Synthesis and Structure-Activity Relationship of a New Series of Anti-Juvenile Hormone Agents: Alkyl 4-(2-Benzylhexyloxy)benzoates and Ethyl 4-Substituted Benzoates

A series of alkyl 4-(2-benzylhexyloxy)benzoates and related compounds were synthesized and investigated for their ability to induce precocious metamorphosis in larvae of Bombyx mori, a clear sign of JH deficiency in the hemolymph of early larval stages. In the alkyl 4-(2-benzylhexyloxy)benzoate series, the methyl and ethyl (KF-13) esters induced precocious metamorphosis at relatively low doses. Replacement of the ester group with an amide, alcohol, oxime, ethyl or 3,4-methylenedioxy group eliminated the activity, indicating that the ester group on the benzene ring is essential for activity. A modification was made between the two benzene rings in KF-13. None of the compounds showed higher activity than KF-13 at low doses. The JH activity of synthesized compounds was assayed using allatectomized 4th instar larvae of B. mori. The aniline analog, which showed stronger precocious metamorphosis.inducing activity than KF-13 at higher doses, had obvious JH activity. The n.propyl ester possessing moderate precocious metamorphosis. inducing activity did not show any JH activity. There was some correlation between the ability of compounds to cause precocious metamorphosis and their JH activity

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

A large number of ethyl [2-(substituted benzyl)hexyloxy]benzoates and related compounds were prepared and their activity to induce precocious metamorphosis was evaluated in larvae of Bombyx mori, which was obviously recognized as a juvenile hormone (JH)-deficiency symptom. Introduction of a methyl, chloro or fluoro substituent at the 2-position on the benzene ring increased the activity in comparison with that of ethyl (2-benzylhexyloxy)benzoate (KF-13) in a dose range of 1-40 μg, however, no consistent dose-response relationship was obtained in these compounds as well as KF-13. The 4-methoxybenzyl analog showed strong precocious metamorphosis.inducing activity at both low and high doses, while introduction of other substituents such as a methyl, chloro, fluoro or ethyl group at the 3- and 4-position on the benzene ring decreased the activity at low doses. The JH activity of synthesized compounds was examined by bioassay using allatectomized 4th instar larvae. In the ethyl [2-(substituted benzyl)hexyloxy]benzoate series, a correlation was observed between JH activity and anti-JH activity; Compounds which induced high percentages of precocious metamorphosis at lower doses had obvious JH activity. Compounds possessing weak precocious metamorphosis-inducing activity showed little JH activity

Synthesis and Anti-Juvenile Hormone Activity of Alkyl 4-(2-Phenoxyalkyloxy) benzoates and Related Compounds

A number of alkyl 4-(2-phenoxyhexyloxy)benzoates and related compounds were synthesized and evaluated their activity to induce precocious metamorphosis in larvae of the silkworm, which was clearly recognized as a juvenile hormone-deficiency symptom. In the alkyl 4-(2-phenoxyhexyloxy)benzoate series, only the methyl and ethyl esters showed precocious metamorphosis-inducing activity. Replacement of the ester group with an ethylcarbamoyl, butanoyl, nitro or a phenoxy group dramatically decreased or eliminated the activity. Both enantiomers of ethyl 4-(4-methyl-2-phenoxypentyloxy)benzoate (13) were prepared by starting with L- and D-leucine. There was no significant difference in precocious metamorphosis- inducing activity between 13R(+)- and 13S(-)-enantiomers. Conversion of the 4-ethoxycarbonyl group of 13 to the corresponding carboxylic acid eliminated the activity, indicating that the methyl or ethyl ester group is indispensable for the activity