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

This 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 P_oct–alk and Δlog P_oct–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 P_oct values (the diff(log P^exp–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.     

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.     

Use of Reversed-Phase High-Performance Liquid Chromatography in QSAR Analysis of 2,4-Dihydroxythiobenzanilide Analogues

Abstract

Thiobenzanilides are found to show strong biological activity as antimicrobial, antimycotic, and tuberculostatic agents. In addition, they are relatively weakly toxic to higher organisms.

A large set of new (N-phenyl-)-2,4-dihydroxybenzenecarbothioamide derivatives was obtained. Preliminary studies showed high microbiological action of some of them. In the process of chromatographic analysis, several different chromatographic parameters were obtained. In case of RP-HPLC, these parameters correspond to hydrophobicity of the solute. Obtained chromatographic parameters exhibited moderate correlation with calculated log P parameter.

Linear dependence of bacteriostatic or fungostatic activity on lipophilicity was observed. The degree of correlation of different parameters was compared. The lipophilicity of analysed tioamides was the most important factor responsible for fungostatic and bacteriostatic activity. In comparison to methanol eluent system, chromatographic parameters obtained in acetonitrile system were better correlated with bioactivity. Conversely with the calculated log P values, the experimentally derived parameters exhibited significant higher correlation to fungostatic activity determined on dermatophytes. While in case of other tested microorganisms log P was comparably or sometimes slightly better correlated.     

Microemulsion electrokinetic chromatography as a suitable tool for lipophilicity determination of acidic,neutral, and basic compounds

In the present work, several MEEKC systems are studied to assess their suitability for lipophilicity determination of acidic, neutral, and basic compounds. Thus, several microemulsion compositions over a wide range of pH values (from 2.0 to 12.0), containing heptane, 1?butanol and different types and amounts of surfactant (SDS or sodium cholate: from 1.3 to 3.3%) are characterized using Abraham's solvation model. The addition of acetonitrile (up to 10%) is also studied, since it increases the resolution of the technique for the most lipophilic compounds. The system coefficients obtained are very similar to those of the 1?octanol/water, used as the reference lipophilicity index, allowing simple and linear correlations between the 1?octanol/water partition values (log P_o/w) and MEEKC mass distribution ratios (log k_MEEKC). Variations in the microemulsion composition (aqueous buffer, surfactant, concentration of ACN) did not significantly affect the similarity of the MEEKC systems to log P_o/w partition.     

Assessment of methods used for predicting lipophilicity: Application to nucleosides and nucleoside bases

Estimating log P (logarithm of “1-octanol to water” partition coefficients) as a measure of lipophilicity for organic compounds is of considerable importance in drug discovery. Several methods have been developed for this purpose, each with its own drawbacks and advantages. In this article, a systematic comparison of three well-documented and fully computerized methods has been attempted for a set of nucleosides and bases. The first method (BLOGP) is based on overall molecular properties derived from a molecular orbital calculation to predict log P. The second method (CLOGP) uses fragmental lipophilicity constants with correction factors and treats log P as an additive-constitutive property. The third method (ALOGP) is based on an additivity scheme of atomic lipophilicity constants, with the constitutive factor governed by an elaborate list of atom types. However, none of these methods take into account conformational flexibility or intramolecular hydrogen bonding, which can cause substantial discrepancy between observations and predictions. A comparison of predictions from each of these methods indicates that the atomic contribution method (ALOGP with r = 0.842 and SD = 0.51) is better than other methods (with r = 0.395 and SD = 1.2 for BLOGP and r = 0.713 and SD = 0.93 for CLOGP) for this class of compounds. Our overall assessment is that we do not have, as yet, a highly reliable, fully computerized log P prediction method applicable to flexible heterocycles such as nucleoside analogs. © John Wiley & Sons, Inc.     

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.     

Solvation in octanol: parametrization of the continuum MST model

This study reports the parametrization of the HF/6‐31G(d) version of the MST continuum model for n‐octanol. Following our previous studies related to the MST parametrization for water, chloroform, and carbon tetrachloride, a detailed exploration of the definition of the solute/solvent interface has been performed. To this end, we have exploited the results obtained from free energy calculations coupled to Monte Carlo simulations, and those derived from the QM/MM analysis of solvent‐induced dipoles for selected solutes. The atomic hardness parameters have been determined by fitting to the experimental free energies of solvation in octanol. The final MST model is able to reproduce the experimental free energy of solvation for 62 compounds and the octanol/water partition coefficient (log P_ow) for 75 compounds with a root‐mean‐square deviation of 0.6 kcal/mol and 0.4 (in units of log P), respectively. The model has been further verified by calculating the octanol/water partition coefficient for a set of 27 drugs, which were not considered in the parametrization set. A good agreement is found between predicted and experimental values of log P_o/w, as noted in a root‐mean‐square deviation of 0.75 units of log P. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1180–1193, 2001     

Lipophilicity measurements of protonated basic compounds by reversed-phase high-performance liquid chromatography : II. Procedure for the determination of a lipophilic index measured by reversed-phase high-performance liquid chromatography

The retention behaviour of protonated basic compounds in reversed-phase high-performance liquid chromatography, using methanol-water mixtures as the eluent, is reported. A minimum is found in the relationship between the logarithm of the capacity factor (log k) and the percentage of methanol (x) in the eluent. The deviation from linearity is postulated to be caused by a dual retention mechanism, namely polar interactions between the solute and eluent molecules in water-poor eluents, and hydrophobic expulsion in water-rich ones. The influence of the pH, pK_a and lipophilicity on retention behaviour is also investigated.     

Drug–Membrane Interaction on Immobilized Liposome Chromatography Compared to Immobilized Artificial Membrane (IAM), Liposome/Water,and Octan‐1‐ol/Water Systems

The objective of this study was to investigate drug–membrane interaction by immobilized liposome chromatography (ILC; expressed as lipophilicity index log K_s) and the comparison with lipophilicity indices obtained by liposome/H₂O, octan‐1‐ol/H₂O, and immobilized artificial membrane (IAM) systems. A set of structurally diverse monofunctional compounds and drugs (nonsteroidal anti‐inflammatory drugs and β‐blockers) were selected in this study. This set of solutes consists of basic or acidic functionalities which are positively or negatively charged at physiological pH 7.4. No correlation was found between log K_s from ILC and lipophilicity indices from any of the other membrane model systems for the whole set of compounds. For structurally related compounds, significant correlations could be established between log K_s from ILC and lipophilicity indices from IAM chromatography and octan‐1‐ol/H₂O. However, ILC and liposome/H₂O systems only yield parallel partitioning information for structurally related large molecules. For hydrophilic compounds, the balance between electrostatic and hydrophobic interactions dominating drug partitioning is different in these two systems.     

Synthesis, structure, and solvatochromic properties of pharmacologically active 5-substituted 5-phenylhydantoins

Abstract  

A series of 5-substituted 5-phenylhydantoins was synthesized and their UV absorption spectra were recorded in the region 200–400 nm in selected solvents of different polarity. The effects of solvent dipolarity/polarizability and solvent–solute hydrogen-bonding interactions were analyzed by means of the linear solvation energy relationship concept proposed by Kamlet and Taft. The lipophilicities of the investigated hydantoins were estimated by calculation of their log P values. The quantitative relationship between the ratio of the contributions of specific solvent interactions and the corresponding lipophilicity parameter is discussed. The correlation equations were combined with the corresponding ED₅₀ values and different physicochemical parameters to generate new equations that demonstrate the reasonable relationships between solute–solvent interactions and the structure–activity parameters. In order to determine a spectroscopic assignment of the absorption bands in different solvents, quantum chemical calculations were done.     

Ionic Partition Diagram of the Zwitterionic Antihistamine Cetirizine

A recent analysis of the lipophilicity profile of cetirizine in the octanol/water and dodecane/water systems revealed a partial intramolecular charge neutralization that can partly explain why cetirizine has pharmacokinetic properties differing from those of first‐generation antihistamines such as hydroxyzine. As conformational changes are the principal driving force for this intramolecular effect, the present study deals with the partitioning of cetirizine and hydroxyzine in an apolar medium well‐suited to reveal intramolecular interactions, namely the 1,2‐dichloroethane/water system. The lipophilicity of the different electrical forms of cetirizine and hydroxyzine was studied by two‐phase titrimetry and cyclic voltammetry. The differences in lipophilicity between the dicationic, monocationic, zwitterionic, and anionic species of cetirizine indicated intramolecular interactions via folded conformations, which render the molecule markedly more lipophilic than expected at physiological pH. Folded conformations were also found to predominate in monocationic and neutral hydroxyzine. The ionic partition diagram of cetirizine indicates that it acts as a proton transporter across interfaces under certain conditions of pH and Galvani potential difference. This study underlines the importance of conformational effects on the partition properties of cetirizine and hydroxyzine, as well as the complexity of its interfacial mechanisms of transfer. In particular, cetirizine can facilitate proton transfer, a property of potential biological relevance.     

Dependence of the distribution constant in liquid–liquid partition equilibria on the van der Waals molecular surface area

The direct calculation of free energy of interactions between a solute j and two immiscible liquids shows a linear dependence between the (logarithm of) the distribution constant in liquid–liquid partition equilibrium log K_j and the van der Waals surface area of the solute. The study provides a thermodynamic proof for the formula log K_BA,j = c₁ log K_BC,j + c₂ that describes the linear dependence between (the logarithm of) the distribution constant for a solute j in a solvent system (B/A) and (the logarithm of) the distribution constant for the same solute in a different solvent system (B/C). This relation has been well proven by various experimental studies and it is frequently used in liquid chromatographic separations as well as in liquid–liquid extractions, but was not explained previously based on thermodynamic results. The theory was verified using the prediction of octanol/water distribution constants log K_ow for a wide range of molecules, including hydrocarbons and compounds with a variety of functional groups. The results have also been verified for the distribution constants in other solvent systems. The expression for the distribution constant obtained in this study also gives a theoretical base for the additive fragment methodology used for the prediction of log K_ow.     

Correlation and prediction of partition coefficient between the gas phase and water, and the solvents dry methyl acetate, dry and wet ethyl acetate, and dry and wet butyl acetate

Experimental partition coefficient data have been compiled from the published literature for the water/methyl acetate, water/ethyl acetate and water/butyl acetate partition systems, log P data, and for the gas/methyl acetate, gas/ethyl acetate and gas/butyl acetate partition systems, log K data. Application of the Abraham solvation parameter model to the sets of partition coefficients leads to equations that correlate the log P data and log K data to 0.18 log units for the three dry alkyl acetate solvents. Slightly larger deviations were noted for solute partition into both wet ethyl acetate and wet butyl acetate. The derived correlations were validated using training set and test set analyses.     

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.     

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.     

Determination of ligand efficiency indices in a group of 7H‐purine‐2,6‐dione derivatives with psychotropic activity using micellar electrokinetic chromatography

Discovering hit compounds and optimization processes in medicinal chemistry nowadays could be improved by predictive tools, based on the relationship between structure of molecules and lipophilic properties. Lipophilicity of drug candidate can affect both the pharmacokinetic and pharmacodynamics properties, in particular, the ability of a molecule to cross the cell membrane. Among the new methods for determination of the lipophilicity of compounds, micellar electrokinetic chromatography (MEKC) is considered to be an appropriate one for bioactive molecules, as it closely mimics the physiological conditions. In this paper MEKC was used for the estimation of the lipophilicity of 24 derivatives of 8‐alkoxy‐7H‐purine‐2,6‐dione, designed and synthesized as potential antidepressant/anxiolytic and antipsychotic agents. The results of experimental method were compared with calculated in silico parameters (AlogPs and milogP by Virtual Computational Laboratory website, log P_Pallas by Pallas 3.1, Mlog P by Marvin, log P_ChemS by ChemSketch, log P_ChemDraw by ChemBioUltra) using Principal Component Analysis (PCA) method. Finally, using estimated log P values for selected compounds ligand – lipophilicity efficiency (LLE), per cent efficiency index (PEI), and binding efficiency index (BEI) parameters were calculated. Applied MEKC procedure could be used for selection of potential lead structure in a group of 7H‐purine‐2,6‐dione derivatives.     

Investigating the Influence of (Deoxy)fluorination on the Lipophilicity of Non‐UV‐Active Fluorinated Alkanols and Carbohydrates by a New log P Determination Method

Property tuning by fluorination is very effective for a number of purposes, and currently increasingly investigated for aliphatic compounds. An important application is lipophilicity (log P) modulation. However, the determination of log P is cumbersome for non‐UV‐active compounds. A new variation of the shake‐flask log P determination method is presented, enabling the measurement of log P for fluorinated compounds with or without UV activity regardless of whether they are hydrophilic or lipophilic. No calibration curves or measurements of compound masses/aliquot volumes are required. With this method, the influence of fluorination on the lipophilicity of fluorinated aliphatic alcohols was determined, and the log P values of fluorinated carbohydrates were measured. Interesting trends and changes, for example, for the dependence on relative stereochemistry, are reported.     

Solvent Extraction Studies of Two Isomeric 5, 7, 7, 12, 12, 14-Hexamethy-1, 4, 8, 11-Tetraazacyclotetradecanes

The distribution ratios of two isomeric 5, 7, 7, 12, 12, 14-hexamethyl-1, 4, 8, 11-tetraazacyclotetradecane, tet c and tet d, in several solvent systems at 25.0°C as functions of hydrogen ion concentration were determined. The protonation constants and the distribution constants of these macrocyclic ligands and their protonated species were obtained from the variations of the distribution ratios in the range of 6<–log [H⁺]<14.     

A Copper‐Catalyzed Multicomponent Reaction and ‘Click Strategy’ for the Stereoselective Synthesis of a New Series of Oxazolone Peptidomimetics with α‐Acylamino Amide and β‐Amido Ketone Structures

A novel ‘click ligation’ strategy for the stereoselective synthesis of a medium‐size library of structurally complex and functionally diverse oxazolone peptidomimetics, which contain α‐acylamino carboxamide or β‐amido ketone residues, is presented. Most of these molecules have lipophilicity constant values (log P) in the qualifying range for cell permeability, and that indicates the possibilities of these new molecules to be used in the search for potential inhibitors for a broad spectrum of enzymes.