Synthesis And Insecticidal Activity Of ?-Dihydroagarofuran Derivatives Targeting The V-ATPase

The vacuolar H⁺-ATPase?V-ATPase? is an ATP-dependent proton pump responsible for the transport of protons across membranes in eukaryotic cells. Researchers are becoming increasingly interested in developing medicines targeting V-ATPases in recent years. Though there are some reports about the exploration of pharmaceutical medicines with V-ATPases as target sites, little attention has been paid to the exploration of insecticides targeting V-ATPases.Recent studies have showed that celangulin-V acted on the H subunit of V-ATPases in insects,causing the death. To explore novel and highly effective insecticides targeting V-ATPases, a series of ?-dihydroagarofuran derivatives were designed and synthesized, and their insecticidal activities were evaluated. The primary methods and results are as follows:1. Synthesis and structure characterization?1? The lead compound 2 was synthesized by the reaction of 1?, 2?, 4?, 6?, 8?, 9?,12-hepthydroxyl-?-dihydroagarofuran?1? with methanesulfonyl chloride and subsequent reduction in the presence of lithium aluminium hydride. The hydroxyls at 1- and 9-positions of compound 2 were protected with acetonide groups to give compound 3, then 3 reacted with sodium hydride with the subsequent treatment with alpha-chloro-o-fluorotoluene to produce3.11. Afterwards, compound 4 was synthesized by the deprotection of compound 3.11 under the catalysis of 0.8% sulfonic acid. Finally, all the target compounds 4.1-4.10 were synthesized by reaction of compound 4 with sodium hydride and subsequent treatment with corresponding haloalkanes. All the ten target compounds are new compounds.?2? The hydroxyl groups at 1- and 9-positions of 2 were protected by ketones including acetone, 3-pentanone, 4-heptanone, 5-nonanone, cyclopentanone, cyclohexanone and cycloheptanone under the catalysis of ferric chloride to produce 3 and 5-10, respectively.Then all the target compounds 3.1-3.11, 5.1-5.11, 6.1-6.11, 7.1-7.11, 8.1-8.11, 9.1-9.11 and10.1-10.11 were synthesized by the reaction of 3 and 5-10 with sodium hydride and subsequent treatment with corresponding haloalkanes. Among the 77 derivatives, 65 of whichare new compounds.?3? The target compounds were mainly characterized by 1H NMR, 13 C NMR and DEPT-135°. In addition, compounds 3.1-3.11, 5.1-5.11, 6.1-6.11, 7.1-7.11, 8.1-8.11, 9.1-9.11 and 10.1-10.11 were also characterized by IR, MS and HRMS. The stereostructure was further confirmed by X-ray crystal diffraction of compounds 6.7 and 8.7.2. Insecticidal activity assayThe insecticidal activity of the 87 target derivatives against the 3rd instar larvae of Mythimna separate was evaluated with the leaf disc method, and the results indicated that compounds 4.2, 4.3, 4.7, 3.7, 3.10, 5.7, 6.3, 6.6, 6.7, 7.3, 7.6 and 8.7 exhibited excellent insecticidal activity at a concentration of 40 mg/m L within 36 h. The results of LD₅₀ determination revealed that the LD₅₀ values of compounds 4.2, 4.3, 3.7, 5.7, 6.3, 6.6, 6.7, 7.6and 8.7 within 36 h were all lower than that of celangulin-V, especially that of compound 6.7?21.1 ?g/g?, about ten times lower than that of celangulin-V?327.6 ?g/g?. This work illustrated that ?-dihydroagarofuran can be novel lead compounds for developing insecticides based on novel mechanism of action.