Novel acetylcholinesterase inhibitors: Synthesis and structure-activity relationships of phthalimide alkyloxyphenyl N,N-dimethylcarbamate derivatives

Based on the multiple binding sites of acetylcholinesterase (AChE), a series of AChE inhibitors: phthalimide alkyloxyphenyl N,N-dimethylcarbamate were designed and synthesized. AChE inhibitory activity and structure-activity relationship of the compounds were researched also. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different alkyloxy chain length and position between phthalimide and phenyl N,N-dimethylcarbamate (PDM). The biological properties of the series were investigated by considering the activity on isolated enzyme. Some of the newly synthesized derivatives, when tested on isolated AChE from head of housefly (Musca domestica), were more active than PDM. The compounds J1, J2 and K1-K8 demonstrated higher inhibitory activity (5- to 404-fold) for AChE than that of PDM. In particular, compound K1 displayed the best AChE inhibition (404-fold higher than PDM), which suggested that phthalimide group of K1 strongly bound at the residues lining the gorge while phenyl N,N-dimethylcarbamate bound at the catalytic site.