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A series of novel 2-amino-5-chlorobenzophenone derivatives ( 3a – 3g ) were prepared by the reaction of 2-(chloroacetamido)-5-chlorobenzophenone and different aniline derivatives by both conventional and microwave methods and structures were confirmed on the basis of their TLC, IR, 1H NMR and CHN elemental studies. Out of the two methods, microwave methods was found to give better yield. All the synthesized compounds were subjected to physicochemical parameters determination for BBB penetration through online software. The log P values of most of our test compounds indicate that test compounds have the potential to be CNS active. The experimentally determined and calculated values of log P are very much similar to values of log P calculated by the online software chemsilico and are in the range required for good CNS activity. The values of other physicochemical parameters like molecular weight, nON value, nOHNH value, n -violations and the number of rotatable bonds of all the test compounds also lie between the ranges that are required for good BBB penetration. The compounds were screened for the skeletal muscle relaxant activity and from the investigation, it is quite apparent that all the 2-amino-5-chlorobenzophenone derivatives ( 3a – 3g ) possess significant differences between control group and treated group, P < 0.001. Among these 2-amino-5-chlorobenzophenone derivatives, the compound bearing o -toluidine as a substituent ( 3e ) possesses the highest skeletal muscle relaxant activity. [ABSTRACT FROM AUTHOR]

The goal of the present paper was to develop a quantitative structure–activity relationship (QSAR) method using a simple statistical approach, such as multiple linear regression (MLR) for predicting the blood–brain barrier (BBB) permeability of chemical compounds. The “best” MLR models, comprised log P and either molecular mass ( M ) or isolated atomic energy ( E isol ), tested on a structurally diverse set of 66 compounds, is characterized the by correlation coefficients ( R ) around 0.8. The obtained models were validated using leave-one-out (LOO) cross-validation technique and the correlation coefficient of leave-one-out- R LOO 2 ( Q 2 ) was at least 0.6. Analysis of a case from legal medicine demonstrated informative value of our QSAR model. To best authors’ knowledge the present study is a first application of the developed QSAR models of BBB permeability to case from the legal medicine. Our data indicate that molecular energy-related descriptors, in combination with the well-known descriptors of lipophilicity may have a supportive value in predicting blood–brain distribution, which is of utmost importance in drug development and toxicological studies. [ABSTRACT FROM AUTHOR]

Numerous papers concerning the research on the role of magnesium in an organism and the effects of its deficiency indicate many causes and mechanisms leading to a negative balance of this macroelement. One of the causes of magnesium deficiency in systems may be its malabsorption from the digestive track resulting from taking compounds complexing magnesium ions or using drugs destructive to saprophytic flora. The results of our experiments testing in vitro the influence of β-lactam of penicillin G on the process of Mg2+ ions absorption through the intestinal membrane from solid dispersions containing phosphatidylcholine (PC 45) and the salts of magnesium glutamate and its derivatives from glycine and arginine ligands are presented in this paper. In order to make solid dispersions containing glutamate magnesium salts, auxiliary substances, polyvinylpyrrolidone (PVP) and phosphatidylcholine (PC45), were used. For the solid dispersions obtained by the Hansch method, partition coefficient in the system n-octanol/phosphate buffer was determined. Log P was calculated for the examined dispersions. Research on the degree of absorption of Mg2+ ions solid dispersions, which was the subject of the experiment, was done by the in vitro method, making use of a model of the intestine (ileum) of a rat. The evaluation of penicillin G influence on the degree of absorption of Mg2+ ions from solid dispersions containing magnesium salts was carried out by the above method. The results of experiments indicate that an additional ligand (glycine, arginine) in the structure of magnesium glutamate particle significantly influences the change of the value of of the kinetic absorption parameter of Mg2+ ions from solid dispersions containing magnesium salts. Introducing an additional ligand induces an accelerated rate of diffusion of the examined salts through the intestine. It has been found that penicillin G hinders the degree of Mg2+ ions absorption of the examined solid dispersions in the small intestine. [ABSTRACT FROM AUTHOR]

Derivatives of (1-methylpiperidin-4-yl) propanoate, with similar biological characteristics, have been reported for patients with Alzheimer disease [1,2]. QSAR study was performed on a set of 40 (1-methylpiperidin-4- yl) propanoate derivatives, downloaded from the PubChem database and aligned over a hypermolecule that mimics the investigated correlational space. The best models describing log P of these (1-methylpiperidin-4-yl) propanoate derivatives were validated by leave-one-out procedure [3] and best predicted within similarity clusters. [ABSTRACT FROM AUTHOR]

We report a quantitative structure-property relationship (QSPR) study regarding Log P. The text includes some comments regarding the influence of diversity of molecules on results of QSPR computation. The calibration (training) set was selected, according to specific molecular diversity/similarity criteria, from certain group of 621 molecules, without oxygen and nitrogen atoms. The calibration set includes 211 molecules (hydrocarbons, halo-derivatives, thioethers, phosphines etc.) having much higher diversity from the point of view of chemical structure, size, shape and lipophilicity. The validation set includes the non-selected 410 molecules. The observed value of Log P is within (0.20, 9.14) range in calibration set and within (1.08, 9.36) range in prediction/validation set. The best QSPR multilinear formula includes three quantum mechanics descriptors and does not include molecular fragments' descriptors. For calibration set, the predictive power of QSPR is high ( r = 0.9489; SEE = 0.4117), close to KOWWIN ( r = 0.9545; SEE = 0.3961) and miLogP ( r = 0.9477; SEE = 0.4736) results. The predictor 'conductor-like screening model area' has largest influence on the value of Log P. The quality of prediction for validation set is good ( r = 0.9517; SEE = 0.4334), close to result obtained by KOWWIN ( r = 0.9676, SEE = 0.3286) and miLogP ( r = 0.9612; SEE = 0.4776). [ABSTRACT FROM AUTHOR]

A set of 40 resveratrol derivatives, downloaded from the PubChem database, was submitted to a QSAR study, following Diudea's algorithm, involving the hypermolecule concept, in a procedure similar to that of the „alignment“ of drug molecules to the biological receptors. The best models describing log P of this set of resveratrols were validated by the leave-one-out procedure, in the external test set and in a new version of prediction by using clusters of similar molecules. The structures have been optimized at HF 6-31G(d,p) level of theory. Topological indices have been computed by TOPOCLUJ software. [ABSTRACT FROM AUTHOR]

The article discusses research which examines the solvent-tolerance of fungi located on an interface between an agar plate and an organic solvent. Topics discussed include development of interfacial bioconversion systems for conversion of water-immiscible substrates with living microbial cells, determining relationship between hydrophobicity of organic solvent and its toxicity, and lack of effectiveness of methylcyclohexane, dibutyl ether and styrene in sterilization of fungal cells.

Thermodynamic analysis of the solubility of benzoylphenylurea ( BPU) derivatives was conducted to investigate the relative importance of crystal packing and hydration for improving solubility with minor structural modification. The contribution of crystal packing to solubility was evaluated from the change in Gibbs energy on the transition from the crystalline to liquid state. Hydration Gibbs energy was estimated using a linear free-energy relationship between octanol-water partition coefficients and gas-water partition coefficients. The established solubility model satisfactorily explained the relative thermodynamic solubility of the model compounds and revealed that crystal packing and hydration equally controlled solubility of the structural analogs. All hydrophobic substituents were undesirable for solubility in terms of hydration, as expected. On the other hand, some of these hydrophobic substituents destabilized crystal packing and improved the solubility of the BPU derivatives when their impact on crystal packing exceeded their negative influence on hydration. The replacement of a single substituent could cause more than a 10-fold enhancement in thermodynamic solubility; this degree of improvement was comparable to that generally achieved by amorphous formulations. Detailed analysis of thermodynamic solubility will allow us to better understand the true substituent effect and design drug-like candidates efficiently. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3524-3531, 2014 [ABSTRACT FROM AUTHOR]

A novel series of chalcone derivatives ( 4a – 8d ) were designed, synthesized, and evaluated for the inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The log P values of the compounds were shown to range from 1.49 to 2.19, which suggested that they were possible to pass blood brain barriers in vivo. The most promising compound 4a (IC 50 : 4.68 μmol/L) was 2-fold more potent than Rivastigmine against AChE (IC 50 : 10.54 μmol/L) and showed a high selectivity for AChE over BuChE (ratio: 4.35). Enzyme kinetic study suggested that the inhibition mechanism of compound 4a was a mixed-type inhibition. Meanwhile, the result of molecular docking showed its potent inhibition of AChE and high selectivity for AChE over BuChE. [ABSTRACT FROM AUTHOR]

The interaction between drug products and polymeric packaging materials is an important topic in the pharmaceutical industry and often associated with high costs because of the required elaborative interaction studies. Therefore, a theoretical prediction of such interactions would be beneficial. Often, material parameters such as the octanol water partition coefficient are used to predict the partitioning of migrant molecules between a solvent and a polymeric packaging material. Here, we present the investigation of the partitioning of various migrant molecules between polymers and solvents using molecular dynamics simulations for the calculation of interaction energies. Our results show that the use of a model for the interaction between the migrant and the polymer at atomistic detail can yield significantly better results when predicting the polymer solvent partitioning than a model based on the octanol water partition coefficient. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3197-3204, 2014 [ABSTRACT FROM AUTHOR]

The knowledge of physicochemical properties of organic compounds becomes increasingly important in pharmaceutical sciences, chemical engineering, and other fields. In this study, we developed UPPER ( Unified Physicochemical Property Estimation Relationships), a comprehensive model for the estimation of 20 physicochemical properties of organic compounds. UPPER is a system of thermodynamically sound relationships that relate the various phase-transition properties to one another, which includes transition heats, transition entropies, transition temperatures, molar volume, vapor pressure, solubilities and partition coefficients in different solvents, and so on. UPPER integrates group contributions with the molecular geometric factors that affect transition entropies. All of the predictions are directly based on molecular structure. As a result, the proposed model provides a simple and accurate prediction of the properties studied. UPPER is designed to predict industrially, pharmaceutically, and environmentally relevant physicochemical properties. It can be an aid for the efficient design and synthesis of compounds with optimal physicochemical properties. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2710-2723, 2014 [ABSTRACT FROM AUTHOR]

A series of novel coumarinazoles were designed, synthesized, and characterized by IR, NMR, MS and HRMS spectra. The bioactive assay for the newly prepared compounds against six bacteria and five fungi manifested that most new compounds exhibited good or even stronger antibacterial and antifungal activities in comparison with reference drugs Chloromycin, Norfloxacin and Fluconazole. Bis-azole alcohols 7a and 7d – e showed better anti- Candida utilis activity than mono-azole derivatives 4a and 4d – e at the tested concentrations, and they were more potent than the clinical Fluconazole. While triazole alcohol 7a gave comparable anti- Candida albicans and anti- Candida mycoderma activity to Fluconazole and better anti-MRSA activity than mono-triazole one 4a and clinical Norfloxacin. 1 H -Benzoimidazol-2-ylthio coumarin derivatives 4e and 7e gave the strongest anti- Escherichia coli JM109 efficacy. Oxiran-2-ylmethoxy moiety was found to be a beneficial fragment to improve antibacterial and antifungal activity to some extent. [ABSTRACT FROM AUTHOR]

Although drug delivery with nanovectors is regarded as one of the paradigm-shifting advances in modern medicine, the compatibility and performance of drug-vector formulations have not been systematically studied in terms of their physicochemistry and pharmacokinetics ( PKs). The drug delivery systems ( DDSs), currently available in clinics or trials, were analyzed based on hydrophobicity and anatomical therapeutic chemical ( ATC) classification of drug payloads. Four major types of DDSs differentiated based on DDS structure and drug hydrophobicity, where payload hydrophobicity decreased: micelles, serum albumin, liposome membrane, and liposome interior. A strong relationship between the increase in half-life in DDS formulation and drug hydrophobicity was found with up to 200-fold greater increase for hydrophilic drugs. The analysis results seemingly integrated PKs, ATC, and hydrophobicity to reinforce the development or optimization of drug delivery vectors and their formulations. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2147-2156, 2014 [ABSTRACT FROM AUTHOR]

Using an amino column (Supelcosil LC-NH2) and different mixtures of acetonitrile-water, quantitative structure-retention relationship models are discussed. These models are based on computed molecular descriptors representing numerically structured features of some saccharides. The obtained results are underlining the lipophilicity/hydrophilicity balance, and how this is controlling the separation of the saccharides. The resulting models ensued are characterized by a highly predictive capacity evaluated through a series of representative statistical indices (R2, Q2, SDEC, SDEP, s, and F). Moreover, using genetic algorithms for selection of the most important descriptors in the model, one-, two-, and three-descriptor models were selected and the contribution of each one was explained. As the majority of the selected descriptors is highly related to the functional groups existing in the molecule and to the effects caused by their presence, the retention mechanism involved in the chromatographic process appears to be mainly controlled by polar interactions. [ABSTRACT FROM AUTHOR]

Abstract: Sixteen novel oleanolic acid triterpenoid saponins were synthesized in an efficient and practical strategy, and their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) and selectivity over T-cell protein tyrosine phosphatase (TCPTP) were evaluated in vitro. The preliminary structure–activity relationship studies demonstrated that sugar-substituted moiety attached to the C-3 and C-28 positions of OA scaffold greatly affected the inhibitory activity against PTP1B and the selectivity over TCPTP. All the compounds showed inhibitory potencies, and compounds 1h, 1i and 1j exhibited remarkably potent inhibitory activities against PTP1B with IC50 values of 1.03, 0.78 and 3.12 μM, respectively. More significantly, compound 1h showed greater than 4 folds selectivity over highly homologous TCPTP. In parallel, the lipophilicity evaluation of all synthesized compounds was tested as a prediction for pharmacological potency. According to the predicted log P values, the predicted Log P results showed that lipophilicity may correlate with the evaluated biological potency. [Copyright &y& Elsevier]

Many weakly basic amine-containing compounds have a strong propensity to become highly concentrated in lysosomes by virtue of an ion-trapping-type mechanism; the substrates for this are referred to as lysosomotropic. We have previously shown that many lysosomotropic drugs can produce a significant expansion in the apparent volume of lysosomes, which can ultimately result in an intracellular distribution-based drug-drug interaction. In this study, we have systematically evaluated the physicochemical and structural features of weakly basic molecules that correlate with their ability to induce an expanded lysosomal volume phenotype ( ELVP) in cultured human fibroblasts. By quantitatively evaluating the cellular accumulation of Lysotracker Red, a fluorescent lysosomotropic probe, the volume of the lysosomal compartment was determined. We specifically explored the influence that lysosomotropism, molecular size, and amphiphilicity had on a molecule's ability to induce an ELVP. The capacity of these molecules to intercalation into biological membranes was also evaluated using a red blood cell hemolysis assay. The present results suggest that a molecule's potency in eliciting an ELVP is influenced by lysosomotropism, amphiphilicity, and its ability to intercalate into biological membranes. Despite being highly lysosomotropic, low-molecular-weight, nonaromatic amines failed to cause an ELVP at all concentrations evaluated. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1572-1580, 2014 [ABSTRACT FROM AUTHOR]

The effects of surfactant type and content on the kinetics of emulsion reconstitution and release of drugs differing in lipophilicity from self-emulsifying microcrystalline cellulose pellets were studied. Furosemide and propranolol were the drugs, medium-chain triglyceride was the oil, and Cremophors ELP, RH40, and RH60 were the surfactants. Pellets were prepared by extrusion/spheronization with emulsions (75% water and 25%, w/w, oil/surfactant/drug). Stability of the emulsions was evaluated from changes in the back-scattered light, and re-emulsification and drug release from light transmittance and UV spectroscopy, respectively. Emulsion stability increased because of the incorporation of the drugs. Re-emulsification depended only on the surfactant content and was expressed by a simple power equation ( [ABSTRACT FROM AUTHOR]

A novel QSAR approach based on correlation weighting and alignment over a hypermolecule that mimics the investigated correlational space was performed on a set of 40 caffeines downloaded from the PubChem database. The best models describing log P and LD50 values of this set of caffeine derivatives were validated against the external test set and in a new predictive model by using clusters of similarity. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

A set of 40 flavonoids, downloaded from the PubChem database, was submitted to a qsar study by using an alignment procedure of the molecules over the hypermolecule, that mimics the investigated correlational space, within the correlation weighting analysis. The best models have been validated in the external test set and in a new version of validation/prediction by using similarity clusters. [ABSTRACT FROM AUTHOR]

A novel QSAR approach, based on correlation weighting and alignment overa hypermolecule, thatmimics the investigated correlational space, was performed on a set of 40 flavonoids, downloaded from the PubChem database. The best models describing log P of this set of flavonoids were validated in the external test set and in a new version of prediction by using similarity clusters. [ABSTRACT FROM AUTHOR]

Highlights: [•] 2-chloro-3-(n-alkylamino)-1,4-naphthoquinones are synthesized and characterized. [•] Single crystal X-ray structures reveal molecular association by hydrogen bondings. [•] Molecular associations of aminonaphthoquinones are revealed by cyclic voltammetry. [•] Antifungal activity is studied against C. tropicalis, C. albicans and C. herbarum. [•] Methyl derivative shows promising antifungal activity. [Copyright &y& Elsevier]

There is growing interest in exploring Digitalis cardenolides as potential antiviral agents. Hence, we herein investigated the influence of structural features and lipophilicity on the antiherpes activity of 65 natural and semisynthetic cardenolides assayed in vitro against HSV-1. The presence of an α,β-unsaturated lactone ring at C-17, a β-hydroxy group at C-14 and C-3β-OR substituents were considered essential requirements for this biological activity. Glycosides were more active than their genins, especially monoglycosides containing a rhamnose residue. The activity enhanced in derivatives bearing an aldehyde group at C-19 instead of a methyl group, whereas inserting a C-5β-OH improved the antiherpes effect significantly. The cardenolides lipophilicity was accessed by measuring experimentally their log P values (n-octanol-water partition coefficient) and disclosed a range of lipophilicity (log P 0.75±0.25) associated with the optimal antiherpes activity. In silico studies were carried out and resulted in the establishment of two predictive models potentially useful to identify and/or optimize novel antiherpes cardenolides. The effectiveness of the models was confirmed by retrospective analysis of the studied compounds. This is the first SAR study addressing the antiherpes activity of cardenolides. The developed computational models were able to predict the active cardenolides and their log P values., (© 2022 The Authors. Chemistry & Biodiversity published by Wiley-VHCA AG, Zurich, Switzerland.)

Introdução – A lipofilia é uma das propriedades físico-químicas que mais influencia a capacidade de uma molécula se movimentar através de compartimentos biológicos. O coeficiente de partição octanol/água (log P) permite, assim, obter uma estimativa da absorção dos fármacos no organismo. A existência de métodos indirectos para um cálculo rápido do log P pode revelar-se de grande importância na análise de listas de compostos com potencial acção farmacológica, reduzindo-as àqueles que se prevêem ter um melhor comportamento biológico. Objectivos – O propósito deste estudo é dar a conhecer um método cromatográfico de RP-HPLC desenvolvido para a determinação indirecta da lipofilia molecular e avaliar a performance de vários programas de cálculo computacional desse mesmo parâmetro. Metodologias – Seleccionaram-se 25 compostos químicos, avaliou-se o log P de cada um deles por RP-HPLC e confrontaram-se os resultados obtidos com os de sete programas computacionais. Resultados – O método RP-HPLC testado demonstrou ser vantajoso em comparação com o convencional shake flask. O programa de cálculo indirecto que proporcionou resultados mais próximos dos experimentais foi o ALOGPS© 2.1. Conclusões – A escolha ideal para a determinação da lipofilia de compostos cujo log P estimado esteja entre 0 e 6 é, sobretudo no que diz respeito à rapidez e simplicidade do processo, o método experimental indirecto RP-HPLC. Quanto aos métodos computacionais concluiu-se que nenhum dos programas, incluindo o ALOGPS© 2.1, demonstrou ser eficaz na avaliação de isómeros pelo que, para estes compostos, será sempre necessário recorrer ao método shake flask ou RP-HPLC.

The diffusion of aroma volatiles in set-type acidified dairy matrices of different composition and structure was investigated using the concentration profile technique ( CPT) in combination with headspace gas chromatography ( HSGC). Multiphase confocal laser scanning microscopy and puncture testing were used to characterize the micro- and macrostructure of the matrices. Aroma volatiles under investigation included diacetyl, ( Z)-3-hexenol, ethyl butanoate, ethyl-2-methylbutanoate, ( Z)-3-hexenyl acetate, ethyl hexanoate and limonene, and covered a wide range of hydrophobicity. CPT in combination with HSGC was found suitable to determine apparent diffusion coefficients at equilibrium. Increased overall protein content decreased the diffusivity of hydrophobic volatiles. At 4% protein content, diffusivity remained unaffected by process-induced changes in the protein network density. Addition of milk fat substantially decreased the mobility of hydrophobic volatiles. In milk fat-containing matrices, the addition of pectin did not change the diffusion properties of the volatiles, independent of their hydrophobicity. Practical Applications This study is relevant to the producers of acidified dairy products such as yoghurt, fresh cheese and quarg. The results specify within which boundaries several core parameters of manufacture, such as the addition of pectin, the intensity of milk heating, shearing and adaptations in protein and fat content, may be changed at a minimized risk of altered aroma delivery during consumption. This information amplifies the technological possibilities of the manufacturers and increases their flexibility in terms of product composition and processing. Aroma suppliers could use the outcomes of this study to modify the composition of their aromas based on dairy product specifications and the hydrophobicity of the individual aroma compounds they are using. [ABSTRACT FROM AUTHOR]

The log P descriptor, despite its usefulness, can be difficult to use, especially for researchers lacking skills in physical chemistry. Moreover this classic measure has been determined in numerous ways, which can result in inconsistant estimates of log P values, especially for relatively complex molecules such as fluorescent probes. Novel measures of hydrophilicity/lipophilicity (the Hydrophilic/Lipophilic Index, HLI) and amphiphilicity (hydrophilic/lipophilic indices for the head group and tail, HLIT and HLIHG, respectively) therefore have been devised. We compare these descriptors with measures based on log P, the standard method for quantitative structure activity relationships (QSAR) studies. HLI can be determined using widely available molecular modeling software, coupled with simple arithmetic calculations. It is based on partial atomic charges and is intended to be a stand-alone measure of hydrophilicity/lipophilicity. Given the wide application of log P, however, we investigated the correlation between HLI and log P using a test set of 56 fluorescent probes of widely different physicochemical character. Overall correlation was poor; however, correlation of HLI and log P for probes of narrowly specified charge types, i.e., non-ionic compounds, anions, conjugated cations, or zwitterions, was excellent. Values for probes with additional nonconjugated quaternary cations, however, were less well correlated. The newly devised HLI can be divided into domain-specific descriptors, HLIT and HLIHG in amphiphilic probes. Determinations of amphiphilicity, made independently by the authors using their respective methods, showed excellent agreement. Quantifying amphiphilicity from partial log P values of the head group (head group hydrophilicity; HGH) and tail (amphiphilicity index; AI) has proved useful for undertanding fluorescent probe action. The same limitations of log P apply to HGH and AI, however. The novel descriptors, HLIT and HLIHG, offer analogous advantages to those seen with HLI over log P. The high correlation between log P and HLI, and the concordance between the two systems for assessing amphiphilicity, provide a powerful tool for QSAR studies. It is possible now to select a probe with missing fragments, and thus no log P, AI or HGH; and to estimate these important descriptors from parameters derived from HLI. [ABSTRACT FROM AUTHOR]

Quantitative structure activity relations (QSAR) models were developed to predict uptake and intracellular localization of probes or dyes in living cells. Many of the QSAR parameters used in such models are determined manually. Unfortunately, this requires a depth of chemical knowledge that biologists who wish to use these predictive tools do not necessarily possess. Moreover, some of the parameters are not easily obtained for all dyes and probes, which further restricts widespread use of QSAR methodology. Alternatives to some of these QSAR descriptors are defined and explained here. Estimation of these novel parameters using molecular modeling software, widely available and readily usable on personal computers in a variety of forms and brands, is described here. QSAR researchers need only draw the molecular structure and, with the proper commands, obtain either the parameters directly or the information to calculate them. I also demonstrate how the same software can generate some of the standard QSAR parameters, e.g., MW, Z, CBN, more reliably and conveniently than the manual procedures. A particularly problematic descriptor is log P, the logarithm of the octanol/water partition coefficient of a probe. This is discussed in detail and a novel alternative measure, the hydrophilic/lipophilic index ( HLI), is introduced together with preliminary validation. [ABSTRACT FROM AUTHOR]

Abstract: Under physiological conditions healthy bones are maintained by a well tightened balance between osteoclast (OCs) and osteoblast (OBs) activity. Disruption of this balance leads to osteoporosis characterized by decline in bone function and skeletal rigidity. Inhibition of 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) could help maintaining the appropriate bone mass density by increasing the level of estradiol and testosterone in bone. Herein, we described the synthesis, the physicochemical properties and the biological evaluation of novel N-methylsulfonamide and retro-N-methylsulfonamide derivatives as 17β-HSD2 inhibitors showing high potency (compound 10f, IC50 = 23 nM), with a good selectivity toward 17β-HSD1 (the isoenzyme responsible of the reverse reaction), and a likely good in vitro ADME profile. It was also shown that the acidity of the phenolic hydroxy correlates with the inhibitory potency, suggesting pKa as a predictive parameter for the activity of this class of inhibitors. [Copyright &y& Elsevier]

It is important to address the tissue permeability of drugs, particularly in tissues that have a blood-tissue barrier, in terms of both lipophilicity and the contribution of transporters. Here, we employed umbilical perfusion in rats to evaluate in vivo fetal-to-maternal transfer clearances of various xenobiotics. We measured fetal-to-maternal clearance (CLfm) of 23 compounds, which have a broad range of lipophilicity. Drugs for which CLfm was more than 300 µL/(mL min) belonged exclusively to Biopharmaceutical Drug Disposition Classification System (BDDCS) class 1 (highly permeable) and those for which CLfm was less than 50 µL/(mL min) belonged exclusively to BDDCS class 3 (poorly permeable). For most drugs, CLfm values were broadly consistent with lipophilicity. However, CLfm of digoxin was saturable and was inhibited by verapamil, suggesting that P-glycoprotein (P-gp)-mediated efflux has a substantially effect on measured clearance. CLfm of mitoxantrone continued to increase slightly at high concentrations of mitoxantrone, but placental-to-maternal clearance of mitoxantrone was saturable, implying that Bcrp1 contributes to mitoxantrone efflux across the placenta. Thus, we measured CLfm by umbilical perfusion and examined the relationship between CLfm and lipophilicity of xenobiotics. Fetal-to-maternal transport clearances measured in this study will be helpful to understand the characteristics of the blood-placental barrier. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3356-3363, 2013 [ABSTRACT FROM AUTHOR]

Pseudopterosin A (PsA) treatment of growth factor depleted human umbilical vein endothelial cell (HUVEC) cultures formulated in hydroxypropyl-×-cyclodextrin (HP×CD) for 42 h unexpectedly produced a 25% increase in cell proliferation (EC50 = 1.34 × 10-8 M). Analysis of dose response curves revealed pseudo-first order saturation kinetics, and the uncoupling of cytotoxicity from cell proliferation, thereby resulting in a widening of the therapeutic index. The formulation of PsA into HP×CD produced a 200-fold increase in potency over a DMSO formulation; we propose this could result from a constrained presentation of PsA to the receptor, which would limit non-specific binding. These results support the hypothesis that the non-specific receptor binding of PsA when formulated in DMSO has ostensibly masked prior estimates of specific activity, potency, and mechanism. Collectively, these results suggest that the formulation of PsA and compounds of similar chemical properties in HP×CD could result in significant pharmacological findings that may otherwise be obscured when using solvents such as DMSO. [ABSTRACT FROM AUTHOR]

In this study, the partition coefficients (Log P) of two series of isoindolines-2-substituted were calculated from the equation obtained for the multilinear correlation between the electronic properties: the highest occupied molecular orbital and the lowest unoccupied molecular orbital energies, and the steric property volume, and the experimental Log P values were determined for some representative isoindolines. Log P values calculated under quantum chemistry were compared with Log P values obtained by the Log P calculation software ALOGPS 2.1 server; the Log P values calculated showed a better correlation with experimental Log P values than those obtained by means of the software. Log P values calculated were also correlated with the antiproliferative activity of some isoindolines-2-substituted determined on HeLa cells, and the correlation obtained shows a quadratic relationship between Log P values calculated and the antiproliferative activity of isoindolines-2-substituted, suggesting a significant effect of Log P values on biological activity of isoindolines. [ABSTRACT FROM AUTHOR]

Quantitative structure–activity relationship (QSAR) modelling of aquatic toxicity for cationic surfactants has received limited attention despite the fact that surfactants of this type are generally more toxic than predicted by general narcosis or polar narcosis equations. Here we report measurement of log P for three types of aromatic quaternary ammonium halides at sub-micellar concentrations, refinement of earlier rules for log P calculation, and development of a hydrophobicity based QSAR, using both calculated and measured log P values, for the aquatic toxicity of quaternary ammonium halides toDaphnia magna. The QSAR for cationics has a substantially larger intercept than the log P-based QSARs for nonionic and anionic surfactants. This is rationalised in terms of the head group interactions with membrane phospholipid in a two-dimensional partitioning model. The effect of the positive nitrogen on the log P contributions of methylene groups along alkyl chains varies, depending on the other groups bonded to the positive nitrogen. We propose a mechanistic explanation, but until these effects can be put on a more predictable quantitative basis it is recommended that, for quaternaries other than the three types discussed here, calculated log P values should not be relied on and experimental values should be determined, e.g. for prediction of toxicity by the QSAR equation reported here. [ABSTRACT FROM AUTHOR]

Abstract: Twenty-six naturally occurring oleanolic acid saponins and their derivatives, 16 of which were synthesized in this study, were preliminarily evaluated against human cancer cells. From SAR studies, the presence of α-l-rhamnosyl residue at the terminal of both C-3 and C-28 position for oleanolic acid bidesmosides was important to enhance cytotoxicity, and introducing more sugar residues at C3–OH of compound 12 with C-28 carboxylic acid is a favorable modification to ameliorate the anticancer activity. Furthermore, α-l-rhamnosyl moiety linked to C2–OH of the first monosaccharide (α-l-alabinose, β-d-xylose, β-d-galactose or β-d-glucose) in C3–OH of oleanolic acid was helpful to improve the cytotoxicity. According to the predicted log P values, lipophilicity of the synthesized saponins was not an important factor for cytotoxicity. [Copyright &y& Elsevier]

A ‘proof-of-concept’ version of a software tool for making transparent predictions of acute aquatic toxicity has been developed. It is primarily limited to semi-quantitative predictions in one species, the ciliated protozoan,Tetrahymena pyriformis. A freely available system, ‘Eco-Derek’, was derived by adapting a well-established, knowledge-based structure–activity and reasoning platform (Derek for Windows, Lhasa Limited). The Derek reasoning code was modified to express potency rather than confidence. Structure–activity relationship (SAR) development utilised a curated version of a published dataset, supplemented with the CADASTER Challenge datasets. Forty-five structural alerts were produced. The dependence on logPwas examined for each alert and entered into the system as qualitative reasoning rules specifying the predicted potency as Very Low, Low, Moderate, High or Very High. Evaluation studies showed: (a) moderate accuracy for the training set but low accuracy for an external test set; (b) non-linearity in the toxicity–logPrelationship for chemicals without identified structural alerts; (c) insufficient differentiation of substituent effects in some of the reactivity-based structural alerts resulting in too few chemicals predicted with Very High toxicity; and (d) the need for additional structural alerts covering polar narcosis and less common reactive or metabolically activated chemical functionality. [ABSTRACT FROM AUTHOR]

A method for removing four triphenylmethane dyes from wastewater by cloud point extraction with the nonionic surfactant Triton X-114 (TX-114) was developed. The triphenylmethane dyes were crystal violet, ethyl violet, malachite green and brilliant green. The cloud point of TX-114 generally increased in the presence of any of the four dyes. In the cloud point system, these dyes were solubilized into a coacervate phase that left a color-free dilute phase. The extraction efficiency of the dyes increased with the temperature, TX-114 concentration, and salt (NaCl and CaCl2) concentration. More than 97% TX-114 in the dilute phase was recovered by adjusting the volume ratio of dichloromethane to the dilute phase. The Langmuir-type adsorption isotherm was used to describe the dye solubilization. The Langmuir constantsmandnwere calculated as functions of temperature. The results showed that the solubilization of the triphenylmethane dyes in the cloud point system was related to the partition coefficient and their molecular structures. [ABSTRACT FROM PUBLISHER]

Abstract: A total of 30 species-specific partition coefficients of three thyroid hormones (thyroxine, liothyronine, reverse liothyronine) and their two biological precursors (monoiodotyrosine, diiodotyrosine) are presented. The molecules were studied using combined methods of microspeciation and lipophilicity. Microspeciation was carried out by 1H NMR-pH and UV-pH titration techniques on the title compounds and their auxiliary derivatives of reduced complexity. Partition of some of the individual microspecies was mimicked by model compounds of the closest possible similarity, then correction factors were determined and introduced. Our data show that the iodinated aromatic ring system is the definitive structural element that fundamentally determines the lipophilicity of thyroid hormones, whereas the protonation state of the aliphatic part plays a role of secondary importance. On the other hand, the lipophilicity of the precursors is highly influenced by the protonation state due to the relative lack of overwhelmingly lipophilic moieties. The different log p values of the positional isomers liothyronine and reverse liothyronine represent the importance of steric and electronic factors in lipophilicity. Our investigations provided clear indication that overall partition, the best membrane transport – predicting physico-chemical parameter depends collectively on the site-specific basicity and species-specific partition coefficient. At physiological pH these biomolecules are strongly amphipathic due to the lipophilic aromatic rings and hydrophilic amino acid side chains which can well be the reason why thyroid hormones cannot cross membranes by passive diffusion and they are constituents of biological membranes. The lipophilicity profile of thyroid hormones and their precursors are calculated and depicted in terms of species-specific lipophilicities over the entire pH range. [Copyright &y& Elsevier]

The binding constants ( Kbs) of 17 aryl propionic acid derivatives (APADs) and related compounds with polyvinylpyrrolidone (PVP K30) and vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64) in aqueous media were determined by affinity capillary electrophoreses (ACE). The Kbs of APAD to polymers increase with octanol-water partition coefficients of the compounds. Kollidon VA64 is a stronger binder than PVP K30 to APAD compounds. The Kbs are greater at pH 4 than at pH 9. Both hydrophobic interaction and hydrogen bonding may be involved. However, hydrophobic interaction appears to be dominant. The ACE method is simple and fast, which could be used to study drug-polymer interaction in aqueous media. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:960-966, 2013 [ABSTRACT FROM AUTHOR]

Abstract: Lipophilicity is a crucial parameter in drug development since it impacts both ADME properties and target affinity of drug candidates. In early drug discovery stage, accurate tools for log P prediction are highly desired. Many calculation methods were developed to aid pharmaceutical scientists in drug research; however almost all suffer from insufficient accuracy and variation of performance in several regions of the chemical space associated with new chemical entities. The low predictive power of existing software packages can be explained by limited availability and/or variable quality of experimental log P values associated with training set used, which stem from various protocols and poorly cover chemical space. In this study, a dataset of 1000 diverse test compounds out of 4.5 million was generated; log P values of 759 purchasable compounds (46% non-ionizable, 30% basic, 17% acidic, 0.5% zwitterionic and 6.5% ampholytes) from this selected set were experimentally determined by UHPLC followed by UV detection or MS detection when necessary. Finally, a data collection of 707 validated log P values ranging from 0.30 to 7.50 is now available for benchmarking of existing and development of new approaches to predict octanol/water partition coefficients of chemical compounds. [Copyright &y& Elsevier]

The retention of some 5,5-disubstituted hydantoins was investigated by reversed phase high performance thin-layer chromatography (RP HPTLC) and reversed phase high-pressure liquid chromatography (RP HPLC). The mobile phases were mixtures of methanol-water and acetonitrile-water in various volume fractions. In order to explore and visualize similarities and differences among the investigated compounds and chromatographic system, Principal Component Analysis (PCA) was used. Results show that the experimental lipophilicity indices estimated from retention data (RM,W, log kw) and PC1 are directly correlated with logP values at a high significant statistical level [ABSTRACT FROM AUTHOR]

An important series of papers by Xiang, Anderson, and coworkers has established the strong correlation between phospholipid bilayer membrane permeability and the 1,9-decadiene/water partition coefficient over a wide range of compounds, elevating the importance of Kdecadiene/w as a predictor of molecular bioavailability. On the basis of a 58-point dataset developed by these authors, this research note develops an optimal correlation predicting log10 Kdecadiene/w in terms of the octanol/water partition coefficient and four of the Abraham solvation parameters, namely A (hydrogen bond acidity), S (polarity/polarizability), E (excess molar refraction), and V (McGowan characteristic volume). The fitted dataset is described to within a root-mean-square error of 0.42, and the probable error in making a prediction for a compound not present therein is 0.49. It is shown that this correlation error for Kdecadiene/w is the dominant source of uncertainty in applying a comprehensive new model of phospholipid bilayer membrane permeability developed in a companion paper (Nitsche and Kasting, submitted for publication), which superposes the effects of molecular size and lipid density upon the decadiene lipophilicity scale. Thus, more experimental studies to augment the limited existing database on Kdecadiene/w are called for. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:136-144, 2013 [ABSTRACT FROM AUTHOR]

Abstract: For the first time a capillary separation based on micellar electrokinetic chromatography (MEKC) with diode array detection (DAD) was developed and validated for the rapid determination of synthetic cannabinoids in herbal blends. Separations were carried out on a 30μm(ID)×40cm uncoated fused silica capillaries. The optimized buffer electrolyte was composed of 25mM sodium tetraborate pH 8.0, 30mM SDS and n-propanol 20% (v/v). Separations were performed at 30kV. Sample injection conditions were 0.5psi, 10s. Diazepam and JWH-015 were used as internal standards. The determination of the analytes was based on the UV signal recorded at 220nm, corresponding to the maximum wavelength of absorbance of the molecules, whereas peak identification and purity check were also performed on the basis of the acquisition of UV spectra between 200 and 400nm wavelengths. Under the described conditions, the separation of the compounds was achieved in 25min without any significant interference from the matrix. Linearity was assessed within a concentration range from 5 to 100μg/mL. The intra-day and inter-day imprecision values were below 2.45% for relative migration times and below 10.75% for relative peak areas. The present method was successfully applied to the direct determination of synthetic cannabinoids in 15 different herbal blend samples requiring only sample dilution. In addition, the developed MEKC separation was also applied to estimate the octanol/water partition coefficients (log P) of these new and poorly known molecules. [Copyright &y& Elsevier]

Abstract: Aqueous amphiphilic compounds may exhibit enhanced skin penetration compared with neat compounds. Conventional models do not predict this percutaneous penetration behaviour. We investigated the potential of the octanol–water partition coefficient (log P) to predict dermal fluxes for eight compounds applied neat and as 50% aqueous solutions in diffusion cell experiments using human skin. Data for seven other compounds were accessed from literature. In total, seven glycol ethers, three alcohols, two glycols, and three other chemicals were considered. Of these 15 compounds, 10 penetrated faster through the skin as aqueous solutions than as neat compounds. The other five compounds exhibited larger fluxes as neat applications. For 13 of the 15 compounds, a consistent relationship was identified between the percutaneous penetration behaviour and the log P. Compared with the neat applications, positive log P were associated with larger fluxes for eight of the diluted compounds, and negative log P were associated with smaller fluxes for five of the diluted compounds. Our study demonstrates that decreases or enhancements in dermal penetration upon aqueous dilution can be predicted for many compounds from the sign of log P (i.e., positive or negative). This approach may be suitable as a first approximation in risk assessments of dermal exposure. [Copyright &y& Elsevier]

The concepts of drug efficiency ( Deff) and Drug Efficiency Index (DEI) have been recently introduced as useful parameters to optimize the absorption, distribution, metabolism, elimination/excretion, and toxicity properties and in vivo efficacy potential of molecules during lead optimization and at pre-clinical stages. The available free drug concentration relative to dose depends on the compound's bioavailability, clearance, and the nonspecific binding to proteins and phospholipids. In this paper, we have demonstrated, using the data of over 115 known drug molecules, that the nonspecific binding can be determined in vitro very efficiently using biomimetic high-performance liquid chromatography measurements. DEI can therefore be estimated from in vitro measurements. The data show that high in vitro DEI values can be associated with lower efficacious dose. A strategy is described of how to use the DEI parameter during early lead optimization. An example is given to highlight the advantages of optimizing on DEI value rather than on potency alone. In order to facilitate the in silico compound design, correlation between in vitro DEI and in silico ligand efficiency parameters such as ligand lipophilicity efficiency has been revealed, suggesting the potential use of these efficiency-related parameters across lead optimization. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4155-4169, 2012 [ABSTRACT FROM AUTHOR]

Abstract: We determined the distribution coefficients of solutes between a polymer film phase (polyvinyl chloride (PVC) with 67% (w/w) dioctyl sebacate (DOS)) and an aqueous phase in a 96-well format. The parallel measurement approach is efficient and uses very little material. Polymer–water distribution coefficients (D pw) at different pH values yield the pKa and polymer–water partition coefficient values (P pw) of the solutes. log P pw of a prominent drug-like compound, 2H-1,2,6-thiadiazine, 3-methyl-5-phenyl-,1,1-dioxide, is in good agreement with clog P, while the pK a value is substantially different from calculated values. This method has been also successfully applied to a library of novel drug-like compounds. log D pw values (at pH 4.0, 7.0, 10.0) of 24 novel drug-like compounds have been determined with good reproducibility with the 96-well plate approach. Differences between experimental values and a variety of available calculated values are significant. This emphasizes the need for laboratory separations-based measurements of log D. [Copyright &y& Elsevier]

Microfluidic devices fabricated using poly(dimethylsiloxane) (PDMS) polymer are routinely used for in vitro cell culture for a wide range of cellular assays. These assays typically involve the incubation of cultured cells with a drug molecule or a fluorescent marker while monitoring a cellular response. The accuracy of these assays depends on achieving a consistent and reproducible concentration of solute molecules in solution. However, hydrophobic therapeutic and fluorescent molecules tend to diffuse into the PDMS walls of the microfluidic devices, which reduce their concentration in solution and consequently affect the accuracy and reliability of these assays. In this paper, we quantitatively investigate the relationship between the partition coefficient (log P) of a series of markers routinely used in in vitro cellular assays including [3H]-dexamethasone, [3H]-diazepam, [14C]-mannitol, [3H]-phenytoin, and rhodamine 6G and their absorption into PDMS microfluidic channels. Our results show that the absorption of a given solute into PDMS depends on the hydrophilic/hydrophobic balance defined by its log P value. Specifically, results demonstrate that molecules with log P less than 2.47 exhibit minimal absorption (<10%) into PDMS channels whereas molecules with log P larger than 2.62 exhibit extensive absorption (>90%) into PDMS channels. Further investigations showed that TiO and glass coatings of PDMS channels reduced the absorption of hydrophobic molecules (log P > 2.62) by 2- and 4.5-folds, respectively. [ABSTRACT FROM AUTHOR]

In the present work we have considered miscellaneous set of 76 industrial chemicals and modeled their logP using topological as well as physicochemical descriptors. The results indicate that the estimation of log P is very much effective when the topological and physicochemical descriptors are used together. The most appropriate model for the estimation (modeling) of log P indicated that by using the combination of topological and physicochemical descriptors. The results are discussed using variety of statistical approaches. [ABSTRACT FROM AUTHOR]