Effects of anti‐ecdysteroid quaternary derivatives of azole analogues of metyrapone on the post‐embryonic development of the red cotton bug ( Dysdercus cingulatus F)

Abstract In order to improve the larvicidal activity of the azole analogues of metyrapone, previously found to have a strong inhibitory activity on ecdysone 20‐monooxygenase (E‐20‐M) from the fleshfly Neobellieria bullata Parker, soft‐alkylated compounds (3‐(1,1‐dimethyl‐2‐oxo‐2‐phenylethyl)‐1‐dodecanoyloxymethyl‐1 H ‐imidazolium chloride, sPIM) and (1‐(1,1‐dimethyl‐2‐oxo‐2‐phenylethyl)‐4‐dodecanoyloxymethyl‐1 H ‐1,2,4‐triazolium chloride, sPTM), derivatives of phenyl‐imidazolyl‐metyrapone (PIM) and phenyl‐1,2,4‐triazolyl‐metyrapone (PTM), respectively, were synthesized. Both sPIM and sPTM, designed as propesticides, inhibited E‐20‐M in vitro at 10 −4   M concentration, which was unexpected since they had been expected to be inactive in vitro and to gain activity only within the organism. sPTM significantly delayed the pupariation of N bullata larvae and this effect could be reversed by the simultaneous application of 20‐hydroxyecdysone (20E), supporting the hypothesis that sPTM can act by interfering with the moulting hormone system. Due to this in vitro activity, sPTM and sPIM cannot be considered to be simple drug precursors, and their structure should contain structural elements (pharmacophores) responsible for the observed biological effects. In order to examine this hypothesis, derivatives of sPTM and sPIM were synthesised in which the hydrolytically labile N + —CH 2 O(CO)— moiety was changed to the more stable N + —CH 2 CH 2 (CO)—group. In three new stable derivatives, a dodecylamino or a phenyl group, respectively, is attached to the carbonyl group to obtain PTM and PIM derivatives quaternised with a 2‐dodecylcarbamoylethyl or a 3‐oxo‐3‐phenylpropyl group. In one derivative, the 2‐oxo‐2‐phenylethyl quaternising group has one fewer carbon atom. In addition to their moderate activity (LC 50  = 10 −6 –10 −5   M ) against the red cotton bug Dysdercus cingulatus F, they delayed development and caused developmental abnormalities, including mortality in the pharate phase, mortality during moulting and wing deformations. These symptoms and the delay in development are characteristic of known compounds inhibiting the synthesis of 20E or interfering in the moulting processes. The facts that the frequent appearance of insects with developmental abnormalities and the delay in development could be reversed by co‐application of 20E indicate that the moulting system might be the site of action. We presume that the quaternary azole derivatives of PIM and PTM can themselves also interact with the moulting system. © 2003 Society of Chemical Industry