Design, Synthesis And Bioassay Of Dual-site Acetylcholinesterase Inhibitor

Acetylcholinesterase (Acetylcholinesterase AChE, EC3.1.1.7) is a key enzyme in the biological nerve conduction, hydrolysis of the acetylcholine in the synaptic cleft, plays the role of the transmission of nerve signals, exist in a wide range of mammals and invertebrates.Based on the AChE structural characteristics, me-too and structure-based drug design applied during our research.136new compounds were synthesized, including serotonin, amino coumarin, p-aminoacetophenone and amino chalcone-substituted benzamides and tacrine derivatives; The synthesized compounds exhibited high inhibition activity towards acetylcholinesterase. Some lead structure was found through SAR. It further described as follows:1. More systematic overview of the AChE structure, function and AChE inhibitors with the current research and development was summarized.2.136New compounds were synthesized. All target compounds were characterized by1H NMR and ESI-MS, elemental analysis.3. The newly synthesized compounds exhibited remarkable inhibition activity to hAChE, Kinetic characterization was carried out.The bioassay results indicate that many coumpounds show good AChE inhibition. In comparison, several compounds displayed much higher (at lest comparable) AChE inhibition potency than the commercialized AChE-inhibitor, Tacrine (Ki=32.12nM):I series Y11080and Y12081on hAChE Ki76.9nM and88.81nM, respectively; II, III series Y10177on hAChE Ki=66nM; Y12103on hAChE Ki=6.47nM, Y10181on hAChE Ki=9.41nM; IV Series, Y10073on hAChE Ki=71nM,those compounds show more remarkable activity than tacrine.Based on kinetic constant (Ki) of Y12100, Y12101, Y12102, Y12103:quinoline> the diaminopyridine isoquinoline pyridine. The V series of test compounds on hAChE tacrine showed same activity with tacrine, which Y12048Ki is34.84nM. Insecticidal activity test was in progress.It screened III o-aminoacetophenone series, Y12103and Y10181on hAChE the performance of a significant inhibitory activity on hAChE Ki6.47nM,9.41nM respectively. Optimization Ⅳ1the functional group is good for in-depth study.4. The preliminary structure-activity relationships of aminoacetophenone substituted benzamide were summarized, and the rules for further structural modification of benzamide were summarized. The path way for further optimization of benzamide-type AChE inhibitors is also concluded and undergoing.