Synthesis and Acetylcholinesterase Inhibitory Evaluation of Coumarin-Linked Carbazole Derivatives

The cholinesterase inhibitory activity was examined of synthetic carbazole-coumarin hybrids, with long chain hydrocarbons, triazole, or piperazine as linkers. The most effective acetylcholinesterase inhibitor was 7-((12-(9H-carbazol-9-yl)dodecyl)oxy)-2H-chromen-2-one (3 l), with an IC50 value of 6.86 mu M and a high selectivity over butyrylcholinesterase. Compound 3 l also exhibited mixed-type AChE inhibition in a kinetic study, with a Ki value of 4.87 mu M. In addition, molecular docking of compound 3 l toward AChE was done to elucidate the inhibition at both the peripheral anionic and catalytic active sites. Furthermore, the HepG2 and Vero cells were unaffected by toxicity from compound 3 l. Therefore, these findings could be exploited to create a number of carbazole-coumarin hybrids for future potential treatments for Alzheimer's disease. In this study, we designed and synthesized a series of carbazole-coumarin hybrids with high selectivity for acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE). Compound 3 l exhibited the most potent AChE inhibition (IC50=6.86 mu M), a mixed-type inhibition, and no toxicity. These findings could offer the potential for the development of carbazole-coumarin hybrids as Alzheimer's disease treatments.image