Quantitative drug design studies. II. Development and application of new electronic substituent parameters.

New electronic substituent parameters for quantitative drug design were developed from the standpoint of the frontier orbital theory using the extended Hückel method. Each substituent was characterized by three constants (E, Re, I), which were derived from the SOMO (solely occupied molecular orbital) energy and the coefficient of the SOMO hybrid orbital responsible for bonding to the parent moiety. These correspond to the SOMO-SOMO energy difference (E), the resistivity of the path (Re), and the flow intensity (I) respectively, when the frontier electron flow occurs between the standard parent and the substituent. They can be regarded as major factors governing the electronic inductive-field effect of the substituent. As the result of analyses of various kinds of biological data, they were found to be excellent and widely applicable parameters to the structure-activity problems. In this paper, the new frontier substituent constant values for 150 kinds of substituents and 58 kinds of equations to which the new constants were successfully applied are presented.