Synthesis and biological profiling of new 1,2,3,4-tetrahydrobenzo[<em>h</em>]naphthyridine-based hybrids as dual inhibitors of β-amyloid and tau aggregation with anticholinesterase activity

DP-128 is a multitarget benzonaphthyridine-6-chlorotacrine hybrid molecule with potent

in vitro anticholinesterase and Aβ42 and tau anti-aggregating activity. While often used

as a reference protein aggregation inhibitor, its further development as an anti-Alzheimer

agent is limited by significant cytotoxicity, suboptimal aqueous solubility and microsomal

stability. Since these drawbacks might arise from its rather high lipophilicity, in this work

we have developed a series of more polar analogues, designed by structural modifications

at the benzonaphthyridine or 6-chlorotacrine moieties or within the eight-atom linker.

Half of the new analogues are indeed slightly more soluble and clearly less cytotoxic than

DP-128, display single-digit acetylcholinesterase inhibitory activity, and retain the Aβ42

and tau anti-aggregating potency of the lead, as well as favourable brain permeation and

high plasma stability. While further optimization of microsomal stability is necessary for

a potential therapeutic use of this class of compounds, hybrids 16 and 17, with similar or

even higher Aβ42 and tau anti-aggregating activity and lower cytotoxicity than DP-128,

might represent novel pharmacological tools for protein aggregation studies.