Molecular Design,Synthesis,and Biological Activity Of Competivive Antagonists Of GABA Receptor

GABA receptors?GABARs?,as one type of important targets of insecticides,are major inhibitory receptors in the central nervous system of insects.In recent years,competitive antagonists of insect GABARs have been proved to exhibt insecticidal activities and become one of the research hotspots in the development of noval insecticides.In this paper,21 novel GABARs competitive antagonists,3-hydroxylisoxazole derivatives,were designed and synthesized according to our previous researches results.The bioactivity and molecular docking studies on these compounds were also performed.The 21 target compounds of 3-hydroxylisoxazole synthesized in this paper have not been reported in previous literature.Their synthetic routes are as follows.Using dimethyl acetylenedicarboxylate as a starting material,3-hydroxyl-5-methoxycarbonylisoxazole?2?was synthesized with hydroxyurea and DBU by addition,elimination and followed cyclization;3-benzyloxy-5-methoxycarbonylisoxazole?3?was synthesized by substitution of 2 with benzyl bromide under basic conditions;3-benzyloxy-5-carbamoylisoxazole?4?was obtained by amideation of 3 using ammonia;3-benzyloxy-5-carbamoyl-4-iodoisoxazole?5?was obtained by substitution reaction of 4 using iodine,palladium diacetate,cesium acetate and Na HCO₃;a series of 4-aryl-3-benzyloxy-5-carbamoylisoxazole?6a-u?were synthesized from 5 by Suzuki coupling reaction with appropriate aryl boronic acids;4-aryl-5-carbamoyl-3-isoxazolol?7a-u?were then prepared by removing the protecting groups of6a-u in hydrobromic acid and aceticacid.All target compounds were characterized by melting point,¹H NMR,¹³C NMR,and HRMS.Electrophysiological tests indicated that all the target compounds exhibited antagonistic activities against housefly and common cutworm GABARs.The IC₅₀ values of some compounds were at the submicromolar level,and the compound 7u showed the highest activity with the IC₅₀ values of 2.0 and 0.9?M for housefly and common cutworm GABARs,resepectively.The insecticidal tests indicated that all target compounds at the concentration of 100 mg/kg had a certain insecticidal activity against common cutworm,and the compound7k and 7u had the highest activity,with both 73%mortality at 100 mg/kg.In this study,3-hydroxylisoxazole derivatives as competitive antagonists of insect GABARs have been designed and synthesized.Their bioactivities have been tested and the docking studies have been performed.These results could provide a new idea or reference for the structural optimization and rational design of following competitive antagonists of insect GABARs.We expected that this study will provide a theoretical basis for discovering novel competitive antagonists of insect GABARs with more potent activity.