4-Aryl-5-carbamoyl-3-isoxazolols as competitive antagonists of insect GABA receptors: Synthesis, biological activity, and molecular docking studies. Issue 2 (15th January 2019)

• Record Type: Journal Article
• Authors: Liu, Genyan; Li, Huaguang; Shi, Jiaying; Wang, Wenjie; Furuta, Kenjiro; Liu, Di; Zhao, Chunqing; Ozoe, Fumiyo; Ju, Xiulian; Ozoe, Yoshihisa
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 2(2019)
• Page Start: 416
• Page End: 424
• Publication Date: 2019-01-15
• Subjects: GABA receptors -- Competitive antagonists -- 3-Isoxazolols -- Insecticidal activity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.12.018
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Competitive antagonists (CAs) of ionotropic GABA receptors (GABARs) reportedly exhibit insecticidal activity and have potential for development as novel insecticides for overcoming emerging resistance to traditional GABAR-targeting insecticides. Our previous studies demonstrated that 4, 5-disubstituted 3-isoxazolols or 3-isothiazolols are an important class of insect GABAR CAs. In the present study, we synthesized a series of 4-aryl-5-carbamoyl-3-isoxazolols and examined their antagonism of insect GABARs expressed in Xenopus oocytes. Several of these 3-isoxazolols exhibited potent antagonistic activities against housefly and common cutworm GABARs, with IC50 values in the low-micromolar range in both receptors. 4-(3-Amino-4-methylphenyl)-5-carbamoyl-3-isoxazolol (3u ) displayed the highest antagonism, with IC50 values of 2.0 and 0.9 μM in housefly and common cutworm GABARs, respectively. Most of the synthesized 3-isoxazolols showed moderate larvicidal activities against common cutworms, with more than 50% mortality at 100 μg/g. These results indicate that 4-monocyclic aryl-5-carbamoyl-3-isoxazolol is a promising scaffold for insect GABAR CA discovery and provide important information for the design and development of GABAR-targeting insecticides with a novel mode of action.