Nada U. Perisic-Janjic

HPTLC chromatography of androstene derivates: Application of normal phase thin-layer chromatographic retention data in QSAR studies

The chromatographic behavior of seven 16-oximino derivatives of 3beta-hydropxy-5-androstene have been investigated using the normal-phase (NP) HPTLC chromatographic mode of the type silica-non-polar diluent (benzene)-polar modifier (acetonitrile, ethyl acetate, or dioxane). The linear relationship between the retention constants (R(M)) and the logarithm of the organic modifier content in the mobile phase allowed for the calculation of R(M)0 values. The influence of substituent in the molecule on extrapolated retention data is discussed. To better understand the retention mechanism in the separation of androstene compounds, the functional group contributions (tauX) were compared with Hansch substituent constants (pi). An attempt to quantitate the lipophilicity of the investigated compounds using normal phase thin-layer chromatographic R(M)0 value was made. Also, the relative lipophilicity values determined previously by RPC as well as activity were compared with NPC data.

Reversed-phase TLC and HPLC retention data in correlation studies with in silico molecular descriptors and druglikeness properties of newly synthesized anticonvulsant succinimide derivatives.

The properties relevant to pharmacokinetics of two series of newly synthesized succinimide derivatives have been studied. The properties under consideration have been either determined empirically, by reversed-phase liquid chromatography (TLC and HPLC technique), or calculated with the use of established theoretical medicinal chemistry/drug design software. Chromatographic techniques allowed determination of the retention constants R(M)⁰ and log k(w), which characterize lipophilicity of compounds. Considering potential pharmaceutical importance of succinimide derivatives, we (i) examined the retention behavior in the reversed-phase liquid chromatographic (RP LC) systems, in both planar and column LC, and (ii) determined the relationships between chromatographic data and selected structural features of analytes that are believed to markedly affect their processes of absorption, distribution, metabolism, excretion and toxicity (ADMETox). Significant relationships were found between the retention constants, R(M)⁰ and log k(w), and the in silico calculated bioactivity descriptors, in particular HIA (human intestinal absorption) and PPB (plasma protein binding) parameters. The R(M)⁰ and log k(w) values of the investigated compounds have been recommended for description of their lipophilicity and evaluating pharmacokinetic properties. In view of results of this study the newly synthesized succinimide agents meet pharmacokinetic criteria of preselection of drug candidates and hence qualify for pharmacodynamic phase of antiepileptic drug development. Best compromising human intestinal absorption and plasma protein binding features appear to be compounds A4, A5, A10 and A11.

Evaluation of the predictive power of calculation procedure for molecular hydrophobicity of some estradiol derivates.

Several calculation procedures for log P values based on the fragmental and atomic contributions are compared with experimental reversed-phase liquid chromatography (RPLC) retention of estradiol derivates. The RPLC experiments were performed on HPTLC and HPLC commercially available stationary phases. Binary solvent mixtures of methanol-water and acetonitrile-water were used as mobile phases. The correlation between log P and various chromatographically obtained hydrophobicity parameters (R(M)0, log k(w) and phi0) are quantified. The R(M)0, i.e., log k(w) were obtained by linear extrapolation of retention to 0% organic modifier. Phi0 values were obtained from the slopes and intercepts of such linear relationship. The mutual relationship between phi(0,MeOH) and phi(0,ACN) values of the compounds were discussed. The obtained statistical results can be summarized in the following order of reliabilities for different log P calculation methods: Broto>ACD/logP>Crippen>Rekker>Viswanadhan.

Chromatographic retention parameters in correlation analysis with in silico biological descriptors of a novel series of N-phenyl-3-methyl succinimide derivatives.

Reversed-phase thin-layer chromatographic (RP TLC) retention coefficients for a newly designed series of N-phenyl-3-methyl succinimide derivatives, of a rationally expected anticonvusant activity, were determined as parameters of their lipophilicity. Basic pharmacokinetic descriptors of the agents were calculated in silico with the use of the established medicinal chemistry/drug design software. Highly significant, predictive relationships were found between the chromatographic retention constants and the bioactivity descriptors, which are assumed to account for drug absorption, distribution, elimination and toxicity (ADMETox) in humans. Among the agents investigated, the compounds with halogen substituent (Compounds nos. 9-13 in Fig. 1), were identified as the best drug candidates, because of their predicted proper pharmacokinetics, and have been selected for further research and development studies on new antiepileptic drugs. At the same time, among the congeners studied these can be indicated, which should not be rationally subjected to bioactivity tests.

RPTLC Study of QSRR and QSAR for Some Benzimidazole Derivatives

Quantitative structure–retention relationships (QSRR) and quantitative structure–activity relationships (QSAR) have been used to study the chromatographic behavior and antibacterial activity of different substituted benzimidazole derivatives active against Erwinia carotovora subsp. carotovora. Linear correlations were found between retention constants, RM0, and partition coefficients, logP, calculated by use of different software products (logPHyper, CSlogP, milogP, AlogP, IAlogP, ClogP, logPKow, and XlogP). A highquality three-variable QSRR model was derived between RM0 and lipophilicity logPKow, hydration energy, and molar volume. A QSAR model was obtained between antibacterial activity and hydration energy, molar refractivity, and CSlogP. The developed QSRR and QSAR models were cross-validated by the high Q2 values obtained by the leave-one-out method.

Study of quantitative structure—retention relationships for s -triazine derivatives in different RP HPTLC systems

Quantitative structure-retention relationships (QSRR) have been used to study the chromatographic behavior of some s-triazines. Retention factors, RM0, on C18 layers corresponding to zero percent organic modifier in the aqueous mobile phase were determined for five mobile phase mixtures: methanol-water, acetone-water, ace-tonitrile-water, 2-propanol-water, and tetrahydrofuran-water and relationships between RM0 values obtained with different organic mobile phase modifiers were examined. A variety of partition coefficients (Alog P, IAlog P, Clog P, Xlog P, log PKowin, ACDlog P) were calculated by use of different software products. The correlation between partition coefficients and chromatographically obtained lipophilicity was analyzed. On the basis of correlations between RM0 and log P, C18 with methanol-water as mobile phase was selected as the best RP HPTLC system for determination of the octanol/water partition coefficient and thus the lipophilicity of the molecules.

Evaluation of the lipophilicity and prediction of biological activity of some N-cyclohexyl-N-substituted-2-phenylacetamide derivatives using RP-TLC

The chromatographic behavior of N-cyclohexyl-N-substituted-2-phenylacetamides was investigated using reversed phase thin-layer chromatography (RP-TLC). RP-TLC was performed on a C-18 bonded phase with different aqueous eluents: water-acetone, water-acetonitrile and water-dioxane. Linear relationship between retention parameters and organic modifier content in the mobile phase allows the extrapolation procedure. From results, it is evident that retention behavior of investigated compound depended on structures of substituents R. The correlation between the chromatographic lipophilic parameters (RM0) and calculated log P values and several pharmacokinetics parameters such as HIA (human intestinal absorption) predictor, the plasma protein binding (PB) predictor, and partition predictor for predicting the biological activity of the blood-brain barrier (BBB) has been studied. The results show that reversed-phase RM0 proved to express lipophilic nature of investigated compounds as well as biological activity.

A comparative study of the lipophilicity of benzimidazole and benztriazole derivatives by RPTLC

Chromatographic retention data RF and RM0 of some benzimidazole and benztriazole derivatives have been estimated by reversed-phase thin-layer chromatography on paraffin oil-impregnated silica gel plates with methanol-water mixtures as mobile phases. A quantitative structure-retention relationship (QSRR) correlation study was performed on a matrix containing retention data derived from chromatographic regression, retention scores provided by principal-components analysis (PCA), and different computed molecular descriptors. By means of multiple regression analysis statistically significant equations relating lipophilicity (estimated as RM0 values) to different descriptors were derived for the sixteen compounds.

Reversed- and normal-phase liquid chromatography in quantitative structure retention–property relationships of newly synthesized seco-androstene derivatives

The rational preselection of drug candidates includes also correlation between physico-chemical properties (lipophilicity, as the key one) and pharmacokinetic properties, as well as pharmacodynamic activity. Lipophilicity can be determined alternatively by chromatographic methods. Chromatographic behavior of nineteen newly synthesized derivatives of 16-cyano-16,17-seco-5-androstene has been studied by reversed-phase and normal-phase thin-layer chromatography (RP- and NP-TLC). Commercial plates RP-C18-HPTLC and water-dioxane and water-acetonitrile, as well as Lux(®) silica gel plates and toluene-dioxane and toluene-acetonitrile mixtures with different volume fractions of the solvents were used. Retention constants RM(0) and C0 for each compound were determined and correlated with (i) theoretical log P values and (ii) pharmacokinetic predictors determined in silico. Significant linear relationship was found between RP TLC retention constants, RM(0), and computational logP values as well as between NP TLC retention constants, C0, and logP. Lipophilicity values for the analytes, determined by RP TLC and NP TLC, were also correlated with computer calculated absorption constants, affinity for plasma proteins, volume of distribution and logarithm of blood-brain permeation. Significant linear relationships were obtained. These relations were further improved by introducing other regressors, as molecular size descriptors (molecular mass and/or volume) and a molecular polarity descriptor (total polar surface area). Retention parameters, RM(0) and C0, are recommended for lipophilicity expression of analyzed compounds. In silico pharmacokinetic descriptors for the analytes can be expressed as function of the lipophilicity determined by chromatographic methods, the size and the polarity of the molecules expressed as molecular mass/volume and total polar surface area. The analyzed seco-androstene derivatives have adequate lipophilicity which should provide druglikeness and good pharmacokinetic profiles and they can be recommended for further studies in which their biological activity would be examined.

RP TLC data in correlation studies with in silico pharmacokinetic properties of benzimidazole and benztriazole derivatives.

Reversed-phase thin-layer chromatographic (RP TLC) retention constants for a newly designed series benzimidazole/benztriazole with expected biological activity were determined as parameters of their lipophilicity and this series was recognized as congeneric. Pharmacokinetic descriptors of the compounds investigated were calculated in silico with the use of the established drug design software. The bioactivity descriptors, which are assumed to predicted drug absorption, distribution, metabolism, elimination and toxicity (ADMETox) in humans, were correlated with retention constants and good statistical parameters were obtained. Multiple regression analysis which was introduced suggested that the absorption through different epithelial membranes (intestinal, blood-brain or erythrocyte membrane) and distribution process depend on retention constants (as measure of lipophilicty) and total polar surface area and molar weight/volume of the analyte. Finally, the compounds with halogen substituent (compounds A4/A7 and A5/A8 in Table 1), were suggested as the best drug candidates, because of their predicted proper pharmacokinetics and have been proposed for further biological tests.