New Acetylcholinesterase Inhibitor Design, Synthesis And Biological Activity Study

AChE inhibitors have been of high interest to the drug discovery of Alzheimer's disease.An outstanding achievement is Rivastigmine the carbamate,which has been the best-selling drug for AD remedies in recent years.By abstracting the current carbamate AChEIs' structures,we found a triangular model of pharmacophores including the phenolic oxygen,the benzene ring,and the protonizable nitrogen.Based on this model,we designed and synthesized 3-aminomethyl,3-amino,and 4-amino analogues of 6-methoxy-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one,in order to discover high potent AChEIs,discuss the structure-relationship and expand the compatibility of the model by means of setting the nitrogen atom in different posts.The primary results of AChE inhibiting tests showed 3-((dimethylamino) methyl)-9-methyl-4-oxo-1,2,3,9-tetrahydro-4H-carbazol-6-yl dimethylcarbamate(20) a higher inhibitory potency than Meptazinol,a moderate AChEI,but didn't reach the level we expected.And the primary results of 5-HT receptor binding tests indicated 6-hydroxy-9-methyl-3-(piperidin-1-ylmethyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one (16),a hit bearing competitive inhibition rate of 89.03%over 8-OH-DPAT,worthy of advanced research.6-Methoxy-1,2,3,9-tetrahydro-4H-carbazol-4-one(4),the key intermediate of Series A,was synthesized by acetic acid catalyzed condensation of(4-methoxyphenyl) hydrazine hydrochloride and cyclohexane-1,3-dione,and the Fischer reaction in Ph₂O subsequently,with an yield of 57%in two steps.This facile approach is suitable for industrial-scale manufacturing and has been applied for China Patent.We have synthesized 31 compounds totally,and 24 among them are novel ones, including the 10 target compounds.