[Quantitative structure-activity relationship of P-amino-diphenyl ether analogues to inhibit cytochrome P-450]

A group of p-amino-diphenyl ether analogues were tested for their activities to prolong the pentobarbital sleeping time in mice and to inhibit the demethylation of p-nitro-anisole catalyzed by untreated mouse hepatic microsomes in vitro. The stepwise multiple regression analyses were used to obtain the quantitative structure-activity relationships between the activities of inhibiting cytochrome P-450 in vitro or in vivo for the analogues and their quantum chemical indexes. The results showed that the inhibiting activities both in vitro and in vivo were correlated with the energy level of the lowest unoccupied molecular orbital (ELUMO), the nucleophilic superdelocalizabilities of the nitrogen (SN(N)) and the oxygen (SN(O)). The inhibiting activities of the analogues to cytochrome P-450 may mainly come from their ability to form cytochrome P-450 metabolic intermediate complex.