New hybrid molecules with 2,3,4,9-tetrahydro-1H-carbazol-1,3,4-oxadiazole-N-phenylacetamide framework as potent cholinesterase inhibitors.
Abstract
Aims
In this study, new 2,3,4,9-tetrahydro-1H-carbazol-1,3,4-oxadiazole-N-phenylacetamide hybrids 8a-n as potential dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for the treatment of Alzheimer's disease (AD) were introduced.
Methods
The target compounds were designed using a molecular hybridization strategy and synthesized via straightforward chemical reactions. They were evaluated in vitro for their inhibitory activity against AChE and BChE. The mechanism of inhibition was investigated through kinetic studies. Computational methods, including molecular docking and molecular dynamics simulations, were employed to analyze binding interactions and complex stability. Finally, the drug-likeness and oral bioavailability of the compounds were assessed.
Results
All synthesized compounds showed significant inhibitory effects against BChE and moderate inhibition against AChE. Compound 8m was identified as the most potent dual inhibitor, being approximately 18-fold more potent against BChE than the standard drug donepezil. Kinetic studies on compound 8m revealed a competitive mode of inhibition against AChE and BChE. Computational analyses confirmed that compound 8m forms more stable interactions and a more stable, compact complex with BChE compared with donepezil, characterized by reduced structural fluctuations and more persistent hydrogen bonding.
Conclusions
Compound 8m is a potent, competitive inhibitor of both AChE and BChE with a favorable drug-like profile and oral bioavailability.