Liu_2020_Eur.J.Med.Chem__112997

Current drugs available in clinic for Alzheimer's disease (AD) treatment can only alleviate disease symptoms without clearly curing or delaying the process of AD. And some AD drugs failed in Phase III clinical trials are only focused on targeting amyloid-beta (Abeta). Therefore, an alternative strategy in AD drug design is meaningful to be involved in the multiple pathogenic factors which can affect each other at multiple levels. Herein, we report a series of ROS-responsive prodrugs based on multi-target-directed ligands (MTDLs) approach, which can specifically release tacrine derivatives and ibuprofen under oxidation of ROS and show acetylcholinesterase (AChE)-inhibiting, neuron-protective and anti-inflammatory effects in extracellular or intracellular assays. Related biological study illustrated that compound 22 was able to permeate blood-brain-barrier (BBB) showing little hepatotoxicity in comparison to tacrine. Besides, 22 hinted a therapeutic clue in AD-treatment by regulating proinflammatory factors (IL-1beta and TNF-alpha) and apoptosis related proteins (Bax, Bcl-2 and cleaved caspase-3). Further spatial memory assays in Abeta-induced AD model showed that 22 enhanced the ability of learning and memory. Our study proves that the strategy of ROS-responsive prodrugs has promise for AD treatments in future and offers a way for AD drug development.