Ethyl 4–[2–(Substituted Benzyl)hexyloxy]benzoates: Anti–Juvenile Hormone Agents with Juvenile Hormone Activity

We have recently discovered ethyl 4–(2–benzylhexyloxy)benzoate (KF–13) as a novel anti–juvenile hormone (anti–JH) agent (Furuta et al., 2007). This compound induced precocious metamorphosis in larvae of the silkworm, Bombyx mori, a clear sign of JH deficiency, and its activity could be completely counteracted by the simultaneous application of methoprene, a JH agonist. Although KF–13 induced obvious precocious metamorphosis at lower doses, its activity drastically decreased with increasing the applied doses. More recently, we have found that KF–13 showed JH activity as well as anti–JH activity for B. mori larvae (Fujita et al., 2008). KF–13 as a JH agonist counteracted the effect of allatectomy, i.e., induction of precocious metamorphosis, in a dose– dependant manner. Therefore, the activity of KF–13 observed in B. mori larvae is a consequence of both JH and anti–JH activity; low precocious metamorphosis– inducing activity of KF–13 at higher doses is due to the counteraction caused by KF–13 itself as a JH agonist. From studies of the structure–activity relationship of KF–13 analogs, the 4–ethoxycarbonylphenoxy moiety and the butyl side chain were apparently essential for both JH and anti–JH activity, and in the ethyl 4–(2–benzylalkyloxy)benzoate series, a correlation was observed between JH activity and anti–JH activity. In order to elucidate the detailed structure–activity relationships of this series of compounds, we further synthesized analogs in which the benzyl moiety of KF–13 was modified, and evaluated their activity to induce precocious metamorphosis and their JH activity against allatectomized 4th instar larvae.