Hryniewicka_2026_Molecules_31_

A novel series of hybrid tetrahydro-beta-carboline (THbetaC)-imidazolium (IM) salts incorporating a fused diketopiperazine scaffold was designed, synthesized, and evaluated as cholinesterase inhibitors for potential application in Alzheimer's disease. The molecular design integrates a Pi-conjugated THbetaC core with a cationic IM moiety to promote dual-site interactions within the acetylcholinesterase (AChE) active-site gorge. All compounds exhibited micromolar inhibitory activity against AChE and butyrylcholinesterase (BChE), with a pronounced preference for AChE. The most active derivative, 12d, showed an IC(50) value of 0.72 microM toward AChE, while compound 12c demonstrated the highest selectivity (SI = 8.4). Structure-activity relationship studies revealed that both stereochemistry and N-alkyl chain length are critical determinants of activity, with S,S-configured derivatives consistently outperforming their R,R-configured analogs. In silico ADMET analysis indicated favorable physicochemical properties and predicted central nervous system permeability, although potential hepatotoxicity highlights the need for further optimization. Molecular docking studies suggested that the most promising compound adopts a dual-binding mode, interacting with both the peripheral anionic site and catalytic active site of AChE. These results identify THbetaC-IM hybrids as a structurally novel and promising scaffold for the development of selective cholinesterase inhibitors, providing a basis for further optimization toward multifunctional anti-Alzheimer agents.