Partitioning and Lipophilicity in Quantitative Structure-Activity Relationships

Abstract

The history of the relationship of biological activity to partition coefficient and related properties is briefly reviewed. The dominance of partition coefficient in quantitation of structure-activity relationships is emphasized, although the importance of other factors is also demonstrated.Various mathematical models of in vivo transport and binding are discussed; most of these involve partitioning as the primary mechanism of transport. The models describe observed quantitative structureactivity relationships (QSARs) well on the whole, confirming that partitioning is of key importance in in vivo behavior of a xenobiotic. The partition coefficient is shown to correlate with numerous other parameters representing bulk, such as molecular weight, volume and surface area, parachor and calculated indices such as molecular connectivity; this is especially so for apolar molecules, because for polar molecules lipophilicity factors into both bulk and polar or hydrogen bonding components. The relationship of partition coefficient to chromatographic parameters is discussed, and it is shown that such parameters, which are often readily obtainable experimentally, can successfully supplant partition coefficient in QSARs.The relationship of aqueous solubility with partition coefficient is examined in detail. Correlations are observed, even with solid compounds, and these can be used to predict solubility. The additive/constitutive nature of partition coefficient is discussed extensively, as are the available schemes for the calculation of partition coefficient.Finally the use of partition coefficient to provide structural information is considered. It is shown that partition coefficient can be a valuable structural tool, especially if the enthalpy and entropy of partitioning are available.

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“…The high regression coefficients indicate that the phenols possibly have the same mode of action against the induction of the enzymes, and that Kow is a strong determinant of toxicity of the phenolic compounds. The octanol-water partitioning coefficient have been adjudged the most important physicochemical parameter related to biological activity (Dearden, 1985). The r 2 values obtained in this study are comparable to those reported in QSAR analyses involving other organisms.…”

Inhibition of Oral Bacteria by Phenolic Compounds. Part 2. Correlations with Molecular Descriptors

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Association of the blood/air partition coefficient of 1,3-butadiene with blood lipids and albumin.

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