LC and Principal Component Analysis in the Lipophilicity Study of Seven Angiotensin II-AT1 Receptor Antagonists (Sartans)

Seven sartans have been chromatographed with acetonitrile-buffer and methanol–buffer in different proportions as mobile phases. The retention values, log k or R _M were extrapolated to zero organic modifier content to obtain the log k _w or R _MW values. Calibration equations were obtained for standards of known lipophilicity. A simple method employing a gradient procedure of 10–100% acetonitrile or methanol in 60 min and standards of the extreme lipophilicity was also elaborated. Chromatographic log P values were compared to those calculated by use of different software products. Finally, principal component analysis was performed to explore and visualize similarities and differences among the drugs and among the methods.

     

Lipophilicity Evaluation of the Products Obtained in the Reaction of N3-Substituted Amidrazones with cis-1,2-Cyclohexanedicarboxylic Anhydride

The lipophilicity of the novel 12 products of the reaction of N³-substituted amidrazones with cis-1,2-cyclohexanedicarboxylic anhydride (4 linear, 4 triazole-like and 4 isoindole ones) with potential pharmacologic activity was evaluated by thin layer and liquid chromatography. Using organic-aqueous eluent systems (with methanol or acetonitrile) on RP18 plates and C18 column, a linear relationship between the volume fraction of modifiers and the retention indices was obtained. The retention values, log k or R _M were extrapolated to zero organic modifier content to obtain the log k _w or R _MW values. 12 compounds with known literature lipophilicity were used as a calibration dataset. The results were compared in a multivariate way with in silico methods (ALOGPs, AC_logP, AB/LogP, COSMOFrag, miLogP, ALOGP, MLOGP, KOWWIN, XLOGP3).     

Lipophilicity Evaluation of the Products Obtained in the Reaction of N3-Substituted Amidrazones with cis-1,2-Cyclohexanedicarboxylic Anhydride

The lipophilicity of the novel 12 products of the reaction of N³-substituted amidrazones with cis-1,2-cyclohexanedicarboxylic anhydride (4 linear, 4 triazole-like and 4 isoindole ones) with potential pharmacologic activity was evaluated by thin layer and liquid chromatography. Using organic-aqueous eluent systems (with methanol or acetonitrile) on RP18 plates and C18 column, a linear relationship between the volume fraction of modifiers and the retention indices was obtained. The retention values, log k or R _M were extrapolated to zero organic modifier content to obtain the log k _w or R _MW values. 12 compounds with known literature lipophilicity were used as a calibration dataset. The results were compared in a multivariate way with in silico methods (ALOGPs, AC_logP, AB/LogP, COSMOFrag, miLogP, ALOGP, MLOGP, KOWWIN, XLOGP3).

     

Determination of the lipophilicity of quinolinesulfonamides by reversed-phase HPLC and theoretical calculations

Reversed-phase high-performance liquid chromatography analyses were used for the determination of the retention factor (log k) of a set of quinolinesulfonamides. The analyses utilized a mixture of acetonitrile/water as the mobile phase. The log k values were linearly dependent on the concentration of acetonitrile and extrapolated to 100% water and gave the lipophilicity parameter log k_w. The parameter log P_HPLC was determined from log k_w values using the calibration curve obtained for five standards. The log P_HPLC parameters are discussed in terms of structure–lipophilicity relationships. Furthermore, the theoretical lipophilic parameters (log P_calc) for all compounds were calculated using chemical programs (e.g., Advanced Chemistry Development (ACD/ logP), miLogP, AlogP, ClogP, and Pallas). The determined log P_HPLC and calculated log P_calc values were compared by linear regression analysis.     

Determination of lipophilicity of γ‐butyrolactone derivatives with anticonvulsant and analgesic activity using micellar electrokinetic chromatography

The lipophilicity of a library of 30 derivatives of dihydrofuran‐2(3H)‐one (γ‐butyrolactone) was determined by MEKC. Calibration curve prepared for ten reference drugs enabled to calculate partition coefficient (log P) for novel compounds. The results of MEKC analysis were compared with lipophilicity coefficients determined by RP‐TLC (R_M0) and computational (Mlog P, Clog P) methods. Good correlation was observed between the results obtained by both experimental methods: the MEKC parameters log k and relative lipophilicity R_MO. The relationship between determined log P values and results of the computational prediction was weaker. Analysis of the relationship between lipophilicity and anticonvulsant activity showed statistically significant differences between mean values of log P coefficients for group of active (2.18) and inactive (1.51) compounds in the maximal electroshock test.     

Chromatographic Evaluation of the Lipophilic Properties of Selected Pesticides

Monolinuron, chlortoluron, diuron, isoproturon, linuron, diflubenzuron, dimefuron, teflubenzuron, and lufenuron have been chromatographed on an RP-HPLC column and on RP-HPTLC plates with methanol–water in different volume proportions as mobile phases. The retention values log k, and R_M were extrapolated to zero methanol content. Chromatographic lipophilicities (log k_w, R_Mw, _o(HPLC), and _{o (TLC)}) were compared with measured (log P_exp) partition coefficients and with values (A log Ps, IA log P, C log P, log P_Kowin, and x log P) calculated by use of five different software products. The most significant correlations were found between the chromatographic lipophilicities and C log P values. Satisfactory linear correlation was also obtained between lipophilicity (log k_w, R_Mw) and the valence Gutman index (M).     

Evaluation of N-Substituted 2,4-Dihydroxyphenylthioamide Fungicide Lipophilicity Using the Chromatographic Techniques HPLC and HPTLC

2,4-Dihydroxyphenylthioamide derivatives modified on the N-aryl ring have substantial fungicidal activity. To determine their quantitative structure–activity relationships their lipophilicity was determined by use of the chromatographic methods column liquid chromatography and thin-layer chromatography. Methanol–water systems were used as mobile phases and the linear dependences of retention (R_M and log k) on volume fraction of organic modifier, φ, were determined. This enabled precise determination of lipophilicity (R_Mw and log k_w) by extrapolation. Correlations were found between quantities characterizing the lipophilicity of the compounds. Deviations enabled discovery of compound structural features which increase or reduce lipophilicity. When these data were correlated with biological activity against the phytopathogenic fungi Alternaria alternata and Botrytis cinerea parabolic dependences were obtained.     

Relationship between the lipophilicity and specific hydrophobic surface area of some pesticides by RP-HPLC and HPTLC

Summary Using methanol-water mixtures as the mobile phases, the retention behaviors of thirty-seven pesticides were determined in RP-HPLC and RP-HPTLC. Regular retention behavior was observed for all the investigated pesticides: theirR _m and logk values decreasing linearly with increasing concentration of methanol in the mobile phase. The lipophilicity and specific hydrophobic surface area values for each compound were obtained and they have a good linear relationship. Although the chemical structures of these pesticides were different, factor analysis proved that the lipophilicity and specific hydrophobic surface area of these compounds have much in common, and the insecticides, fungicides and herbicides could not be distinguished from each other according to their lipophilicity parameters obtained from chromatography method.     

Estimating the lipophilicity of a number of 2‐amino‐1‐cyclohexanol derivatives exhibiting anticonvulsant activity

The lipophilicity of a number of N‐acyl derivatives of trans‐ or cis‐: racemic, (1R,2R)‐ or (1S,2S)‐aminocyclohexanol (1–13) exhibiting anticonvulsant activity was investigated. Their lipophilicity (R_{m 0}) was determined using reversed‐phase thin‐layer chromatography (RP‐TLC) with mixtures of methanol and water as mobile phases. The partition coefficients of compounds 1–13 (log P) were also calculated using two computer programs (Pallas and Chem DU) and compared with R_{m 0}. Copyright © 2009 John Wiley & Sons, Ltd.     

Determination of lipophilicity for antitumor acridinone derivatives supported by gradient high-performance liquid chromatography method

The lipophilicity values of selected acridinone (imidazoacridinone and triazoloacridinone) derivatives were measured by gradient reversed-phase high-performance liquid chromatography (RP-HPLC) using a C18 stationary phase with a water/acetonitrile mixture as a mobile phase. The retention times obtained served as input data and appropriate log k_w values (i.e., the retention factor log k_w extrapolated to 0% organic modifier) as an alternative to log P were calculated using the DryLab program. The relationships between the lipophilicity (log k_w) and the chemical structure of the studied compounds, as well as correlation between experimentally determined lipophilicities (log k_w) and log P data calculated using some commonly available software, are discussed.     

Fast Determination of Lipophilicity by HPLC

A rapid method for the determination of lipophilicity by reversed-phase high-performance liquid chromatography is presented with a study of a set of 29 molecules representing various functional groups. The use of a short column packed with a polar-embedded phase and octanol-saturated water as eluent for direct measurement of log k _w is described. Extrapolation for log k _w measurements can be avoided for solutes having log P in the octanol/water system of less than 3.2. The gain in terms of productivity and simplicity of analysis over the direct measurement shows the usefulness of this method for industrial applications. Good correlations between log P values found in the literature and measured log k _w values were obtained.     

RP-HPLC determination of the lipophilicity of bispyridinium reactivators of acetylcholinesterase bearing a but-2-ene connecting linker

New acetylcholinesterase reactivators with either a (E) or (Z)-but-2-ene connecting linker were recently prepared. The purity of the compounds was checked by HPLC and was found to be sufficient for in-vitro screening. All the discussed bispyridinium reactivators were analyzed by reversed-phase high performance liquid chromatography (RP-HPLC) to measure lipophilicity. The procedure was performed under isocratic conditions with methanol as organic modifier in the mobile phase using an end-capped non-polar C₁₈ stationary phase RP column. Relationships between the lipophilicity (logarithm of the RP-HPLC capacity factor, log k) and chemical structures of the studied compounds are discussed. Lipophilicity was different for the (E) and (Z) compounds and varied among the compounds in each of these groups. The lipophilicity differences also indicated an apparent influence of intramolecular interactions. Lipophilicity calculations (log P/Clog P) by means of commonly used software were not successful due to the presence of quaternary nitrogen atoms in the molecules of the reactivators.     

Study of the Lipophilic Character of Xanthine and Adenosine Derivatives: II. Relationships Between Log K', RM and Log P Values

Abstract

The log k' values of a series of xanthine and adenosine derivatives were measured by means of a reversed-phase HPLC. The HPLC data were shown to be well correlated with previously reported R_M and R_MC18 values. The equations describing the relationships log k'/R_M and log k'/R_MC18 allowed the calculation of the log k' values of some compounds, which were not tested in the HPLC system. Since the relationship log k'/log P is very close to the previously described relationships R_M/log P and R_MC18/log P one can conclude that reversed-phase TLC and HPLC are very similar in describing the lipophilicity of the compounds.     

Lipophilicity data for some preservatives estimated by reversed-phase liquid chromatography and different computation methods

The chromatographic behavior of some preservatives was performed by reversed-phase high-performance liquid chromatography on C18 (LiChroCART, Purosphere RP-18e), C8 (Zorbax, Eclipse XDB-C8), CN100 (Säulentechnik, Lichrosphere) and NH₂ (Supelcosil LC-NH₂) columns. The lipophilicity estimated for the first time on the first three columns are comparable and very well correlated. The mobile phase was a mixture of methanol–water (0.1% formic acid) in different volume proportions from 40% to 60% (v/v) for RP-C18, RP-C8 and RP-CN100 column (exception for parabens on RP-C8 column—the methanol concentrations being from 55% to 65%) and from 30% to 50% (v/v) for RP-NH₂. Highly significant correlations were obtained between different experimental indices of lipophilicity (log k_w, S, φ₀, mean of k and log k, and scores of k and log k corresponding to the first principal component) and computed log P values, and C8 column seems to be more suited for estimating the lipophilicity of the investigated compounds. These direct correlations offer a very good opportunity to derive powerful predictive models via Collander-type equations. The reliability of scores values as lipophilic indices is shown by their high correlation with the log K_ow obtained using classical “shake-flask” technique, log k_w and also some of the computed log P values. In addition, the results obtained applying PCA to the retention data may be used in interpreting the molecular mechanism of interactions between eluents and stationary phases with different polarity and to explain the chromatographic behavior of compounds. Finally, the “congeneric lipophilicity chart” described by the scores corresponding to the first principal component has the effect of separating compounds from each other more effectively from congeneric ((dis)similarity) point of view. The parabens and tert-butylhydroquinone appeared to be the most lipophilic preservatives.     

Retention Behavior of Some Compounds Containing Polar Functional Groups on Perfluorophenyl Silica-Based Stationary Phase

A retention study on perfluorophenyl silica-based stationary phase was undertaken for some organic compounds containing different polar functionalities. The dependence of the retention factor on the content of organic modifier (acetonitrile, or methanol) in mobile phase was fitted by polynomial equations. The only exception was observed for adenine, which showed a sigmoidal dependence for the retention factor versus organic modifier content. The extrapolated values of retention factor for water as mobile phase (log k _w) from these dependences were well correlated with octanol–water partition constants (log K _ow), excepting the values for hexachlorocyclohexane isomers and adenine. Temperature dependences of the retention factor obeyed the van’t Hoff equation with thermodynamic parameters similar to those obtained in reversed phase on C8 or C18 stationary phases, excepting two statines whose dependences of ln k on the reciprocal value of absolute column temperature were nonlinear. Again, adenine had an atypical behavior with decrease in the retention factor with the increase in column temperature, due to possible tautomeric equilibria of this compound in presence of water, in accordance with theoretical models reported by literature. Charge modeling with MarvinSketch package program revealed charged centers from analyte molecule that could interact differently with charge centers from stationary phase.     

Lipophilicity of Some Preservatives Estimated by RP-TLC Using Stationary Phases with Different Polarity

Lipophilcity of some preservatives was determined by reversed phase high performance thin layer chromatography (RP-HPTLC) using methanol–water mixtures in different volume proportions as mobile phase on three stationary phases of different polarity: RP-18F_254s, RP-18WF_254s and CNF_254s plates. The R _M values decreased linearly with increasing methanol concentration in the mobile phase in all cases. The regression determination coefficients obtained for all stationary phases were excellent (higher than 0.98 in most cases). The chromatographic behavior of the preservatives on the RP-HPTLC plates used in this study is similar and in a very good agreement with their polarity. Good chromatographic regularities found for retention factors and by applying principal component analysis for all three types of stationary phases indicate that the same lipophilic interactions are dominants in all cases. The relationships between different RP-HPTLC retention parameters (R _M0 , b, scores of R _F -PC1/R _F and scores of R _M -PC1/R _M ) and various calculated log P values of the same preservatives show highly significant correlations for all types of stationary phases.     

Prediction of ortho substituent effect in alkaline hydrolysis of phenyl esters of substituted benzoic acids in aqueous acetonitrile

The second-order rate constants k for the alkaline hydrolysis of phenyl esters of meta-, para- and ortho-substituted benzoic acids, X-C₆H₄CO₂C₆H₅, in aqueous 50.9% acetonitrile have been measured spectrophotometrically at 25°C. The log k values for meta and para derivatives correlated well with the Hammett σ_m,p substituent constants. The log k values for ortho-substituted phenyl benzoates showed good correlations with the Charton equation, containing the inductive, σ_I, resonance, σ^○ _R, and steric, E _s ^B, and Charton υ substituent constants. For ortho derivatives the predicted (log k _X)_calc values were calculated with equation (log k _ortho)_calc = (log k ^H _AN)_exp + 0.059 + 2.19σ_I + 0.304σ^○ _R + 2.79E _s ^B ? 0.0164ΔEσ_I — 0.0854ΔEσ^○ _R, where DE is the solvent electrophilicity, ΔE = E _AN — E _H20 = ?5.84 for aqueous 50.9% acetonitrile. The predicted (log k _X)_calc values for phenyl ortho-, meta- and para-substituted benzoates in aqueous 50.9% acetonitrile at 25°C precisely coincided with the experimental log k values determined in the present work. The substituent effects from the benzoyl moiety and aryl moiety were compared by correlating the log k values for the alkaline hydrolysis of phenyl esters of substituted benzoic acids, X-C₆H₄CO₂C₆H₅, in various media with the corresponding log k values for substituted phenyl benzoates, C₆H₅CO₂C₆H₄-X.     

Optimized Method for the Determination of Flavonoid Glycosides and Aglycones

The relationship R_M=f (log % S; S- modifier) of several flavonoids and their sugar derivatives was examined by using chromatographic systems chosen by preliminary experiments. The dependence for flavonoid aglycones was flat in the whole mobile phase concentration. Two types of the R_M=f (log % S) plots, related to the size of sugar molecule, were found. For glycosides with smaller sugar moiety (arabinose or glucose) the plot was almost parallel, while plots of derivatives with larger sugar moiety (rutose) were convergent. After plotting the relationship R_M=f (log % S), even if standards are not available, it is possible to qualify the examined compound as containing single or complex sugar moiety. For all mentioned above compounds the R_M=f (log %S) values were given. Silica gel Si60 was used as polar adsorbent. Mobile phase composition was determined in preliminary experiments; it was composed of two solvents: methanol in ethyl acetate in increasing concentration of methanol: 5 – 20%.