Interpretation of some pharmacological structure/activity relationships using molecular orbital calculations.

This thesis is concerned with the search, on an empirical basis, for quantitative structure/activity relationships (QSARs) relating the drug activity of a given type of molecule to indices of its biochemical reactivity. The utility of such relationships lies in their ability both to ellucidate the mechanism of drug action, and to predict the drug activity of an untested molecule of the same type. Most of the reactivity indices used herein are electronic properties of the molecule, obtained from CNDO/2 MO calculations. In Chapter 1, the basis for using the form of QSAR known as the linear free energy relationship (LFER) to explain in vivo as well as in vitro drug activities is discussed. Section 1 of Chapter 2 is a review of the Huckel MO reactivity indices and their use in QSARs. Section 2 introduces SCF MO theory and the ZDO approximation. The types of index which may be calculated from SCF wavefunctions are discussed, along with their pharmacological applications. The indices used in the present work are propounded in Section 3. An MO and regression program (MOREG), which calculates these indices and uses them to produce QSARs, is described. MOREG calculations on series of antitumour phenyl triazenes and a-formylthiosemicarbazone (N)-heterocycles are described in Chapters 3 and 4, respectively. In Chapter 5, similar calculations are described for two series of CNS depressant 1,4-benzodiazepines. The extension of the CNDO/INDO program to a form permitting calculations on the antitumour PtCl2(NH3)2 analogues is described in Chapter 6