The Design,Synthesis And Insecticidal Activity Of N-[4-(Benzofuran-5-yl)Thiazol-2-yl]Alkyl Amide

Acetylcholinesterase inhibitors can inhibit the activity of acetylcholinesterase in insects,and increase the level of choline in insects in a short time,which is the main reason of poisoning to death.As we all know,organophosphorus pesticides and carbamate pesticides are the two representative pesticides of acetylcholinesterase inhibitors,however,these inhibitors can inhibit the activity of cholinesterase both in vivo human and animal,causing central nervous system disorders or even death.Taking the strong inhibitory activity of carbamate acetylcholinesterase inhibitors into account,we use Carbofuran as a leading compound to design a new molecular skeleton through fragment-based drug discovery,molecular hybridization,and pharmacophore models.Molecular docking studies of 24 N-[4-(benzofuran-5-yl)thiazol-2-yl]alkyl amide compounds were performed to illustrate the mode of action of this class combining with acetylcholinesterase.It seems that the compounds have the same position and mode of interaction with carbofuran.Moreover,the thiazole group has a?-?conjugate structure with the TYR334 amino acid residues and strong intermolecular forces with TRP279 amino acid residues.On the basis of the docking result,we executed a second design to modify the structure in consideration of post-degradable and synthetic route.In addition,the bonding energy between most of the compounds and acetylcholinesterase in electrophorus electricus is greater than that of carbofuran,while the binding energy between these compounds and acetylcholinesterase in human is less than that of carbofuran,which demonstrated the feasibility of our design.The target compounds N-[4-(benzofuran-5-yl)thiazol-2-yl]alkyl amide were synthesized from 4-hydroxyacetophenone and 2,3-dihydro-2,2-dimethyl-7-benzofuranol by etherification,Friedel-Crafts acylation,?-bromation reaction,and cyclization with thiourea and then acylation with anhydride/acylchloride.The structures of the compounds were characterized by ~1H NMR.What's more,the diacylated compounds were also simulated and characterized.The inhibition of acetylcholinesterase and insecticidal activities of target compounds A1~A31(except A4 for insecticidal activity)were tested.The inhibition of acetylcholinesterase indicated that A14,A30 exhibit considerable or even stronger inhibitory activities than that of Carbofuran.The preliminary bioassays for insecticidal activity among compounds A1~A31(except for A4)indicated that A3,A9,A10,A12,A15,A16,A17,A19,A22,A23,A26,A27,A29 have good insecticidal activities against Aphis fabae and Tetranychus urticae with the effective component concentration of 500 mg/L.The differences between enzyme activities and insecticidal activities of the target compounds may be affected by lipo-hydro partition coefficient and hydrophobic constant.In addition,the insight of structure-function relationship of these compounds revealed that the difference of substituent group in R~1,R~2 and R~3 may have different influences on insecticidal activities.These results laid the foundation for futher structure modification.