New multifunctional melatonin-derived benzylpyridinium bromides with potent cholinergic, antioxidant, and neuroprotective properties as innovative drugs for Alzheimer's disease.

A novel series of melatonin-derived benzylpyridinium bromides have been designed, synthesized, and evaluated as multi-functional anti-AD agents with cholinesterase inhibitory, antioxidant, and neuroprotective activities. In vitro studies showed that most of these compounds exhibited potent inhibitory activity toward h-AChE and h-BuChE, and good antioxidant capacity in the ORAC assay. In particular, compound 19 was the most attractive derivative, showing the highest potency to inhibit ChEs (AChE: IC50 = 0.11 µM; BuChE: IC50 = 1.1 µM) and good antioxidant ability (ORAC (trolox) = 3.41). Kinetic and molecular modeling studies indicated that 19 was a mixed-type inhibitor, binding simultaneously to active and peripheral sites of AChE. Moreover, 19 also showed good neuroprotective effects in human SH-SY5Y neuroblastoma cells. Taken together, these results suggested that compound 19 might be a promising multi-target drug candidate worthy of further pursuit.