing process of the protein microbeads with a marketized human IgG solution. Process variants such as dehydration time, temperature, excipients, drying conditions, and initial protein concentration were evaluated in terms of the quality of IgG microbeads and their reversibility. The hydrophobized SPG membrane produced a narrow size distribution of the microbeads, which were further enhanced by shorter dehydration time, low temperature, minimized the residual solvents, lower initial protein concentration, and addition of trehalose to the IgG solution. Final reversibility of the IgG microbeads with trehalose was over 99% at both low and high protein concentrations. Moreover, the formulation was highly stable under repeated mechanical shocks and at an elevated temperature compared to its liquid state. Its in vivo pharmacokinetic profiles in rats were consistent before and after the 'microbeadification'., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The current 2D culture model systems developed for drug screening are not sufficient to reflect the characteristics of in vivo solid tumors. Therefore, more effective in vitro tumor model systems must be developed for translational studies on therapeutic drug screening and testing. Herein, we report a new ultra-low adhesion (ULA) hydrogel for generating 3D cancer cell spheroids as tumor models in vitro. N-octanoyl glycol chitosan (OGC) was synthesized and coated onto the surface of a typical cell culture dish. Cell spheroids were effectively formed on the OGC-coated surface, and phenotypes of the tumor cells were well maintained during culture. More importantly, U373-MG cells cultured on OGC-coated plates were more resistant to doxorubicin than cells cultured on typical plates. Our OGC-based ULA system may offer a convenient method for 3D cell culture to provide enhanced performance in cancer research, drug screening and toxicology., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The lipophilicity of a drug is an important parameter for its eventual development by the pharmaceutical industry. It is usually measured by HPLC following partition of the compound between water and 1-octanol. We present here an alternative, simple, sensitive and quantitative 1 H nuclear magnetic resonance (NMR) method for the experimental measurement of partition coefficients of natural compounds and pharmaceutical drugs. It is based on measuring concentrations in the water phase, before and after partitioning and equilibration between water and octanol, using the ERETIC (Electronic Reference To Access In Vivo Concentration) technique. The signal to noise ratio is improved by a Water Suppression by Excitation Sculpting sequence. Quantification is based on an electronic reference signal and does not need addition of a reference compound. The log P values of 22 natural metabolites and four pharmaceutical drugs were determined and the experimental results are in excellent agreement with literature data. The experiments were run on ~2 mg material. This technique proved to be robust, reproducible and suitable for log P values between -2 and +2., (© 2021 John Wiley & Sons, Ltd.)

Inspired by the successful application of the embedded cluster reference interaction site model (EC-RISM), a combination of quantum-mechanical calculations with three-dimensional RISM theory to predict Gibbs energies of species in solution within the SAMPL6.1 (acidity constants, pK a ) and SAMPL6.2 (octanol-water partition coefficients, log P) the methodology was applied to the recent SAMPL7 physical property challenge on aqueous pK a and octanol-water log P values. Not part of the challenge but provided by the organizers, we also computed distribution coefficients log D 7.4 from predicted pK a and log P data. While macroscopic pK a predictions compared very favorably with experimental data (root mean square error, RMSE 0.72 pK units), the performance of the log P model (RMSE 1.84) fell behind expectations from the SAMPL6.2 challenge, leading to reasonable log D 7.4 predictions (RMSE 1.69) from combining the independent calculations. In the post-submission phase, conformations generated by different methodology yielded results that did not significantly improve the original predictions. While overall satisfactory compared to previous log D challenges, the predicted data suggest that further effort is needed for optimizing the robustness of the partition coefficient model within EC-RISM calculations and for shaping the agreement between experimental conditions and the corresponding model description., (© 2021. The Author(s).)

A multiple linear regression model called MLR-3 is used for predicting the experimental n-octanol/water partition coefficient (log P N ) of 22 N-sulfonamides proposed by the organizers of the SAMPL7 blind challenge. The MLR-3 method was trained with 82 molecules including drug-like sulfonamides and small organic molecules, which resembled the main functional groups present in the challenge dataset. Our model, submitted as "TFE-MLR", presented a root-mean-square error of 0.58 and mean absolute error of 0.41 in log P units, accomplishing the highest accuracy, among empirical methods and also in all submissions based on the ranked ones. Overall, the results support the appropriateness of multiple linear regression approach MLR-3 for computing the n-octanol/water partition coefficient in sulfonamide-bearing compounds. In this context, the outstanding performance of empirical methodologies, where 75% of the ranked submissions achieved root-mean-square errors < 1 log P units, support the suitability of these strategies for obtaining accurate and fast predictions of physicochemical properties as partition coefficients of bioorganic compounds., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

We applied the COSMO-RS method to predict the partition coefficient logP between water and 1-octanol for 22 small drug like molecules within the framework of the SAMPL7 blind challenge. We carefully collected a set of thermodynamically meaningful microstates, including tautomeric forms of the neutral species, and calculated the logP using the current COSMOtherm implementation on the most accurate level. With this approach, COSMO-RS was ranked as the 6st most accurate method (Measured by the mean absolute error (MAE) of 0.57) over all 17 ranked submissions. We achieved a root mean square deviation (RMSD) of 0.78. The largest deviations from experimental values are exhibited by five SAMPL molecules (SM), which seem to be shifted in most SAMPL7 contributions. In context with previous SAMPL challenges, COSMO-RS demonstrates a wide range of applicability and one of the best in class reliability and accuracy among the physical methods., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The physicochemical properties of a drug molecule determine the therapeutic effectiveness of the drug. Thus, the development of fast and accurate theoretical approaches for the prediction of such properties is inevitable. The participation to the SAMPL7 challenge is based on the estimation of logP coefficients and pK a values of small drug-like sulfonamide derivatives. Thereby, quantum mechanical calculations were carried out in order to calculate the free energy of solvation and the transfer energy of 22 drug-like compounds in different environments (water and n-octanol) by employing the SMD solvation model. For logP calculations, we studied eleven different methodologies to calculate the transfer free energies, the lowest RMSE value was obtained for the M06L/def2-TZVP//M06L/def2-SVP level of theory. On the other hand, we employed an isodesmic reaction scheme within the macro pK a framework; this was based on selecting reference molecules similar to the SAMPL7 challenge molecules. Consequently, highly well correlated pK a values were obtained with the M062X/6-311+G(2df,2p)//M052X/6-31+G(d,p) level of theory., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Partition coefficients quantify a molecule's distribution between two immiscible liquid phases. While there are many methods to compute them, there is not yet a method based on the free energy of each system in terms of energy and entropy, where entropy depends on the probability distribution of all quantum states of the system. Here we test a method in this class called Energy Entropy Multiscale Cell Correlation (EE-MCC) for the calculation of octanol-water logP values for 22 N-acyl sulfonamides in the SAMPL7 Physical Properties Challenge (Statistical Assessment of the Modelling of Proteins and Ligands). EE-MCC logP values have a mean error of 1.8 logP units versus experiment and a standard error of the mean of 1.0 logP units for three separate calculations. These errors are primarily due to getting sufficiently converged energies to give accurate differences of large numbers, particularly for the large-molecule solvent octanol. However, this is also an issue for entropy, and approximations in the force field and MCC theory also contribute to the error. Unique to MCC is that it explains the entropy contributions over all the degrees of freedom of all molecules in the system. A gain in orientational entropy of water is the main favourable entropic contribution, supported by small gains in solute vibrational and orientational entropy but offset by unfavourable changes in the orientational entropy of octanol, the vibrational entropy of both solvents, and the positional and conformational entropy of the solute., (© 2021. The Author(s).)

Purpose: Development of hyaluronic acid conjugated metformin-phospholipid sonocomplexes (HA-MPS), a biphasic complexation product compiled for enhancing both the lipophilicity and targeting potential of Metformin (MET) to CD44 receptors on pancreatic cancer., Methods: MET was chemically conjugated to hyaluronic acid (HA) via amide coupling reaction. Then, the HA conjugated MET was physically conjugated to Lipoid™S100 via ultrasound irradiation. A combined D-optimal design was implemented to statistically optimize formulation variables. The HA-MPS were characterized through solubility studies, partition coefficient, drug content uniformity, particle size and zeta potential. The optimized HA-MPS was tested via proton nuclear magnetic resonance, infrared spectroscopy to elucidate the nature of physicochemical interactions in the complex which was further scrutinized on molecular level via molecular docking and dynamic simulation., Results: The solubility and partition studies showed a lipophilicity enhancement up to 67 folds as they adopted inverted micelles configuration based on the packing parameter hypothesis. The optimized HA-MPS showed 11.5 folds lower IC 50 , extra 25% reduction in oxygen consumption rate, better reduction in hypoxia-inducible factor and reactive oxygen species in MiaPaCa-2 cells., Conclusion: These results proved better internalization of MET which was reflected by abolishing hypoxic tumour microenvironment, a mainstay toward a normoxic and less resistant pancreatic cancer., Competing Interests: The authors have no conflicts of interest to report in this work., (© 2021 Farag et al.)

Currently, rapid evaluation of the physicochemical parameters of drug candidates, such as lipophilicity, is in high demand owing to it enabling the approximation of the processes of absorption, distribution, metabolism, and elimination. Although the lipophilicity of drug candidates is determined using the shake flash method ( n -octanol/water system) or reversed phase liquid chromatography (RP-LC), more biosimilar alternatives to classical lipophilicity measurement are currently available. One of the alternatives is immobilized artificial membrane (IAM) chromatography. The present study is a continuation of our research focused on physiochemical characterization of biologically active derivatives of isoxazolo[3,4- b ]pyridine-3(1 H )-ones. The main goal of this study was to assess the affinity of isoxazolones to phospholipids using IAM chromatography and compare it with the lipophilicity parameters established by reversed phase chromatography. Quantitative structure-retention relationship (QSRR) modeling of IAM retention using differential evolution coupled with partial least squares (DE-PLS) regression was performed. The results indicate that in the studied group of structurally related isoxazolone derivatives, discrepancies occur between the retention under IAM and RP-LC conditions. Although some correlation between these two chromatographic methods can be found, lipophilicity does not fully explain the affinities of the investigated molecules to phospholipids. QSRR analysis also shows common factors that contribute to retention under IAM and RP-LC conditions. In this context, the significant influences of WHIM and GETAWAY descriptors in all the obtained models should be highlighted.

In this study quantum mechanical methods were used to predict the solvation energies of a series of drug-like molecules both in water and in octanol, in the context of the SAMPL6 n-octanol/water partition coefficient challenge. In pharmaceutical design, n-octanol/water partition coefficient, LogP, describes the drug's hydrophobicity and membrane permeability, thus, a well-established theoretical method that rapidly determines the hydrophobicity of a drug, enables the progress of the drug design. In this study, the solvation free energies were obtained via six different methodologies (B3LYP, M06-2X and ωB97XD functionals with 6-311+G** and 6-31G* basis sets) by taking into account the environment implicitly; the methodology chosen (B3LYP/6-311+G**) was used later to evaluate ΔG solv by using explicit water as solvent. We optimized each conformer in different solvents separately, our calculations have shown that the stability of the conformers is highly dependent on the solvent environment. We have compared implicitly and explicitly solvated systems, the interaction of one explicit water with drug-molecules at the proper location leads to the prediction of more accurate LogP values.

Results are reported for octanol-water partition coefficients (log P) of the neutral states of drug-like molecules provided during the SAMPL6 (Statistical Assessment of Modeling of Proteins and Ligands) blind prediction challenge from applying the "embedded cluster reference interaction site model" (EC-RISM) as a solvation model for quantum-chemical calculations. Following the strategy outlined during earlier SAMPL challenges we first train 1- and 2-parameter water-free ("dry") and water-saturated ("wet") models for n-octanol solvation Gibbs energies with respect to experimental values from the "Minnesota Solvation Database" (MNSOL), yielding a root mean square error (RMSE) of 1.5 kcal mol -1 for the best-performing 2-parameter wet model, while the optimal water model developed for the pK a part of the SAMPL6 challenge is kept unchanged (RMSE 1.6 kcal mol -1 for neutral compounds from a model trained on both neutral and ionic species). Applying these models to the blind prediction set yields a log P RMSE of less than 0.5 for our best model (2-parameters, wet). Further analysis of our results reveals that a single compound is responsible for most of the error, SM15, without which the RMSE drops to 0.2. Since this is the only compound in the challenge dataset with a hydroxyl group we investigate other alcohols for which Gibbs energy of solvation data for both water and n-octanol are available in the MNSOL database to demonstrate a systematic cause of error and to discuss strategies for improvement.

The water-octanol partition coefficient is an important physicochemical property for small molecule drug design. Here, we report our participation in the SAMPL6 logP prediction challenge with free energy perturbation (FEP) calculations in the water phase and in the 1-octanol phase using Drude polarizable force fields. Root mean square error (RMSE) and mean absolute error (MAE) of our prediction are equal to 1.85 and 1.25 logP units. The errors are not evenly distributed. Out of eleven SAMPL6 solutes, FEP/Drude performed very badly on three molecules (deviations all larger than 2 logP units) but good on the remaining eight (deviations all less than 1 logP unit). We find while FEP converges well within one nanosecond in water, simulations in 1-octanol need much longer simulation time and possibly more independent runs for sampling. We also find out that 1-octanol, albeit being a non-polar solvent, still polarizes solute molecules and forms stable hydrogen bonds with them. At the end, we attempt to reweight FEP trajectories with QM/Drude calculations and discuss possible caveats in our simulation setup.

The α v β 3 integrin receptors have high expression on proliferating growing tumor cells of different origins including non-small-cell lung cancer. RGD-containing peptides target the extracellular domain of integrin receptors. This specific targeting makes these short sequences a suitable nominee for theranostic application. DOTA-E(cRGDfK) 2 was radiolabeled with 68 Ga efficiently. The in vivo and in vitro stability was examined in different buffer systems. Metabolic stability was assessed in mice urine. In vitro specific binding, cellular uptake, and internalization were determined. The tumor-targeting potential of [ 68 Ga]Ga-DOTA-E(cRGDfK) 2 in a lung cancer mouse model was studied. Besides, the very early diagnostic potential of the 68 Ga-labeled RGD peptide was evaluated. The acquisition and reconstruction of the PET-CT image data were also carried out. Radiochemical and radionuclide purity for [ 68 Ga]Ga-DOTA-E(cRGDfK) 2 was >%98 and >%99, respectively. Radiotracer showed high in vivo , in vitro , and metabolic stability which was determined by ITLC. The dissociation constant ( K d ) of [ 68 Ga]Ga-DOTA-E(cRGDfK) 2 was 15.28 nM. On average, more than 95% of the radioactivity was specific binding (internalized + surface-bound) to A549 cells. Biodistribution data showed that radiolabeled peptides were accumulated significantly in A549 tumor and excreted rapidly by the renal system. Tumor uptake peaks were at 1-hour postinjection for [ 68 Ga]Ga-DOTA-E(cRGDfK) 2 . The tumor was clearly visualized in all images. [ 68 Ga]Ga-DOTA-E(cRGDfK) 2 can be used as a peptide-based imaging agent allowing very early detection of different cancers overexpressing α v β 3 integrin receptors and can be a potential candidate in clinical peptide-based imaging for lung cancer., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Nazanin Pirooznia et al.)

Background: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, which still has high prevalence worldwide. In addition, cases of drug resistance are frequently observed. In the search for new anti-TB drugs, compounds with antimycobacterial activity have been developed, such as derivatives of pyrazinoic acid, which is the main pyrazinamide metabolite. In a previous study, the compounds were evaluated and showed moderate antimycobacterial activity and no important cytotoxic profile; however, information about their pharmacokinetic profile is lacking., Objective: The aim of this work was to perform physicochemical, permeability, and metabolic properties of four pyrazinoic acid esters., Method: The compounds were analyzed for their chemical stability, n-octanol:water partition coefficient (logP) and apparent permeability (Papp) in monolayer of Caco-2 cells. The stability of the compounds in rat and human microsomes and in rat plasma was also evaluated., Results: The compounds I, II and IV were found to be hydrophilic, while compound III was the most lipophilic (logP 1.59) compound. All compounds showed stability at the three evaluated pHs (1.2, 7.4 and 8.8). The apparent permeability measured suggests good intestinal absorption of the compounds. Additionally, the compounds showed metabolic stability under action of human and rat microsomal enzymes and stability in rat plasma for at least 6 hours., Conclusion: The results bring favorable perspectives for the future development of the evaluated compounds and other pyrazinoic acid derivatives., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A novel approach for dispersive liquid-liquid microextraction based on the use of deep eutectic solvent as a disperser was presented for the first time. The procedure was automated based on an in-syringe flow system coupled with UV-Vis detection and demonstrated by the determination of chromium (VI) in beverages. This analytical task was used as a proof-of-concept example. The automated extraction procedure involved the aspiration of aqueous sample into a syringe pump with homogeneous mixture of extraction solvent (1-oсtanol) and deep eutectic solvent (tetrabutylammonium bromide - formic acid) containing color-forming reagent (1,5-diphenylcarbazide). This led to decomposition of deep eutectic solvent in aqueous phase resulting in dispersion of extraction solvent, oxidation of 1,5-diphenylcarbazide to 1,5- diphenylcarbazone in the presence of chromium (VI), and formation of colored chromium (III) complex with 1,5-diphenylcarbazone and its fast extraction. In this case composition of deep eutectic solvent played a key role for analyte extraction. Tetrabutylammonium bromide promoted mass transfer between aqueous phase and the extraction solvent droplets as a salting out agent, bromide ion acted as an ion-pare agent for analyte complex extraction, formic acid provided required pH value for analyte complex formation. Under the optimal conditions the limit of detection, calculated from a blank test based on 3s, was 0.2 μg L -1 . The automated dispersive liquid-liquid microextraction using deep eutectic solvent as disperser can be considered as an available, efficient, rapid and environmentally friendly sample pretreatment approach., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Deep-sea natural products have been created by unique marine organisms that thrive in a challenging environment of extreme conditions for its inhabitants. In this study, 179 deep-sea natural products isolated from 2009 to 2013 were investigated by analysing their physicochemical properties that are important indicators of the ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) profile of a compound. The study and analysis of these molecular descriptors and characteristics enabled the defining of these compounds in various chemical spaces, particularly as an indication of their drug-likeness and position in chemical space and is the first to be conducted to analyse deep-sea derived natural products. It was found that ~40% of all deep-sea natural products were drug-like and 2/3 were within Known Drug Space (KDS), highlighting the high drug-likeness of a significant proportion of deep-sea natural products, most of which have already been shown to have notable biological activities, that should be further investigated as potential therapeutics. Furthermore, this study was able to reveal the general structural differences between compounds from Animalia, Bacteria and Fungi organisms where it was observed that natural products from members of the Animalia kingdom are structurally more varied than compounds from bacteria and fungi. It was also noted that, in general, fungi-derived compounds occupy a more favourable position in drug-like chemical space and are a rich and promising source of biologically-active natural products for the purposes of drug development and therapeutic application., Competing Interests: The author declares no conflict of interest.

An efficient and environment-friendly microextraction method, namely, β-cyclodextrin assisted liquid-liquid microextraction, based on solidification of the floating organic droplets method coupled with HPLC is investigated for the sensitive determination of trace neonicotinoid pesticide residues. In this method, β-cyclodextrin is used as a disperser solvent, while 1-octanol is selected as an extraction solvent. β-cyclodextrins was found to decrease interfacial tension and increase the contact area between the organic and water phases with the help of centrifugation. A cloudy solution was rapidly formed and then centrifuged to complete phase separation. Various key parameters influencing extraction efficiency were systematically investigated and optimized; they include salt addition, concentration of β-cyclodextrin, and volume of extraction solvent (1-octanol). Under optimum conditions, good linearity was obtained with coefficient for determination (R 2 ) greater than 0.99. A low limit of detection, high enrichment factor, and good recovery (83 - 132) were achieved. This proves that the proposed method can be applied to determine trace neonicotinoid pesticide residues in natural surface water samples., Competing Interests: The authors declare no conflicts of Interest.

A polymer inclusion membrane (PIM) that contains a polyvinyl chloride (PVC) polymer matrix and 1-octanol (OCT) as specific carrier (PO-PIM) was prepared to investigate the mass transfer behaviour of phenol in aqueous solutions. Results showed that the mass transfer behaviour of the PO-PIM for phenol conformed to the first-order kinetics. In addition, the mass transfer efficiency for phenol reached the maximum when the OCT content was 82.8 wt%. The mass transfer activation energy (E a ) was 14.46 kJ mol -1 , which indicated that intramembranous diffusion was the main controlling factor in the mass transfer process. The introduction of hydrophobic additives, such as kerosene, liquid paraffin and vegetable oil, into the PO-PIM could remarkably improve its stability. In an aqueous solutions of phenol ranging from 0 mg L -1 to 9000 mg L -1 , the initial flux (J 0 ) of kerosene/PVC/OCT-PIM (KPO-PIM) was positively correlated with the initial concentration of phenol. For a stripping solution with a feed solution pH of 2.0 and a sodium hydroxide concentration of 0.1 mol L -1 , the maximum permeability coefficient during stable mass transfer reached 12.55 μm s -1 . At a mass transfer area of 3.14 cm 2 , an enrichment factor (EF) of 3.5 for 200 mg L -1 of phenolic aqueous solution was achieved within 48 h through KPO-PIM., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Two-liquid-phase reaction media have long been used in bioconversions to supply or remove hydrophobic organic reaction substrates and products to reduce inhibitory and toxic effects on biocatalysts. In case of the terminal oxyfunctionalization of linear alkanes by the AlkBGT monooxygenase the excess alkane substrate is often used as a second phase to extract the alcohol, aldehyde, and acid products. However, the selection of other carrier phases or surfactants is complex due to a large number of parameters that are involved, such as biocompatibility, substrate bioavailability, and product extraction selectivity. This study combines systematic high-throughput screening with chemometrics to correlate physicochemical parameters of a range of cosolvents to product specificity and yield using a multivariate regression model. Partial least-squares regression shows that the defining factor for product specificity is the solubility properties of the reaction substrate and product in the cosolvent, as measured by Hansen solubility parameters. Thus the polarity of cosolvents determines the accumulation of either alcohol or acid products. Whereas usually the acid product accumulates during the reaction, by choosing a more polar cosolvent the 1-alcohol product can be accumulated. Especially with Tergitol as a cosolvent, a 3.2-fold improvement in the 1-octanol yield to 18.3  mmol  L -1 is achieved relative to the control reaction without cosolvents., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hydantois have been identified as constituents of a number of pharmacologically active molecules. In the present study, we have examined in vitro antiproliferative activity against human colon cancer cell lines HCT-116 of three series of 3-(4-substituted benzyl)-hydantoins with various substituent attached in position 5 of the hydantoin ring. Since the investigated compounds have recently been synthesized and show antiproliferative activity, a good understanding of the properties of the potential drug responsible for their pharmacokinetics is an important goal for their further development. One of the important properties is lipophilicity. Lipophilicity has been assessed by reversed-phase liquid chromatography (high-performance thin-layer chromatography and high-pressure liquid chromatography) by means of direct and indirect (using calibration curve) methods. Chromatographic lipophilicity indices in addition to calculated logP values were compared by hierarchical cluster analysis. The linear solvation energy relationship approach was used to understand and compare the types and relative strength of the molecular interactions that occur in the chromatographic as well as in the n-octanol-water partitioning systems. Finally, correlation between in silico pharmacokinetic predictors and antiproliferative activity was examined. Preliminary quantitative structure-activity relationship modeling indicates that pharmacokinetic predictors capture only one-quarter of all chemical features that are important for antiproliferative activity itself. Among selected descriptors are chromatographic lipophilicity indices., (© 2019 John Wiley & Sons, Ltd.)

A novel solid/liquid phase microextraction (SLPME) technique was developed and applied to the simultaneous determination of five bisphenol-type endocrine disrupting chemicals (EDCs) including bisphenol A, bisphenol S, bisphenol F, bisphenol B and bisphenol AF. The method is based on the use of a graphene oxide nanoribbon-reinforced hollow fiber (GONRs-HF) and 1-octanol. GONRs were longitudinally unzipped from multiwalled carbon nanotubes (MWCNTs) by means of chemical oxidation and carefully characterized. GONRs were dispersed in ultrapure water with the assistance of surfactant and then immobilized into the wall pores of HF. Compared with CNTs, the hydrophilicity of GONRs was improved, and a uniform dispersion was formed. This simplifies the preparation process and reduces waste of materials. The pores and lumen of GONRs-HF were filled with 1-octanol, and then the whole assembly was used for the extraction of the analytes. In comparison with different extraction modes, GONRs-HF-SLPME exhibits a more effective extraction performance for five bisphenol-type EDCs. Response surface methodology was used to optimize experimental parameters affecting the extraction efficiency. The enrichment factors are in the range from 76 to 127 with good inter-fiber and batch-to-batch reproducibility. The method shows good linearity with determination coefficients (R 2 ) higher than 0.9985. The limits of detection are in the range of 0.1-0.4 μg L -1 . Recoveries from spiked real samples are between 83% and 114% with relative standard deviations between 1.6% and 7.8%. Graphical abstract Schematic presentation of the preparation of graphene oxide nanoribbons (GONRs) with multiwalled carbon nanotubes (MWCNTs), immobilization of GONRs into the pores of hollow fiber (HF), and application for solid/liquid phase microextraction (SLPME) of five bisphenol-type endocrine disrupting chemicals in three kinds of real samples.

The final fate of many drugs is release into the natural aquatic environment. It is necessary to assess the toxicity caused by this situation and the associated concerns for human beings. Zebrafish (Danio rerio) is a common biomodel used to assess toxicity in aquatic environments. The zebrafish embryo toxicity test was selected to evaluate the acute toxicity of several drugs (diphenhydramine, gentamicin, tobramycin, enalapril and lidocaine) due to the lack of such information. Lethal and sublethal effects were detected, and the LC 50 values of the drugs ranged from 11.0 mg/L to 422·10 2 mg/L. For all of the drugs tested, these values were higher than the concentrations found in the natural environment. Therefore, there was a low environmental toxicological risk. Nevertheless, teratogenic effects were also recorded when embryos of zebrafish were exposed to caffeine (control drug), diphenhydramine and lidocaine at lower concentrations than the respective LC 50 values. Quantitative structure-activity relationship analysis was also performed to analyse these drugs and other chemicals with pharmaceutical uses as well as previous toxicological data in this vertebrate after 48 h of exposure. It is estimated that the partition coefficient, log P, is the main physicochemical property related to the ecotoxicological data and can be used for the development of a mathematical model., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The partitioning of active pharmaceutical ingredients (API) in emulsions is influenced by various factors, such as composition of the phases, emulsifier type and concentration, and temperature. Therefore, the chemical stability of the API can be influenced by its partitioning into the aqueous phase as degradation is typically facilitated in water. With increasing emulsifier concentration from 0.15% to 5.0%, more betamethasone dipropionate (BDP) was solubilized in polysorbate 80 micelles leading to a small, but increased fraction of BDP exposed to the aqueous phase along with preferential partitioning of BDP to the aqueous phase and thus increased degradation. Similarly, by enhancing solubility and partitioning to the aqueous phase, the addition of polyethylene glycol 400 also led to increased BDP degradation. Due to pH dependent degradation of BDP, increasing emulsifier concentrations resulted in a more pronounced degradation of BDP at pH 8, which is beyond the stability optimum, whereas at pH 5 the API was sufficiently stable and no differences in concentration were detected within 12 weeks even under accelerated conditions. No significant differences were seen with the varying emulsifier concentrations regarding ex vivo skin penetration., (Copyright © 2019 Elsevier B.V. All rights reserved.)

An electromembrane extraction followed by HPLC-UV technique was developed and validated for quantification of leuprolide and triptorelin in rabbit plasma. The influencing parameters on the extraction efficiency were optimized using experimental design methodology. The optimized conditions were found to be; supported liquid membrane: a mixture of 1-octanol and 2-ethyl hexanol (1:1) containing 10% v/v di(2-ethylhexyl) phosphate, applied voltage: 5 V, extraction time: 5 min, pH of the donor phase: 4.5 and pH of the acceptor phase: 1.0. The optimized method was validated for linearity, intraday and interday precision, and accuracy in rabbit plasma. The range of quantification for both peptides was 0.5-1000 ng/mL with regression coefficients higher than 0.994. Relative recoveries of leuprolide and triptorelin were found to be 80.3 and 75.5%, respectively. Limits of quantification and detection for both peptides were found to be 0.5 and 0.15 ng/mL, respectively. The validated method was successfully applied to pharmacokinetic study of the 1-month depot formulations of each peptide after subcutaneous administration to rabbits., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Lipophilicity must be necessarily determined in drug discovery since this physicochemical property will directly influence the pharmacokinetics of a drug as its pharmacodynamics profile. Pyridoclax is an original lead, recently identified as very promising in treatment of chemoresistant cancers. The partition coefficient (Kp) of this anticancer drug was determined by microplate assays, well adapted in drug discovery, since being rapid, and requiring only poor drug amounts. The analytical approach was performed either by UV derivative spectrophotometry after validation thanks to a set of basic, neutral and acid reference substances, or originally, by raw fluorescence spectrophotometry by taking advantage of the pyridoclax intrinsic fluorescence. Large unilamellar vesicles (LUVs) were formulated from soybean-, egg-, or dipalmitoyl-phosphatidylcholine, characterized in terms of granulometric properties, ζ potential (determined by DLS), and of phospholipid content (quantified by 1 H NMR, also in presence of cholesterol). Whatever the detection method used, log Kp of pyridoclax were in the same magnitude order, and pyridoclax appeared as a lipophilic compound. It was also established that interactions between this lead and biomimetic membranes were influenced by the relative fluidity of the membranes, as confirmed by results of a liposome leakage assay., (Copyright © 2019 Elsevier B.V. All rights reserved.)

It is well known that surfactants increase the solubility of hydrophobic organic compounds and cause adverse environmental effects. The removal of these compounds from the contaminated soil or ground-water is particularly difficult due to their water soluble feature. In this work, an ultra-high performance hydrophilic interaction liquid chromatographic method was developed for the separation of oligomers of Triton X-100 octylphenol-polyethoxylate non-ionic surfactant. Liquid chromatography-mass spectrometry (LC-MS) was used to identify the Triton X-100 compounds. There was a 44 mass unit difference between two adjacent peaks that is the molar mass of one ethylene oxide group (⁻CH 2 CH 2 O⁻). A quadratic retention model was applied for the estimation of retention of the examined non-ionic surfactant and the optimization of gradient elution conditions. The optimized method was suitable for the baseline separation of 28 Triton X-100 oligomers in five minutes.

Intramolecular hydrogen bonds (IMHBs) affect the lipophilicity and physicochemical properties of small organic molecules and drug candidates. Considering IMHBs in drug design is an important strategy for improving the lipophilicity and physicochemical properties of drug candidates. However, how IMHBs affect the lipophilicity and partition coefficients are not well understood. Based on the relationship between the effect of IMHBs on the experimental partition coefficients and the H-bonding capabilities of H-bond forming atoms, we explore how IMHBs affect water/n-octanol partition coefficients, water/chloroform partition coefficients, water/hexadecane partition coefficients and lipophilicity. We found that IMHBs may increase or decrease or have no effect on water/n-octanol partition coefficients, but always increase water/chloroform partition coefficients, water/hexadecane partition coefficients and lipophilicity. We introduced ΔHBC, which is the difference between the calculated and actual H-bonding capabilities of molecules, for assessing the propensity of molecules to form IMHBs and the relative strengths of IMHBs. This study may help to improve the physicochemical properties of drug candidates and increase the success of drug design., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Molecular dynamics simulations have been performed to compute the solvation free energy and the octanol/water partition coefficients for a challenging set of selected organic molecules, characterized by the simultaneous presence of functional groups coarsely spanning a large portion of the chemical space in druglike compounds and, in many cases, by a complex conformational landscape (2-propoxyethanol, acetylsalicylic acid, cyclohexanamine, dialifor, ketoprofen, nitralin, profluralin, terbacil). OPLS-AA and GAFF2 parametrizations of the organic molecules and of 1-octanol have been done via the Web-based automatic parameter generators, LigParGen [ Dodda et al. Nucl. Acids Res. 2017 , 121 , 3864 ] and PrimaDORAC [ Procacci J. Chem. Inf. Model. 2017 , 57 , 1240 ], respectively. For the water solvent, three popular three-point site models, TIP3P, SPCE, and OPC3, were tested. Solvation free energies in water and 1-octanol are evaluated using a recently developed nonequilibrium alchemical technology [ Procacci et al. J. Chem. Theory Comput. 2014 , 10 , 2813 ]. Extensive and accurate simulations, including all possible combinations of organic molecule, solvent, and solvent model, are allowed to assess the accuracy with regard to solvation free energies of the latest release of two widespread force fields, OPLS and GAFF. The collected data are relevant in the evaluation of the predictive power of these classical force fields (and of the related support software for automated parametrization) with regard to binding free energies in a drug-receptor system for industrial applications.

The fluorination-induced changes in the logP (1-octanol/water partition coefficient) of ligands were examined by molecular dynamics simulations. The protocol and force field parameters were first evaluated by calculating the logP values for n-alkanes, and their monofluorinated and monochlorinated analogs. Then, the logP values of several test sets (1-butanol, 3-propyl-1H-indole, and analogs fluorinated at the terminal methyl group) were calculated. The calculated results agree well with experiment, and the root mean square error values are 0.61 and 0.68 log units for the GAFF and GAFF2 force fields, respectively. Finally, the logP estimation was extended to a drug molecule, TAK-438, for which fluorination-induced abnormal logP reduction has been observed experimentally. This abnormal change was qualitatively reproduced by the molecular dynamics simulations. We found that the abnormal logP reduction can be mainly attributed to the effect of fluorination-induced dipole change. Our results suggest that molecular simulation is a useful strategy to predict the fluorination-induced change in logP for drug discovery applications.

Direct measurement of the n-octanol partition coefficients (K OW ) for highly hydrophobic organic chemicals is extremely difficult because of the extremely low concentrations present in the water phase. n-Butanol/water partition coefficients (K BW ) are generally much lower than K OW due to the increased solubility of solute in the alcohol saturated aqueous phase, and therefore become easier to measure. We measured the K BW for 25 neutral organic chemicals having measured log K OW s ranging from 2 to 9 and 4 additional highly hydrophobic chemicals, with unmeasured K OW s, having estimated log K OW s ranging from 6 to 18. The measured log K BW and log K OW values were linearly related, r 2  = 0.978, and using the regression developed from the data, K OW s were predicted for the 4 highly hydrophobic chemicals with unmeasured K OW s. The resulting predictions were orders of magnitude lower than those predicted by a variety of computational models and suggests the estimates of K OW in the literature for highly hydrophobic chemicals (i.e., log K OW greater than 10) are likely incorrect by several orders of magnitude., (Published by Elsevier Ltd.)

In this study, the application of a mixture of organic solvents as a supported liquid membrane for improving the efficiency of the electromembrane extraction procedure was investigated. The extraction process was followed by high-performance liquid chromatography analysis of two model drugs (verapamil and riluzole). In this research, four organic solvents, including 1-heptanol, 1-octanol, 2-nitrophenyl octyl ether, and 2-ethyl hexanol, were selected as model solvents and different binary mixtures (v/v 2:1, 1:1 and 1:2) were used as the supported liquid membrane. The mixture of 2-ethyl hexanol and 1-otanol (v/v, 2:1) improved the extraction efficiency of model drugs by 1.5 to 12 times. It was found that extraction efficiency is greatly influenced by the level of electric current. In this study, for various mixtures of organic solvents, the electric current fluctuated between 50 and 2500 μA, and the highest extraction efficiencies were obtained with low and stable electric currents. Finally, the optimized extraction condition was validated and applied for the determination of model drugs in urine and wastewater samples., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

As drug discovery moves increasingly toward previously "undruggable" targets such as protein-protein interactions, lead compounds are becoming larger and more lipophilic. Although increasing lipophilicity can improve membrane permeability, it can also incur serious liabilities, including poor water solubility, increased toxicity, and faster metabolic clearance. Here we introduce a new efficiency metric, especially relevant to "beyond rule of 5" molecules, that captures, in a simple, unitless value, these opposing effects of lipophilicity on molecular properties. Lipophilic permeability efficiency (LPE) is defined as log D 7.4 dec/w - m lipo cLogP + b scaffold , where log D 7.4 dec/w is the experimental decadiene-water distribution coefficient (pH 7.4), cLogP is the calculated octanol-water partition coefficient, and m lipo and b scaffold are scaling factors to standardize LPE values across different cLogP metrics and scaffolds. Using a variety of peptidic and nonpeptidic macrocycle drugs, we show that LPE provides a functional assessment of the efficiency with which a compound achieves passive membrane permeability at a given lipophilicity.

Theaflavins, the orange-red pigments contained in black tea, have attracted attention as a result of their health-promoting effects. However, their synthetic preparation, in which the enzymatic oxidation of catechol-type catechin is followed by the quinone-induced oxidative dimerization of selectively combined catechol- and pyrogallol-type catechins, provides only a low yield. In the present study, we found that a 1-octanol/buffer biphasic system improved the yield of theaflavin 3-gallate in a tyrosinase-catalyzed synthetic reaction with (-)-epicatechin and (-)-epigallocatechin gallate. When the enzymatic reaction proceeded in a buffer solution, oxidized (-)-epigallocatechin gallate was preferentially used for self-dimerization. However, self-dimerization was suppressed in the octanol phase, allowing oxidized (-)-epigallocatechin gallate to participate in coupling with (-)-epicatechin quinone, leading to effective production of theaflavin 3-gallate. Furthermore, the preferential localization of theaflavin 3-gallate in the octanol phase prevented (-)-epicatechin-quinone-induced degradation.

Background: Many novel drug delivery systems have been extensively studied to exploit the full therapeutic potential of SN38, which is one of the most potent antitumor analogs of camptothecins (CPTs), whose clinical application is seriously hindered by poor water solubility, low plasmatic stability, and severe toxicity, but results are always unsatisfactory., Methods: In this study, combining the advantages of prodrug and nanotechnology, a lipophilic prodrug of SN38, SN38-PA, was developed by conjugating palmitic acid to SN38 via ester bond at C 10 position, and then the lipophilic prodrug was encapsulated into a long-circulating liposomal carrier by film dispersion method., Results: The SN38-PA liposomes were characterized as follows: an average particle size of 80.13 nm, an average zeta potential of -33.53 mv, and the entrapment efficiency of 99%. Compared with CPT-11, SN38-PA liposome was more stable in close lactone form, more efficient in conversion rate to SN38, and more potent in cytotoxicity against tumor cells. Pharmacokinetic study showed that SN38-PA liposome had significantly enhanced plasma half-life (t 1/2 ) value of SN38 and increased area under the curve (AUC) of SN38, which was 7.5-fold higher than that of CPT-11. Biodistribution study showed that SN38-PA liposome had more active metabolite SN38 in each tissue. Finally, the pharmacodynamic study showed that SN38-PA liposome had higher antitumor effect with the antitumor inhibition rate of 1.61 times than that of CPT-11., Conclusion: These encouraging data merit further investigation on this novel SN38-PA liposome., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

This work describes the separation performance of a star-shaped truxene-based material (denoted as EDOTT) as the stationary phase for capillary gas chromatography (GC). The EDOTT capillary column achieved the column efficiency of 5920 plates/m by n-dodecane, 4890 plates/m by naphthalene and 3960 plates/m by 1-octanol at 120 ℃. Its selectivity and retention behaviour were investigated by a number of mixtures of diverse analytes and their isomers. As a result, it showed advantageous performance for separations of apolar to polar analytes, especially phenols and alcohols, over its analogous TTT, TDT and TFT stationary phases. In addition, the EDOTT capillary column was investigated for its column loadability, repeatability and thermal stability, and was finally applied for the determination of isomer impurities in real samples. This work provides an alternative truxene-based stationary phase with high selectivity for polar analytes and demonstrates the key role of structural modification in developing a family of stationary phases with specific selectivity for targeted analytes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Biphasic dissolution models were proposed to provide good predictive power for in vivo absorption kinetics. However, up to date the impact of hydrodynamics in mini-scale models are not well understood. Consequently, the aim of this work was to investigate different setups of a previously published mini-scale biphasic dissolution model (miBIdi-pH-II) to better understand the relevance of hydrodynamics for evaluating kinetic parameters and to simultaneously increase the robustness of the experimental model. As a first step, the hydrodynamics within the aqueous phase were characterized by in silico simulations of the flow patterns. Different settings, such as higher rotation speeds of the paddles, the implementation of a second propeller into the aqueous phase, and different shapes of aqueous stirrers were investigated. Second, to evaluate the results of the in silico simulations, in vitro experiments with glitter were carried out. Last, the same settings were applied in the miBIdi-pH-II using dipyridamole (DPD) as model compound to estimate kinetic parameters by applying a compartment-based modelling approach. Both in vitro experiments with glitter or DPD demonstrated the adequateness of the previous in silico hydrodynamic simulations. The use of higher rotation speeds and a second aqueous propeller resulted in more homogeneous mixing of the aqueous phase. This resulted in faster distribution of dissolved active pharmaceutical ingredient (API) into the octanol phase. A kinetic model was successfully applied to quantify the influence of hydrodynamics on the partitioning rate of the API into the octanol phase. In conclusion, the combination of in silico and in vitro methods was demonstrated to be powerful for investigating the flow patterns within the miBIdi-pH-II. A comprehensive understanding of the hydrodynamics and the respective influence on the dissolution and apparent partitioning into the octanol phase in the biphasic dissolution model was obtained and completed by using a compartmental kinetic model. This model allowed successful quantification of how the hydrodynamics influence the partitioning of API into the octanol phase., (Copyright © 2018. Published by Elsevier B.V.)

Due to high mobility and specific toxic actions of the ionizable pharmaceuticals in surface water with a normal range of pH, the pharmaceuticals should be removed before being discharged. Therefore, this study investigated the adsorptive interactions between cationic pharmaceuticals and a popular adsorbent (i.e., activated charcoal) frequently used in water treatment processes. For that, we performed isotherm experiments and then the results were plotted by Langmuir model to determine the adsorption affinity (b) and capacity (q m ). Afterwards, to interpret the adsorption behaviors, two simple prediction models were developed based on quantitative structure-activity relationships (QSAR). In the modelling, molecular weight (MW), polar surface area (PSA), and octanol-water partitioning coefficient (log P) were used as model parameters. In the results, the combinations of these three parameters could predict the adsorption affinity and capacity in R 2 of 0.85 and 0.80, respectively. The robustness of models was validated by leave-one-out cross-validation (Q 2 LOO ) and the estimated Q 2 LOO values were 0.60 and 0.55 for the adsorption affinity and capacity, respectively, which are higher than the acceptability of standard i.e., 0.5., (Copyright © 2018 Elsevier B.V. All rights reserved.)

It is well known that the critical body residue (CBR) can be estimated via bioconcentration factor (BCF). However, the relationship between CBR and BCF in zebrafish has not been carried out based on bio-uptake kinetics for nitro-aromatics. In this paper, the time-variable concentrations and CBRs in zebrafish were determined for five nitro substituted benzenes. The result shows that CBR values can well be calculated from the BCF and external critical concentrations (LC 50 ). Although CBRs measured from 5 h exposure period are greater than the CBRs obtained from 96 h for the five nitro-aromatics, no significant difference was observed, indicating that the CBR approach is a truer measure of chemical levels in exposed organisms and an ideal indicator to reflect the toxicity of a chemical. The bio-uptake can well be described by first-order kinetics and reach steady-state within 48 h. Almost same BCF values are obtained from the ratio of concentration in the fish (C f ) and in the water (C w ) at apparent steady-state and the ratio of the rate constants of uptake (k 1 ) and depuration (k 2 ) assuming first-order kinetics. The toxicity ratio (TR) can reflect the difference of internal critical concentrations and be used to identify mode of action., (Copyright © 2018 Elsevier Inc. All rights reserved.)