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

Abstract

<p>DP-128 is a multitarget benzonaphthyridine-6-chlorotacrine hybrid molecule with potent</p><p>in vitro anticholinesterase and Aβ42 and tau anti-aggregating activity. While often used</p><p>as a reference protein aggregation inhibitor, its further development as an anti-Alzheimer</p><p>agent is limited by significant cytotoxicity, suboptimal aqueous solubility and microsomal</p><p>stability. Since these drawbacks might arise from its rather high lipophilicity, in this work</p><p>we have developed a series of more polar analogues, designed by structural modifications</p><p>at the benzonaphthyridine or 6-chlorotacrine moieties or within the eight-atom linker.</p><p>Half of the new analogues are indeed slightly more soluble and clearly less cytotoxic than</p><p>DP-128, display single-digit acetylcholinesterase inhibitory activity, and retain the Aβ42</p><p>and tau anti-aggregating potency of the lead, as well as favourable brain permeation and</p><p>high plasma stability. While further optimization of microsomal stability is necessary for</p><p>a potential therapeutic use of this class of compounds, hybrids <strong>16 </strong>and <strong>17</strong>, with similar or</p><p>even higher Aβ42 and tau anti-aggregating activity and lower cytotoxicity than DP-128,</p><p>might represent novel pharmacological tools for protein aggregation studies.</p>