Verano_2026_Biomolecules_16_593

DP-128 is a multitarget benzonaphthyridine-6-chlorotacrine hybrid molecule with potent in vitro anticholinesterase and Abeta42 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 Abeta42 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 Abeta42 and tau anti-aggregating activity and lower cytotoxicity than DP-128, might represent novel pharmacological tools for protein aggregation studies.