Synthesis and Larvicidal Activity of Novel Thenoylhydrazide Derivatives
Abstract
A pair of chemical isomeric structures of novel N-tert-butylphenyl thenoylhydrazide compounds I and II were designed and synthesized. Their structures were characterized by MS, IR, 1H NMR, elemental analysis and X-ray single crystal diffraction. The regioselectivity of the Meerwein arylation reaction and the electrophilic substitution reaction of N-tert-butyl hydrazine were studied by density functional theory (DFT) quantum chemical method. The larvicidal tests revealed that some compounds I had excellent larvicidal activity against Culex pipiens pallens. As the candidates of insect growth regulators (IGRs), the larval growth inhibition and regulation against Culex pipiens pallens were examined for some compounds, especially I1 and I7. Compounds I1 and I7 were further indicated as an ecdysteroid agonist by reporter gene assay on the Spodoptera frugiperda cell line (Sf9 cells). Finally, a molecular docking study of compound I7 was conducted, which was not only beneficial to understand the structure-activity relationship, but also useful for development of new IGRs for the control of mosquitos.
Introduction
Diacylhydrazines were as molting hormone analogs by mimicing the mode of 20-hydroxyecdysone (20E)1,2 since N’-tert-butyl-N,N’- dibenzoylhydrazine (RH-5849) was reported as the first nonsteroidal ecdysone agonist in the mid of 1980s3,4 (Fig. 1). The subsequent RH-5992 (tebufenozide)5,6, RH-0345 (halofenozide)7,8 and RH-2485 (methoxyfenozide)9,10 were developed. As a new class of insect growth regulators (IGRs), diacylhydrazines have attracted considerable attention in recent years11,12,13,14,15,16,17,18,19,20,21,22,23,24,25. The Fujita and Nakagawa group11,12,13,14,15,16 was focused on the modification of substituents on the di-benzoyl groups, and QSAR (Quantitative Structure Activity Relationship) research was studied based on the molecular libraries to guide the further design of the molting hormone analogs. The low water and organic solvent solubility limited the biological efficacy of the diacylhydraines. Therefore, some studies were focused on reconstruction and modification of the N’-tert-butyl linker to improve this drawback17,18,19,20,21,22,23,24,25. The replacement of the benzene ring with benzoheterocycles containing oxygen26,27,28,29,30 brings the recent products ANS-118 (chromafenozide)31,32, and JS-11833,34.
Figure 1: The structures of ecdysteroids and nonsteroidal ecdysone agonists.
Full size image
The complex crystal structures of the ligand-binding domains (LBDs) of ecdysone receptor (EcR) from Heliothis virescens (HvEcR) with ponasterone A (one of the ecdysteroids) and BYI06830 (a nonsteroidal agonist) were reported35. As demonstrated in the crystal structures, the binding pockets of HvEcR for BYI06830 and ponasterone A were partially overlapped. However, the aromatic ring of BYI06830 away from the t-butyl group was oriented in an extra pocket that was not occupied by ponasterone A. The difference between the binding modes revealed new insights to improve the agonist activity of diacylhydrazines by modifying the aromatic ring moiety away from the t-butyl group. Structure-activity relationship studies elucidated that hydrogen bonds between the amide N-H group of diacylhydrazines and amino acid residues of the LBD of EcR played a critical role in bioactivity35,36. As indicated in 3D QSAR studies37,38,39, physical chemical properties, such as electrostatic, steric and hydrophobic parameters of the ligands, were key factors affecting the binding affinity of molting hormone agonists.
Encouraged by the above discovery, in our previous work40,41,42,43,44,45,46, a series of diacylhydrazines with broad spectrum biological activity were designed and synthesized, and interestingly, the intermediate N-tert-butyl mono-acylhydrazide showed much better insecticidal activity than that of the diacylhydrazide44.
Thiophene is the bioisoster of furan, which also possesses diverse and significant bioactivities47,48,49,50. For the purpose of discovering novel lead compounds with bioactivity, a pair of chemical isomeric structures of N-tert-butylphenyl thenoylhydrazide compounds I and II were designed and synthesized in this letter. Their larvicidal activity was evaluated.
Materials and Methods
Instruments
All the melting points were determined with a Cole-Parmer melting point apparatus (Cole-Parmer, Vernon Hills, Illinois, USA) while the thermometer was uncorrected. IR spectra were recorded on a Nicolet NEXUS-470 FTIR spectrometer (International Equipment Trading Ltd., Vernon Hills, Illinois, USA) with KBr pellets. 1H NMR spectra were recorded with a Bruker DPX300 instrument (Bruker, Fallanden, Switzerland), while tetramethylsilane was used as an internal standard. Analytical thin-layer chromatography (TLC) was carried out on silica gel 60 F254 plates, and spots were visualized with ultraviolet (UV) light. Elemental analyses (C, H and N) were carried out with a Flash EA 1112 elemantal a (...truncated)