History and Development of QSAR

Richet [2] discovered that the toxicity of organic compounds inversely follows their water solubility. Such a relationship corresponds to eq. 2, where A [) are the differences in biological activity values, caused by corresponding changes in the chemical and especially the physicochemical properties, AC. 

Strictly speaking, still today there is no way to apply eq. 1 to biological data. All QSAR equations correspond to eq. 2, because only the differences in biological activities are quantitatively correlated with changes in lipophilicity and/or other physicochemical properties of the compounds under investigation. 

QSAR methodology rapidly developed from the mid fifties on Bruice, Kharasch, and Winzler [8] formulated group contributions to biological activity values in a series of thyroid hormone analogs, which may be considered as a first Free Wilson-type analysis. Zahradnik [9 — 11] tried to apply the concept of the Hammett equation (eq. 3) [12], which at that time was used for three decades to describe the reactivity of organic compounds in a quantitative manner, also to biological data (eq. 4). 

Tj in this biological Hammett equation stands for the activity value of the i member of a series, Te, is the biological activity value of the ethyl compound of the same series, P is a substituent constant (corresponding to the electronic a parameter 

In 1962 Hansen [13] derived the first (and for a long time the only one) real Hammett-type relationship between the toxicities of substituted benzoic acids and the electronic a constants of their substituents (eq. 38, chapter 3.5). In the same year the first QSAR publication of Corwin Hansch on The correlation of the biological activity of phenoxyacetic acids with Hammett substituent constants and partition coefficients [14] appeared. 

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