Discovery of Novel Tryptanthrin Derivatives with Benzenesulfonamide Substituents as Multi-Target-Directed Ligands for the Treatment of Alzheimer's Disease

Based on the multi-target-directed ligands (MTDLs) approach, two series of tryptanthrin derivatives with benzenesulfonamide substituents were evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro biological assays indicated most of the derivatives had good cholinesterase inhibitory activity and neuroprotective properties. Among them, the target compound 4h was considered as a mixed reversible dual inhibitor of acetylcholinesterase (AChE, IC50 = 0.13 +/- 0.04 mu M) and butyrylcholinesterase (BuChE, IC50 = 6.11 +/- 0.15 mu M). And it could also potentially prevent the generation of amyloid plaques by inhibiting self-induced A beta aggregation (63.16 +/- 2.33%). Molecular docking studies were used to explore the interactions of AChE, BuChE, and A beta. Furthermore, possessing significant anti-neuroinflammatory potency (NO, IL-1 beta, TNF-alpha; IC50 = 0.62 +/- 0.07 mu M, 1.78 +/- 0.21 mu M, 1.31 +/- 0.28 mu M, respectively) reduced ROS production, and chelated biometals were also found in compound 4h. Further studies showed that 4h had proper blood-brain barrier (BBB) permeability and suitable in vitro metabolic stability. In in vivo study, 4h effectively ameliorated the learning and memory impairment of the scopolamine-induced AD mice model. These findings suggested that 4h may be a promising compound for further development as a multifunctional agent for the treatment of AD.

Automated summary

In this study, two series of tryptanthrin derivatives with benzenesulfonamide substituents were synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease (AD) using the multi-target-directed ligands approach. The derivatives demonstrated good cholinesterase inhibitory activity and neuroprotective properties. Compound 4h showed promising dual inhibitory effects on acetylcholinesterase and butyrylcholinesterase, as well as the potential to prevent the formation of amyloid plaques. It also exhibited significant anti-neuroinflammatory potency and suitable blood-brain barrier permeability. In vivo studies further confirmed the effectiveness of compound 4h in ameliorating learning and memory impairment in an AD mouse model.