Anti-juvenile hormone activity of ethyl 4-[(7-substituted 1,4-benzodioxan-6-yl)methyl]benzoates and their effect on the juvenile hormone titer in the hemolymph of the silkworm, <i>Bombyx mori</i>

Abstract

A series of ethyl 4-[(7-substituted 1,4-benzodioxan-6-yl)methyl]benzoates was synthesized and evaluated for their anti-juvenile hormone (anti-JH) activities to induce precocious metamorphosis in silkworm (Bombyx mori) larvae. The introduction of bulky alkyloxy substituents on the 7-position on the benzodioxan ring significantly increased activity. Ethyl 4-[(7-benzyloxy-1,4-benzodioxan-6-yl)methyl]benzoate (4c) showed the most potent activity among the test compounds, and its median-effective dose (ED 50 ) value was 41 ng/larva. The JH I, II, and III concentrations in the hemolymph of the 3rd instar larvae treated with compound 4c were determined by ultra-high-performance liquid chromatography/mass spectrometry (UHPLC/MS) after using a simple purification method. Compound 4c clearly decreased the JH I and II titers of 3rd instar larvae within 24 hr after treatment, and prevented JH I spike usually found immediately after 4th instar molting.

Synthesis of 1,4‐benzodioxan derivatives and the evaluation of their biological activity as a novel juvenile hormone signaling inhibitor

“…Ethyl 4‐([7‐hydroxy‐1,4‐benzodioxan‐6‐yl]methyl)benzoate ( 1 ), a key intermediate of NY‐04, was prepared according to a previous report 14 . All reaction steps are shown in Scheme 1.…”

“…Ethyl 4-([7-hydroxy-1,4-benzodioxan-6-yl]methyl)benzoate (1), a key intermediate of NY-04, was prepared according to a previous report. 14 All reaction steps are shown in Scheme 1. The structures of all compounds were confirmed by proton nuclear magnetic resonance ( 1 H NMR), and the final products were also confirmed by high-resolution mass spectrometry (Supporting Information, Appendix S1).…”

“…13 Ethyl (E)-4-([7-benzyloxy-1,4-benzodioxan-6-yl]methyl)benzoate (NY04) has been reported to exhibit strong precocious metamorphosis-inducing activity in silkworm larvae (Fig. 1), 14 with a median effective dose (ED 50 ) of 41 ng/larva. When NY04 was topically applied to third-instar larvae, the Juvenile hormone I (JH I) titer in the hemolymph decreased within 24 h and remained low until precocious pupation.…”

Identification of novel juvenile-hormone signaling activators <i>via</i> high-throughput screening with a chemical library

“…Regarding compounds related to JH, this partial agonist activity has been only reported previously for ethyl 4-[2-(t-butylcarbonyloxy) butoxy] benzoate compounds. [21][22][23][24][25]…”

Physiological Activities of Anti-Juvenile Hormone Agents Against Insects and Their Role For Devising Fourth Generation Insecticides: A Comprehensive Review

“…Fujita et al (2007) synthesized two ETB analogues: Ethyl 4-[2-(6-methyl-3-pyridyloxy)hexyloxy]benzoate and ethyl 4-(2phenoxyhexyloxy)benzoate which induced precocious metamorphosis in larvae of B. mori. Recently, Yamada et al (2016) synthesized a series of ethyl 4-[(7-substituted 1,4-benzodioxan-6-yl) methyl]benzoates and evaluated their anti-JH activities on B. mori. The compound Ethyl 4-[(7-benzyloxy-1,4-benzodioxan-6-yl) methyl]benzoate showed the most potent activity, since JH I and JH II titers of 3 rd instar larvae decreased within 24 hr of treatment.…”