Inhibition of rat hepatic aryl hydrocarbon hydroxylase activity by a series of 7-hydroxy coumarins: QSAR studies.

1. Molecular orbital calculations, by the Modified Intermediate Neglect of Differential Overlap (MINDO/3) method, of a series of twenty-five 8-acyl-7-hydroxy coumarins show that the inhibition of aryl hydrocarbon hydroxylase (AHH) activities (cytochrome P4501, CYP1 activity, primarily CYP1A1) for 23 of these compounds is related to their structural parameters. The two remaining compounds are the only chlorinated derivatives; these are inactive towards the AHH system and were excluded from the quantitative structure-activity relationship (QSAR) analysis. 2. The results of multiple regression analyses show that AHH activity is dependent on the energy of the highest occupied molecular orbital, E(HOMO), in a single variable expression for the 23 compounds. However, a three-variable expression involving superdelocalizabilities provides a more significant correlation with biological activity. 3. The inactivity of the two chlorinated derivatives can be rationalized in terms of their low degree of molecular planarity, as estimated by the area/depth2 parameter, which presumably precludes them from interaction with CYP1.