Synthesis and insecticidal activity of novel carbamate derivatives as potential dual-binding site acetylcholinesterase inhibitors

In biological systems, bivalent ligands often possess increased functional affinity for their receptors compared with monovalent ligands. On the basis of the structure of acetylcholinesterase (AChE), a series of novel carbamate heterodimetic derivatives were designed and synthesized with the aim of increasing the potency toward AChE inhibition. The AChE inhibitory ability of all the novel compounds was tested using AChE obtained from the brain of the housefly. The bioassay results showed that compounds 6j, 6k, 6m, 6n, 6p, and 6q had increased inhibitory activities in comparison with parent phenyl N-methylcarbamate (MH) at the concentration of 100 mg/L. Among them, the most potent AChE inhibitor of these compounds was 6q (IC(50) = 12 μM), which showed 62-fold greater AChE inhibitory activity than that of MH and 12-fold greater activity than metolcarb (MT), which suggested that the 3-nitrophenoxy moiety of compound 6q was able to interact with the aromatic amino acid residues lining the gorge and the phenyl N-methylcarbamate moiety was able to interact with the catalytic sites of AChE, simultaneously. The insecticidal activities of compounds 6j, 6k, 6m, 6n, 6p, and 6q were further evaluated. Consistent with the result in vitro bioassay, those compounds demonstrated better activities against Lipaphis erysimi than parent compound MH at the concentration of 300 mg/L, and compound 6q showed the best insecticidal activity, causing 98% mortality after 24 h of treatment.