Elucidation of the chemical structure necessary to the molting hormonal activity and the prediction of the hormone-receptor binding mode

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Dibenzoylhydrazine analogs with various kinds of substituents were chemically synthesized, and their molting hormonal activity was measured using cultured integument system prepared from rice stem borer, Chilo suppressalis. The structure-activity relationship for these compounds was quantitatively analyzed using Hansch-Fujita method to show that the greater the molecular hydrophobicity, the greater the activity. In addition, the electron donating substituents at the benzoyl moiety bound to-N (t-Bu) -, as well as the electron withdrawing ortho-substituent, are favorable to the activity. Introduction of the bulky groups were unfavorable at any positions. Although the 2-dimensional (2D) structures of ecdysone and dibenzoylhydrazine molecules are extremely different, their 3D-structures look similar between them by comparing their X-ray structures. The structure activity relationship for the combined set of ecdysones and dibenzoylhydrazines, as well as their alkyl and benzyl analogs, was quantitatively analyzed using one of the 3D quantitative structure-activity relationship (QSAR) methods, comparative molecular field analysis (COMFA). CoMFA results showed that the bezoyl moiety bound to-NH-corresponds to the alkyl chain of ecdysones, and two carbonyl oxygens play a role of 20-and 22-OH oxygens of 20-hydroxyecdysones. The information regarding the favorable and unfavorable electrostatic-and steric-fields to the activity obtained in the CoMFA analysis seems to be very important to predict the binding site of ecdysone receptor and design the compounds. Some of the dibenzoylhydrazine analogs show the neuroactivity on the cockroach nerve system, and to the insect whole body as well. Therefore, we have to pay attention to their toxicological matter in the mammalian system.