Hydrophobic Fragmental Constants Research Articles

Antileishmanial pyrazolopyridine derivatives: synthesis and structure-activity relationship analysis.

Three series of 4-anilino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic esters were synthesized as part of a program to study potential anti-Leishmania drugs. These compounds were obtained by a condensation reaction of 4-chloro-1H-pyrazolo[3,4-b]pyridine with several aniline derivatives. Some of them were also obtained by an alternative pathway involving a Mannich-type reaction. The hydrophobic parameter, log P, was determined by shake-flask methodology, and using the Hansch-Fujita addictive hydrophobic fragmental constants. These compounds were tested against promastigote forms of Leishmania amazonensis. The very promising results showed the 3'-diethylaminomethyl-substituted compounds as the most active [IC50 = 0.39 (21) and 0.12 microM (22)]. Molecular modeling, using semiempirical AM1 method, predicted the most active compounds through the low-energy conformers superimposition on amodiaquine structure. QSAR equations, derived from the IC50 values against L. amazonensis, showed the hydrophobic (log P) and Sterimol steric (L and B2) parameters as most significant contributions on biological activity.

The role of hydrophobic microenvironments in modulating pKa shifts in proteins.

The screened Coulomb potential (SCP) method, combined with a quantitative description of the microenvironments around titratable groups, based on the Hydrophobic Fragmental Constants developed by Rekker, has been applied to calculate the pK(a) values of groups embedded in extremely hydrophobic microenvironments in proteins. This type of microenvironment is not common; but constitutes a small class, where the protein's architecture has evolved to lend special properties to the embedded residue. They are of significant interest because they are frequently important in catalysis and in proton and electron transfer reactions. In the SCP treatment these special cases are treated locally and therefore do not affect the accuracy of the pK(a) values calculated for other residues in less hydrophobic environments. Here the calibration of the algorithm is extended with the help of earlier results from lysozyme and of three mutants of staphylococcal nuclease (SNase) that were specially designed to measure the energetics of ionization of titratable groups buried in extremely hydrophobic microenvironments. The calibrated algorithm was subsequently applied to a fourth mutant of SNase and then to a very large dimeric amine oxidase of 1284 residues, where 334 are titratable. The observed pK(a) shifts of the buried residues are large (up to 4.7 pK units), and all cases are well reproduced by the calculations with a root mean square error of 0.22. These results support the hypothesis that protein electrostatics can only be described correctly and self-consistently if the inherent heterogeneity of these systems is properly accounted for.

Correlation between hydrophobic and molecular shape descriptors and retention data of polycyclic aromatic hydrocarbons in reversed-phase chromatography on non-liquid-crystalline, nematic, and smetic stationary phases

The local anisotropic ordering of side-chain liquid-crystalline polymer (SCLCP) stationary phases has been revealed statistically. For this purpose the RP HPLC separation of polycyclic aromatic hydrocarbons (PAH) on silica coated with three classes (non-liquid-crystalline, nematic, and smectic) of side-chain polymer (SCP) has been compared. The logarithm of the capacity factor (logk) was correlated with three PAH descriptors-the connectivity index (χ) or the hydrophobic fragmental constant (logP), the length-to-breadth ratio (L/B), and a non-planarity term (Np). Statistical results revealed good correlation between the model and experimental data, enabling the different stationary phases to be compared. Recognition of solute size seems similar for each class of polymer but solute non-planarity recognition grows continuously as ordering of the liquid-crystal polymer increases. Recognition of solute lengthening is non-existent for non-liquid-crystalline polymers and suddenly, appears with liquid crystalline polymers. Shape recognition is better for smectic than for nematic SCP. The predictive, ability of this model was tested on highly condensed aromatic compounds. The connectivity index, χ, did not seem appropriate for such systems. its replacement by Rekker's hydrophobic, fragmental constant, logP, was necessary for fitting the retention of these solutes on liquid-crystalline stationary phases.

Modelling of solute retention in the reversed-phase high-performance liquid chromatography system with the chemically bonded 3-cyanopropyl stationary phase

We investigated the applicability of three models of solute retention (devised by Snyder et al., Schoenmakers et al., and Kowalska) for reversed-phase high-performance liquid chromatography (RP-HPLC) for description of the chromatographic behaviour of 25 test solutes in the RP-HPLC systems with the 3-cyanopropyl stationary phase and the methanol+water eluent. The employed test solutes considerably differed with respect to molecular structure, as they belonged to chemical classes of (i) benzene and alkylbenzenes, (ii) hydroxyaromatics, and (iii) crown ethers. In the case of the chemically bonded stationary phases, the 3-cyanopropyl phase included, one encounters the mixed mechanism of solute retention with the contributory effects of partition and adsorption. From our investigations, it comes out that the retention model proposed by Schoenmakers et al. (i.e., model II) is the best suited for description of the chromatographic behaviour of solutes on such packings, while the remaining two models (i.e., models I and III) perform less accurately. An additional investigation was performed with aid of the relationship between the retention parameters (i.e., log k) of the employed test solutes and the logarithms of their partition coefficients (log P) in the octanol/water system (as calculated from the hydrophobic fragmental constants after Rekker), depending on the quantitative composition of the binary eluent. The greater is the deviation of the log k vs. log P relationship from linearity (as monitored by the decreasing values of the respective linear correlation coefficients, r), the less pronounced becomes the contribution of partition and hence the importance of adsorption for the overall retention increases. Thus, the log k vs. log P study was performed in order to follow the partition↔adsorption balance with the changing volume proportions of methanol in the mixed eluent, and ultimately to link an extent of contamination of the nominal reversed-phase partition mechanism by adsorption with the predictive power of models I–III. Finally, an effort was undertaken aimed at demonstration of a considerably enhanced performance of model III, when applied to the experimental conditions that corresponds better with the theoretical assumptions of this approach.

Synthesis, properties, and pharmacokinetic studies of N2-phenylguanine derivatives as inhibitors of herpes simplex virus thymidine kinases.

Two series of selective inhibitors of herpes simplex virus types 1 and 2 (HSV1,2) thymidine kinases (TK) have been developed as potential treatment of recurrent virus infections. Among compounds related to the potent base analog N2-[m-(trifluoromethyl)phenyl]guanine (mCF3-PG), none was a more potent inhibitor than mCF3PG itself. Compounds related to the nucleoside N2-phenyl-2'-deoxyguanosine (PhdG), but with alkyl, hydroxyalkyl, and related substituents at the 9-position in place of the glycosyl group of PhdG, retained significant but variable inhibitory potencies against the HSV TKs. The most potent inhibitor of HSV1 TK among 9-substituted derivatives, 9-(4-hydroxybutyl)-N2-phenylguanine (HBPG), was a competitive inhibitor with respect to the substrate thymidine but was not itself a substrate for the enzyme. Water solubilities and 1-octanol:water partition coefficients for the 9-substituted N2-phenylguanines were linearly but oppositely related to the sum of hydrophobic fragmental constants (sigma f) of the 9-substituents. Four of the inhibitors were given as solutions to mice by iv and ip routes, and the time course of their plasma concentrations was determined by HPLC analysis of the parent compounds. HBPG was completely absorbed by the ip route, and the plasma concentration could be prolonged by use of suspension formulations. HBPG is a candidate for animal trials of the ability of TK inhibitors to prevent recurrent herpes virus infections.

Drug Lipophilicity in QSAR Practice: I. A Comparison of Experimental with Calculative Approaches

AbstractExperimental and calculated data of drug lipophilicity, i.e. octanol/water partition coefficients (log Pobs) and hydrophobic fragmental constants (Σf, C log P) have been compared for the following four groups of drugs: antiarrhythmics (AA), β‐blockers (BB), phenothiazines (PT) and benzamides (BA).Measured log P values indicate significantly varying lipophilicity ranges in the case of these four groups (AA>BB>BA>PT).Comparison of the two calculative approaches with observed log P values yields almost identical qualities. Strongest discrepancies between calculative and experimental data are discussed on the basis of putative experimental pitfalls or in relation to structurally derived miscalculations.

Partition coefficients of crown ethers

AbstractBenzo and dibenzo crown ethers become more water soluble as the number of oxyethylene units increase. Moreover, the solubility in water is larger than expected on the basis of calculations using empirical models, viz., “the fragment model” and “the substituent model”. New hydrophobic fragmental constants of the oxyethylene fragment, f (‐OCH2CH2‐) = −0.17, and of the veratrole fragment, f[C6H4(OCH2‐)2] = 0.99, for the system 1‐octanol/water have been determined experimentally. Using these values, reliable partition coefficients of macrocyclic polyethers can be calculated. Comparison of the benzo crown ethers with the open‐chain model compounds surprisingly did not reveal a macrocyclic effect on the partition coefficient.

Separation of peptides by multimode chromatography on a column packed with vinyl alcohol copolymer gel

Several mechanisms of peptide separation in high-performance liquid chromatography were observed to occur on the Asahipak ® GS-320 packed with vinyl alcohol copolymer. Neutral rather than acidic mobile phases were employed as they were found to result in higher retention of many peptides on the GS-320. For neutral peptides, the retention volume corresponded to the Rekker's hydrophobic fragmental constant, with a correlation coefficient of 0.71. Peptides with acidic residues eluted early, as an effect of ionic exclusion; those with basic residues were retained longer, owing to an ion-exchange effect. The ionic interactions were shown to involve the car☐ylic group present on the gel polymer. The net result was found to be excellent separation of hydrophilic as well as hydrophobic peptides, related to differences in their isoelectric points. The combination of these complex mechanisms, together with the size-exclusion effect of the GS-320 gel for separation of proteins and other large molecules and for analysis with a mobile phase high in acetonitrile content, makes possible high-resolution isocratic analysis of peptides, which cannot be achieved on octadecylsilica or ion-exchange columns.

Chromatography of organometallic and organometalloidal derivatives of amino alcohols : IV. Comparison of retention behaviour in gas-liquid, thin-layer and high-performance liquid chromatography

The applicability of thin-layer and high-performance liquid chromatography for separation of organometalloid derivatives of amino alcohols has been demonstrated. Diastereomers have been separated for several compounds. The relative amounts of the isomers have been shown to depend on the number and nature of the substituents. The way in which the substituents influence retention is similar to that observed earlier in gas-liquid chromatography (GLC). A relationship between the capacity factors on Zorbax CN and the logarithm of the concentration of the mobile phase polar component can be expressed by linear equations. In the reversed-phase mode, retention is linearly correlated with the sum of Rekker's hydrophobic fragmental constants for the substituents. A model is proposed which allows the retention in the reversed-phase mode to be evaluated from GLC retention parameters.

Local composition models in pharmaceutical chemistry. II. Differentiation of hydrophobic fragmental constants

A method of analysis based on the UNIQUAC model has been developed to examine in more detail the hydrophobic fragmental constants for three different organic solvent/water systems. The three organic solvents, i.e. 2,2,4-trimethylpentane, chloroform and octan-1-ol, have been chosen to represent different chemical characteristics. This analysis allows one to differentiate fragmental values into a non-specific size term, which is due to the possible arrangment that a fragment has in space and specific interaction effects both with water and the organic phase. This differentiation of fragmental values permits the design of a universal scale of interaction terms relative to 2,2,4-trimethylpentane as a standard reference solvent. The interaction terms are discussed in terms of proton donating-accepting abilities of both the solvent and the fragment.

Liquid Chromatographic Behavior of Nitrogen Compounds

Abstract Chromatographic behavior of nitrogen compounds differed from others. The column efficiency was poor for the compounds and sometimes solutes were not eluted out from a column. Therefore, the elution volume of alkylamines, anilines, pyridines, pyrazines, quinolines and aminopolyaromatic hydrocarbons was measured on a methacrylate gel and octadecyl bonded silica gels in pH controlled acetonitrile/water mixtures. The solvent effect on the dissociation constant differs from that obtained for aromatic acids. The values in acetonitrile/water mixtures are smaller than those obtained in 100% water. The linear relation between log P and log k′ values is obtained in eluents of pH 7 where the retention of these compounds is maximized. Some hydrophobic fragmental constants are proposed from this result. Prediction of retention time of these compounds from their log P values can be done in the individual groups on octadecyl bonded silica gels in pH controlled acetonitrile/water mixtures.

The effects of hydrophobic-lipophilic interactions on chemical reactivity: 2. Solvent effects on the aggregation and self-coiling of long-chain molecules

The kinetics of the hydrolysis of p-nitrophenyl esters of straight chain carboxylic acids with various chain lengths, viz., acetate (C 2), octanoate (C 8) dodecanoate (C 12) and hexadecanoate (C 16) was investigated in ten aquiorgano binary solvent systems. In the Φ = 0.50 (50% v/v) solvent mixtures, aggregation and coiling-up of C 16 occur only in HOCH2CH2OH-H2O and Me2SOH2O, in which kC8/kC16 >> 1, whereas the hydrolytic behaviors of C 16 and C 8 are similar in all other solvents. But at Φ =0.30, C 16 aggregates and coils-up in all solvent mixtures except the t-BuOH-H2O system. If the kC8/kC16 values in the Φ =0.30 media are taken as an arbitrary standard, the order of decreasing hydrophobic-lipophilic interactions between the solvent and substrate molecules for the various solvents are as follows : HOCH2CH2OH > Me2SO > CH3OCH2CH2OH > DMF ˜ CH2OCH2CH2OCH3 > dioxane > ethanol ˜ acetone ˜ acetonitrile > t-BuOH. When kC8/kC16 >> 1, there is a large difference in the activation parameters between C 16 and its shorter counterparts. No simple correlation can be found between log (kC8/kC16) and various solvent polarity parameters, but log (kC8/kC16) correlates with Rekker's hydrophobic fragmental constants (f) of the organic components of these solvent systems (r = 0.976), indicating that the major factor which controls the hydrolysis of long-chain esters here is the hydrophobic-lipophilic interactions. Apparently, this is the first example of an application of Rekker's f constants to a correlation between solvent property and chemical reactivity in terms of rate constants.

Optimization of retention time of aromatic acids in liquid chromatography from log P and predicted pKa values

AbstractFor optimization of liquid chromatography separations, several approaches have been reported, among them the use of the hydrophobic fragmental constant, as proposed by Rekker [1]. The fragmental constant is derived from the partition coefficients of various solutes between octanol and water and represents a summation of solubility parameters: van der Waals volume, π ‐ π interactions, hydrogen bonding, etc. With these constants the optimization of reversed phase mode liquid chromatography using octadecyl bonded silica gels as packing was feasible, although large error was found for the eluent with a high concentration of organic modifier or water. This is probably due to the heterogeneous solvation of the surface of the packings and to various solvent effects. In addition, when the acid dissociation constant was known, the retention times of aromatic acids in the ionic form were also predicted using the hydrophobic fragmental constant and the dissociation constant. By comparison of the previous data and a method proposed by Perrin et al. [2] it was possible to predict the dissociation constant of aromatic acids and optimize separation in reversed phase mode liquid chromatography using octadecyl bonded silica gels as packing. Furthermore, an equation for calculating the capacity ratios in a given pH eluent was proposed and the predicted and observed capacity ratios of aromatic acids in several eluents were examined in order to improve the above system.

Relationship Between Molecular Structure and Cytochrome P450−Metabolic Intermediate Complex Formation

Complexation of ferrous cytochrome P450 by metabolic intermediates formed during NADPH−catalyzed metabolism of compounds structurally related to orphenadrine was studied. This so−called metabolic intermediate complexation was determined in rat liver microsomes, obtained from phenobarbital−pretreated rats, at 455nm using 33 μM of the orphenadrine derivatives. Using secondary amine derivatives with various N−alkyl substituents, a parabolic relationship between the logarithm of percentage of cytochrome P450 complexation and hydrophobic fragmental constant was observed. The derivative with a bulky tertiary butyl group, however, was devoid of metabolic intermediate−complexing activity. This indicates that steric factors besides lipid solubility may govern the complexing activity; also substitution at the phenyl group affects metabolic intermediate complex formation.

The position of reversed-phase thin-layer chromatography amongst solvent partitioning techniques

Summary A few years ago we introduced the hydrophobic fragmental constant, f , in order to promote a better understanding of lipophilicity values measured by partition measurements. A similar R M fragmentation is now proposed for reversed-phase thin-layer chromatographic data. These fragmental values allow t closer examination of Collander-type regressions and open the way for a re-interpretation of the intercept terms of these regressions.

Hydrophobicity and chromatographic behaviour of aromatic acids found in urine

In reversed-phase liquid chromatography, the capacity ratios of urinary compounds were related with their hydrophobicity calculated by Rekker's hydrophobic fragmental constants. The retention behaviour of these compounds differed from that of non-ionizable compounds whose retention time can be predicted in different mixtures of acetonitrile and water as eluent and on an octadecyl silica packing from their calculated hydrophobicity. However, the calculated values for hydrophobicity and/or those derived from the results obtained for non-ionizable compounds could be useful to analyze the metabolites of acidic compounds in urine. The retention behaviour of all the compounds on gradient elution is also discussed.

Hydrophobicity and Retention in Reversed Phase Liquid Chromatography

Abstract Reversed phase liquid chromatography retention data for several compounds are examined in relationship to their hydrophobicities. Alcohols and various aromatics are used to compare hydrophobicities in aliphatic and aromatic compounds. Capacity factors, k1, can be correctly evaluated by using the hydrophobic factors (log P) derived from the hydrophobic fragmental constants. Appropriate solvent mixtures to achieve good separations can be choosen from graphical data.

An approach to the prediction of retention times in liquid chromatography

AbstractThe utility of Rekker's hydrophobic fragmental constant has been examined for optimization of reversed‐phase mode liquid chromatographic separations. The chromatographic behavior of about 60 non‐ionic compounds was measured in different acetonitrile/water mixtures and the logarithm of their capacity factors (log k) was correlated with their calculated hydrophobicities (log P). Linear relations were found in each case between log k and log P. The slope of the various lines was related to the percentage concentration of acetonitrile in the mobile phase. It was shown that, by using nine stand ard compounds and measuring their capacity factors in five eluents with different acetonitrile concentrations, the retention time could be predicted for 60 compounds. Calculation of the concentration of the organic modifier was also possible in a system of well coated octadecyl bonded packings with acetonitrile/water mixtures as eluent. Prediction of the capacity factor was accomplished to within 5% error.

Some typical behaviours of the β-dodecenyl 8-hydroxyquinoline—II: Its distribution between aqueous and organic phases

The distribution of the β-dodecenyl 8-hydroxyquinoline (active substance of Kelex 100, noted βoxH) between aqueous and organic phases has been studied as a function of the acidity. The acido-alkaline transformations of the reagent explain the shape of the curves log D = f(pH). The formation of micelles by association of several ion-pairs ( βoxH 2 +, HSO 4 −) is also thought to happen in acidic media. These micelles have little influence on the distribution coefficient D, even when pH ≲ 0. Such an aggregation could be responsible for the third phase formation we observe in the absence of polar modifiers. Calculations based on the “hydrophobic fragmental constants” introduced by Rekker lead to P = 10 7.34 for the partition coefficient between water and octanol. This value is slightly higher than P = 10 6.7 experimentally measured (P = 10 6.5 for the system water/kerosene). The two values 6.7 and 7.34 show that P βoxH octanol is close to 10 7. The experimental determination may be underestimated because of the mechanical dispersion of minute quantities of the organic phase in the aqueous solution and because of the presence of residual oxine in the available β-dodecenyl 8-hydroxyquinoline. Finally we propose P βoxH = 10 7.3 (water/octanol) and the acidity constants p K A 1 = 11.2 and p K A 11 = 4.4.

Hydrophobicity Parameter--Capacity Factor Relationships of Iodoamino-Acids

The application of hydrophobicity parameters for the prediction of retention of a series of iodoamino acids and related compounds has been examined. On non-polar stationary phases with isocratic elution conditions these compounds exhibit a linear relationship between the logarithm of the octanol-water partition coefficient calculated from hydrophobic fragmental constants and the logarithm of the capacity factor. Using these relationships it is possible to predict the retention characteristics of a homologous compound from a minimum set of k′ measurements , e.g., k′ for diiodothyropropionic acid from diiodo to tetraiodo-thyroacetic acid k′ data. On a μBondapak-C18 column, the reverse iodothyronine isomers have a greater retention than the corresponding normal isomers with the same elution conditions. However, as a series the reverse isomers also follow a linear relationship which allows the influence of proximity effects and aromatic substitution orientation on partition coefficients to be determined.