Taherkhani_2026_RSC.Med.Chem__

A novel series of seventeen carbazole-acrylamide-pyridinium-N-phenylacetamide hybrids (12a-q) was designed and synthesized as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for potential Alzheimer's disease therapy. Their inhibitory activity was evaluated against both enzymes using tacrine and galantamine as reference standards. Tacrine exhibited IC(50) values of 58.34 nM against AChE and 160.50 nM against BChE, while galantamine showed 124.72 nM and 216.23 nM, respectively. The synthesized derivatives demonstrated IC(50) values ranging from 6.41 to 74.93 nM against AChE and from 38.05 to 191.96 nM against BChE. All compounds were more potent than galantamine, and most outperformed tacrine as well. Compound 12i was the most potent AChE inhibitor (IC(50) = 6.41 nM), showing 9.1-fold and 19.5-fold higher potency than tacrine and galantamine, respectively. Compound 12g was the strongest BChE inhibitor (IC(50) = 38.05 nM), with 4.2-fold and 5.7-fold higher activity than tacrine and galantamine. Kinetic analysis revealed that all of the most potent compounds act as competitive inhibitors. Cytotoxicity evaluation revealed that compounds 12i and 12g exhibited lower toxicity toward HEK293 cells than sorafenib, with favorable selectivity toward SH-SY5Y cells. These results establish the carbazole-acrylamide-pyridinium scaffold as a promising lead for developing safer cholinesterase inhibitors for Alzheimer's disease.