Synthesis And Insecticidal Activity Of Pyrido[1,2-a]pyrimidine Mesoionic Compounds Containing Benzo[b]thiophen

Mesoionic compounds have attracted more and more attention due to their excellent biological activities.Triflumezopyrim was the first mesoionic insecticide developed by Corteva.The mechanism of action is novel,different from traditional neonicotinoid insecticides.It is an inhibitor of nicotinic acetylcholine receptors.In this paper,triflumezopyrim was used as the lead compound and benzo[b]thiophene structure with lipophilicity and various biological activities was introduced into the 3-position of the mesoionic ring.A series of pyrido[1,2-a]pyrimidine mesoionic compounds containing benzo[b]thiophene were designed and synthesized.The insecticidal activity of the title compounds against the bean aphid（Aphis craccivora）and the white-backed planthopper（Sogatella furcifera）were tested by spray method.The preliminary mechanism of action of compound L14 was studied by enzyme activity assay,proteomics,and molecular docking.The main work is summarized as follows:1.Introducing benzo[b]thiophene structures into mesoionic compounds.Forty pyrido[1,2-a]pyrimidine mesoionic compounds containing benzo[b]thiophene were designed and synthesized,title compounds were confirmed by ¹H NMR,¹³C NMR,HRMS,and single-crystal diffraction.2.The biological activity test results of the title compounds indicated that they had moderate to outstanding insecticidal activity against A.craccivora and moderate insecticidal activity against S.furcifera.In particular,compounds L14,L25,L27,and L34 still had a lethality rate of more than 90%at 100μg/m L,which was comparable to the control drug triflumezopyrim.Compound L14 exhibited significant insecticidal activity against A.craccivora,with an LC₅₀ value of 1.82±0.04μg/m L,which was superior to triflumezopyrim(LC₅₀=4.76±0.33μg/m L).Compound L24 and L25 had100%lethality against S.furcifera at 200μg/m L,which was comparable to triflumezopyrim.3.The results of the enzyme activity test showed that compound L14 had no inhibitory effect on acetylcholinesterase（Ach E）and glutathione-S-transferase（GST）with the increase of action time.Compound L14 had a certain inhibitory effect on ATPase,but the inhibition rate is low.The inhibition rates of Na⁺K+-ATPase at 12 h,24 h,and 36 h were 16.3%,5.3%,and 5.2%,respectively.The inhibition rates of Ca²⁺Mg²⁺-ATPase at 12 h,24 h,and 36 h were 14.5%,9.8%,and 0.8%,respectively.The enzymatic activity of compound L14 towards carboxylesterase（Car E）increased by 34.9%and 54.7%at 12 h and 24 h,respectively.It showed weak inhibition at 36 h,and the inhibition rate was 4.0%.4.Molecular docking and label-free quantitative proteomics experiments showed that compound L14 had similar docking results with triflumezopyrim.Compound L14has a more stable binding force.Differentially expressed proteins treated with compound L14 in A.craccivora were associated with biological processes such as mitochondrial dysfunction,cytoplasmic protein catabolism,and ultimately neuronal death.compound L14 might act on the central nervous system of aphids,and interact with nicotinic acetylcholine receptors.