A comparative study concerning chromatographic retention and computed partition coefficients of some precursors of peraza crown ethers

Retention indices for some precursors of peraza crown ethers were determined by reversed phase high-performance thin layer chromatography on RP-18 plates with methanol-water in different volume proportions as mobile phase. The Log P values for the same compounds were calculated using different computer programs: SciQSAR, SciLogP, Chem3D Ultra 8.0, XLOGP (based on atom contributions), Chemaxon and KOWWIN (based on atom/fragment contributions), cLogP (based on fragmental contributions), ALOGPS and IAlogP (based on atom-type electrotopological-state indices and neural network modeling). A comparative study concerning lipophilic parameters (R_M0, b and ϕ0) and computed partition coefficients has been developed. Taking into account the correlation coefficients between determined and calculated Log P values, it seems that R_M0 and b are less suitable than ϕ₀ for estimating lipophilicity of the compounds investigated, and cLogP and ALOGPS provide the best correlations with experimental values.     

Analysis of anticancer platinum(II)-complexes by microemulsion electrokinetic chromatography: separation of diastereomers and estimation of octanol-water partition coefficients

Microemulsion electrokinetic chromatography (MEEKC) was applied for the separation and lipophilicity estimation of oxaliplatin and eight novel anticancer oxaliplatin derivatives. Solubility and permeability have to be balanced in modern drug development, and the octanol-water partition coefficient (log P) still represents one of the most useful quantifiable parameters providing a reasonable estimation of a drug's lipophilicity. Therefore, the capacity factors from MEEKC were correlated to log P values derived by the traditional shake flask method. The MEEKC method was accomplished using a microemulsion of heptane/sodium dodecyl sulfate (SDS)/butanol in phosphate buffer at pH 7.4 and 37 degrees C with all analytes being in a neutral state during the run. This experimental setup allowed a baseline separation of all platinum complexes within 11 min. Remarkably, beside the very good resolution and precision of the measurements, separation of diastereomers of the complexes and quantification of the diastereomeric ratios could be achieved. Correlating the capacity factors with the corresponding log P values resulted in a linear dependency with a correlation factor of r = 0.9935. Consequently, the applied MEEKC method was found to be a highly valuable technique not only for the separation of platinum complexes but as well for the estimation of the octanol-water partition coefficient with many advantages in comparison to other methods.     

Structure-retention and mobile phase-retention relationships for reversed-phase high-performance liquid chromatography of several hydroxythioxanthone derivatives in binary acetonitrile-water mixtures

The reversed-phase high-performance liquid chromatographic (RP-HPLC) behavior of some newly synthesized hydroxythioxanthone derivatives using binary acetonitrile-water mixtures as mobile phase has been examined. First, the variation in the retention time of each molecule as a function of mobile phase properties was studied by Kamlet-Taft solvatochromic equations. Then, the influences of molecular structure of the hydroxythioxanthone derivatives on their retention time in various mobile phase mixtures were investigated by quantitative structure-property relationship (QSPR) analysis. Finally, a unified model containing both the molecular structure parameters and mobile phase properties was developed to describe the chromatographic behavior of the systems studied. Among the solvent properties, polarity/polarizability parameter (π^*) and hydrogen-bond basicity (β), and among the solute properties, the most positive local charge (MPC), the sum of positive charges on hydrogen atoms contributing in hydrogen bonding (SPCH) and lipophilicity index (log P) were identified as controlling factors in the RP-HPLC behavior of hydroxythioxanthone derivatives in actonitrile-water binary solvents.     

Investigation of lipophilicity of anticancer-active thioquinoline derivatives

The lipophilicity of a series of anticancer propargylthioquinoline derivatives has been investigated using chromatographic and computational methods. The parameters of relative lipophilicity (R(MO) and logk0) of the tested compounds were determined experimentally both by reversed-phase thin layer (RP-TLC), and high-performance liquid chromatographic methods (RP-HPLC, LiChrospher RP18 column), with mixtures of acetonitrile and water as mobile phases. Their phospholipophilicity (logk(0IAM)) was determined using immobilized artificial membrane HPLC (IAM. PC DD2 Regis column). Mobile phase acetonitrile concentrations were in the ranges 50-90% (RP-TLC), 55-90% (RP-HPLC) and 35-60% (IAM-HPLC). The R(M), logk and logk(IAM) values of the compounds investigated were linearly dependent on acetonitrile concentration. The analysis led to the calculation of R(MO), logk0 and logk(0IAM) parameter values for each of the tested compounds. Their partition coefficients (logP) were also calculated with the Pallas and CAChe programs. The obtained results indicated that, among experimental methods, both RP-TLC and RP-HPLC gave similar results, and these methods enable the determination of lipophilicity of derivatives of thioquinolines. Using the IAM-HPLC technique a simple method of estimation of phospholipoplilicity was described. The CAChe program might better predict calculated lipophilicity logP values, and therefore is a useful tool for the early stage of design of new propargyl thioquinolines.     

Determination of the lipophilicity of some aniline derivatives by reversed-phase thin-layer chromatography. The effect of the organic phase in the eluent

Summary The lipophilicity of aniline and 36 ring-substituted aniline derivatives was determined by reversed-phase thin-layer chromatography using methanol, acetone and acetonitrile as the organic phase. The R_M value of each compound linearly decreased with increasing concentration of the organic solvent, Acetonitrile showed the highest and methanol the lowest solvent strength, however, the difference between the solvent strength of methanol and acetone was negligible. The site of the substitution considerably influenced the lipophilicity particularly in the case of –NO₂ groups. Good correlation was found between the R_M value extrapolated to zero organic phase concentration and the partition coefficient between n-octanol:water. The change in the R_M value caused by a 1% increase of the organic phase concentration also correlated with the partition coefficient, however, it was of secondary importance. The lipophilicity parameters determined by reversed-phase thin-layer chromatography correlated to a lesser extent with the calculated lipophilicity values of aniline derivatives.     

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.     

Evaluation of the lipophilicity of bile acids and their derivatives by thin-layer chromatography and principal component analysis

The lipophilic character of bile acids and their glyco- and tauro-conjugates was studied. The classical R(Mo) values were measured by means of reversed thin-layer chromatography using a mixture of methanol-water as the solvent system and compared with the factors scores obtained by principal component analysis based also onto the TLC-retention data. The reliability of the factor scores values as lipophilic indices are shown by their high correlation with the classical R(Mo) values. In addition, a better correlation was observed between scores corresponding to the first principal components and the partition coefficients (log P) of bile acids. Finally, the "lipophilicity chart" described by the first two components has the effect of separating compounds from each other most effectively from the congeneric aspect point of view.     

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.     

Platinum(II)-based hydrogen-evolving catalysts linked to multipendant viologen acceptors: experimental and DFT indications for bimolecular pathways

Three new [PtCl(2)(bpy)] derivatives tethered to 2, 4, and 6 dicationic viologen moieties, [PtCl(2)(MV2)](4+) (1), [PtCl(2)(MV4)](8+) (2), and [PtCl(2)(MV6)](12+) (3), have been synthesized (MV2(4+)=5-ethoxycarbamoyl-5'-(N-R(1)-carbamoyl)-2,2'-bipyridine, MV4(8+)=5,5'-bis(N-R(1)-carbamoyl)-2,2'-bipyridine, and MV6(12+)=5,5'-bis(N-R(2)-carbamoyl)-2,2'-bipyridine, in which R(1)=Asp(NH-VG)-NH-VG, R(2)=Asp(NH-VG)-Asp(NH-VG)-NH-VG, and VG=-(CH(2))(2)-(+)NC(5)H(4)-C(5)H(4)N(+)-CH(3)). In spite of the higher charge storage capacity of 2 and 3 due to the higher number of acceptor groups (VG groups), compound 1 with the lowest number of VG tethers has turned out to exhibit an outstanding catalytic performance towards the hydrogen evolution from water. Quantitative analysis of UV/Vis-NIR absorption spectral changes during the photolysis for 2 and 3 reveal that approximately 2 electrons per molecule are stored over the acceptor groups during the photolysis, and the storage events saturate after 20 min. As for 1, the total number of electrons stored per molecule increases once during the initial 10 min and then abruptly decreases down to around 0.1 electrons per molecule at 20 min, during which the storage is maximized at 10-20 min with 0.6-0.7 electrons stored per molecule, thereby indicating that the rates of radical formation and consumption are balanced during the photochemical hydrogen evolution reaction. The electrical conductivity measurements reveal that ion-pair adducts (adducts with PF(6)(-) ions in solution) are formed by 2 and 3 but are not given by 1 under the catalysis conditions. These, together with the results of molecular mechanics calculations, reveal that stack of two [PtCl(2)(bpy)] units becomes unfavorable as the number of sterically bulky and highly charged VG units per molecule increases. We have therefore concluded that dimerization that leads to the formation of a Pt-Pt association is a key step in the effective catalytic enhancement with [PtCl(2)(bpy)]-type catalysts.     

Determination of the lipophilicity of some aniline derivatives by reversed-phase thin-layer chromatography. The effect of salts

Summary The lipophilicity of aniline and 36 ring-substituted aniline derivatives was determined by reversed-phase thin-layer chromatography using NaCl, KCl, MgCl₂, CaCl₂, AlCl₃ and tetramethyl-ammoniumhydroxide, either adsorbed on the silica surface before impregnation or added to the eluent. In most cases the salts decreased the retention power of silica resulting in enhanced mobility of the aniline derivatives. The monovalent cations had the lowest, while AlCl₃ and tetramethylammoniumhydroxide had the highest impact on selectivity. This phenomenon can be explained by the different ion charges. The correlation between the R_M values and the partition coefficient between n-octanol: water were in all cases inferior to those obtained in salt-free systems this means that the presence of salts modifies differently the lipophilicity of aniline derivatives.     

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.     

Reversed-phase ion-pair systems to predict partition coefficients of β-carbolines by HPLC and TLC

Summary A group of 17 β-carbolines was studied in HPLC and TLC systems in order to predict their partition coefficients (log P values). On account of the basic or acid character of some of these compounds, an ion pairing system gave the best results. Both HPLC and TLC data were comparable for log P prediction but severe pH conditions required the use of TLC plates. Retention data are quantitatively related to lipophilicity (expressed as the Hansch constant) and polarity (as the inductive constant) of the solute molecule.     

Parallel synthesis and study of fluorous biphasic partition coefficients of 1H,1H,2H,2H-perfluoroalkylsilyl derivatives of triphenylphosphine: a statistical approach

A library of fluorous, (1H,1H,2H,2H-perfluoroalkyl)silyl-substituted derivatives of triphenylphosphine, Ph(3-a)P[C(6)H(5-y)[SiMe(3-b)(CH(2)CH(2)C(x)F(2x+1))(b)](y)-pos](a) [a = 1-3; b = 1-3; x = 4, 6, 8, or 10; pos = 3, 4 (y = 1) or 3,5 (y = 2)], was prepared using parallel synthetic techniques. Upon variation of these four parameters, a total of 108 different fluorous phosphines can be synthesized. Using factorial design, 37 phosphines were selected and their partition coefficients in the typical fluorous biphasic solvent system PFMCH/toluene (PFMCH = perfluoromethylcyclohexane) determined. By fitting of the partition coefficient data to linear functions of the parameters a, b, and x, the partition coefficients of the remaining 71 fluorous phosphines, which were not prepared, could be predicted. Using this approach, some unexpected trends in the dependence of the partition coefficient on variations of the four parameters became clear, resulting in a better understanding of the optimum fluorous substitution pattern for obtaining the highest partition coefficient (P). In this way, the partition coefficient was increased by 2 orders of magnitude, i.e., from the initial value P = 7.8 for 1(3, 2, 6, C4) to P > 238 for 1(2, 3, 6, C3C5). Para- and 3,5-substituted phosphines showed irregular behavior in the sense that elongation or increase of the number of perfluoroalkyl tails did not necessarily lead to higher partition coefficients. Particularly high values were found for phosphines containing a total of 72 fluorinated carbon atoms on the meta position(s) of the aryl rings. Linear relationships were found between the predicted log P of 1(a, b, x, C4) and the experimentally determined log P values of fluorous diphosphines [CH(2)P[C(6)H(4)(SiMe(3-b)(CH(2)CH(2)C(6)F(13))(b))-4](2)](2) and monophosphines Ph(3-a)P(C(6)H(4)(CH(2)CH(2)C(6)F(13))-4)(a). One of the most fluorophilic phosphines, i.e., 1(3, 1, 8, C3C5), was applied and efficiently recycled in rhodium-catalyzed, fluorous hydrosilylation of 1-hexene by HSiMe(2)Ph using PFMCH as the fluorous phase and the substrates as the organic phase. It was demonstrated that a higher partition coefficient of the ligand in PFMCH/toluene at 0 degrees C indeed resulted in less leaching of both the catalyst and the free ligand during phase separation.     

Whole-molecule calculation of log p based on molar volume, hydrogen bonds, and simulated 13C NMR spectra

The prediction of Log P is usually accomplished using either substructure or whole-molecule approaches. However, these methods are complicated, and previous whole-molecule approaches have not been successful for the prediction of Log P in very complex molecules. The observed chemical shifts in nuclear magnetic resonance (NMR) spectroscopy are related to the electrostatics at the nucleus, which are influenced by solute-solvent interactions. The different solvation effects on a molecule by either water or methanol have a strong effect on the NMR chemical shift value. Therefore, the chemical shift values observed in an aqueous and organic solvent should correlate to Log P. This paper develops a rapid, objective model of Log P based on molar volume, hydrogen bonds, and differences in calculated 13C NMR chemical shifts for a diverse set of compounds. A partial least squares (PLS) model of Log P built on the sum of carbon chemical shift differences in water and methanol, molar volume, number of hydrogen bond donors and acceptors in 162 diverse compounds gave an r2 value of 0.88. The average r2 for 10 training models of Log P made from 90% of the data was 0.87+/-0.01. The average q2 for 10 leave-10%-out cross-validation test sets was 0.87+/-0.05.     

Chromatographic and computational screening of anisotropic lipophilicity and pharmacokinetics of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimides

The present study is focused on a series of newly synthesized 1-aryl-3-ethyl-3-methylsuccinimide derivatives, as potential anticonvulsants. The retention behavior of eleven succinimide derivatives was determined by using reversed phase high performance liquid chromatography (RP-HPLC) and reversed phase high performance thin layer chromatography (RP-HPTLC). The estimated retention behavior was correlated with partition (logP) and distribution coefficients (logD). These high correlations pointed out that the determined retention parameters (logk₀ and R_M⁰) can be considered chromatographic (anisotropic) lipophilicity of the studied succinimide derivatives. The structural properties, which dominantly affect the chromatographic lipophilicity, were determined as well. The significant correlations between the chromatographic lipophilicity and plasma protein binding (PPB), Madin-Darby Canine Kidney (MDCK) cells permeability, volume of distribution (Vd) and absorption constant (Ka) indicate the strong influence of lipophilicity on pharmacokinetics of 1-aryl-3-ethyl-3-methylsuccinimide derivatives. These derivatives have also been tested applying Comprehensive Medicinal Chemistry (CMC) drug-like rules which confirmed their drug-like properties. Besides, their blood-brain penetration (BBB) ability has been estimated applying the set of Clark’s rules and by using Pre-ADMET software. Regarding toxicity, it was predicted that only one compound from the set might have toxic effects by blocking the hERG potassium channel. The present study reveals which molecular features in the structure of novel succinimide derivatives could be crucial for their lipophilicity, and consequently for their pharmacokinetic properties. The results indicate that the newly synthesized series of succinimide derivatives should be further considered in design of novel anticonvulsants.     

Complex formation between dodecylpyridinium chloride and multicharged anionic planar substances

The complex formation between dodecylpyridinium chloride (DPC) and multicharged anionic planar substances, 14 azo dyes and 3 benzene- or naphthalenesulfonates, has been studied by the potentiometric titration using a surfactant selective electrode. The agreement between the observed maximum binding number and the number of anionic charges (n) on dye molecules showed n:1 complex formation. The binding isotherms were found to be composed of two types of binding; one is the noncooperative binding observed at low surfactant concentrations and the other is the cooperative binding at the higher concentrations. The microscopic binding constant for the noncooperative binding was found to take the values in the range of 50-200 mol(-)(1) dm(3) for many of the substances, but, takes more large values up to 2500 mol(-)(1) dm(3) for the substances which have a large hydrophobic part or the structure of separate hydrophobic and hydrophilic regions. A multiple regression analysis showed that the data of the corresponding standard free energy change of binding were well interpreted by the equation (in unit of kJ mol(-)(1)) DeltaG degrees = - 5.85 log P(S) - 1.68 log P(D) - 2.12z + 28.4, where P(S) and P(D) are the partition coefficients of the surfactants and planar substances in the 1-octanol/water system and z is the number of anionic charges on the planar molecules. At the beginning of the cooperative binding, precipitate formation was observed for almost all of the present systems. Among these, some of the dyes having the structure of separate hydrophobic and hydrophilic regions formed a needlelike crystal, which was accompanied by a hysteresis phenomenon in the binding isotherm. The stable complex formation by both the hydrophobic and electrostatic interactions between the surfactant and the planar substances was found to be important for the crystal formation. Depending on the manner of arrangement of the charged groups on the planar substances, the origin of the binding cooperativity was ascribed to the interactions between surfactants bound to one planar-substance molecule or to the association of the complexes. It was also found that the present small binding systems are useful as the model of ligand binding to protein local structures.     

Thermodynamic parameters for the binding of inorganic and organic anions by biogenic polyammonium cations

Thermodynamic parameters for the interaction of protonated biogenic polyamines with inorganic or organic polyanions were studied potentiometrically (H(+)-glass electrode) and calorimetrically, at 25 degrees C. No background salt was used in the measurements to avoid interferences, and the formation constants and formation enthalpies were extrapolated to zero ionic strength. Species formed are ALH(r) [L=Cl(-), SO(4)(2-), HPO(4)(2-), P(2)O(7)(4-) and P(3)O(10)(5-); tartrate, malate, citrate, glutamate, 1,2,3-propanetricarboxylate, 1,2,3,4-butanetetracarboxylate], with r=1,2...(n+m-2) and r=1,2...(n+m-1) for inorganic and organic ligands, respectively (n, m=maximum degree of protonation of amine and ligand, respectively). The stability of the various species formed is a function of charges involved in the formation reaction. DeltaH(0) values are generally positive, and therefore these complexes are entropically stabilized. Results are discussed in connection with several previously reported data on similar systems. DeltaG(0) and TDeltaS(0) follow a linear trend as a function of polyammonium cation and inorganic or carboxylic anion charges. DeltaG(0) and TDeltaS(0) charge relationships are reported. In particular, mean values of DeltaG(0) and TDeltaS(0) for single interaction were calculated: DeltaG(0)=7.0 kJ mol(-1) n(-1), TDeltaS(0)=9.1 kJ mol(-1) n(-1) and DeltaG(0)=5.7 kJ mol(-1) n(-1) and TDeltaS(0)=8.7 kJ mol(-1) n(-1), for the species of inorganic and organic polyanions, respectively (n=number of possible salt bridges). A linear relationship was also found for TDeltaS(0) versus DeltaG(0), whose equation is TDeltaS(0)=-7-1.39 DeltaG(0) (with r=0.9409; r, correlation coefficient). The body of correlations found for these thermodynamic parameters shows quite good predictive value.