chelators can modulate β-
amyloid accumulation, protect against tau hyperphosphorylation, and block
metal-related oxidative stress, and thereby hold considerable promise as effective anti-AD drugs. At present, a growing interest is focusing on increasing the efficacy and targeting of
chelators through
drug design. To this end, we have developed a new class of multifunctional prochelators from three FDA- approved drugs
rasagiline,
rivastigmine, and
donepezil or
tacrine. HLA20 A was designed by merging the important pharmacophores of
rasagiline,
rivastigmine, and
donepezil into our newly developed multifunctional
chelator HLA20. M30D was constructed using the key pharmacophoric moieties from
rasagiline,
rivastigmine, and
tacrine. Experiments showed that both compounds possess potent anti-
acetylcholinesterase (AChE) activity in vitro with weak inhibition of
butyrylcholinesterase (BuChE), and without significant
metal-binding activity. M30D was found also to be a highly potent
MAO A inhibitor with moderate inhibition of
MAO B in vitro. Both HLA20 and M30D can be activated by inhibition of AChE to release active
chelators HLA20 and M30, respectively. HLA20 and M30 have been shown to be able to modulate
amyloid precursor
protein regulation and
beta-amyloid reduction, suppress oxidative stress, and passivate excess
metal ions (Fe, Cu, and Zn). Compared with the activated
chelator HLA20 or M30, both HLA20A and M30D exhibited lower cytotoxicity in SH-SY5Y
neuroblastoma cells, substantiating the prochelator strategy for minimizing toxicity associated with poor targeted
chelators.