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There are two potential approaches for quantitative structure-activity relationships modeling of aquatic toxicity of surfactants. One is to try to relate toxicity to parameters describing the surfactant properties, which can be measured or calculated. The other approach is to try to apply to surfactants parameters such as log P ( P=octanol/water partition coefficient), which can also be used to relate toxicity to structure for nonsurfactants. This paper compares the two approaches and presents new data supporting the second approach as the more mechanistically relevant. Further refinements in the calculation method for log P are presented. [ABSTRACT FROM AUTHOR]

Purpose. To check the influence of structuralcharacteristics on theirpermeation through the blood—brain barrier (BBB), a set of radioactive[99mTc]chelates bearing amine groups was synthesizedand tested in vitro as well as in vivo. Methods. Compounds with different log P and pKa values wereobtained by complex forming reactions of [99mTc]pertechnetate withvarying substituents. Transport was studied in rats and mice, as wellas in an ECV304 cell culture model. Results. In vitro higher permeation was found for compounds withelectron attracting substituents in β-position to the amine group (pKavalues 7.4 to 8.3) than for those with more basic amine groups (pKavalues > 8.9) even for similar log DpH 7.4. In vivo brain uptake between0.8 and 4.8;pc of the injected dose (ID) per organ was found for theformer, whereas <0.4% ID were present for the latter. Conclusions. Three structurally diverse classes of [99mTc]chelatesshowed distinct patterns with regard to brain uptake in vivo and BBBpermeability in vitro which could not be predicted by their lipophilicityalone. The close correlation between the data from rats and mice andthose obtained with cell cultures render the ECV304 cells an attractivemodel for the screening of new compounds. [ABSTRACT FROM AUTHOR]

Background: The derivatives of Phenytoin conjugated with various anilines were synthesized. The synthesized derivatives were evaluated for different physicochemical parameters along with log P values using different software programs to discover their ability to cross the blood brain barrier. The pharmacological activities such as antianxiety, skeletal muscle relaxant and anticonvulsant were evaluated by using different models., Objective: The new Phenytoin derivatives were synthesized and evaluated for different properties to predict CNS activity. The drugs synthesized by chloroacetylation and then different aniline were added to it. The compounds were evaluated for their different CNS activity by using different methods., Methods: The compounds were synthesized by firstly chloroacetylating the phenytoin and then different substituted anilines were added to it. The compounds were evaluated for antianxiety activity, muscle relaxant activity and anticonvulsant activity by using different models., Results: The number of derivatives of Phenytoin was synthesized and various physicochemical parameters were optimized which revealed that the compound containing chloro groups such as C2 and C5 exhibited significant potential when compared with the standard drug Diazepam., Conclusion: It was portrayed that the synthesis, computational studies and evaluation of anticonvulsant, antianxiety and skeletal muscle relaxant activity of new Phenytoin derivatives were carried out. The compounds were productively synthesized and portrayed by molecular docking studies. The compounds also exhibit mild to moderate similarity with respect to standard drug. The synthesized drugs have the potential to be optimized further to engender new scaffolds to treat various CNS disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Since the dawn of quantitative structure-properties relationships (QSPR), empirical parameters related to structural, electronic and hydrophobic molecular properties have been used as molecular descriptors to determine such relationships. Among all these parameters, Hammett σ constants and the logarithm of the octanol- water partition coefficient, log P, have been massively employed in QSPR studies. In the present paper, a new molecular descriptor, based on quantum similarity measures (QSM), is proposed as a general substitute of these empirical parameters. This work continues previous analyses related to the use of QSM to QSPR, introducing molecular quantum self-similarity measures (MQS-SM) as a single working parameter in some cases. The use of MQS-SM as a molecular descriptor is first confirmed from the correlation with the aforementioned empirical parameters. The Hammett equation has been examined using MQS-SM for a series of substituted carboxylic acids. Then, for a series of aliphatic alcohols and acetic acid esters, log P values have been correlated with the self-similarity measure between density functions in water and octanol of a given molecule. And finally, some examples and applications of MQS-SM to determine QSAR are presented. In all studied cases MQS-SM appeared to be excellent molecular descriptors usable in general QSPR applications of chemical interest. [ABSTRACT FROM AUTHOR]

The lipophilicity of a representative number of hydantoin derivatives was experimentally determined by RP-HPLC. The stationary phase of RP-HPLC proved a good model to simulate effects of membrane transport. These experimental values were correlated to theoretically estimated lipophilicity values on the basis of global minima structures of the compounds studied. Both these lipophilicity and structure similarities within a proposed pharmacological model for binding the hydantoin derivatives along the sodium channel were classified with respect to their biological activity. [ABSTRACT FROM AUTHOR]

The toxic effects that organic solvents have on whole cells is an important drawback in the application of these solvents in environmental biotechnology and in the production of fine chemicals by whole-cell biotransformations. Hydrophobic organic solvents, such as toluene, are toxic for living organisms because they accumulate in and disrupt cell membranes. The toxicity of a compound correlates with the logarithm of its partition coefficient with octanol and water (log Pow). Substances with a log P ow value between 1 and 5 are, in general, toxic for whole cells. However, in recent years different bacterial strains have been isolated and characterized that can adapt to the presence of organic solvents. These strains grow in the presence of a second phase of solvents previously believed to be lethal. Different mechanisms contributing to the solvent tolerance of these strains have been found. Alterations in the composition of the cytoplasmic and outer membrane have been described. These adaptations suppress the effects of the solvents on the membrane stability or limit the rate of diffusion into the membrane. Furthermore, changes in the rate of the biosynthesis of the phospholipids were reported to accelerate repair processes. In addition to these adaptation mechanisms compensating the toxic effect of the organic solvents, mechanisms do exist that actively decrease the amount of the toxic solvent in the cells. An efflux system actively decreasing the amount of solvents in the cell has been described recently. We review here the current knowledge about exceptional strains that can grow in the presence of toxic solvents and the mechanisms responsible for their survival. [ABSTRACT FROM AUTHOR]

Nowadays, we consume very large amounts of medicinal substances. Medicines are used to cure, halt, or prevent disease, ease symptoms, or help in the diagnosis of illnesses. Some medications are used to treat pain. Ibuprofen is one of the most popular drugs in the world (it ranks third). This drug enters our water system through human pharmaceutical use. In this article, we describe and compare the biodegradation of ibuprofen and ibuprofen derivatives—salts of L-valine alkyl esters. Biodegradation studies of ibuprofen and its derivatives have been carried out with activated sludge. The structure modifications we received were aimed at increasing the biodegradation of the drug used. The influence of the alkyl chain length of the ester used in the biodegradation of the compound was also verified. The biodegradation results correlated with the lipophilic properties (log P). [ABSTRACT FROM AUTHOR]

The Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) challenges focuses the computational modeling community on areas in need of improvement for rational drug design. The SAMPL7 physical property challenge dealt with prediction of octanol-water partition coefficients and pK a for 22 compounds. The dataset was composed of a series of N-acylsulfonamides and related bioisosteres. 17 research groups participated in the log P challenge, submitting 33 blind submissions total. For the pK a challenge, 7 different groups participated, submitting 9 blind submissions in total. Overall, the accuracy of octanol-water log P predictions in the SAMPL7 challenge was lower than octanol-water log P predictions in SAMPL6, likely due to a more diverse dataset. Compared to the SAMPL6 pK a challenge, accuracy remains unchanged in SAMPL7. Interestingly, here, though macroscopic pK a values were often predicted with reasonable accuracy, there was dramatically more disagreement among participants as to which microscopic transitions produced these values (with methods often disagreeing even as to the sign of the free energy change associated with certain transitions), indicating far more work needs to be done on pK a prediction methods., (© 2021. The Author(s).)

The increased risk of illness and disability is related to the age inevitable biological changes. Oxidative stress is a proposed mechanism for many age-related diseases. The crucial importance of polyphenol pharmacophore for aging process is largely described thanks to its effects on concentrations of reactive oxygen species. Resveratrol (3,5,4′-trihydroxy-trans-stilbene, RSV) plays a critical role in slowing the aging process but has a poor bioavailabity after oral intake. In this present work, a series of RSV derivatives was designed, synthesized, and evaluated as potential antioxidant agents. These derivatives contain substituents with different electronic and steric properties in different positions of aromatic rings. This kind of substituents affects the activity and the bioavailability of these compounds compared with RSV used as reference compound. Studies of Log P values demonstrated that the introduction of halogens gives the optimum lipophilicity to be considered promising active agents. Among them, compound 6 showed the higher antioxidant activity than RSV. The presence of trifluoromethyl group together with a chlorine atom increased the antioxidant activity compared to RSV. [ABSTRACT FROM AUTHOR]

Two pairs of 4- and 5-aminopyridazinone regioisomers were prepared and the logarithm of their octanol/water partition coefficients (log P) was determined experimentally. The experimental log P values of the 4-isomers were found to be significantly higher than those of the respective 5-isomers. The log P values were also calculated by 3DNET, Q log P, Ghose–Crippen, Villar, ScilogPUltra and KOWWIN (with EVA) methods. Of them, only the last two methods were able to reproduce the observed tendency. [Copyright &y& Elsevier]

Some technologically important physicochemical properties of lansoprazole were investigated. This compound is very unstable, especially in aqueous solutions with low pH. It has one acidic and two basic dissociation constants. Lansoprazole has relatively high solubility in solutions with high pH and is well partitioned from aqueous to n-octanol phase. Under conditions examined in this study, lansoprazole was not hydroscopic and did not decompose at higher relative humidities. [ABSTRACT FROM AUTHOR]

The aim of the study was to determine the antioxidant activity and assess the lipophilicity and skin penetration of eugenyl chloroacetate (EChA), eugenyl dichloroacetate (EDChA), and eugenyl trichloroacetate (ETChA). Identification of the obtained products was based on gas chromatography (GC), infrared spectroscopy (FTIR/ATR), gas chromatography coupled with mass spectrometry (GC-MS), and the analysis of 13 C-NMR and 1 H-NMR spectra. The antioxidative capacity of the derivatives obtained was determined by the DPPH free radical reduction method, while the octanol/water partition coefficient (shake-flask method) was tested to determine the lipophilicity of these compounds. In the next stage of testing EDChA and ETChA-(compounds characterized by the highest degree of free radical scavenging), the penetration of DPPH through pig skin and its accumulation in the skin were evaluated. For comparison, penetration studies of eugenol alone as well as dichloroacetic acid (DChAA) and trichloroacetic acid (TChAA) were also carried out. The antioxidant activity (DPPH, ABTS, and Folin-Ciocalteu methods) of the fluid that penetrated through pig skin was also evaluated. The in vitro pig skin penetration study showed that eugenol derivatives are particularly relevant for topical application. The obtained derivatives were characterized by a high level of antioxidant activity estimated after 24 h of conducting the experiment, which indicates long-term protection against reactive oxygen species (ROS) in the deeper layers of the skin.

Molecular polarity governs lipophilicity, which in turn determines important agrochemical and environmental properties, such as soil sorption and bioconcentration of organic compounds. Since the C-F bond is the most polar in organic chemistry, the orientation of fluorine substituents originating from the rotation around C-C(F) bonds should affect the polarity and, consequently, the physicochemical and biological properties of fluorine-containing agrochemicals. Accordingly, this study aims to determine the most likely conformers of some fluorine-containing agrochemicals and to correlate their molecular dipole moments with the respective n -octanol/water partition coefficients (log P ), in order to investigate the dependence of the lipophilicity with the molecular conformation., (Copyright © 2020, Silva et al.; licensee Beilstein-Institut.)

Objectives: The aim of this study was to determine the acid dissociation constant (pKa) of piroxicam using high performance liquid chromatography (HPLC) and ultraviolet-visible (UV-Vis) spectrophotometry, and to determine the partition coefficient (Log P), distribution coefficient (Log D), and "Log kw" values of piroxicam using HPLC., Materials and Methods: The HPLC studies were performed on a reversed-phase ACE C18 (150x4.6 mm ID, 5 μm) column at a flow rate of 1.0 mL min -1 . The detector was set to 360 nm. Log D at different pH values (3.0-6.5) was examined with a phosphate buffer (20 mM) and acetonitrile (30:70 v/v) mixture as the mobile phase. For pKa determination, HPLC studies were performed with a mixture of phosphate buffer (20 mM) and methanol within the pH range of 3.50-6.00. Log kw measurements were performed with phosphate buffer (20 mM) and MeOH (from 20:80 v/v to 10:90 v/v) mixtures within the pH range of 3.50-6.00. UV-Vis spectrophotometric pKa measurements were performed at 285 nm wavelength., Results: The pKa value of piroxicam was found to be 5.3 by HPLC and 5.7 by UV-Vis spectrophotometry. Log P of piroxicam was determined as 1.58 in our experimental conditions. Log D values were 1.57, 1.57, 1.44, 1.13, and 0.46 for pH values of 3.17, 3.79, 4.44, 5.42, and 6.56, respectively., Conclusion: In the literature, different Log P (3.1, 2.2, and 0.6) and pKa (6.3 and 4.8) values were reported for piroxicam. The Log P (1.58) and pKa (5.3 and 5.7) values obtained for piroxicam in our study were within the range of the literature values. All these results indicate that different experimental approaches used for the determination of physicochemical properties could provide different values. Although UV spectrophotometry is easy to apply, HPLC is a unique technique for simultaneous determination of pKa, Log D, and Log P values of compounds., Competing Interests: Conflicts of interest: No conflict of interest was declared by the authors. The authors alone are responsible for the content and writing of the paper., (©Copyright 2020 Turk J Pharm Sci, Published by Galenos Publishing House.)

Now, it has been evidenced that Covid19 (SARS-CoV-2) infects the brain tissues. Along with this, a challenge has been raised for research professionals to find effective drugs for its treatment since the recent spread of this virus from Wuhan, China. Targeting the treatment of brain infection, it has also been a challenge that the clinical drug should have good CNS penetration ability to cross the blood-brain barrier.

Blind predictions of octanol/water partition coefficients at 298 K for 11 kinase inhibitor fragment like compounds were made for the SAMPL6 challenge. We used the conventional, "untrained", free energy based approach wherein the octanol/water partition coefficient was computed directly as the difference in solvation free energy in water and 1-octanol. We additionally proposed and used two different forms of a "trained" approach. Physically, the goal of the trained approach is to relate the partition coefficient computed using pure 1-octanol to that using water-saturated 1-octanol. In the first case, we assumed the partition coefficient using water-saturated 1-octanol and pure 1-octanol are linearly correlated. In the second approach, we assume the solvation free energy in water-saturated 1-octanol can be written as a linear combination of the solvation free energy in pure water and 1-octanol. In all cases here, the solvation free energies were computed using electronic structure calculations in the SM12, SM8, and SMD universal solvent models. In the context of the present study, our results in general do not support the additional effort of the trained approach.

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 SAMPL Challenges aim to focus the biomolecular and physical modeling community on issues that limit the accuracy of predictive modeling of protein-ligand binding for rational drug design. In the SAMPL5 log D Challenge, designed to benchmark the accuracy of methods for predicting drug-like small molecule transfer free energies from aqueous to nonpolar phases, participants found it difficult to make accurate predictions due to the complexity of protonation state issues. In the SAMPL6 log P Challenge, we asked participants to make blind predictions of the octanol-water partition coefficients of neutral species of 11 compounds and assessed how well these methods performed absent the complication of protonation state effects. This challenge builds on the SAMPL6 p[Formula: see text] Challenge, which asked participants to predict p[Formula: see text] values of a superset of the compounds considered in this log P challenge. Blind prediction sets of 91 prediction methods were collected from 27 research groups, spanning a variety of quantum mechanics (QM) or molecular mechanics (MM)-based physical methods, knowledge-based empirical methods, and mixed approaches. There was a 50% increase in the number of participating groups and a 20% increase in the number of submissions compared to the SAMPL5 log D Challenge. Overall, the accuracy of octanol-water log P predictions in SAMPL6 Challenge was higher than cyclohexane-water log D predictions in SAMPL5, likely because modeling only the neutral species was necessary for log P and several categories of method benefited from the vast amounts of experimental octanol-water log P data. There were many highly accurate methods: 10 diverse methods achieved RMSE less than 0.5 log P units. These included QM-based methods, empirical methods, and mixed methods with physical modeling supported with empirical corrections. A comparison of physical modeling methods showed that QM-based methods outperformed MM-based methods. The average RMSE of the most accurate five MM-based, QM-based, empirical, and mixed approach methods based on RMSE were 0.92 ± 0.13, 0.48 ± 0.06, 0.47 ± 0.05, and 0.50 ± 0.06, respectively.

Partition coefficients describe the equilibrium partitioning of a single, defined charge state of a solute between two liquid phases in contact, typically a neutral solute. Octanol-water partition coefficients ([Formula: see text]), or their logarithms (log P), are frequently used as a measure of lipophilicity in drug discovery. The partition coefficient is a physicochemical property that captures the thermodynamics of relative solvation between aqueous and nonpolar phases, and therefore provides an excellent test for physics-based computational models that predict properties of pharmaceutical relevance such as protein-ligand binding affinities or hydration/solvation free energies. The SAMPL6 Part II octanol-water partition coefficient prediction challenge used a subset of kinase inhibitor fragment-like compounds from the SAMPL6 [Formula: see text] prediction challenge in a blind experimental benchmark. Following experimental data collection, the partition coefficient dataset was kept blinded until all predictions were collected from participating computational chemistry groups. A total of 91 submissions were received from 27 participating research groups. This paper presents the octanol-water log P dataset for this SAMPL6 Part II partition coefficient challenge, which consisted of 11 compounds (six 4-aminoquinazolines, two benzimidazole, one pyrazolo[3,4-d]pyrimidine, one pyridine, one 2-oxoquinoline substructure containing compounds) with log P values in the range of 1.95-4.09. We describe the potentiometric log P measurement protocol used to collect this dataset using a Sirius T3, discuss the limitations of this experimental approach, and share suggestions for future log P data collection efforts for the evaluation of computational methods.

The steady growth of inflammatory diseases of the udder in dairy cattle forces us to look for the causes of this phenomenon in the context of growing chemical pollution of the environment and feeds. Within the framework of this concept, an analysis was made of the polarity level of the three toxic impurity groups, which are commonly present in dairy cattle feeds. These impurities are presented by mycotoxins, polyaromatic hydrocarbons (PAH) and persistent organic pollutants (POP). It has been determined that 46% of studied mycotoxins (n = 1500) and 100% of studied polyaromatic hydrocarbons (n = 45) and persistent organic pollutants (n = 55) are lipophilic compounds, prone to bioaccumulation. A comparative evaluation of the sorption capacity of four adsorbents of a different nature and polarity with respect to the simplest PAH, naphthalene and lipophilic estrogenic mycotoxin, zearalenone in vitro has been carried out. The highest efficiency in these experiments was demonstrated by the reversed-phase polyoctylated polysilicate hydrogel (POPSH). The use of POPSH in a herd of lactating cows significantly reduced the transfer of aldrin, dieldrin and heptachlor, typical POPs from the "dirty dozen", to the milk. The relevance of protecting the main functional systems of animals from the damaging effects of lipophilic toxins from feeds using non-polar adsorbents, and the concept of evaluating the effectiveness of various feed adsorbents for dairy cattle by their influence on the somatic cell count in the collected milk are discussed. [ABSTRACT FROM AUTHOR]