Log Poct Research Articles

The lipophilic behaviour of organic compounds:2. The development of an aliphatic hydrocarbon/water fragmental system via interconnection with octanol-water partitioning data

A hydrophobic fragmental system was developed for application in the study of aliphatic hydrocarbon/water (ahc/w) partitioning. The final version presented here is based on an optimized coupling of the ahc/w-system with f-constants for octanol/water partitioning. A total of 70 f-values are now available in the aliphatic hydrocarbon/water system. The aliphatic hydrocarbon/water system appears to be especially useful in the evaluation of log Poct data for compounds with comparatively high lipophilicity. As a first, preliminary validity check the new system is applied to pharmaco-chemical studies on penetration of blood-brain barrier by drugs and simple organic compounds.

PKa, log Poct and HPLC Capacity Factor on a Porous Polymer Gel in the Study of a Series of 2-Benzamido-5-Nitrothiazoles

Partitioning of 15 derivatives of 2-benzamido-5-nitrothiazole between octanol and Tris/HCl buffers yields values for acidity constant in water (Ka), partition coefficient (Poct), extraction constant of base-cation ion-pair (Ke). pKa’s have also been measured by spectrophotometric titration in an acetonitrile/water (10:90 v/v) solvent mixture. Lipophilicity has also been determined using HPLC on a styrene/divinylbenzene polymeric stationary phase in methanol/water and acetonitrile/water media. Correlations between log Poctand HPLC capacity factor log k′ are established. On the basis of our results, the fragmental contribution of the benzamide moiety in the CLOGP program could be corrected.

Multivariate analysis of experimental and computational descriptors of molecular lipophilicity.

Two experimental (log P, R(Mw)) and 17 calculation descriptors for molecular lipophilicity (fragmental, atom-based or based on molecular properties) were investigated by multvariate analysis for a database of 159 compounds including both simple structures as well as more complex drug molecules. Principal component analysis (PCA) of the entire database exhibits a clustering of chemical groups; preciseness of clustering corresponds to chemical similarity. Thus, diversity searching in databases might effectively be performed by PCA on the basis of calculated log P. The comparative validity check of experimental and computational procedures by regression analysis and PCA was performed with a chemically balanced, reduced data set (n = 55) representing 11 chemical groups with 5 members each. Regression of experimental descriptors (log Poct versus RMW) proves that chromatographic data, obtained under well-defined experimental conditions, can be used as valid substitutes for log P. Regression of calculated versus experimental lipophilicity data shows a superiority of fragmental over atom-based methods and approaches based on molecular properties, as indicated by correlation coefficients, slopes and intercepts. In addition, PCA revealed that fragmental methods (Rekker-type, KOWWIN, KLOGP) sense the compound ranking in log P data to almost the same extent as experimental approaches. For atom-based procedures and CLOGP, both the comparability of absolute values and the sensing of the compound ranking in the database are slightly less. This trend is more pronounced for the methods based on molecular properties, with the exception of BLOGP.

A Systematic Study on the Complexation of Quaternary Ammonium Salts and Neutral Phenols.

Complexation of quaternary ammonium salts (Q+X-) and undissociated, neutral phenols (ArOH) in homogeneous organic solutions was systematically investigated to afford a reliable quantitative basis for a new model of anionic potentiometric response to neutral phenols, displayed by organic liquid membranes based on Q+X-. IR, 1H- and 13C-NMR, and UV studies indicated complexation of Q+X- and ArOH in 1 : 1 stoichiometry in nonpolar organic solvents such as benzene and chloroform. The stability constant (Ks) of the complex was affected by the acidity and lipophilicity of the ArOH component as well as the size of X- of the Q+X- component; stronger complexes were formed by ArOH with a lower pKa and higher log Poct, as well as by Q+X- with a smaller ionic radius for X-. These results suggest that the major driving force for complexation is hydrogen bonding interactions between X- and the phenolic OH. The Ks values were found to be parallel with the magnitudes of anionic potentiometric responses by membranes based on Q+X-, indicating that the complexation of ArOH by Q+X- plays an important role in the anionic potentiometric responses. The significance of proton dissociation from the Q+X-·ArOH complex was also discussed.

Lipophilicity Behavior of Model and Medicinal Compounds containing a suilfide, sulfoxide, or sulfone moiety

AbstractThis study was designed to unravel lipophilicity changes associated with the oxidation state of the S‐atom in model compounds, drugs, and metabolites, special attention being given both to intermolecular and intramolecular effects. The methods used were experimental (potentiometry, CPC, and shake‐flask techniques to measure lipophilicity, 13C‐NMR spectroscopy to investigate tautomeric equilibria) and computational (quenched molecular dynamics and molecular lipophilicity potential). Simple, monofunctional model compounds were used to assess intermolecular forces, as revealed by the Δlog Poct–alk and Δlog Poct–chf parameters. Drugs and their metabolites proved to be good probes to study intramolecular effects in both neutral and anionic forms, as revealed by the difference between calculated and experimental log Poct values (the diff(log Pexp–calc) parameter). Sulindac and its metabolites showed a normal partitioning behavior, whereas the lipophilicity of sulfmpyrazone and its metabolites' was markedly affected by tautomeric and conformational equilibria.

Hydrophobicity Parameters Determined by Reversed-Phase Liquid Chromatography. XII. Comparison of Capacity Factors and Octane/Methanol-Water Partition Coefficients for Monosubstituted Pyrazines, and Effect of Octanol Added to both Partitioning Systems.

Partition coefficients (P) of pyrazine and its COOMe derivative (strong hydrogen bond acceptor), were measured for the octane/aqueous methanol partitioning system (PO/M-W) at different methanol (MeOH) concentrations and the dependence of log PO/M-W on the methanol concentration was compared to the corresponding change in log k' (k' : capacity factor) obtained by reversed-phase liquid chromatography with aqueous methanol. Next, in order to make the chromatographic system approximate more closely to the octanol/water partitioning system, a small quantity of octanol was added to the eluents and also to the octane/aqueous methanol partitioning system and further comparisons were made. It was found that the octanol effect was minimum at 50% MeOH, suggesting that the chromatographic system with eluents containing about 50% MeOH has properties more similar to the octanol/water partitioning system than with eluents of other compositions. This confirms our previous result that the log k' parameter obtained at 50% MeOH yields a better correlation with log Poct (Poct : octanol/water partition coefficient) than those obtained at other mobile phase compositions in the range from 5 to 70% MeOH.

Differential inhibitory effects of phenytoin, diclofenac, phenylbutazone and a series of sulfonam ides on hepatic cytochrom e P4502C activity in vitro, and correlation with som e m olecular descriptors in the dwarf goat (Caprus hircus aegagrus).

1. The aim of the present study was to investigate the potency of various sulfonamides to inhibit tolbutamide hydroxylation (a CYP2C activity) in hepatic microsomal fractions and hepatocytes of the dwarf goat. Also a number of suggested substrates for human CYP2C9 was investigated. 2. From Dixon plots (microsomal fractions) it was observed that all compounds were competitive inhibitors of tolbutamide hydroxylation. Phenytoin (PT) showed the lowest Ki. Ki for the sulfonamides ranged between 205 and 4546 μM, sulfadoxine having the lowest Ki followed by sulfadimethoxine, sulfamoxole, sulfadimidine and sulfaphenazole. 3. In hepatocytes sulfaphenazole and diclofenac were the most potent inhibitors. 4. Out data indicate that PT, diclofenac (DF) and phenylbutazone (PBZ) are relative strong competitive inhibitors of tolbutamide hydroxylation and they are probably also substrates for the same enzyme. Differential inhibition of tolbutamide hydroxylation by sulfonamides was observed. 5. Correlation of structural parameters with the inhibition constant or the inhibition in hepatocytes showed that molecular volume, polarisability and molecular surface area are important parameters in determining the rate of inhibition of tolbutamide hydroxylation by sulfonamides in both microsomes and hepatocytes. In addition, log Poct are also involved oct in determining inhibition constants in microsomal fractions.

Correlations Between n-Octanol/Water Partition Coefficients and RP-HPLC Capacity Factors of 1,2-Dithiole-3-thiones and 1,2-Dithiol-3-ones

From the experimental n-octanol/water partition coefficients (log Poct) of 33 1,2-dithiole-3-thiones and 18 1,2-dithiol-3-ones and their respective log k′, Collander-type relationships were established at various volume fractions of methanol in the mobile phase and on an ODS 2 stationary phase. Collander-type relationships were also established between log Poct and log k0 (capacity factor extrapolated to 0% of organic modifier). The correlations are good, and their parameters depend on the volume fraction of organic modifier, as expected. These relationships were used to evaluate the log Poct of seven very lipophilic dithiolethiones (3.7<log P<7.2). Extrapolated values were compared with calculated values from fragmental constants determined in a previous work and with those given by Rekker.

Prediction of Chromatographic Retention Values (RM) and Partition Coefficients (log Poct) Using a Combination of Semiempirical Self-Consistent Reaction Field Calculations and Neural Networks

Prediction of Chromatographic Retention Values (RM) and Partition Coefficients (log Poct) Using a Combination of Semiempirical Self-Consistent Reaction Field Calculations and Neural Networks

Structural Properties Governing Retention Mechanisms on RP-HPLC Stationary Phases Used for Lipophilicity Measurements

Abstract In this study, the retention mechanisms on the Supelcosil LC-ABZ stationary phase were analyzed by linear solvation free-energy relationships (LSERs). In a first phase, a set of 60 compounds was selected by cluster analysis from a large set (253) compounds of known van der Waals volume (Vw), polarity/polarizability (π∗), H-bond donating acidity (α) and H-bond acceptor basicity (β). The capacity factors log k' at 40% methanol and the log kw values were shown to be highly correlated with octanol/water partition coefficients (log Poct) and to contain pratically the same structural information, as assessed by LSERs. Test sets of model compounds and dipeptides were used to validate the log kw/log P and log k'/log P relations. For anions and zwitterions, specific interactions with the stationary phase occur which produce systematic deviations in the log k/log P relations.

Mechanism of ligand binding to α1-acid glycoprotein (orosomucoid): correlated thermodynamic factors and molecular parameters of polarity

Eight ligands were used in this study, four basic, three neutral and one acidic. Their binding to serum alpha 1-acid glycoprotein (orosomucoid) was measured at several temperatures, and the data were analysed together by a general model with three unknowns, number of binding sites, delta H0 and delta S0. The partition coefficients of the ligands were measured in octanol/water and heptane/water systems (log Poct. and log Phep.), and their molecular volumes were calculated by molecular modelling techniques. These structural properties allow determination of polarity parameters (delta log Poct.-hep., lambda oct. and lambda hep.) which encode in different proportions the various polar interactions between the solute and the aqueous and organic phases, i.e. hydrogen-bonding capacity and dipolarity/polarizability. This study shows that good correlations exist between delta H0 or delta S0 and polarity parameters, such that the enthalpic contribution to binding increases with increasing polarity of the ligands, mainly hydrogen-bond-donor acidity, whereas their entropic contribution to binding decreases.

Method for Determination of Partition Coefficients by High-Performance Liquid Chromatography: Application to O-Hydroxylbenzenesulfonanilides

Abstract The capacity factors (log k) for 26 compounds of widely varying structural types were determined by high-performance liquid chromatography method using methanol—water as mobile phase and ODS column as stationary phase in which free silanol groups were fully suppressed. These determined log k′ values are correlated with known partition coefficient (log Poct) values of 26 compounds and the regression parameters show that accordingly there are two sets of correlation lines when 26 compounds are divided into two data sets depending on their hydrogen-bonding ability. The factors which caused different partitioning mechanisms of the compounds are discussed. As an application, the partition coefficients of a series of o-hydroxylbenzenesulfonanilides (HBSA) were determined by using obtained relative correlation line and then correlated with their anthelmintic activities.

Calculating log Poct from structures

Calculating log Poct from structures

Hydrophobicity Parameter of Diazines. III: Relationship of Partition Coefficients of Monosubstituted Diazines and Pyridines in Different Partitioning Systems

The logarithm of the 1-octanol-water partition coefficient value (log POCT) was compared with those from CHCI3-water (log PCL) and di-re-butyl ether-water (log PE) for (di)azines substituted singly by nonhydrogen-bonding and hydrogen-accepting substituents (2- substituted pyrazines, 2-substituted pyrimidines, 5-substituted pyrimidines, and 2-substituted pyridines). The difference between log PM and log PCL for diazines was primarily governed by the number of hydrogenbonding sites in the substituent. For 2-substituted pyridines, the difference in the hydrogen-bonding association of the ring N-atom with octanol from that with CHCi3 was also significant. In the relationship between log POCT and log PE, the hydrogen-bonding solvations of the ring N-atom(s), as well as the hydrogen-accepting substituent with octanol, should be taken into account because the butyl ether acts as a nonhydrogenbonding solvent.

Reversed-phase high-performance liquid chromatography for evaluating the lipophilicity of pharmaceutical substances with ionization up to log Papp = 8

The RP-HPLC determination of drug lipophilicity was evaluated for its potency as a substitute for the determination of log POct−W values. The relation of log kw to log Papp (= log POct−W at pH 7.4) is linear for a testset including protonable nitrogen bases. The method is reproducible on different columns (with the same brand and type of the stationary phases) and needs no recalibration then. Three series of substituted benzene homologues (one hydrogen bond acceptor and two weak donor groups) demonstrate structure-retention effects.

Physicochemical properties and transport behaviour of piribedil: Considerations on its membrane-crossing potential

The lipophilicity (expressed by log Poct) and H-bond donor acidity (expressed by Δ log Poct-hep) of the dopaminergic agonist piribedil in different ionization states were investigated in order to assess its capacity for crossing membranes. The present study showed that piribedil has a relatively high lipophilicity (log Poct = 2.84) and is a non- or very weak H-bond donor (Δ log Poct-hep = 0.75), implying optimal properties for transmembranal transport. Based on its microscopic ionization behaviour as studied by 13C-NMR spectroscopy and (log P − log P+) value (5.04) (a measure of the stability of the ionic vs neutral species in a lipidic phase), protonation proved to be very unfavourable in water-saturated octanol due to the hindrance of solvation by the two bulky groups adjacent to the piperazinyl amino group. In addition, transport of piribedil across a lipophilic membrane was studied according to first-order kinetics in a three-compartment model. The effects of lipophilic counterions on the partitioning behaviour and transfer kinetics were examined and shown to be non-existent at equimolar concentrations.

A Study on pKaappand Partition Coefficient of Substituted Benzoic Acids in SDS Anionic Micellar System

Apparent ionization constants (pK) of a series of m- and p- substituted benzoic acids were measured by potentiometric titrations in an anionic micellar system (SDS, Sodium Dodecyl Sulphate). From these data, the binding constant K and the partition coefficient between micellar and aqueous pseudophases Pmic, were estimated for each derivative. Collander type regressions between log Pmic and log Poct are discussed. pK values correlate well with a linear combination of σ, πoct and MR molecular descriptors.

The Antifungal Activity of Some Aliphatic and Aromatic Acids

The present paper deals with the relationship between biological activities of some aliphatic and aromatic acids and their physico-chemical parameters expressing the influence of hydrophobic factors. The test strain in the biotest of growth inhibition was the fungus Fusarium moniliforme CCMF-180 and Penicillium expansum CCMF-576. Significant relationship between antifungal activities of un-ionized form of aliphatic acids and their capacity factors (log k'0) extrapolated to pure water, partition coefficients determined in 1-octanol-water system (log Poct) and the first order of molecular connectivity indices (1χ) were calculated. The ionized form of aliphatic acids were antifungally active too. For benzoic acids significant relationships between antifungal activities and capacity factors of anionic form (log k'ia) were calculated.

Percutaneous Penetration of Drugs: A Quantitative Structure–Permeability Relationship Study

Human skin permeation data taken from the literature were analyzed for quantitative relationships with physicochemical properties and structural descriptors. No correlations exist with molecular weights and solvent-accessible surface areas. In most cases, skin permeation was inversely correlated with the parameter ∆log Poct-hep (i.e., log Poctanol minus log Pheptane), which is mainly a measure of the H-bond donor acidity of the solutes. Lipophilicity itself, as expressed by log Poctanol, also contributes positively to skin permeation in some cases. The results of this quantitative structure–permeability relationship study are interpreted in terms of a unified mechanistic model whereby drugs can permeate via an intercellular route (correlation with both ∆log Poct-hep and log Poct) and/or a transcellular route (correlation with log Poct only).

Activité de la glutathion peroxydase dans les érythrocytes de nouveaux-nés alimentés par le lait maternel ou artificiel

In this study, the retention factors (log k) of 44 polar neutral compounds were measured using hydrophilic interaction chromatography (HILIC). This retention parameter was compared with experimental log Palk obtained by a traditional method (shake-flask) or with the calculated log Palk for the most hydrophilic compounds. A good correlation was obtained between log k90 (measured with a mobile phase containing 90% acetonitrile) and log Palk. In contrast, no correlation was obtained between the retention factor and log Poct. This method could thus represent an advantageous alternative and reliable method to characterise the lipophilicity of polar compounds in an alkane/water system by chromatography, providing an important insight in (Q)SAR studies to predict drug permeation through numerous biorelevant membranes.