Design, Synthesis And Activity Evaluation Of Bivalent Organophosphorus And Neonicotinoid Insecticides

In biological systems, multivalent binding provides a broad range of benefits that are not achievable with the corresponding monovalent interactions. Multivalent interactions induce receptor clustering, such as the bivalent ligand mediated protein dimerization, wich would result in bivalent interaction is much tighter than monovalent interaction. And multivalent interactions can enhance ligand selectivity. Design and synthesis multivalent ligand to interact with the multiple sites of the receptor, in order to causes synergistic effect, result in a high-affinity system and enhance selectivity of the ligand, this theoretical hypothesis was described as the"cluster effect". The activities of some multivalent drug molecules were significantly enhanced by their cluster effect. However, little has been reported about the applications of cluster effect in new pesticide discovery. Since the cluster effect has been applied in drug design, we believe that the theoretical hypothesis can serve as reference and guidance for the discovery of new agrochemical.Organophosphorusac act as classical acetylcholinesterase(AChE) inhibitors. The geometry of the active-site gorge of AChE, with specific sites at its two extremities, Tyr70, Tyr121, Trp279 and Asp72 lining the entrance gorge of AChE, that is peripheral anionic site of AChE(PAS). Through binding to both catalytic and peripheral sites of the enzyme, a series of dual binding site AChE inhibitors have been designed and synthesized.The cluster effect, combined with information about the structure of acetylcholinesterase, led us to design and synthesize 20 bivalent organphosphorus compounds as potential acetylcholinesterase inhibitors. We anticipated that the target compounds would bind to both catalytic and peripheral sites of the enzyme that leading to more stable AChE-organphosphorus complexes.The insecticidal activity of all target compounds was evaluated. In the preliminary bioassay test,some bivalent organphosphorus compounds have been showed insecticidal activity against cotton aphid(Aphis gossypii) and housefly(Musca domestica Linnaeus). Topical application method was used to test medium lethal quantity of Musca domestica, LD50 values of PSG2(6a), PSG3(6b) and PSDG(6c) were 1.71, 1.74, 1.51μg/No.;LD50 values of PSOL4(3i), SPhOL4(9i) and SPhAL4(9b) were 1.72, 3.64, 0.788μg/No.;LD50 values of SPhAL7(9e), SPhAL8(9f) and SPhAL9(9g) were 1.15, 2.62, 19.0μg/No. However, the activity of bivalent organphosphorus compounds was not so good on Helicoverpa armigera, Spodoptera exigua and Tetranychus cinnabarinus.In search for neonicotinoid insecticides with high activities, seven novel bivalent compounds were prepared from imidacloprid as precursor compound. Their structures were confirmed by 1H NMR and elemental analysis. The preliminary bioassay indicated that these compounds showed insecticidal activities. The average mortality of IMAC4 (12a)and IMAC6(12c) to macrosiphum avenae at the concentration of 100mg/L reached 78.4% and 77.3% respectively(24h); The mortality of IMAC4(12a) to locusta migratoria manilenis at the concentration of 100mg/L reached 77.5%(72h). But the activity of these compouds was not as good as imidacloprid, the control pesticide.We used acetylthiocholine idodide as the substrate of the enzymatic reaction and 5,5'-dithio-bis (2-nitrobenzoic acid) for the measurement of cholinesterase activity by the conventional spectrophotometric method of Ellman. The IC50 values of SPhAL7(9e), SPhAL8(9f), PSOL4(3i), PSG3(6b), PSDG(6c) and ethion were 0.021, 0.830, 0.484, 14.581, 10.521, 0.044mM respectively, the compounds SPhAL7(9e), SPhAL8(9f) and PSOL4(3i) showed good AchE inhibitory activity, especially SPhAL7(9e) was very good, even better than ethion. In summary, we designed and synthesised some bivalent compounds as potential AChE inhibitors by cluster effect, the study provides a basis for the further related work and were worth further studying.