The study of the lipophilicity of alpha-(4-phenylpiperazin-1-yl)-gamma-phthalimidobutyramides using chromatographic and computational methods

The lipophilicity of the series of alpha-(4-phenylpiperazin-1-yl)-gamma-phthalimido-butyramides (1-8) has been investigated. Several methods, like reversed-phase thin-layer chromatography and high-performance liquid chromatography using reversed-phase RP18 and IAM.DD2 columns, were applied to determine RMO, log k0 and log k(0IAM) factors. The RP-TLC investigations were performed in mixtures of acetone-water and acetonitrile-water. For RP-HPLC method mixtures of acetonitrile, water and 0.01% TFA were used as the mobile phases while for IAM.DD2 investigations mixtures of acetonitrile and water were applied. The partition coefficients of compounds (1-8) were also calculated with the Pallas and CAChe programs. All the obtained data, both from experimental methods and computational calculations, were compared and a suitable conclusion was reached.     

Determination of lipophilicity of alpha-(4-phenylpiperazine) derivatives of N-benzylamides using chromatographic and computational methods

This paper describes the evaluation of lipophilicity of alpha-(4-phenylpiperazine) derivatives of N-benzylamides. We employed reversed-phase thin-layer chromatography (RP-TLC) and reversed-phase high performance liquid chromatography (RP-HPLC) as experimental methods, using mixtures of acetonitrile and water as the mobile phases with addition of 0.1%TFA in the HPLC experiments. Retention parameters (R(M)) and capacity factors (log k) determined by applying these methods were linearly dependent on the acetonitrile concentration and enabled us to estimate the relative lipophilicity factors: R(M0) and log k(0). These factors were compared with the calculated partition coefficients C log P obtained using several software packages. The results indicate that both experimental methods (RP-TLC and RP-HPLC) yielded similar results, and these methods enable determining the lipophilicity of alpha-(4-phenylpiperazine) derivatives of N-benzylamides. Significant correlations were found between log P values calculated by Pallas, ALOGPS and C log P Chem3D programs and the experimental data.     

Lipophilicity characterization by reversed-phase liquid chromatography of some furan derivatives

Lipophilicity is one of the properties which influences the partition of a substance in biological media. The present study reports on the chromatographic behaviour of a newly synthesised series of furan derivatives by RP-HPLC and RP-TLC, with methanol-water and acetonitrile-water as mobile phases, in order to establish if the linear relationships between the retention parameters (log k, R(M)) and the concentration of organic modifier in the mobile phase, phi, allows the extrapolation procedure. Good correlations between the retention parameters were obtained by RP-HPLC and RP-TLC, and the concentration of organic modifier (methanol, acetonitrile) in the mobile phase was established for the studied furan derivatives. However, for the discussed compounds, acetonitrile has a lower sensitivity to changes in the structures. A good correspondence was obtained between the extrapolated parameters for the methanol-water mobile phase when using RP-HPLC and RP-TLC. However, stronger interactions occur in RP-TLC between the compounds and the residual silanol groups than in RP-HPLC.     

The lipophilicity estimation of 5-arylidene derivatives of (2-thio)hydantoin with antimycobacterial activity

The lipophilicity of antituberculotic 5-arylidene derivatives of (thio)hydantoin, thioacetazone and isoniazid has been determined by reversed-phase thin-layer chromatography (RP-TLC). Mixtures of acetone and water (with acetone content 60-85%) were used as the mobile phase. The R(M) (relative lipophilicity) of each compound (except isoniazid) decreased linearly with the increasing concentration of acetone. The partition coefficients (log P) of the compounds were calculated by the use of eight computer programs (ClogP, KowWin, XlogP, AlogPs, CAChe, Pallas, Interactive analysis and Slipper) and compared with the experimental lipophilicity (R(M0)). According to the observations the best tools for in silico predicting log P of (2-thio)hydantoins are programs KowWin and AlogPs.     

Lipophilicity characterization of new N-phenylamino-azaspiranes as potential anticonvulsant agents

The lipophilicity of a library of N-phenylamino-2-azaspiro[4.4]nonane- and [4.5]decane-1,3-dione derivatives has been determined by reversed-phase thin-layer chromatography with n-propanol-Tris buffer (pH 7.4) mixtures as mobile phases. Examination of chromatographic behaviour revealed a linear correlation between R(M) values and the concentration of n-propanol in the mobile phase. The partition coefficients (logP) were also calculated by use of the PrologP module of the Pallas computer program. Comparison of R(M0) values and calculated (logP(PALLAS)) data revealed the correlation expressed by the equation: logP(PALLAS) = 0.9995 R(M0) + 1.3451 (n = 28; r = 0.8971; F = 107.13; p < 0.05). The role of the lipophilicity in the anticonvulsant activity of a set of compounds examined is discussed: the active anticonvulsants were less lipophilic than inactive ones.     

Comprehensive evaluation of lipophilicity of biogenic amines and related compounds using different chemically bonded phases and various descriptors

The retention behavior for a series of biogenic amines and related sympathomimetic drugs has been investigated in reversed-phase thin-layer chromatography using RP-2, RP-8, RP-18W, and Diol stationary phase and mixtures of phosphate buffer (pH = 7.10) and methanol in different proportions as mobile phases. Several methodologies like arithmetic mean of experimental retention values, extrapolation to zero methanol concentration procedure and principal component analysis were applied to retention data values (R(M)) in order to determine relevant parameters (mean of R(M) - mR(M), R(M0), and scores corresponding to the first principal component - PC1/R(M) respectively) encoding information on the lipophilic behavior of compounds. High similarities in lipophilicity behavior of investigated amines were highlighted by mR(M) and PC1/R(M) lipophilicity indices for all of the studied stationary phases. The experimental results were compared with some computed lipophilicity parameters expressed as distribution coefficients at working pH (logD), partition coefficients (logP(N), logP(I), and diff(logP(N-I))) concerning both neutral and fully protonated species and difference between both species, and also with various lipophilicity values (logP) generated by different commonly used software. Significant correlations were observed between the experimental lipophilicity indices mR(M) respectively PC1/R(M) and diff(logP(N-I) ) values in all cases.     

A Comparative Study of the Lipophilicity of Metformin and Phenformin

The results presented in this paper confirm the beneficial role of an easy-to-use and low-cost thin-layer chromatography (TLC) technique for describing the retention behavior and the experimental lipophilicity parameter of two biguanide derivatives, metformin and phenformin, in both normal-phase (NP) and reversed-phase (RP) TLC systems. The retention parameters (R_F, R_M) obtained under different chromatographic conditions, i.e., various stationary and mobile phases in the NP-TLC and RP-TLC systems, were used to determine the lipophilicity parameter (R_MW) of metformin and phenformin. This study confirms the poor lipophilicity of both metformin and phenformin. It can be stated that the optimization of chromatographic conditions, i.e., the kind of stationary phase and the composition of mobile phase, was needed to obtain the reliable value of the chromatographic lipophilicity parameter (R_MW) in this study. The fewer differences in the R_MW values of both biguanide derivatives were ensured by the RP-TLC system composed of RP2, RP18, and RP18W plates and the mixture composed of methanol, propan-1-ol, and acetonitrile as an organic modifier compared to the NP-TLC analysis. The new calculation procedures for logP of drugs based on topological indices ⁰χ^ν, ⁰χ, ¹χ^ν, M, and M^ν may be a certain alternative to other algorithms as well as the TLC procedure performed under optimized chromatographic conditions. The knowledge of different lipophilicity parameters of the studied biguanides can be useful in the future design of novel and more therapeutically effective metformin and phenformin formulations for antidiabetic and possible anticancer treatment. Moreover, the topological indices presented in this work may be further used in the QSAR study of the examined biguanides.     

Estimation of the lipophilicity of antiarrhythmic and antihypertensive active 1-substituted pyrrolidin-2-one and pyrrolidine derivatives

The lipophilicity of some antiarrhythmic and antihypertensive active 1-[2-hydroxy- or 1-[2-acetoxy-3-(4-aryl-1-piperazinyl)propyl]pyrrolidin-2-one derivatives (1-12) has been investigated. Their lipophilicity (R(MO) and log k') was determined by reversed-phase thin-layer chromatography and reversed-phase high-performance liquid chromatography with mixtures of acetonitrile and Tris buffer as mobile phases. The partition coefficients of compounds 1-12 (log P(ScilogP)) were also calculated with the ScilogP program. Comparison of R(MO), log k' and calculated log D(7.0 ScilogP) values enabled calculation of clog D(7.0 TLC) and clog D(7.0 HPLC) values. Preliminary quantitative structure-activity relationship studies indicated that for active compounds there is a dependence between affinity for alpha(2)-adrenoceptors and their clog D(7.0 HPLC) values.     

Immobilized artificial membrane chromatography with mass spectrometric detection: a rapid method for screening drug-membrane interactions.

A high-performance liquid chromatography (HPLC)/electrospray ionization mass spectrometry method for measuring drug-membrane interactions was developed using immobilized artificial membrane (IAM) fast-screening mini-columns. The HPLC mobile phase consisted of phosphate-buffered saline (i.e., 5.0 mM phosphate buffer at pH 7.4, 1.35 mM KCl, and 68.5 mM NaCl) and acetonitrile. This method facilitated the measurement of IAM retention time of over ten compounds in one experiment, significantly reducing analysis time compared with the earlier IAM-HPLC method. The particular electrospray source used demonstrated the ability to tolerate the high salt-containing nonvolatile buffer used for retention time measurement.     

Lipophilicity of some guaianolides isolated from two endemic subspecies of Amphoricarpos neumayeri (Asteraceae) from Montenegro

In this study 10 guaianolide-type sesquiterpene gamma-lactones named amphoricarpolides, isolated from the aerial parts of two endemic subspecies of Amphoricarpos neumayeri (ssp. neumayeri and ssp. murbeckii Bosnjak), were investigated by means of reversed-phase thin-layer chromatography. Methanol-water and tetrahydrofuran-water binary mixtures were used as mobile phase in order to determine lipophilicity parameters R (0) (M) and C(0). Some of the investigated compounds were screened for their cytotoxic activity against HeLa and B16 cells. Chromatographically obtained lipophilicity parameters were correlated with calculated logP values and IC(50) values. Principal component analysis identified the dominant pattern in the chromatographically obtained data.     

HPTLC and magnetochromatography of new complexes of carboxylates with transition metals or rare earth elements and their ligands – study of lipophilicity

Nineteen new complexes of carboxylates with transition and rare elements as central ions and their ligands were characterized by chromatographic analyses. The parameter of relative lipophilicity (R _M0) of the tested compounds was determined experimentally by the reversed‐phase high‐performance thin layer chromatography method with mixtures of various organic modifiers (acetonitrile, acetone, dioxane) and water as a mobile phase. The extrapolated R _M0 values were compared with the logP values calculated from the molecular structures of tested solutes. Similarities between the lipophilicity indices were analysed by principal component analysis and linear regression. Thin‐layer chromatography combined with a magnetic field has been proposed as a complementary method for determination of lipophilicity of the investigated compounds. The chromatograms in the field and outside it were developed simultaneously in two identical chromatographic chambers. One of them was placed in the external magnetic field of 0.4 T inductivity. We proved that chelation causes a drastic change in compound lipophilicity, but all complexes did not exhibit enhanced activity as compared with the parent ligand. Also in the magnetic field the retention of some complexes changed, which means that the presence of the field influences the physicochemical properties of the compounds and their interactions with the stationary phase.     

Lipophilicity analysis of newly synthetized quinobenzothiazines by use of TLC

Lipophilicity is a very important property of chemical compound taking into consideration in drugs design. Relationships between biological activity, among others lipophilicity, and chemical structure (QSAR) of the compound are very often used by researches. Especially important is the kind of substituents connected to the basic structural fragment and how it changes the lipophilicity of the compound. The aim of this study was to determine the parameters of lipophilicity of quinobenzothiazine derivatives using reversed phase - thin-layer chromatography (RP-TLC), which would enable one to determine the structure–activity relationship. The objective of our work is a series of 15 newly synthetized quinobenzothiazines. They were analyzed by thin-layer chromatography (TLC) with the use of two different mobile phases consisting of methanol or acetone as organic modifiers. For all compounds investigated, the values of lipophilicity obtained from computational method were also determined. Cluster analysis was carried out too for all data of lipophilicity obtained. Low correlation was found between values of experimental lipophilicity and lipophilicity from computational methods for newly synthetized compounds.     

Lipophilicity determination of N-( benzothiazol-2-yl )-α-amino alkyl phosphonic diesters by RP-HPLC and RP-HPTLC

Using methanol-water mixtures as the mobile phase,the chro-matographic retention parameters k' and Rf were determined by reversed-phase high-performance liquid chromatography(RP-HPLC)and reversed-phase high-performance thin-layer chromatography(RP-HPTLC)for N-(benzothiazol-2-yl)-o) amino alkyl phosphonic diesters and the correlation with lipophilicity parameter(ClogP)was established.Logkw values obtained from RP-HPLC and R values obtained from RP-HPTLC can be used to evaluate the lipophilicity of this kind of compounds.Chromatographic method is a good alternative for lipophilicity measurement.     

Comparison of the retention behavior of β-blockers using immobilized artificial membrane chromatography and lysophospholipid micellar electrokinetic chromatography

We have demonstrated that significant differences exist between the retention of eight β-blockers analyzed with immobilized artificial membrane (IAM) and lysophospholipid micellar electrokinetic capillary (LMEKC) chromatographic methods. The general retention trends are maintained with highly hydrophilic compounds such as atenolol eluting first and more hydrophobic compounds such as propranolol eluting last. The retention order, however, is different and would result in major ranking differences. LMEKC demonstrates a better correlation with liposomal partitioning (R²=0.95) than does IAM chromatography (R²=0.60). LMEKC, with its higher efficiency, can allow a more specific evaluation of lipophilicity than IAM chromatography and is useful in the analysis of pharmaceutical candidates, particularly for ranking purposes.     

Octanol/water partitioning simulation by reversed-phase high performance liquid chromatography for structurally diverse acidic drugs: Effect of n-octanol as mobile phase additive

The role of n-octanol as mobile phase additive for the lipophilicity assessment of 45 structurally diverse acidic drugs both at neutral (pH 2.5) and ionized form (pH 7.4) was investigated. Extrapolated retention factors logk(w) were determined on a BDS C18 column using methanol as organic modifier and different amounts of n-octanol as mobile phase additive. For more polar compounds, the effect of n-octanol in retention was found to decrease as their lipophilicity increased. In the case of carboxylic acids and oxicams, the differentiation in retention, in presence and absence of n-octanol, could be further attributed to the attenuation of polar interactions, concerning mainly hydrogen bonding. At pH 2.5, the use of n-octanol saturated buffer, without further addition of n-octanol in the mobile phase, led to 1:1 correlation with logP. At physiological pH, 1:1 correlation was obtained between logD(7.4) and logk(w)(oct) indices upon addition of 0.25% n-octanol, in the case of weak acids. For strongly ionized compounds, a good correlation was also established under the same conditions. The corresponding equation, however, possessed a large negative intercept and a slope lower than unity.     

Chromatographic determination of hydrophobicity of dialkylimidazolium ionic liquids using selected stationary phase

The determination of hydrophobicity of ionic liquids (ILs) is essential for the reason that some of these salts' classes are of toxic character. The conventional shake flask method of logP estimation fails in case of ILs. This is connected with their ionic character. Therefore other methods need to be developed and optimized. Chromatographic methods seem to be the proper ones. For that reason, several specific stationary phases (octadecyl, octyl, aminopropyl, alkylamide, cholesterolic, immobilized artificial membrane, phenyl) have been used for the determination of logk(w) of alkylimidazolium ILs. Then, logk(w) were used for the correlation with calculated logP for ILs. Depending on applied calculation procedure, high values of determination coefficient were obtained for alkyl-based silica stationary phases or for more specific column packing. This result is very promising as it has already been proven that several, different in nature, stationary phases can be successfully used for estimation of logP of IL cations.