Comparison of measured and calculated lipophilicity of substituted aurones and related compounds

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Abstract

A molecule library containing 55 aurone- and thioaurone-type structures has been designed and synthesised. Reversed phase high performance liquid chromatographic (RP-HPLC) method has been developed to separate these compounds and to characterise their lipophilicity by experimental method (k′). The experimental lipophilicity data have been compared with the computer calculated lipophilicity parameters (CLOGPs) of the same molecules. In general, good correlations between the measured and calculated lipophilicities have been found with the exception of structure isomers and compounds capable for hydrogen bonding. The chromatographic method was suitable to separate the structure (ortho and para) isomers of aurone and thioaurones and was sensitive enough to differentiate their lipophilicities. Our findings suggest the usefulness of the chromatographic method in fast characterisation of the lipophilicity of structurally closely related molecules.

Introduction

In the last decade there was a huge rise in the number of de novo synthesised molecules due to the appearance of combinatorial chemistry both in random and focused molecule libraries [1]. Increasing number of compounds tested in biological and/or biochemical assays of increasing cost induced a serious need for invention of rational methods in drug design [2]. The so-called “drug-likeness” has been recognised as one of the most important parameter influencing the fate of a molecule in the preclinical phase. It means that some selected physico-chemical parameters (e.g. log P, pKa, hydrogen-bonding ability) of most of the therapeutically used compounds fall into the same range. A new compound with one parameter out of these ranges still could be useful in therapy but a compound having two or three deviant parameters is hardly expected to become a drug [3]. This situation enhanced the necessity of characterising new compounds by physico-chemical methods. One of the current approaches in rational drug design is to estimate lipophilic character of the new drug candidates as this property plays an important role in the mechanism of their biological action [3], [4], [5].

Lipophilicity of a non-ionic compound whose partition is independent of pH is commonly characterised by the n-octanol/water (biphasic) partition coefficient (Pow, and log Pow). The method used most conventionally to determine log Pow is the shake flask method. However, there are serious technical difficulties to measure compounds with very high log Pow (≥6.5) [6], [7]. A simple choice to substitute this method is the use of RP-HPLC to characterize lipophilic properties of a compound [8], [9], [10]. Another possibility to characterise lipophilicity is the computerised estimation frequently based on fragment approach [8], [25]. In the former case the properties of the molecules can be characterised directly by the chromatographic retention derived from their distribution between the stationary and mobile phases [11]. On the basis of retention factor (k′) determined by a highly effective, fast and well-automated experimental method biological activity of the members of a molecule library can be predicted [3] making unnecessary to process all members of the library in time-, sample- and labour-consuming biological tests [12].

Aurones and their derivatives belong to the large and diverse family of flavonoids. During the past decades numerous biological activities have been published such as the inhibition of platelet aggregation, analgetic, antiasthmatic, anti-inflammatory, antiallergic, antihyperlipidemic and coronary dilation effects [13], [14], [15], [16], [17], [18]. Recently, limited cytotoxic effect of various aurones has also been reported [19].

The aim of the present work was to separate the members of aurone and aurone derivative libraries by suitable RP-HPLC method. Our intention was to characterise their lipophilicities by experimentally determined values (log k′) and to correlate these experimental lipophilicities with the calculated ones (CLOGP).

Section snippets

Synthesis of aurones and related compounds

Aurones (sublibrary I) were prepared from the corresponding 2′-hydroxychalcones by treating with mercury(II) acetate [20] or trimethylsilyl azide [21] (for structure of synthesized aurone derivatives and sublibraries see Fig. 1). 1-Thioaurones (sublibrary II) and related analogues (AG) were synthesized by the piperidine-catalyzed condensation of 1-thiocoumaran-3-one and the corresponding aldehyde in hot methanol solution. Sulphoxide (H) was obtained from thioaurone (II/a, Table 1) by

Results of the HPLC measurements

A library consisting of 55 structurally related compounds have been investigated. Based on their structural features the library could be further divided into four sublibraries. Sublibrary I contains the aurone (I/a) and its derivatives substituted in various positions (Table 1, sublibrary I). The sublibraries II and III are the so-called thioaurones and their sulphones where X=S or X=SO2 (Table 1, sublibraries II and III, see Fig. 1) while in the sublibrary IV nitrogen (X=NH) is incorporated

Conclusions

Separation of 55 aurone derivatives possessing similar chemical structure could be obtained within 24 min. Beyond the check of the chromatographic purity an experimental physico-chemical parameter characterising the lipophilicity of the compounds (retention factor, k′) can be obtained during the course of the analysis. Good linear correlation was found between the experimentally determined (log k′) and the computer calculated (CLOGP) lipophilicity parameters. In the case of isomers (e.g. ortho-

Acknowledgements

This work was supported by the following grants: OTKA 37188, 32415; ETT 232/2001; NKFP–1/041 (MEDICHEM), NKFP–1/A/0020/2002 (MOLDIAG), Hungarian State Eötvös Foundation.

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