Discovery of a Novel Series of Tricyclic Oxadiazine 4a-Methyl Esters Based on Indoxacarb as Potential Sodium Channel Blocker/Modulator Insecticides

Abstract

Indoxacarb, a commercialized oxadiazine insecticide, nearly irreversibly blocks open/inactivated, but not resting sodium channels. The structure−activity relationships showed that the substituents at the position of the chiral atom in the oxadiazine ring are very important to the biological activity of oxadiazine insecticide. Here we synthesized a series of tricyclic oxadiazine 4a-methyl ester derivatives. The chiral atom in the oxadiazine ring has been epimerized and substituted with either pyrethric acid or cinnamic acid derivatives. Benzene ring in the tricyclic moiety was substituted with a chlorine, fluorine, or bromine atom, and nitrogen-linked benzene ring was substituted with a trifluoromethyl or trifluoromethoxy group. Toxicity of these compounds against Spodoptera litura F. was evaluated. Diastereoisomers of most toxic compounds J7 and J9 with pyrethric acid moiety were separated by flash column chromatography. The more polar diastereoisomers, J7-L-Rf and J9-L-Rf, and compounds J24 and J26 with cinnamic acid moiety exhibited highest insecticidal activities. We further used Monte Carlo energy minimizations to dock compound J7 and J24 in the NavMs-based homology model of the open cockroach sodium channel. In the low-energy binding modes, the compound interacted with residues in the inner pore and domain interfaces, which previously were proposed to contribute to receptors of pyrethroids and sodium channel blocker insecticides. Our results define compound J7 and J24 as a potentially useful optimized hit for the development of multiple sites sodium channel blocker or modulator.

Azobenzene-Semicarbazone Enables Optical Control of Insect Sodium Channels and Behavior

“…Attaching the photoswitch to the exterior of bioactive molecule is an effective strategy to obtain photochromic ligands . Referencing the structure development process of metaflumizone, ,, the 4-trifluoromethoxyphenyl position and 4-trifluoromethoxyphenyl position could be replaced by the photoswitch on the basis of the original compound structure (Figure ). The 4-trifluoromethoxyphenyl position was to use the photoswitch to replace directly, and ABM01 – 03 were synthesized.…”

Diastereoselective Synthesis of Nonplanar 3-Amino-1,2,4-oxadiazine Scaffold: Structure Revision of Alchornedine

“…According to general procedure TP3 (method 1), 3 (1 equiv, 1 g, 3.3 mmol) was treated with NaBH 4 (4 equiv, 0.5 g, 13.2 mmol) in MeOH (30 mL) to afford 4 as colorless oil (1 g, 99%) without further purification. 1 (5). According to general procedure TP4, 4 (1 equiv, 500 mg, 1.6 mmol) was reacted with NHPI (1.5 equiv, 400 mg, 2.5 mmol), PPh 3 (1.8 equiv, 771 mg, 2.9 mmol), and DEAD (1.8 equiv, 0.46 mL, 2.9 mmol) in THF (15 mL) at rt.…”

“…[2][3][4] Among them, the six-membered heterocycle oxadiazines containing one oxygen and two nitrogen atoms have been considered as important skeletons because of their interesting potential in organic and medicinal chemistry. [5][6][7][8][9][10] Unlike their aromatic triazine counterparts, the bivalent character of the oxygen atom endows oxadiazines with an interesting nonaromatic and non-planar geometry which has recently been highlighted and utilized in drug discovery through the concept of "escape from flatland" developed by F. Lovering et al 11,12 Among the different types of oxadiazines classified on the basis of the positions of their heteroatoms, we focused our work on the 3-amino-1,2,4-oxadiazine (AOXD) scaffold (Figure 1). This scaffold is particularly interesting because it presents two stereogenic sp 3 centers; the presence of the bivalent oxygen atom in the α-position of the guanidine moiety affects pKa, strongly decreasing the basicity of the guanidine moiety.…”

Assessment of the Potential Toxic Effects of an Insecticide Non-Selective (ALPHYTHRINE) on Daphnia magna

“…Daphnia (Figure 1) come from a continuous culture in our laboratory, they are cultivated at constant temperature and photoperiod [4][5][6][7] for treatment, after performing a series of preliminary tests with different concentration ranges, five neonates are placed in test tubes containing 10 ml of medium For treatment, after carrying out a series of preliminary tests with different concentration ranges, five neonates are placed in test tubes containing 10 ml of medium and the desired concentration of (Alphythrine) ISO (ISO/DIS 6341.2). The insecticide alphythrine, the active ingredient of which is deltamethrines (Figure 2), is manufactured in Algeria, was the subject of this work.…”